A NEURODYNAMIC THEORY OF
SCHIZOPHRENIA
AND RELATED DISORDERS
Robert Miller
Preface and Acknowledgements
Preface and Acknowledgements
Perhaps the most serious deficiency in research
today - not only in psychiatry but in American
science in general - is the absence of an overall
theoretical framework. The accumulation of
empirical observations, rather than the
formulation of integrative theories is favored by
the mechanisms involved both in the awarding of
funds and in the editorial policy of most journals.
Although scientific literature is now filled with
important and well-documented findings, few if
any investigators consider as one of their principal
functions the integration of these findings into new
theories of behavioral function. To understand the
mechanism by which a psychosis of known etiology
(e.g. amphetamine psychosis) is induced, for
example, might require the integration of
information about amphetamine’s pharmacology,
and its effect on biogenic amine metabolism,
neurophysiology, various enzyme systems and of
course behavior. While an extensive literature of
excellent work exists in each of these areas, and
while the individual investigator may consider
work in his own discipline in formulating these
ideas, little effort has been directed towards a
detailed examination of knowledge from many
disciplines with a view to theory development.
These words were written not recently, but a generation
ago by A.J.Friedhoff (1971). They have been echoed many
times more recently, and the situation Friedhoff described
has not changed fundamentally since he wrote: That
situation is now a characteristic of most countries which
attempt to take science seriously, not only North America.
The number of “important and well documented findings”
has undoubtedly increased greatly, but the imbalance
between the bounty of experimental findings and the dearth
of unifying concepts has probably become even more
glaring. It is with such criticism of much of modern
biological psychiatry in mind that the present synthesis is
attempted.
Closely related to the lack of attention to theory in
biological psychiatry, is another misconception. Over the
last generation, psychiatry world-wide has paid particularly
close attention to operationalized procedures for diagnosis,
and replicability of diagnoses. This followed from careful
studies under the auspices of the World Health
Organization, in the late 1960s (Cooper et al, 1969;
Kendell et al, 1971; Karno and Norquist, 1989), showing
that diagnostic practices for psychotic illness in different
parts of the world were very different: For instance,
diagnostic labels on one side of the Atlantic were used in a
different way from those on the other. As a result, the
relative incidence of schizophrenia vs manic depressive
illness was very different on the two sides, despite the fact
that,
with
detailed
instruments
for
assessing
phenomenology, it was found that the range of patients’
2
symptoms (and their frequency) were much the same. Since
then great attention has been given to constructing schemes
of diagnosis which ensure that different psychiatrists, faced
with the same range of patients will come up with similar
sets of diagnoses. This is undoubtedly of great value in
improving communication between researchers. However,
the prestigious schemes of psychiatric description and
diagnosis produced in response to these pressures have not
hitherto attempted to justify concepts of illness in terms of
underpinning disease theories. The various disease entities
formulated by schemes such as the DSM-III/DSM-IV
system in North America, or the PSE-Catego system in the
United Kingdom may thus have sacrificed conceptual
validity in favor of replicability. In this writer’s view, this
tendency represents a misunderstanding of the process of
classification and concept formation, as it has occurred in
the past in the most successful examples taken from the
history of science generally. This point needs to be
expanded:
In any branch of science, the first, and most
fundamental steps, upon which the establishment of that
branch depends, involve the definition and validation of
concepts, that is the process of classification. Until a
classificatory scheme has been established, validated and
has become generally accepted, there is uncertainty about
the concepts with which one must reckon in any further
attempts to understand or explain one’s subject matter.
Unfortunately however there is no sure way of recognizing
the most fruitful way of classifying a set of phenomena in
advance of the actual revelation of how things should be
understood or explained. That revelation is the most
difficult step in any branch of science. Pending that
revelation, a very unsatisfactory situation may exist,
sometimes for a long period of time. A classificatory
scheme may be established and hang in mid-air, so-tospeak, sometimes for many generations, with no more
secure intellectual support than the authority of those who
initially proposed the scheme and the faith of their
followers. Only when the superior usefulness of one
classificatory scheme for expounding some explanatory
structure built upon it becomes clearly evident do the
concepts of the scheme become validated in a manner
which can command general agreement.
Psychiatry is currently attempting to establish itself as a
science with the power to explain, and it is therefore not a
matter for surprise that classification of mental illnesses
and abnormal mental states has recently been regarded as
an issue of great importance. Spitzer and Williams (1980)
writing in “Comprehensive Textbook of Psychiatry” give
the purposes of classification as “communication, control
and comprehension”. However, control is made more
effective if one also comprehends; and communication is
more important for what we understand than for what we
do not. Hence, as in any other science, the third of these
aims - the intellectual one of comprehension - must, in the
long term, take precedence over the other two more
Preface and Acknowledgements
pragmatic aims. Nevertheless, psychiatric classification,
including that of the major psychoses with which we are
concerned here, at present serves the first two pragmatic
aims to a greater extent than the third. Concepts are defined
for immediate practical purposes of empirically-based
treatment and prognosis, and for other related pragmatic
purposes, rather than for any more fundamental
understanding. These concepts therefore do not have the
secure validation that applies to other established scientific
concepts, or to many disease entities in other branches of
medicine.
There are virtually no true disease theories in
psychiatry, except perhaps on the border with neurology.
As far as schizophrenia is concerned, this weakness goes
back as far as Kraepelin at the turn of the last century. His
work on dementia praecox attempted to define a new
disease concept. In the absence of defining etiopathological
evidence, he used evidence about the long-term course of
illness as a key element in his definition of disease entities.
This aroused controversy in his own time, and has been the
source of controversy ever since.
Nowadays the tentative and provisional nature of
present schemes of classification is obscured because of the
enormous authority they are given by professional
organizations. Researchers find themselves constrained to
think only in terms of the disease concepts used in these
authoritative but convention-based classificatory schemes.
In addition, the implicit assumption is made in these
schemes that mental illnesses should be defined as separate
categories, rather than as extremes of dimensions, where
the distribution of characteristics over a population may
show a complete continuity between normality and extreme
pathology. As a result, the use of these schemes may often
actually be a barrier to creative thinking. They hinder
attempts to work out categories or dimensions that really
can be validated in a fundamental way, by reference to
disease theories. For much of the last century this was
inevitable. In modern times this weakness has been pointed
out many times by (e.g. Kendell, 1987; Kringlen, 1994),
but nevertheless persists. It is indeed regrettable that it
persists at a time when there really are sufficient empirical
data, in at least some areas of the study of mental illness, to
establish theory-based categories or dimensions of illness.
The reason why it persists (in this author’s view) is now a
result of the structure of scientific and medical institutions
rather than a necessity dependent on the current state of
factual knowledge of mental illnesses, or on what is really
required for advancement of understanding.
What is a disease theory? It is a coordinated set of
arguments which relate a defined fundamental cause to
symptoms, to the course of the illness (and the symptoms at
each stage), to laboratory findings about the illness
conducted on living patients, whether biological or
psychological or psychophysiological, to postmortem
findings, and of course to effective treatments. The
coordinated reasoning which links all these together is what
validates a concept of illness. For psychiatric illnesses a
variety of short-cuts has been proposed over the years: As
just mentioned Kraepelin relied heavily on the course of
illnesses, followed over many years, and its supposed
correlation with psychological symptoms to define
concepts of illness: Illnesses whose long-term course
differed in severity were classed differently. However,
according to such a criterion, cases of rheumatic fever
which have no recurrences or long-term complication, and
which do not become chronic would be put in a different
class of illness from those cases which do, although, as we
now know, they have the same underlying cause. The
characteristic time course of symptoms in the short term
(episodic vs continuous), could be held as a sure pointer,
for instance to the difference between schizophrenia and
manic-depressive illness. However, a little understanding
of servo theory indicates that, for any system with a
number of positive and negative feedback loops, and
associated delays, minor change in the controlling
parameters could bring about a radical shift from stability
at one extreme situation to that at another, or to oscillation
(“hunting”) between the two, at a wide range of oscillation
frequencies. The system would be basically the same in all
cases, but due to very minor changes would appear quite
different. Some modern operationalized schemes of
diagnosis rely entirely on the symptom pattern within a
defined period of time. One difficulty with this is that even
with this limited scope for definition of an illness, there
may be a large number of different conventions for the
groupings of symptoms needed to define a particular
illness. This is particularly true for an illness whose
symptom patterns are as complex as those of schizophrenia.
According to the doctrine that symptom patterns are
sufficient to define an illness, the many different
manifestations of syphilis should be classed as different
diseases, as indeed they were, until it was discovered that
they all had the same underlying cause. It might be thought
that for an illness with a hereditary tendency, those of its
features which tend to “breed true” must be keys to the real
disease entity. However, the symptom pattern of any illness
(and notably so for mental illness) results from the
combination of the underlying causes of the illness, and a
variety of other features, not themselves pathological,
which may vary between persons. Thus, when a pattern of
symptoms “breeds true” one does not know if it is the
underlying cause which is inherited, or the ancillary
contributions which may determine the way the illness
expresses itself. One may try to define disease entities by
the different classes of treatment which are effective in
some illnesses, but not in others. This could sometimes be
getting close to the fundamental nature of an illness, but
again is influenced by many things other than the basic
cause. Steroid hormones such as cortisone have been used
to treat a wide variety of illnesses which we know from
other information have quite diverse causes.
For schizophrenia and related illness, any of these
criteria (and many more) have been put forth as
demonstrating the conceptual validity of one or another
definition. But none of these criteria, taken singly, really
establishes conceptual validity. Only the coordinated
reasoning that pulls all these threads together is capable of
that. If such coordinated reasoning is rigorous enough
within itself, and withstands sufficient explicit tests and
attempts at falsification to be convincing, is the conceptual
3
Preface and Acknowledgements
validity of a disease concept established. Then we have a
true disease theory; and we have a validated scheme of
classification, which survives on its own merits, rather than
on the authority of its proponents, and the faith of their
adherents.
If such an attempt at coordinated reasoning is
successful, it may be expected to disregard some traditional
concepts and distinctions. We may find that illnesses
traditionally kept separate (though a relationship is
acknowledged) come together; and we may also find that
some groups of patients often included within a particular
disease entity can no longer be so included.
For the time being, to define the subject for study, we
must have a provisional, relatively loose definition. For this
purpose we use the encompassing phrase “Schizophrenia
and related disorders”. This phrase includes the illnesses
termed schizophrenia, manic depressive illness,
schizoaffective psychosis, schizophreniform psychosis.
Psychotic depression could also fall within the spectrum of
disorders to be considered. We are also interested in
psychological and other abnormalities of those at risk (e.g.
genetically) for schizophrenia but not showing major
illness (e.g. in what is called schizotypal personality
disorder). Each of these conditions should themselves be
allowed relatively flexible definitions, so that we do not,
right at the beginning, lose the phenomenological richness
by over-rigorous categorization. For the same reason,
phenomenology of schizophrenia is sometimes documented
in terms of autobiographical writings (collected in
Appendix 3), so that the reader, perhaps sceptical of
diagnostic systems, can stay in touch with the basic raw
data. As we proceed, and the coordinated reasoning of the
theory is developed, the definition and inter-relationship of
the above diagnostic terms will be refined, other diagnoses
will be compared, and some of these terms will be split. At
the end of this work, after the theory has been presented, its
implications for a more solidly-based typology will be
summarized.
Schizophrenia is, in a sense, like an onion: There are
several layers of understanding. If we do not dissect the
outer layers off neatly and accurately, we have no hope of
seeing the deeper “core” of the onion in its correct shape.
This book falls into several major parts, each with several
chapters. Part I is a succinct summary of the whole
argument, starting with a historical and philosophical
introduction (Chapter 1), followed by synopses of the main
steps in development of the theory (Chapter 2). In this
presentation of the essence of the theory, there is no
extensive reference to original papers dealing with
empirical studies, but instead the chapter will refer forward
to the sections and subsections in later parts, where the
empirical evidence is discussed in detail. Part I of the book
is intended to be read from beginning to end, along with the
final summary in Chapter 13. The later chapters (forming
Parts II to V) deal in detail with the empirical evidence
from which the theory is derived. They can also be read
from beginning to end. However, they may sometimes be
rather indigestible, and so may be better regarded as
sources of reference, rather than flowing text. Part II
(Chapters 3 and 4) deals with background evidence about
4
genetic and environmental factors predisposing to
schizophrenia. Part III (Chapter 5) deals with the “outer
layer of the onion” – its most obvious features, as revealed
in acute psychotic episodes. This leads to a fundamental
question, about the origin of such active and acute
psychosis in schizophrenia, which cannot be answered at
this stage. To form a basis for answering this question, and
for revealing the deeper nature of schizophrenia and related
disorders we then turn to the enduring trait features of these
disorders. Part IV (Chapters 6-10) deals with psychological
evidence about trait abnormalities. Part V (Chapters 11 and
12) deals with biological evidence (electrophysiology and
brain morphology), and Part VI (Chapter 13) provides a
brief summing up of the concept of schizophrenia as it has
by then emerged. In the course of these extensive sections,
it will be clear that the distinction between the active state
of psychosis and the enduring traits, present even when
psychosis is well controlled by medication, is a very
important one for the author. This distinction is introduced
initially in Chapter 5. However, the distinction between
state and trait aspects of schizophrenia is not a
straightforward one, and the precise distinction will
become clearer toward the end, as will the causal
mechanisms which make psychotic breakdowns likely in
persons who have the trait characteristics.
The title of this book (“A neurodynamic theory of
schizophrenia”) needs a word of explanation. It is not to be
seen as a rival to other approaches to understanding
schizophrenia, such as the “neurodevelopmental theory”,
and indeed, in Part V and elsewhere, reference is made to
developmental aspects of brain morphology in
schizophrenia. However, the title is meant to indicate the
levels of organization over which explanatory arguments
are constructed. In principle, these levels could reach
upwards from molecular genetics to developmental
processes and growth factors, to structure of brain cells and
tissues. Then it can reach to physiological processes in the
brain, to cybernetics of nervous tissue, and related
psychological processes, to influences of the psychological
environment on the emergence of schizophrenia, and lastly
to the manifest symptoms. However, to construct
explanatory arguments reaching all the way from molecular
genetic factors to symptoms may be too ambitious, and the
lower levels of this hierarchy are beyond the author’s
expertise. Therefore, the scope of the explanatory
arguments developed here concentrate mainly on the span
from cytology of nervous tissue and neuronal dynamics up
to the level of the classic symptoms and other
psychological abnormalities which define the disorder. For
these reasons, the book is entitled “A neurodynamic theory
of schizophrenia, and related disorders”.
As author, I should explain the origin of this book, that
is how a neuroscientist, working in an anatomy department
should become so deeply involved with the subject of
schizophrenia. It is in fact a very personal quest. As a
young man, I was at one stage a medical student at Oxford
University, becoming increasingly fascinated by the
workings of the brain, though I tended to focus on
scholarship, and assimilation of theories from many
published sources, rather than experimental work.
Preface and Acknowledgements
However, in the early 1960s, I also suffered severe
psychological problems, consisting, initially, of dramatic
fluctuations of mood. This eventually led, in 1967, to a
catastrophic psychotic breakdown, which finished any
chance I had of completing the medical degree, and put me
out of action (as far as developing a career for myself) for
nearly three years, a long time at the age of twenty-four.
Eventually, I retrained as a scientist, and after obtaining a
doctorate at Glasgow University, I was able to return to
Oxford as a post-doctoral researcher, and to my previous
focus of interest in the brain. At that time I had another
brief period in hospital - the result of curtailing the
medication I was prescribed - when I learned that the
diagnosis given for my illness was in fact schizophrenia. I
see no reason to object to that, but it will be clear, even to
those who have read only this far in the Preface, that I
regard the concept of illness labeled in this way, whatever
its clinical utility, as lacking a secure scientific validity.
After that, I realized that I had an excellent grounding in
the neuroscience of the time, a very accurate memory of
my periods of illness, my wits were (mainly) intact, and I
also was well aware that, at that time, there was only a very
limited understanding of the disorder I had suffered. These
factors determined the choice I made of the area on which
my research would subsequently focus. In 1977 I emigrated
to New Zealand, and was there able to start realizing the
dream of what I now call “library-based theory” of brain
function. As far as the study of psychotic illnesses goes, the
1980s and early 1990s were dominated by attempts to
understand the theory of psychosis and its relation to
dopamine. However, eventually it was forced on me that
this is only part of the problem of schizophrenia. Research
since then has attempted to develop a theory for the
underlying constitution out of which psychotic episodes
develop. The present work attempts to integrate these two
bodies of theory into a coherent whole.
There are many organizations and individuals I wish to
acknowledge. First I must express my debt to the
University of Otago. I am especially indebted to the
Department of Anatomy and Structural Biology, and the
three persons who have headed that Department since I
arrived in 1977, the late Bill Trotter (1922-2001), Gareth
Jones, who was chairman between 1984 and 2003, and, in
recent years, Helen Nicholson. It was they who provided
the essential intellectual environment in which it was
possible to bring this work to completion. I consider myself
very fortunate to have found such a supportive niche in
which to do my research. In 1999 I resigned my paid
position at Otago, but retained most valuable links with the
university and the department, as Honorary Fellow. Since
then I have had two years of paid employment in the
Northern hemisphere: In 2003-2004 I was able to work at
the Zentral Institut für Seelische Gesundheit at Mannheim,
Germany, making use of the excellent library there. This
visit
was
supported
by
the
Deutsche
Forschungsgemeinschaft, to whom I give my sincere
thanks. A year later, I was able to spend eleven months in
Montreal, in association with the Department of Psychiatry
at McGill University, again making use of the superb
libraries at that university. During this period I was
supported by the Jewish Community Endowment Fund to
whom I am also enormously grateful. One other
organization deserves my full-hearted thanks - the
Schizophrenia Fellowship of New Zealand. I have had a
close association with this organization, since its
foundation in 1977, the year I arrived in New Zealand. I
believed then that many of the ideas on which psychiatric
practice in relation to schizophrenia was founded where
fatally flawed, notwithstanding the excellent clinical skills
of some psychiatrists. Therefore, I wanted to avoid what
was said in the textbooks, and get as close to the raw
evidence on this subject as possible. With no basic medical
(let alone psychiatric) qualification, it was through my
contacts in the Schizophrenia Fellowship that this became
possible. The many heartbreaking stories I have heard in
my contacts with the families in the Schizophrenia
Fellowship, as well as the sharp insights I have gained
about symptoms, from talking with people who have
experienced them, have greatly deepened both my concern
for and my understanding of this disorder. Amongst the
many individuals who have supported and encouraged me,
and fostered my development as a scientist, and as a
student of psychotic disorders, I would like to mention the
following: First, I acknowledge the important part played
by the late George Gordon (1920-2002). He was my
supervisor of studies throughout my undergraduate years,
and it was in his laboratory, as a post-doctoral student, that
I did single-unit recording work, which provided the
empirical basis for much of my later theoretical work,
including the “central hypothesis” for schizophrenia, whose
implications are explored in the present work. I also thank
the late Charles Phillips (1916-1994), who gave me much
vital support during a difficult period in 1973, and later was
of great help in publication of my first book, in 1980. I
thank Peter Usherwood, my doctoral supervisor for seeing
me through the thesis, and, since then for all his steadfast
support and friendship. I thank a number of scientists
working in Otago whose experiments have complemented
some of my theoretical work, especially in relation to the
actions of the transmitter dopamine - Jeff Wickens, Brian
Hyland, Dorothy Oorschot, Jason Kerr, John Reynolds and
the late Mark Tunstall. I thank my friends in Tübingen especially Valentino Braitenberg, Almut Schüz, and Neils
Birbaumer - who have supported me in many ways in the
years during which this work was being assembled. (In fact
Valentino, independently, has used assumptions about
“axonal delay lines”, closely related to the “central
hypothesis” in the present work, to explain aspects of
cerebellar function.). In Kingston Ontario, I thank my longtime collaborator, Rick Beninger for the insights we have
jointly developed about the relation between the functions
of dopamine and psychotic symptoms. There are three
experienced psychiatrists who I would also like to thank.
Guy Chouinard has been a friend and collaborator since
1989, and has supported and guided me in many aspects of
the present work. Eric Chen has been a sounding-board in
discussion of some of the most difficult parts of the theory
presented here. Pat McGorry, pioneer of early intervention
for psychotic disorders, gives me faith that mental health
services for psychotic disorders can be better than they
5
Preface and Acknowledgements
were. In the actual production of this work, the help of
several ever-willing people in Otago should also be
thanked: Robbie McPhee for all artwork, Ross MarshallSeeley for supervising my computing and word-processing
requirements, the always-efficient and courteous staff of
Otago University Medical Library, and Peter Herbison for
his expertise in the statistical meta-analyses presented in
Chapter 12. Lastly I thank Kate Ball for her participation in
many discussions of the theory presented here. At the time
of finalizing this work, she understands more than anyone,
apart from the author, the details of the reasoning on which
this theory is based.
The scientific literature on which this work is based has
been surveyed up to June 2007. Data for the meta-analyses
6
in Chapter 12 (tabulated in Appendix 6) were finalized
around November 2005. The decision to publish it on-line
was taken reluctantly, after unsuccessful approaches to
about eight international publishing houses. This may be an
indication that, for serious scientific monographs,
especially if they are large and complex, the future lies with
the internet. Hard copy, and electronic copies will be
archived within the library system of Otago University.
Robert Miller
Dunedin, August 2007
Chapter 1.
History and philosophy of the disease concept, and their application to models and
theories of mental illness
1.1.
Historical development of disease concept.
In antiquity, the Hippocratic school, which flourished
between 450 and 350 B.C., regarded medicine as the
practical art of curing. Each case was considered on its
merits, though similarities between cases were used to guide
treatment (Bernal, 1964; p.187). Diseases were due to natural
rather than divine causes, and philosophy was not
recommended as a basis for medical practice. The doctrine of
the four humors, first advocated by Empedocles at the start
of this period, led to the idea that diseases come from
“within”, reflecting an imbalance between normal factors
within the body. This may be regarded as the origin of
“physiologic” concepts of disease. The four humors bore no
real relation to physiology, but much later the same doctrine
of imbalance between real physiological factors within the
body as the cause of disease, continued this tradition. In such
a concept of disease, it is likely that the imbalances are
regarded as quantitative departures from normal, rather than
qualitative abnormalities. Such physiologic concepts of
disease would thus tend to be expressed dimensionally rather
than categorically. In addition, in such a concept of disease,
it is difficult to make a sharp separation between the disease
and the patient: The disease is an imbalance within the
patient. From this period until well after the Renaissance,
medicine was guided by the humoral theory, until empirical
investigations supplanted it.
The other philosophical tradition has its roots in
Aristotle, who suggested that individual things and classes of
things could have their “essences”, those features which an
individual thing (or a universal) could not lose without losing
their special identity. Much later, in the seventeenth century,
in the writings of Thomas Sydenham (1624-1689), this was
the origin of “ontological” or “essentialist” concepts of
disease. Sydenham challenged the humoral/physiologic view
of antiquity. He emphasized careful clinical description of
each patient, and as a result, was able to assert that illnesses,
like plants, fell into natural types (Bynum, 1993). The
disease essence is then conceived to be separate from the
person who is afflicted: Unlike the humoral or physiologic
concept of disease, such diseases may be imposed on the
person from outside, though this is not a necessary aspect of
the ontological view of disease. Emergence of the idea that
diseases could have their essences separate from the patient
was encouraged by the work of Linnaeus (1707-1778),
whose approach was avowedly Aristotelian. As a botanist,
his work on classification of plants is well known. He
suggested that there were essences, the same for all members
of a plant species. His contemporary, Buffon (1707-1788),
advocated, in contrast, that “nature knows only the
individual”, and suggested that classifications such as
Linnaeus’ were imposed on Nature as a matter of
convenience, but did not correspond to the underlying
realities. Linnaeus was also medically trained, and produced
another essentialist classification, that of diseases (Bynum,
1993). Accordingly, diseases were conceived categorically
rather than dimensionally. Early clinical description of some
illnesses (e.g. those associated with fever) clearly supported
this ontological viewpoint, that there were specific disease
entities.
For botanical classification we now have sound
theoretical reasons why Linnaeus was correct and Buffon
incorrect: The essence of a plant species is defined by its
characteristic genetic make-up, which, amongst many other
things, permits faithful sexual reproduction of that essence
only with members of the same species, so that the essence is
transmitted quite categorically except in a few exceptional
cases. For classification of diseases, theoretical reasons for
adopting
ontological
rather
than
physiologic
conceptualizations are more complex and less clear cut.
In the nineteenth century, the focus was on identifying
symptoms and syndromes with particular anatomicallydetected lesions in specific internal organs. During this phase
there was no clear commitment on the underlying
philosophical issue of physiologic vs ontological concepts of
illness. However, with the success of bacteriology under
Pasteur (1822-1895), the essences of many important
illnesses could be redefined in terms of the effects of specific
micro-organisms invading the body from outside. In a
somewhat less categorical manner, Virchow (1821-1902)
had advocated an essentialist view of other sorts of disease,
based on the category of cellular change occurring in the
body, by which diseases could be defined and diagnosed
(Maulitz, 1993). Definition of abnormal variants of specific
genes, or of autoantibodies to specific body proteins are
other modern versions of essentialist definitions of diseases.
In the latter cases they reflect internal abnormalities rather
than ones imposed from outside. In all these types of illness
we now know that there are sound bases, similar to that
which applies to botanical classification, for classifying on
7
History and Philosophy
the basis of clearly separate categories, each with their own
essence.
However, for other types of disease, which became more
significant in the twentieth century, for instance degenerative
and other chronic diseases, the ontological view did not fit so
well. For these, knowledge of the underlying mechanisms
suggested that there was a quantitative imbalance of
endogenous processes, a reversion to the concept of an
imbalance of natural humoral factors, as believed before the
Renaissance. For instance the idea of hypertension implies
an increase in blood pressure along a continuous variable,
rather than a categorical departure from normality.
1.2.
History of the disease concept, as applied
to mental illness.
In the field of mental disorders, certain concepts of
disease such as “mania” and “melancholia” go back to
antiquity, were referred to by Hippocrates, and were
subsequently attributed to imbalance in the humoral system.
Thus in general they were conceived as “physiologic
imbalances”. In the early post-Renaissance world, writers on
mental illness slightly amended the humoral view, by
allowing, in addition, a mixture of external causes, both
biological and socio-environmental (Brown, 1993; p 440).
Sydenham, who tried to identify the essences of disease, as
did Linnaeus for plant species, did not follow this through to
mental disorders: For him, “hysteria” (in those days having
characteristics similar to epilepsy, and considered by
Sydenham to be a mental disorder), was really defined by
exclusion, an illness which did not add up to any then-known
disease (Hunter and MacAlpine, 1963; pp 221)
A century after Sydenham, the Scot, William Cullen
(1710-1790) (originator of the word “neurosis”, still much in
use today) wrote of mental illness as occurring when there
was “some inequality in the excitement of the brain”, for
when this happened “recollection cannot properly take place,
while at the same time other parts of the brain, more excited
and excitable, may give false perceptions, associations and
judgments” (cited by Brown, 1993; p. 441). As a result
Cullen was able to conceive of insanity as originating as a
dynamic disturbance of the brain, which may have no
discernible gross anatomical traces therein. For Cullen, such
diseases were not ontological, had no discrete “essence”
(Bynum, 1993). This concept of dynamic imbalance in the
brain, which did not stretch the old humoral concept very far,
is quite similar to that advocated here by the present author.
After the French revolution Philippe Pinel (1745-1826)
was an important figure, and though influenced by Cullen,
himself emphasized psychological factors in mental illness,
together with careful listening to patients telling their story,
and a rejection of somatic treatment (Brown, 1993). As a
result of careful clinical studies, the school of psychiatry
founded by Pinel and his pupil Esquirol (1772-1840) defined
a variety of syndromes: “Démence précoce” was defined by
Morel, “Folie circulaire”, the precursor of the modern
concept of manic-depressive psychosis or bipolar disorder by
Falret, and “Délire de Persecution”, precursor of paranoia, by
Lasègue. Falret was also the first to suggest that the course of
an illness was useful in delineating psychiatric entities:
8
“for... the idea of a natural course of illness that can be
foreseen presupposes the existence of a natural kind of
disease” (see Beumont, 1992). This appears to be one of the
first definite suggestions that mental illness could be
conceived in an ontological manner, as a series of essences
of disease afflicting a patient, rather than as an imbalance of
endogenous factors. The tradition was developed by
Kahlbaum and Kraepelin in Germany, and survives
implicitly today in many operationalized schemes of
psychiatric classification1.
The concept of psychosis appears at about this time, but
its history is complex and curious, and was not based on the
French school of syndromology. While the term “neurosis”
goes back to Cullen, “psychosis” arose later, implying
disorder of general function of nervous system, but without
fever (Berrios, 1987). In the early nineteenth century
“neurosis” implied “organic”, while “psychosis” referred to a
psychological or experiential state. At this time “neurosis”
was a much larger concept than it is now, and psychosis was
smaller. In the mid-nineteenth century Von Feuchtersleben
(1847: see Berrios, 1987) could assert that every psychosis
was also a neurosis (i.e. involved disorder of the brain as
well as experiential disorder), though the converse need not
be so. By the early twentieth century, psychoses were
considered to be divisible into organic and functional types
(see Bonhoeffer, 1909). The former had identifiable
biological causal agents (e.g. cerebral damage, infection or
poisoning), while the latter were without discernible
anatomical findings or other evidence of a definite cause.
Nowadays there are some national differences in the use of
the word “psychosis”. In the English-speaking world, the
term generally implies “a break with reality”, in other words,
a state dominated by delusions, hallucinations and other
related symptoms. In some European traditions however, the
use of the term corresponds more closely to its original use,
an experiential disorder with or without identified physical
basis, and not necessarily including hallucinations and
delusions.
In Germany, at the start of the nineteenth century, the
teachings of Kant were influential. He taught that both
psychology and psychiatry should be branches of
philosophy, not of medicine (a tradition that was of relevance
even in the twentieth century when figures like Jaspers and
Heidegger were professional philosophers, but also deeply
interested in psychiatry and psychology). Thus, in the early
nineteenth century German psychiatry was mentalist. It was
only a reaction to this mentalism which brought somatic
1 The subsequent history of psychiatry in France is
described by Pichot (1967; 1992). Compared to German
psychiatry, French psychiatry has tended to be more clinical
and descriptive, with less concern for systematization of
mental disorders. However, since the early twentieth century,
the criterion of “chronic deteriorating course” has been used
rather systematically in defining schizophrenia (Pichot, 1982).
As a result, schizophrenia has a somewhat narrower definition
than in Britain or USA; and other delusional states, not
fulfilling this criterion, have assumed greater importance.
Moves to develop a nation-wide consensus on psychiatric
diagnosis in France occurred later than in UK and USA (see
Pull et al, 1987a,b).
History and Philosophy
psychiatry to prominence in Germany (Beumont, 1992). By
the middle of the nineteenth century there was vigorous
debate between “Somatikers” and “Psychikers” (Brown,
1993, pp.438). By 1880, the “somatikers” were in the
ascendancy, and Germany was becoming pre-eminent in
psychiatry, with more professors of psychiatry than in either
France or England. Amongst these was Griesinger, who was
clear in his belief that the mental diseases were brain
diseases, and also believed that “psychosis” was a unitary
concept. A more enduring influence was Kahlbaum, who
adopted the French concern with sorting mental illnesses into
syndromes, and, following Falret, took the long-term course
of an illness to be one of its more important characteristics.
Kahlbaum’s continuation of the French attention to defining
syndromes, led to the first description of catatonia, while his
pupil Hecker first described hebephrenia. Their aim was to
work towards genuine disease categories. By the end of the
century, the question was not so much whether mental
disorders could be classified as disease states, but rather how
that should be done. The definitive achievement of this was
left to Kalhbaum’s successor, Emil Kraepelin.
Although, by the end of the nineteenth century, the
“somatikers” were clearly dominant in Germany, Kraepelin
was critical of the mythological nature of many of their
conjectures about the brain (Beumont, 1992). He
concentrated on clinical detail rather than pathological or
laboratory findings. Kahlbaum’s project of defining disease
entities within psychiatry seemed more feasible when the
many manifestations of syphilis became unified within a
single bacteriological theory. Before that, the classification
of the chronic psychoses was impossible because they could
not easily be separated from the many cases of general
paralysis. Once these were identified and separated, more
serious study became possible of the remaining cases.
Kraepelin followed the idea of Falret and Kahlbaum that
longitudinal progression of an illness was an important
characteristic (Berrios and Hauser, 1988). Primed with this
idea, he had been struck early in his career by the fact that
some asylum patients showed progressive development of
dementia, and came to resemble one another. Having reached
this conclusion, he set to work cataloguing the symptoms in
all patients, to work out ways of predicting which patients
would show such progressive deterioration. As a result he
unified Morel’s “démence précoce”, Heckers' “hebephrenia”
and Kahlbaum’s “catatonia” to give a disease concept to
which he gave the Latinized name “dementia praecox”. In
this, Kraepelin, considered that he was making a conceptual
synthesis similar to that which had recently been achieved in
the case of syphilis (Shorter, 2005; p. 270). The criterion for
defining dementia praecox, and the key for classification of
symptoms was the long term course of the illness (i.e.
progressive deterioration, not characteristic of the other
entities he defined, paraphrenia and manic depressive
illness). Within this general concept of a deteriorating
disease, subtypes were recognized - catatonic, hebephrenic,
paranoid - corresponding in general to the syndromes
recognized by earlier researchers.
The model of disease represented by these entities,
suggested initially by Falret and Kahlbaum and brought to
clear form by Kraepelin was clearly ontological: With
“dementia praecox” Kraepelin thought he was defining a
disease essence. However, the long term course of an illness
does not bear as close a relation to its underlying cause as
does an identifiable microorganism. Thus, it is easy to point
out the circularity in Kraepelin’s method 2. Moreover,
although the distinction between deteriorating and nondeteriorating diseases was the defining criterion for
Kraepelin’s disease categories, Kraepelin recognized that a
minority of those with the symptom picture usually
associated with deterioration, did in fact recover (13%
according to Lehmann, 1980). In addition, towards the end of
his career Kraepelin was forced to the conclusion that the
dichotomy between dementia praecox and manic-depressive
psychosis in terms of symptom picture was not as sharp as he
initially proposed (Berrios, 1987). Thus, despite the authority
which has been given Kraepelin’s concepts of disease since
his death, he was himself aware, by the end of his life, of
major inadequacies in his categorization.
Eugen Bleuler (1857-1939), the Swiss psychiatrist, gave
us the name “schizophrenia” (or rather “the group of
schizophrenias”) in place of “dementia praecox”. He did not
to have a single defining criterion (such as deterioration, for
Kraepelin), and did not assume schizophrenia to have the
inevitable deterioration assumed in Kraepelin’s main works
(Lehmann, 1980). Thus Bleuler’s concept could cope with
the proportion of atypical cases, recognized by Kraepelin,
who did not deteriorate. He accepted the three main subtypes
defined by Kraepelin, adding a fourth – “simple
schizophrenia”. He described mental symptoms in a manner
similar to Kraepelin, but, having been influenced by the
totally different ideas of Sigmund Freud, he saw in them the
play of psychological and social factors in the environment
as well as a brain disorder. He also reconceptualized many of
these symptoms, so that most of them became secondary to
the primary processes which, for him, were disturbances of
affect, association and volition. He assumed he was
describing a disease, but it is difficult to specify what his
criteria were for defining that disease category. One
presumes these were put together subjectively, which is
doubly unsatisfactory when a concept is defined in which
there are rather different subdivisions, and no etiological or
pathological basis to unify them.
2
For instance, David Hill (1983, p.77) writes: "The
tautology is obvious. First one excludes from the construct
those who do not meet the outcome criterion. Second, one gives
the construct a title - x. Third, one cites as evidence for the
construct the fact that all who have disease x also have a
common outcome - y. That disease x results in outcome y is a
hypothesis which cannot be disproved if x is defined in terms of
the presence or absence of outcome y." Hill then quotes from
Kraepelin to show that this was actually part of Kraepelin's
thinking. However, in defence of Kraepelin, it should be
pointed out that pioneer efforts in classification are very likely
to be circular in this sense. This is because they are
constructions attempting to make sense of a chaos of
information. They are conjectures for future generations to
evaluate, rather than tested and verified hypotheses. Hill's
criticism could just as well be applied to Linnaeus's botanical
classification, at the time it was first advanced, for instance in
the authoritative claim that the reproductive parts of plants were
most important as a basis for classification.
9
History and Philosophy
In the years after Kraepelin and Bleuler, there were
various attempts at modification of, or addition to,
Kraepelin’s scheme. Some of these represent personal choice
in style of classification, between the “lumpers”, seeking a
simple system, and the “splitters” who prefer a more
complex system, which preserves more of the richness of the
raw data. In 1933, Kasanin (Lehmann, 1980) proposed an
additional category - schizoaffective disorder - whose
symptoms had aspects of both schizophrenia and manicdepressive psychosis. This development was intended to
cope with the proportion of cases, recognized by Kraepelin,
where the symptom picture was intermediate between that of
dementia praecox and manic-depressive psychosis. In 1939,
Langfeldt also introduced the term “schizophreniform
psychosis” to accommodate the fact that some patients had
episodes of illness, which were symptomatically
characteristic of schizophrenia, but short-lived (Lehmann,
1980). From this distinction Langfeldt also derived a division
between “reactive” and “process” schizophrenia, the latter
having the poor prognosis of Kraepelin’s concept. This
distinction guided much research in the 1950s and 1960s,
and is mainly used nowadays in Scandinavia. The term
“schizophreniform psychosis” is still used widely, and in
DSM-III, refers to a schizophrenia-like illness with duration
less than six months.
Kraepelin was not the only researcher in the late
nineteenth century to offer a system of classification of
major mental disorders. Wernicke also had a scheme of
classification, based on cerebral localization within
multiregion systems of the brain. This scheme was
superceded by Kraepelin’s mainly because of Wernicke’s
untimely death. However, there are recent signs of renewed
interest in Wernicke’s system (Wright et al, 1999). In the
middle years of the twentieth century, the Wernicke tradition
developed independent of Kraepelin’s ideas, particularly in
the work of Kleist and Leonhard (see Ban, 1982). These
researchers regarded the features of the end-states of illness,
rather than those of the acute phase, as the key to
classification. From data on the end-state, both researchers
made a major subdivision within the schizophrenias, and
each subdivision had its own subtypes. According to Kleist
(following Wernicke), each major type results from
impairment in one or more neurological systems. Those
which affected just a single system were referred to as
“systematic” schizophrenias, those which affected several, as
“unsystematic”.
Leonhard (1959; see English translation, 1979), working
mainly after World War II, adopted the same terminology,
but based it on possible genetic differences between types, as
is the case for subgroups in certain neurological diseases. He
thus hoped to subdivide a heterogeneous population of
patients into a series of smaller but more homogeneous
subgroups. As a result, a scheme of classification was
constructed with many more entities than in previous
schemes, to cope with the many different courses and
symptomatic end-states a schizophrenic illness might have.
His scheme is better known on the continent of Europe,
especially in Würzburg, than in the English speaking world.
The best known of Leonhard’s concepts in the Englishspeaking world is the division of affective illness into
10
unipolar disorder (i.e. depressive illness) and bipolar illness
(manic-depressive illness). With regard to schizophrenia,
some of Leonhard’s entities will be mentioned later in this
book, and so it is appropriate to give an introduction to his
scheme. The “cycloid psychoses” were distinguished by their
benign prognosis, as indicated by an acute illness always
followed by complete remission. The schizophrenias
themselves were divided into two main groups - the
unsystematic and the systematic schizophrenias. The
“unsystematic” schizophrenias were envisaged to have
clearer genetic determinants than the “systematic” ones. The
unsystematic forms (affective paraphrenia, periodic catatonia
and cataphasia) varied considerably from each other in
symptom picture in the acute productive stage. Periodic
catatonia (reviewed by L.R.Gjessing, 1974) was an entity
originating with Kraepelin (1909) who described cases of
periodically recurring catatonic excitement, separated by
regular intervals. The whole group of schizophrenias
included 2-3% of cases of periodic catatonia (according to
both Kraepelin and R Gjessing). However, Stober et al
(2002) gives a lifetime prevalence in the general population
of 0.1%, equivalent to about 10% of all cases of DSM-III
schizophrenia. Similar discrepancies between studies in
prevalence of this subtype are documented by Ban et al
(1984). It is thus likely that this condition is not yet
adequately defined, in part because the periodic symptoms
can appear right at the beginning of the illness, or later after
a more typical schizophrenic illness, and so are often
indistinguishable from more typical cases, in the short term.
Leonhard’s systematic schizophrenias included the classical
Kraepelinian subtypes (catatonic, hebephrenic and
paraphrenia). Despite modern drug therapy, these subtypes,
according to Leonhard, commonly showed an end-state of
irreversible impairment. Since (according to Leonhard) they
have a much weaker tendency to be inherited than the
unsystematic types, Leonhard takes them to arise from
influences in the psychosocial domain or the physical aspects
of the environment. Leonhard’s claims about the different
role of inheritance in his different subtypes are discussed in
section 3.4.1. A key point in interpreting that issue is how
Leonhard’s subtypes correspond to schizophrenia defined in
modern operational schemes like DSM-III. This question has
not been well studied, but in a twin study of Franzek and
Beckmann (1998) it is reported that 100% of cases of
“systematic schizophrenia” also fit DSM-III-R criteria for
schizophrenia, while only about two-thirds of cases of
“unsystematic schizophrenia” do so.
Another relatively recent trend is to greatly simplify the
subtyping of schizophrenia. Crow (1990a,b) has developed
the concept of a “continuum of psychosis”, with no sharp
cut-offs, but a continuous dimensional change, between
schizophrenia in its various forms, schizoaffective disorder,
bipolar affective disorder, or indeed unipolar depression.
Another simplifying principle used by both Crow (1980,
1982, 1985) and Andreasen and Olson (1982) is to employ
the conceptual distinction between positive and negative
symptoms, which originated in the nineteenth century. In this
way of thinking, positive symptoms are abnormal because
something is added onto normal function, while negative
symptoms are abnormal because some function, normally
History and Philosophy
present, is missing. This distinction, originally made about
individual symptoms, has then been applied to define
syndromes of schizophrenia itself (Type I and Type II, in the
writings of Crow; “positive schizophrenia” and “negative
schizophrenia” according to Andreasen and Olson).
During the first half of the twentieth century, it is
apparent that grouping of symptoms to give definitions of
schizophrenia and related disorders was accomplished in a
rather subjective fashion, varying according to the writer.
Moreover, in most of the above schemes, the criteria for
allotting a patient to one or other diagnosis, or subtype was
not stated in explicit operationalized manner, so that
replicability of diagnosis between psychiatrists was not good.
In response to these perceived inadequacies, Kurt Schneider
produced the first operationalized scheme of diagnosis for
schizophrenia, published in English in 1959. In contrast to
early dichotomies between the psychikers and the
somatikers, Schneider was ready to accept that any psychosis
was both psychic and somatic. He writes (1949/59): “
‘Organic psychosis’ will not do as a . . .title because we
regard schizophrenia and cyclothymia as ‘symptomatic’,
attributable to primary organic causes (as yet unknown) in
the same way as all illnesses are organic”. Schneider put
particular emphasis on symptoms, observed at one point in
time, for characterizing an illness. However, he also
recognized that the relation between these symptoms and the
eventual diagnosis was more indirect than for other types of
disease. In contrast to Kraepelin, he did not regard
longitudinal data about course and outcome as pertinent in
reaching a diagnosis. He emphasized certain psychotic
symptoms which represent the most severe departure from
normal psychology as being of special importance in
distinguishing cyclothymia (i.e. the manic phase of manicdepressive illness) from schizophrenia. These included the
following: audible thoughts; voices heard arguing, or
commenting on the patient’s actions; the experience of
influences playing on the patient’s body (somatic passivity
experiences); thought withdrawal; volitional acts that are
experienced by patients as the work or influence of others.
These symptoms were designated by Schneider as symptoms
of “first rank”, of such significance in diagnosis that they
should overrule any other symptoms present at the same
time. This ranking was the forerunner of the hierarchical
nature of parts of the British Present State Examination. It
was also the start of the operationalizing of psychiatric
diagnosis, which is so much a part of today’s psychiatric
culture, with its emphasis on inter-rater reliability.
After World War II, British psychiatry was much
influenced by developments on the continent of Europe. The
explicitness of Schneider’s criteria was influential in the
development of the British instrument for description and
classification of psychiatric symptoms - the Present State
Examination (PSE)(Wing et al, 1974). This includes 140
symptoms, whose definition and scoring is carefully
specified. As with Schneider’s criteria, data on course and
outcome were of no significance in definition of disease
categories. The CATEGO program combines these 140
symptoms to give 38 syndromes, which are then further
combined to give diagnostic classes. These do not have quite
the same implication as a formal diagnosis, and there is no
suggestion that they correspond to disease entities. The
diagnostic category “S”, incorporates information about a
variety of symptoms of schizophrenia, with Schneider’s
symptoms of first rank playing an important part in its
definition. In the first chapter of Wing et al (1974) it is
suggested, quoting Hempel (1959), that “the ideal
classification should be mutually exclusive, and jointly
exhaustive; that is each object should be allocated to one
class and to one class only, and a class should be allowable
for each object, thus ensuring a minimum of uncertainty and
ambiguity”. Thus, the P.S.E. is explicitly categorical in
approach, although it does not intend to identify disease
types. The categorical nature of the P.S.E. is adopted for
pragmatic reasons associated with clinical practice, rather
than for theoretical reasons associated with the nature of the
underlying disease entities. Another feature of the P.S.E.,
which appears in the transformation of syndromes into
diagnostic classes, is that it is hierarchical. In other words, if
a class low in the hierarchy is identified in a patient, together
with one higher in the hierarchy, the higher class is taken to
subsume the lower one, and becomes the designated class.
(For instance, psychotic symptoms override depressive ones,
and schizophrenic symptoms override other psychotic
symptoms, while Schneider’s symptoms “trump” them all.)
This hierarchical principle has its counterpart within modern
biological taxonomy, where it is referred to as the “cladistic”
approach to classification (e.g. Parshall and Priest, 1993).
American psychiatry in the middle years of the twentieth
century did not consider that formal diagnosis was very
important (Lorr, 1966). Diagnostic schemes under DSM II3
were thus not explicit, though for schizophrenia they were
based generally on Bleuler. They produced a far higher
incidence of schizophrenia than European or British criteria.
However, by 1980, this was no longer the case (Kendell,
1987). At that time the most widely used schemes in North
America were those of Feighner, the Research Diagnostic
Criteria (RDC) and the newly-published DSM-III. All of
these took the presence of manic or depressive symptoms as
exclusion criteria for the diagnosis of schizophrenia. Unlike
European and British systems, they insisted on a minimum
duration of symptoms (2 weeks for Feighner, 6 months for
RDC and DSM-III), though they made no assumptions about
long-term course in their categorization. Since the
DSMIII/IV systems are now the most widely used worldwide, some detail should be given on the underlying style of
these systems and their assumptions.
DSM-III, DSM-III-R and DSM-IV were produced for
several purposes: clinical, research, educational but, in the
introduction to DSM-IV it is stated that “Our highest priority
has been to provide a helpful guide to clinical practice”
(American Psychiatric Association, 1994). In contrast to
DSM-II, DSM-III “introduced a number of important
methodological innovations, including explicit diagnostic
criteria, a multiaxial system and a descriptive approach that
attempted to be neutral with respect to theories of etiology”.
However, two features of DSM-III/IV show a clear, though
implicit commitment on the important theoretical issue
“DSM”: Diagnostic and Statistical Manual, of the
American Psychiatric Association, in its various editions
3
11
History and Philosophy
referred to above: This issue is whether mental illnesses have
an “essence” (for instance one which might be imposed from
outside as in certain other classes of illness) as opposed to a
physiologic imbalance of factors which must come from
within, and which would be difficult to separate from the
patient or the “person”. These features of the DSM-III/IV
systems belie their alleged neutrality on theoretical issues.
First, DSM-III and DSM-IV are explicitly categorical
rather than dimensional classifications4. As in the P.S.E., this
choice is for pragmatic reasons, associated with clinical
decision making, rather than as a commitment to a particular
concept of mental illness. Thus, in the introduction to DSMIV, it is emphasized that, despite the categorical nature of the
DSM-IV system, there are likely to be many patients whose
condition is intermediate between the categories defined
therein. Some advantages of a dimensional approach are
admitted, but these are outweighed by the practical
disadvantages. (For instance it is suggested that dimensional
classifications are less familiar and less vivid, and there is no
agreed basis for the appropriate dimensions.) Nevertheless
the categorical presentation of the classification makes it
more difficult to formulate disease theories based on
dimensional concepts, or physiologic imbalances, even
though theoretical arguments (discussed below) suggest that
this is more appropriate.
The second indication that an implicit theoretical choice
has been made about the nature of mental illness comes in
the very definition of mental illness. In the introduction to
DSM-IV, the comment is made that “a common
misconception is that classification of mental disorders
classifies people, when actually what are being classified are
disorders that people have”. This statement is used to justify
the humane preference for usages such as “a person with
schizophrenia” rather than “a schizophrenic” 5. However, it
also seems to be saying that mental illness is imposed on the
person, rather than being an imbalance of the internal factors
which go to make up a person6. This implicit choice of the
4 Analysis of the structure of symptom groupings in
DSM-III-R, by Gara et al (1992) suggests that it is in fact a
hybrid of categorical constructs of disease with some other
principle (perhaps dimensional).
5 With regard to the choice between word usages like “a
person with schizophrenia” as opposed to “a schizophrenic”,
the present author, like the authors of DSMIII/IV, prefers the
former usage. However, the present author's reason for this
preference is different from that in DSM III/IV: It is not based
on a presumption about whether the illness is imposed upon
the person, rather than being part of the person. Instead this
preference is adopted because the former of these two usages
is of greater therapeutic benefit to patients: The best way to
encourage the integration of a person, whether sick or healthy,
is to treat them as an integrity, and help them to develop such
integrity as they are capable of. The former usage thus
encourages patients suffering from schizophrenia to
reintegrate their personality as far as they can, whereas the
latter tends to dismiss the patient as permanently “invalid” as
a person.
6 Schneider has a more complex view on this matter. He
writes (1949/1959, p. 95): “Psychosis, and in particular
schizophrenia, always involves an over-all change, and
therefore individual phenomena have only a limited claim for
12
ontological concept of mental illness is particularly striking
when it comes to personality disorders, which, in DSM-IV
are assessed in a different section (different “axis”) from the
other mental disorders. For instance, the personality variant
“schizotypal personality disorder” (SPD) is widely regarded
as having a relation to the vulnerability to schizophrenia and
other endogenous psychotic illnesses, but comes in a quite
different section of the manual from schizophrenia. The
situation becomes yet more complex when it is realized that
patients who will receive the DSM-III diagnosis of
schizophrenia also have, in the premorbid phase, an
increased likelihood of satisfying criteria for DSM-III
personality disorders, and not only the schizotypal
personality (Hogg et al, 1990). If the DSM-IV definition of
mental disorder is applied to personality disorders, it makes
the paradoxical implication that a personality disorder is an
“illness a person has” (the person presumably nevertheless
remaining in some sense as a stable entity throughout), rather
than something abnormal actually within the person. The
contrasting viewpoint seems more plausible: Viewed from a
“physiologic” or dimensional viewpoint, personality variants
may arise from imbalance in the very factors which go to
make up a person, and, as such, are trends along the same
dimension which, in more extreme form, leads to the major
mental disorders.
Two general observations can be made as comments on
this brief survey of the history of the disease concept in
psychiatry since the Renaissance. First, considering the wide
range of definitions which have been offered for concepts of
mental illness over the centuries, and their regular change
over the centuries, a degree of scepticism is entirely
appropriate. At different times, and in the hands of different
investigators, the complex phenomenology of mental illness
has been subdivided in all sorts of ways. Schemes vary
idiosyncratically according to whether the subdivision is into
few or many categories, the explicitness vs implicitness of
the process of categorization, and the criteria on which the
categorization is based. Such history would give anyone
pause before accepting many of the modern categories of
psychiatric illness as anything more than currently
fashionable conventions. Such scepticism is especially
appropriate for that central concept in psychiatry,
schizophrenia, and its distinction from manic-depressive
illness. Even the authoritative scheme of Kraepelin, still a
major influence a hundred years after its first formulation,
has survived merely because there has been no better
alternative. It has always been subject to unanswered
criticism, even from its originator, and cannot in any sense
be claimed to have withstood critical test.
The widespread adoption of operationalized criteria for
diagnosis has improved consensus between psychiatrists
using the same criteria. However, this does not constitute
support for the conceptual validity of such diagnostic
review in themselves. . . A psychotic phenomenon is not like
a defective stone in an otherwise perfect mosaic. Psychotic
individuals . . .are no less closed microcosms than normal
persons, or the bodily organism itself, and as such they have
their own particular principle of unity.” However Schneider
also admits next that “a psychotic patient can sometimes stand
apart from his psychosis as a person.”
History and Philosophy
schemes. Diagnoses of disorders in the schizophrenia
spectrum may change between successive episodes of illness.
Stable diagnoses are found in no more than 60-80% (varying
with the diagnosis), as summarized in Appendix 1A. There is
a tendency for the proportion of cases with the schizophrenia
diagnosis to increase over time, and for that of other related
diagnoses to decrease (Appendix 1B). The stability of DSMIII diagnosis over time is less than its reliability between
raters at any one time (Y.R.Chen et al, 1996). Moreover the
reliability of DSM-III across races is a point of concern (see
section 4.9.). This was examined by Loring and Powell
(1988), by asking a range of 488 psychiatrists to give a
DSM-III diagnosis for two case histories. While the same
information was provided to all psychiatrists upon which to
base the diagnosis, the race and gender of the supposed
“patient” was varied between psychiatrists. The difference
made by this variable was very large. Admittedly this was no
indication of the reliability of DSM-III when used under
research conditions: In this study psychiatrists were the
experimental subjects, rather than the researchers, and the
results probably reflect the reliability of DSM-III in the
circumstance of a routine clinical examination rather than in
research studies. Nevertheless, the pointed question must be
asked: Does the current parceling of psychiatric disorders, in
schemes such as DSM-III or DSM-IV, define real disease
entities; or does it merely codify distinctions which are
unclear both conceptually, and in practice? The parceling of
psychiatric disorders may be as much a human construction
as is the conventional distinction, on the basis of size alone,
between a horse and a pony. The latter is a quite replicable
criterion, but sacrifices conceptual validity, since, as we all
know, ponies are really a subclass of horse. The same
comment might apply to current operationalized diagnostic
schemes.
The other general comment which can be made is that,
at least since the time of Pinel, systems for classification and
description of mental illness have generally been avowedly
atheoretical. This harks back to the original Hippocratic
tradition, that philosophy had no place in the healing art of
medicine. The lesson from the dark ages, when humoral
theory held up progress for many centuries perhaps
reinforces the tendency for medicine, even today, to be
strictly empirical, rather than theory-based. Modern attempts
to create “theories” of mental disorder, such as those of
Freud, are now largely dismissed as pseudo-science, and
have entrenched the tendency in psychiatry to scorn more
genuine attempts to build underlying theory. It may be true
that “there is nothing so practical as a good theory” 7; but, for
something as complex as medicine, the corollary has seemed
more appropriate that “there is nothing so impractical as a
bad theory”. We see the scepticism of theory in Pinel, whose
tradition was that of careful clinical description, directed at
defining nosological categories and avoiding speculation
about etiology or pathology. His pupil, Esquirol wrote “I
have observed the symptoms of madness and have studied
the ways, the habits and needs of lunatics . . keeping my
attention on the facts, I have brought together those of a
7
An aphorism adopted by many, but probably originating
with James Clerk Maxwell
similar nature. I described them as I saw them. I have rarely
sought to explain them” (Beumont, 1992). Kraepelin,
Schneider, the British PSE and the American DSMIII/IV
systems are all also atheoretical descriptive or classificatory
schemes, attempting to be neutral with regard theories of
causation. Schneider (1949/59), while asserting the special
value of certain symptoms for distinguishing schizophrenia
from cyclothymia, also writes (p.133) that “the value of these
symptoms is. . only related to diagnosis; they have no
particular contribution to make to the theory of
schizophrenia.”
The quotation with which the Preface to this work
begins suggests that the scorn of theory in psychiatric
research is one its biggest weaknesses. General medicine
nowadays considers itself to have a fully scientific basis
(although its day to day application is always an art).
Psychiatry likewise aspires to be scientific. Acquaintance
with history of scientific progress as a whole shows that it
has always involved interaction between experiment and
theory, between observation and idea. To study a major
natural phenomenon, such as mental illness within the
framework of science, but without being concerned with
underlying theory is deeply paradoxical. The lessons coming
from the humoral theory or from Freudian psychoanalytic
theory should not be that one should scorn all engagement
with theory. It should be that researchers should look with
critical imagination for good theories, rather than judge the
merits of theory by reference only to its worst examples. The
discussion above about DSM-III/IV indicates that the
attempt to eschew theoretical implications cannot be
successful. Theoretical implications, are bound to creep into
any classificatory system, whatever the intention behind the
system. This being so, theoretical biases should, in this
author’s opinion, be openly declared.
Despite the atheoretical nature of psychiatry, some
useful theoretical and philosophical reasoning is now
possible. Some of this is of a general nature, which
constrains the sort of classification or typology which can be
offered in the field of mental illness. These general issues are
discussed in the next section. However, they in turn have
influence on the possibilities for further expansion of specific
theoretical reasoning, which might permit the construction of
true disease theories. Later sections of this chapter discuss
the direction in which one should look for a true disease
theory of schizophrenia. The detailed expansion of specific
theoretical arguments referring to schizophrenia then
dominate the rest of this book.
1.3.
Models of illness: the medical model and
alternatives.
In science the word “model” is used in several different
ways. Here it is used to refer to a general framework of
ideas, or philosophy, within which more detailed and explicit
theories may be developed. In the area of major mental
illness, many such frameworks for thinking are possible. One
cannot envisage formulation of true theories until one has
specified the model to be used, that is, the general approach
or philosophy to be adopted.
In the medical (or biomedical) model of illness, theories
13
History and Philosophy
of disease are based on abnormal processes defined at the
biological level. For general medicine, the biomedical model
has allowed the classification of diseases into a number of
types. These include disorders classed as infectious,
hereditary,
degenerative,
autoimmune,
neoplastic,
psychosomatic, developmental, traumatic and so on.
Generally these classes of illness (except possibly
psychosomatic disorders) occur as much in animals as in
humans. Each of these classes has its own specific disease
theories. In terms of earlier debates about mental illness they
are primarily somatic rather than psychic theories.
The biomedical model certainly applies to disorders of
the nervous system, since there are many highly respectable
disease theories and disease entities in neurology. However,
as the preceding discussion of the history of concepts of
mental illness shows, there has been and still is dispute about
where major mental disorders, such as schizophrenia fit into
the classification. There are some indications that one or
other of the above types may apply to schizophrenia:
Schizophrenia has a genetic component to it, although the
pattern of inheritance is not simple, nor as strong as is
sometimes claimed (Chapter 4). It is also common nowadays
to regard schizophrenia as a “neurodevelopmental disorder”,
a proposal discussed in Chapter 12. Some researchers have
suggested that schizophrenia may be a disorder related to an
infective agent (e.g. Torrey et al, 1988), an autoimmune
disorder (Knight et al, 1987), or a degenerative disorder
(Harrison, 1995). However, major mental disorders are
confined mainly to humans, and this is specifically true for
schizophrenia. This argues against fitting schizophrenia into
the above classification of illnesses, which applies generally
across species.
The applicability of the biomedical model to
schizophrenia has often been explicitly challenged. This is
part of a wider questioning, in some circles, of the biological
approach to psychiatry. Historically these challenges have
come from a variety of directions, discussed by Siegler and
Osmond (1966, 1974; see also Siegler et al, 1969). In the
nineteenth century, the moral view of mental illness was
influential, where correctional or educational methods were
employed to encourage patients to “take responsibility” for
their behavior (Siegler and Osmond, 1966). Early in the
twentieth century, the psychoanalytic view was pioneered by
Freud. It was suggested that psychiatric symptoms arise from
repressed childhood emotional trauma, which needs to be
brought to consciousness before the underlying problem
could be resolved. Although Freud himself did not apply his
method to schizophrenia his followers did so, with the result
that, in one chapter of recent psychiatric history, insightoriented psychotherapy was a common treatment for
schizophrenia. Bad parenting was held to be a dominant
cause of schizophrenia (Bateson et al, 1956; Bateson, 1973).
Another view of schizophrenia which challenges the
biomedical model suggests that the mentally ill are victims
of labeling, by a society which cannot tolerate deviance
(Lemert, 1951; Becker,1973). Some have gone so far as to
suggest that mental illness does not actually exist (Szasz,
1972). It has been suggested that mental illness in individuals
is a reflection of intolerable tensions generated within a
family (Laing and Esterson, 1964), or of “sickness” (in some
14
sense) within society as a whole (Siegler et al, 1969). These
alternative models lack support from systematicallycollected evidence and comparison with control groups.
They took no notice of the evidence, available at the time of
publication, on genetics or effective pharmacotherapy, and
they have not needed to take notice of brain mechanisms in
understanding schizophrenia. Although the psychological
and social ideas they are based on have some credibility and
may be relevant to our larger-scale appreciation of mental
illness, none of them give precise clues to the exact nature of
symptoms and other features of schizophrenia, nor have they
proved themselves in terms of the effectiveness of treatment
offered on their basis. Empirical studies in an
anthropological framework give no support to the “labeling”
theory of major mental illness (Murphy, 1976). The World
Health Organization transnational study of schizophrenia
(World Health Organization, 1973), using an instrument for
eliciting symptoms which was replicable across very
different cultures, found that similar phenomenology
occurred across very different cultures, and was thus unlikely
to be simply a product of social factors within a particular
culture.
Nevertheless, there are some well established facts that
are not easily compatible with the biomedical model applied
to schizophrenia. The WHO transnational study of
schizophrenia, revealed that people who met diagnostic
criteria for schizophrenia in developing countries had better
long-term outcomes than those in the developed “Western”style countries (Leff et al, 1992; Jablensky, 2000). Although
this fact was established more than twenty years ago, little
subsequent research has looked for the reason for this
remarkable difference8. In addition, more recent work,
especially that conducted in Britain and Holland, on the
incidence of schizophrenia in some immigrant groups,
suggests that there may be major contributory causes in the
psychosocial realm (see Chapter 5). Using the “biomedical
model”, psychiatric researchers have so-far failed to come up
with detailed disease theories, comparable in rigor to those
for other established disease theories (including neurological
disorders). In the atheoretical vacuum favored in psychiatry,
bitter controversy can still flourish, about these fundamental
issues.
The advent of neuroleptic drugs in the 1950s showed
that drug treatment, as used in other well-defined classes of
disease, can often be remarkably effective. This has been one
of the strongest lines of support for a biomedical model of
schizophrenia. Here again there is controversy however. The
classical neuroleptic drugs have never been popular with
patients, because of their frequently unpleasant side effects.
As a result, in some quarters, the beneficial effects of these
drugs were discounted, and these drugs have been branded as
no more than “chemical straitjackets”. Advocates of such
viewpoints have generally also jettisoned the biomedical
model of mental illness. The appearance of a new generation
of antipsychotic drugs, with fewer and less serious side
effects is beginning to weaken this line of argument, and thus
8 A recent study (Patel et al, 2006) has raised questions
about the WHO findings, and suggested that a systematic reexamination of the issue is needed.
History and Philosophy
to strengthen the biomedical model of schizophrenia. Genetic
studies by Kety and co-workers (see Chapter 4) gave further
support for a biomedical model. Using subjects who were
adoptees and therefore brought up outside their biological
family, they separated the genetic factors from psychosocial
influence from a family where a parent had schizophrenia.
Despite these lines of support for the biomedical model, its
applicability to schizophrenia is not yet completely
established. It cannot be so until a comprehensive disease
theory for the schizophrenias has been constructed and
becomes accepted.
1.4.
Specific versions of the medical model
applied to schizophrenia.
At present, two specific versions of the biomedical
model applied to schizophrenia have wide currency. The
stress-vulnerability (or “stress-diathesis”) model accounts for
the fact that psychosocial as well as biological factors are
relevant to the manifestations of schizophrenia. An
underlying constitutional weakness is supposed to exist in
the brain, but its expression as illness (or as relapse when
there is a previous history of illness) is influenced in a major
way by psychosocial stresses from the patient’s environment.
In general terms, this seems an accurate way to conceive
schizophrenia, and distinguishes major mental illness from
most neurological disorders of the brain, where social factors
do not have such a decisive impact. However, the stressvulnerability model has not yet been developed in a way
which gives a specific account of all features of
schizophrenia, nor has it led to precise definition of the
nature of either the underlying vulnerability in the brain, nor
the characteristics of the stress which make the latent
vulnerability manifest as illness. Thus, while in general it is
likely to be correct as a “model”, it has not served as a basis
for construction of a proper disease “theory”.
Another version of the biomedical model applied to
schizophrenia views this illness as a “neurodevelopmental”
disorder. This is based mainly on two features of the illness:
It has a tendency to be inherited at least in a substantial
proportion of cases (Chapter 3); and, as revealed by CT or
MRI scans, brain morphology deviates from normality, most
of this deviation predating onset of illness, rather than being
caused by it (Chapter 12). Much of what is known of this
morphological deviance is about the relative size of different
components of the forebrain in schizophrenia, compared to
control groups. Any disorder with a hereditary tendency and
associated with morphological deviance which predates the
manifest illness can be regarded as a developmental disorder,
although this is a far cry from a well-reasoned disease
theory. Developmental biology of mammals has not yet
unraveled the detailed relation between genetic factors and
morphological variation in the adult. We have scarcely
begun to understand the relation between the genetic factors
predisposing to schizophrenia and deviations in brain
morphology (see Jones and Murray, 1991). The
abnormalities we know about - mainly in the size of brain
components - are only indirectly related to aspects of brain
cytology likely to be under direct genetic control. Moreover
there is little understanding of how morphological factors
relate to neurocybernetic functions whose disturbance leads
to the symptoms of schizophrenia. Thus, we would appear to
be a long way from constructing logical arguments relating
symptoms
of
schizophrenia
to
the
underlying
neurodevelopmental abnormalities, let alone the basic
genetic abnormality. As Jones and Murray (1991) have
written: “genes code for proteins, not for auditory
hallucinations in the third person”. Thus, the
neurodevelopmental hypothesis, while no doubt true in
general terms, holds little promise of delivering in the near
future a closely reasoned argument relating causal factors
(partly genetic) to symptoms and other key features of the
illness. Given this rather unpromising scenario, is there any
approach to this complex illness which might deliver
arguments of sufficient precision to be called a theory?
1.5.
Information sources for a theory of
schizophrenia.
In the Preface to this work, the question was posed:
What is a disease theory? The answer given was
(paraphrasing) “a series of arguments which give a
comprehensive explanation of why the disease is how it is,
rather than of some other nature”. To create a theory of
disease, we need coordinated reasoning, providing an
explanation of all of its important features, within an overall
framework of causation. In this process, observed correlation
between variables will undoubtedly be important. However,
correlation may be very indirect, and is not the same as
explanation or causation. For that one needs to show the
logical links between phenomena as examples of more
fundamental causal principles. The skill in using correlative
data in construction of explanatory arguments and theories
comes in selecting correlations where one suspects the
variables to be relatively directly linked in causal terms.
There is a degree of art or subjectivity in this process, whose
success can only be judged when the explanatory argument
is successfully assembled.
The previous subsection suggests that we are currently
some way from assembling an explanatory argument of
schizophrenia based on developmental neurobiology or its
genetic basis. However, three other areas of research have
produced abundant and detailed evidence, likely to have
closer logical and causal relations to functional disturbance
in schizophrenia than developmental biology and its genetic
basis.
(i) The symptoms of schizophrenia (especially the
psychotic ones), may seem strange, yet are striking and
distinctive. Their singular nature suggests that they are
specific pointers to the nature of an underlying disease
process, if only we knew how to interpret them. They can
admit few rigorous explanatory arguments. Although
strange, we need not assume them to be totally alien. It
would be better to assume that these symptoms arise by
modifications and distortions of normal human psychological
processes. If we could clarify the links between normal
psychology and its disturbance in schizophrenia, we would
open an important door on the nature of the illness.
(ii) Laboratory studies of schizophrenia, have also
revealed a great deal about abnormal psychology, behavior
15
History and Philosophy
and psychophysiology, both in the psychotic phases of
schizophrenia, and in intervening periods when less dramatic
disablement is present. This evidence is based on a century
of development and progressive refinement of methods of
psychological investigation of normal integrated brain
function. Because of the sophistication of experimental
design used in these studies the information it has revealed
about schizophrenia, taken in its entirety, is likely to be an
accurate pointer to the underlying disturbances of
information processing in schizophrenia, despite difficulty in
interpretation.
(iii) The results of the above investigations, applied to
schizophrenia, are expressed using psychological concepts,
which provide a concise summary (or “model”) of results
within the discipline of psychology. As an early example of
this, Eugen Bleuler was concerned with the underlying
theory of schizophrenia, but this was formed entirely in
terms of psychological concepts. He had no idea of its
neurobiological basis. A truly explanatory argument, on the
other hand, is one which crosses levels, by explaining
findings at the psychological level in terms of underlying
neurobiology. There is information now available on a wide
range of neurobiological measures in schizophrenia. This
constitutes the third large block of knowledge about
schizophrenia, essential in theory construction. It includes a
rich literature on structural deviations from the norm, found
using CT or MRI scanning; a smaller, but intriguing
literature using neuropathological investigations on postmortem brains; functional brain imaging, which reveals
unusual patterns of cerebral activation; neurochemical
imaging of an increasing variety of transmitters, receptors
and other chemical markers; electrophysiology, including
EEG power spectra, evoked and event-related potentials.
These, and many other approaches, provide insight into
abnormalities at the brain level in schizophrenia.
Such knowledge about schizophrenia has arisen as part
of the developing history of our understanding of normal
psychology and normal brain function and structure, both in
humans and in experimental animals. In the last generation,
knowledge in these areas has increased enormously. Such
analysis has probed at a deeper level for animal brains, than
in the human brain, and more deeply into normal structure
and normal neural or psychological function than in the
abnormal situation of schizophrenia. The insights from the
normal case, and in animals, are of vital importance in
interpreting the evidence we have about schizophrenia. For
the normal situation studied in experimental animals, a new
discipline has emerged, in which true explanations of
psychological and behavioral data in terms of underlying
brain biology are created. This is the integrated science of
brain and behavior.
The challenge we face is to extend this approach to
human cerebral processes and to the abnormal situation. The
issues are not trivial. Of course the structure of the human
brain follows the basic plan of all mammalian brains. The
forebrain consists of the same structural components cerebral neocortex, striatum, thalamus, hippocampus etc with cell types in each structure being similar in humans and
experimental mammal species. Because of the ethical
limitations on human experimentation, knowledge about
16
patterns of axonal connectivity, and ultrastructure of the
human brain is at a backward state compared with equivalent
data in animals. Nevertheless, ideas about the interplay
between the different components of the forebrain, put
forward with reference to animal brains, are likely to apply,
with some changes, to the human brain. Most obvious of the
biological differences is the fact that the human brain is
much larger than that of even the most advanced subhuman
primates, with regions such as the prefrontal cortex showing
special expansion compared to all other species.
While biological knowledge of the human brain is not as
good as that of the animal brain, psychological studies are,
on the whole, more advanced than in any animal. For
example, humans can be given more explicit instructions in
psychological testing. Many psychological tests devised for
humans are inapplicable to experimental animals. However,
an increasing number of tests are being devised which have
equivalent versions for humans and various subhuman
species. The results of such work give support to the
developments at the biological level inferring close parallels
between the functioning of human and animal brains. Given
this, it is also clear from psychological investigations that
hemispheric specialization is an important principle in the
human brain. Somewhat similar lateral specialization may
exist in a variety of subhuman mammalian species, but has
had less attention from experimentalists than that in humans.
Lateral specialization may be more important in humans than
in most subhuman species.
The neurobiological basis of hemispheric specialization
in humans has been largely a matter of conjecture and
hypothesis, rather than established fact. However, drawing
on morphological, physiological and large amounts of
psychological evidence, an overall theory for the
neurobiological basis of human cerebral lateralization was
recently advanced (Miller, 1996a). This fits much evidence.
More critical tests of it have been suggested, for which
results are not yet available.
Thus, despite constraints on biological investigations of
the human brain, explanatory principles first put forward for
animal brains are coming to be applied to the human brain.
The integrated science of brain and behavior, where true
explanatory arguments may be made, first developed with
reference to animals, is beginning to have impact on the
study of the human brain and human psychology.
In developing a theory of schizophrenia, the task is
therefore to use the increasingly coherent body of
information and ideas from normal animals and normal
humans, explaining psychological and behavioral data in
neurobiological terms, to elucidate the relation between brain
abnormalities and the symptoms and abnormal psychology in
that illness. The challenge is to explain the abnormalities at
the psychological and symptomatic level in terms of
underlying neural activity. To this author, this is at present a
more promising arena in which to construct explanatory
arguments than that spanning from genetic factors,
developmental abnormalities and the eventual manifestations
of schizophrenia.
History and Philosophy
1.6.
illness.
The neurodynamic concept of mental
Given these directions for theory construction, this book
focuses on a version of the medical model of disease which
does not apply outside the brain, and has its special
application almost entirely to the human brain: This is the
“neurodynamic” model of illness. It has application to some
neurological disorders but is viewed as having more general
application to mental illnesses of various types. What are the
characteristics of this class of illness?
Conceptually this class of illness is defined by a
disturbance of the dynamic fluctuation of activity in the
brain, rather than a deficit due to gross structural damage or
cellular loss. In simplest form these dynamic fluctuations can
give rise to symptoms which change rapidly, even on a
second-by-second basis, in contrast to structural damage
which tends to cause stable deficits in function. In analogy,
one may liken such dynamic disturbance to disturbed
weather patterns in the atmosphere, in contrast to the solid
terrain on which rain falls. These two sorts of disturbance in
the brain are not, of course, entirely separable. Structural
damage to the brain sometimes causes rapidly fluctuating
symptoms (e.g. abnormal movements in Huntington’s
chorea). Moreover, a disturbance which arises essentially
from the fluctuating dynamics of nervous activity, if often
repeated, might lead to brain cell loss, a structural rather than
a dynamic abnormality, as in some types of epilepsy.
Nevertheless, in a broad sense, this distinction is useful.
For illnesses which arise from disturbed brain dynamics,
one expects little evidence for actual structural abnormality,
such as cell loss produced by identified pathological
processes, or tissue damage. This statement is readily
accepted for most mental illnesses. It is debatable whether it
applies to schizophrenia (an issue discussed in detail in
Chapter 12). For the time being it is noted that solid evidence
of pathological processes at the level of nervous tissue must
at present come from study of post-mortem brains, rather
than from morphological brain scanning. This is necessarily
conducted when patients die at an advanced age, rather than
at the age at which schizophrenia has its onset and most
dramatic manifestations. Moreover, study of post-mortem
brain is exceedingly slow work. While there are a number of
intriguing post-mortem findings in the literature, they are
remarkable more for their diversity than for their uniformity.
There are relatively few attempts at replication, and even
fewer successful replications. The findings that have been
made are thus a rather heterogeneous collection, including
evidence of abnormal cellular architecture, and deficits in
cell numbers in some cases. In such work it is seldom clear
at what stage of life these abnormalities first appear. There is
no evidence that either a reduction in cell numbers, or
changes in cellular architecture are present when the illness
is first manifest, in late adolescence or early adulthood.
On the other hand, morphological evidence acquired by
brain scanning does provide evidence of structural deviance
of the brain in schizophrenia, and this is detectable right at
the start of the illness, as soon as patients are identified.
Generally such evidence concerns the size of the brain and
its subdivisions, relative to control groups. Change in brain
size does not necessarily imply abnormality of brain tissue as
a pathologist would detect it. Differences in the size of the
brain is also seen in comparisons between male and female.
In quantitative terms, these are much greater than those
between normal and schizophrenia. For this reason the word
“deviance” (in a statistical sense) rather than “abnormality”
is preferred. The changes in size of brain components seen in
schizophrenia, could, in themselves, be no more pathological
than in these normal variants. However, the existence of
deviation from normal in volume of brain components turns
out to be an indication of much more important differences
from normal. This book develops a theory of the cellular
basis for these volume differences. In a strict sense, these
cellular changes do not represent pathology as a
neuropathologist would understand the term. However, the
book also shows how they are reflected in abnormal
dynamics of brain function, which are themselves more
directly related to the manifestations of illness.
The most striking symptoms of schizophrenia have a
number of characteristics in common which can more
plausibly be attributed to dynamic disturbance of the brain,
than to structural damage: These symptoms are mainly
internal experiences rather than objective signs. Positive
symptoms (delusions, hallucinations and passivity
experiences) are more distinctive and pathognomonic of this
illness than are negative ones (signs of functional
loss)(Klosterkötter et al, 1995). Such symptoms are often
highly structured, even creative, and are subjectively
meaningful to patients, perhaps abnormally so. All these
things imply a degree of integrity of brain mechanisms,
although those mechanisms are used in an abnormal manner.
The meaning associated with symptoms is distinctively
human, as are the illnesses themselves as a whole. This
implies some degree of integrity of distinctively human
cognitive processes, specifically those underlying linguistic,
semantic and conceptual processing of information.
There is another specific implication of these highly
structured internal experiences which convey such powerful
meaning to the subject (spurious as it may be): In a general
theoretical account of mammalian forebrain function, Hebb’s
concept of cell assemblies is of central importance (Hebb,
1949). Cell assemblies are considered to be distributed nets
of nerve cells selected from a much larger number of cells in
the cortex and other parts of the forebrain. When activated
they, rather than single cells, are considered to be the vehicle
for representing meaning. Since the most distinctive
symptoms of schizophrenia are often highly meaningful, it
must be envisaged that the distributed cell assembly
configurations of the normal brain are still in operation,
though the dynamics of their operation is far from normal. In
this respect, major mental illness, such as schizophrenia, may
be separated from epilepsy, where often there is an
identifiable discrete focus of activity - something very
different from a cell assembly - and, apart from an initial
aura, a seizure is characterized by lapses of consciousness,
rather than creation of spuriously meaningful mental images
on a background of a fully alert (even hyperalert) state of
consciousness.
The negative symptoms of schizophrenia are more
difficult to deal with from a theoretical point of view. This is
mainly because it is difficult to separate a variety of quite
17
History and Philosophy
separate origins for these symptoms (see review in Carpenter
et al, 1988). Some of the negative symptoms may arise
directly from the disturbed brain dynamics as on-going traits,
and be capable of rigorous explanation in these terms. Other
origins to such symptoms may be self-protection from overstimulation, a concomitant of psychosis, a reflection of postpsychotic depression, depression as a reaction to adverse
social events as patients attempt to make their way in the
world, or to excessive doses of medication (etc). With such
complexity, the negative symptoms in themselves are not a
secure guide to start theory construction. However, there is
also a large experimental literature on experimental findings
associated with the negative symptoms and related
psychological deficits. Thus, although the negative
symptoms in themselves are difficult to deal with in a
theoretical sense, the general area of the enduring traits,
present before as well as after any psychotic episodes, is one
where good theoretical arguments relating disturbed brain
dynamics to symptoms and abnormalities in experimental
psychology can be sought. One may expect these traits to be
mainly functional impairments. An important finding
however, is that some of them can be seen as performance
which is sometimes superior to normal (see Chapters 6-10).
In
previous
generations,
the
concept
of
“psychodynamics” was much employed in relation to mental
illness, but without any clear relation to brain function. In the
present formulation of the concept of schizophrenia as a
neurodynamic illness, the “dynamics of the mind” is also of
considerable interest, with respect to both positive and
negative symptoms. However, this is totally different from
the older “psychodynamics”: The development of the
concept of neurodynamic illness will, it is hoped, permit the
emergence of a new psychodynamics closely related to
observable or inferable dynamic fluctuations in the brain.
Assuming that the underlying cause of schizophrenia is
disturbed brain dynamics, one would not expect to find
localizing signs, as commonly found in neurological
disorders. Minor, and un-localized nervous system
abnormality may be present, before an illness becomes
manifest, indicative of some sort of functional imbalance in
the brain. The departures from normal expected in a
neurodynamic illness would occur in global measures of
brain function such as electrographic recording (including
various methods of analysis of EEG, AEP and ERP), and
brain activation as assessed by functional brain imaging or
transmitter turnover.
Apart from these features of neurodynamic illness,
psychosocial influences are expected to play a larger part
than in neurological disorders of the brain, relating not only
to outcome of an established illness, but possibly also to its
initiation. The topic is discussed in detail in Chapter 4 (and
again in Chapter 13). As a whole, the influence of
psychosocial environment on neurodynamic disorders is
what one would expect from the “stress/diathesis” model, the
broader framework within which the neurodynamic category
of illness is cast.
18
1.7.
Implications of the “neurodynamic”
concept for taxonomy of schizophrenia and related
disorders.
Dynamic neurology, advocated in the previous section,
as a model for schizophrenia, must be based on the interplay
of a host of factors which may be balanced (or be in
imbalance) in a variety of ways. If one does not assume an
origin to such illnesses as discrete “essences”, these
interacting factors are likely to be mainly quantitative
divergences from normal rather than qualitative ones. Thus,
on theoretical grounds, the neurodynamic model of mental
illness does not suggest categorical classification, unless
there is a clear indication that the dimensional interactions
lead to a sharp bifurcation between the characteristics of
different disease or between them and normality.
As discussed above, all systems of psychiatric typology
so far devised have been categorical, not dimensional.
However, empirical studies of the psychometric aspects of
mental illness, and specifically the functional psychoses, do
indeed suggest that dimensional typology is a better way of
representing them than categorical ways. Claridge (1972)
stressed that clinically and genetically there are no sharp
dividing lines amongst the functional psychoses which might
be used to define schizophrenia. He suggested that
schizophrenia might be conceived as the extreme of a
personality variable, for which there is complete continuity
(over a population of people) between normal health and
severe pathology. Specifically he compared the personality
background from which schizophrenia emerges as similar to
the “creativity” dimension of personality. He also noted a
number of unusual correlations in schizophrenia, between
different psychophysiological measures. He took these to
indicate that abnormal organization of mechanisms for
arousal and attention are the neurobiological basis of the
relevant personality variant. Fifteen years later Claridge
(1987) revisited this issue, reviewing more recent evidence
that schizophrenia as an illness can be related to dimensions
of personality as studied in normal populations. A variety of
personality scales have been used showing that the ways in
which people with schizophrenia differ from normal also
identify a proportion of people in the healthy population
without definite mental illness. There appears to be no single
coherent personality dimension for representing such
similarity: Different dimensions are tapped by the different
scales, and these do not correlate with one another. Claridge
also reviews more recent data trying to specify the biological
substrate of personality dimensions related to schizophrenia.
This includes psychophysiological and neuropsychological
studies, as well as studies of hemispheric laterality. The
suggestion that personality variants have a basis in styles of
information processing related to physiological function of
the brain goes back as far a Pavlov (1941). However,
Claridge admits that “a unifying theme has yet to emerge”
for the attempts to give a biological underpinning to the
personality dimension aspects of schizophrenia.
Another type of empirical evidence from which a
dimensional representation of schizophrenia and related
disorders may be inferred is from the statistics of clustering
of symptoms. It was part of the Kraepelinian dichotomy that
History and Philosophy
the symptoms of manic-depressive illness should be
separable from those of dementia praecox, and it has been
argued that such a bimodal distribution of symptoms, with a
rarity of mixed forms, would indicate a genuine split
between two disease entities. However, surveying modern
research Kendell and Brockington (1980) write: “No-one has
ever succeeded in obtaining unambiguously bimodal
distribution which has been replicable on a second series of
patients. Either an obstinately unimodal distribution has been
found, or a bimodal distribution has been claimed but not
been reproduced by other workers, or the shape of the curve
has been ambiguous and not clearly either uni- or bimodal.”
They cite two studies referring specifically to the distinction
between manic-depressive illness and schizophrenia, as
supporting detail for this statement: Kendell and Gourlay
(1970) using discriminant function analysis of a 38-item
description of groups of newly-admitted patients diagnosed
as schizophrenic and manic-depressive, failed to show a true
bimodal distribution of symptoms between schizophrenia
and manic-depressive illness. In a later study, Brockington et
al (1979) applied a discriminant function analysis to
information on psychotic patients which included history,
present symptoms and follow-up data. While a function was
derived from a first group of patients (mainly based on
follow-up symptoms) which gave a bimodal distribution, it
did not carry over to another group. The authors conclude
that these patients did not fall naturally into two groups.
Grayson (1987) indeed argues on statistical grounds that
even if such bimodality of symptom distribution was
demonstrated it need not indicate a binary split between
disease entities.
Cloninger et al (1985) performed an analysis of
symptoms in 1739 persons from a psychiatric out-patient
clinic, 56 of whom had the “definite” diagnosis, and 33 the
“probable” diagnosis of schizophrenia. They found that a
cluster of four symptoms (persecutory delusions, delusions
of control, auditory hallucinations and mood-incongruent
delusions) tended to occur as a stable syndrome throughout a
6-12 year follow-up period. Scores for 2 or more on this
cluster (3 or more if there were also spending sprees during a
period of elation) were highly discriminating for a diagnosis
of schizophrenia. Notably, the distribution of scores for this
cluster was bimodal, across the whole sample, and the
authors considered this the first demonstration of
schizophrenia as categorically separate from other
psychiatric patients. However, their claim was that
schizophrenia has “natural boundaries” distinguishing it from
“other psychiatric patients”. They did not demonstrate a
categorical separation from “affective psychosis”, or other
disorders in the schizophrenia spectrum, a task which is
inherently more difficult.
Another way of assessing whether dimensional or
categorical representations of functional psychoses are
preferable, deriving from Kraepelin’s outcome criterion of
classification, is to determine whether the split in terms of
symptoms gives categorically different predictions of
outcome. If there really is a separation of disease entities
between manic-depressive illness and schizophrenia, there
should be a non-linear relation between symptom profile and
outcome with an area of the symptom dimension for which
outcome changes more abruptly as the symptom profiles
changes than within the symptom profiles of the presumed
more “typical” examples of the two main entities. However,
in terms of correlation between symptoms and outcome in
patient groups with schizophrenia and manic-depressive
illness, Kendell and Brockington (1980) found no evidence
of such discontinuity. Van Os et al (1996c) compared the
use, for prediction of outcome, of categorical representations
of functional psychoses as found in DSM-III-R or ICD-10,
with their own dimensional representation, obtained by
factor analysis. The dimensional data gave far better
correlations with most outcome measures than the DSM-IIIR or ICD-10 categories.
As stated in the introduction to DSM-IV, it is at present
quite uncertain what should be the dimensions along which
mental illness in general, and schizophrenia in particular are
best described. The best way of characterizing personality
dimensions would be for each dimension to correspond to an
explicit biological variable. The start of modern personality
typology, in the work of Pavlov on dogs (Pavlov, 1941), was
indeed supposed to be based on variations in brain biology,
that is the balance between (and stability of) processes of
excitation and inhibition. Pavlov refers several times to
schizophrenia in this context. However, his suggestions were
not very detailed. The personality inventories of Eysenck,
which led to the sort of typology advocated by Claridge also
had little explicit biological underpinning, and Claridge’s
own work, though including psychophysiological measures,
does not tie the personality variable down to fundamental
biology of the brain. From what we know of the dynamics of
the brain, there is a very large number of biological factors
whose quantitative value in an individual brain might be
reflected in personality. These include a wide variety of
structural characteristics (e.g. the richness of cortico-cortical
connections - which might determine associations - and their
conduction delays), the activity of various neuromodulators
or neurotransmitters (e.g. any of the monoamines or
neuropeptides), the average amplification factor for synaptic
transmission in a wide variety of pathways in the brain, and
the balance between major entities in the forebrain (cortex
and hippocampus, cortex and striatum, thalamus and cortex,
left and right hemispheres). Thus, even though we have
reason for believing that dimensional typology of mental
abnormalities is in general better than categorical
classification, there is at present a degree of subjectivity in
the choice of definitions of personality variables. This will
continue to be the case, until we can establish a logical
relation between key biological variables controlling brain
dynamics and the personality or psychopathological
characteristics which emerge as a result. Only then can the
notion of dimensional typology be expressed in such a way
as to give an objective typing of mental illness, one that can
command a consensus over time, and between countries and
cultures. Again we realize the need for the complex and
coordinated reasoning within a psychobiological theory of
mental illness.
1.8.
Summary.
This chapter has reached the conclusion that the
illnesses included under the term “schizophrenia”, and those
19
History and Philosophy
related to them, are best conceptualized in terms of a
continuously-variable dimension, or a combination of several
dimensions. In such a framework, these illnesses are likely to
occupy relatively uncommon extreme positions on the
relevant dimensions, with the range of normality being
somewhere distant or even at the other end of the relevant
dimensions. The idea of these illnesses being categorically
different from normality, though embodied in almost all
diagnostic schemes, is not supported by a range of empirical
evidence, and also is unlikely from inferences which can be
made from various features of these illnesses, about the
underlying disturbance of the brain.
Given this, the best model of these illnesses, within
which a disease theory might be constructed, is the
biomedical model, rather than any alternative which does not
include details of brain biology. Slightly more specific than
this, schizophrenia can plausibly be viewed in terms of the
stress/vulnerability model, where expression of the illness
requires both constitutional abnormalities in the brain, and
stress factors. The latter might be either of physical
(biological) nature or psychosocial stressors. The
constitutional abnormalities in the brain can themselves be
regarded as in some sense developmental in origin. However,
neither
the
stress/vulnerability
model
nor
the
neurodevelopmental concept are at present likely to be very
useful in constructing a closely-reasoned disease theory.
Therefore within these broad models, it is probably
necessary to adopt a version of the biomedical model
different from any of those used for constructing all classical
disease theories, which apply to other species and to diseases
other than those included in psychiatry. Various features of
schizophrenia and related illnesses suggest that these
versions of the biomedical model can be designated as
disturbances of “neurodynamics”. This is a new version of
the biomedical model, and although it may have application
to some neurological disorders, its real province is within the
disorders studied in psychiatry.
Even given a dimensional concept and this more specific
neurodynamic framework for studying schizophrenia, a
succinct definition of the illness escapes us at the start of this
work. The dimensions along which schizophrenia is to be
plotted are uncertain, and therefore so is the definition of
schizophrenia. In this context it is appropriate to quote from
a recent lecture by N.McI.James (1992), commenting on the
recent trend, embodied in DSM-III and similar schemes,
towards operationalized diagnosis. He writes:
“Despite more than fifteen years of usage of this
relatively refined and confined picture of
schizophrenia, we have not, I believe, come very
close to the etiology or pathogenesis of the illness.
What then has gone wrong with this line of
research that is so fundamental to the very basis
of all other approaches? For if we cannot define
what it is that we are studying, how can we ever
begin to do so? It is a melancholy fact therefore
that the very definition of what we are attempting
to research is still so unsatisfactory. Have we
barked up the wrong tree, gone out on a limb, or
is the trunk itself rotten?”
20
With respect, this author suggests that the problem is not
any of these three. The problem is a misconception of the
relation between definition and explanation. A simpleminded view suggests that the former must always precede
the latter. So it is when a disease entity is defined by a one
sharply-abnormal feature, or a small number of such
features, which covary very well. In these cases, the
definition is clear at the start, and the problem of explanation
can then proceed from that definition. But consider another
example, the illness of syphilis and its many sequelae. This is
quite an apt model, since its elucidation was a major medical
advance at the time Kraepelin formulated his influential
concept of dementia praecox. In this case manifestations of
the illness were many, varied and endlessly complex. In this
case, the definition of the illness as one, rather than a variety
of quite separate entities was not achieved until the causal
agent, the spirochete, had been discovered. Here explanation
came before definition.
Another example, from outside medicine, is perhaps
even more germane. Two hundred years ago, studies by
alchemists focused around a complex and debatable concept
called “phlogiston”. This was somehow related to many
chemical reactions, to fire, to the commonplace notion of
“hotness” which at that time did not have a proper scientific
definition, and, in medicine, to fever. Nowadays the concept
of phlogiston is long abandoned. In its place are truly
scientific concepts, heat energy, temperature (properly
defined), and the energy changes occurring when atoms and
molecules take part in chemical combinations. These
concepts, unlike “phlogiston”, were integrated and closely
linked with the preceding corpus of scientific knowledge and
ideas. In particular these newer concepts were derived from
the concept of energy as it had been defined in earlier years
of scientific history, when the focus had been on mechanics
rather than chemistry.
Our current concept of schizophrenia is in some ways
similar to that of phlogiston two hundred years ago. It is not
complete nonsense. Likewise, phlogiston represented a
groping towards an adequate concept which most scientists
at the time knew was there to be formulated, if only they
were clever enough. Schizophrenia also is generally accepted
as a very real concept underlying urgent medico-social
problems, even though we cannot quite grasp that concept in
adequately precise terms. However our concept of
schizophrenia, like phlogiston in the eighteenth century,
while not nonsense, cannot at present be characterized as
totally coherent sense. In particular it has been defined
mainly with a language that is not integrated with the current
corpus of scientific knowledge and ideas. It is defined only
within its own domain. There are thus inevitable circularities,
and endless debate about what schizophrenia “really” is. The
situation is only resolvable when we find the underlying
causes of schizophrenia. The criterion for a scientificallyvalid definition is that it will support comprehensive and
rigorous explanatory arguments. As argued above this is
likely to be by the definition of appropriate dimensions for
analysis, rather than of sharply distinct categories. Those
dimensions need to be rooted in the wider corpus of
contemporary scientific knowledge, and especially in brain
History and Philosophy
biology. The present definitions of schizophrenia are likely
to remain relevant, but we will know their real importance
only when we can define the illness in a language common
to other domains of science, permitting rigorous
explanations. In other words, as with the demystification of
“phlogiston”, or the unraveling of the concept of syphilis,
definition will follow rather than precede explanation.
To spell out the problem in this way is not intended to
make it more difficult. It is intended to make clear that the
issues are far more fundamental than in routine science. We
have not only to unravel the cause of schizophrenia, but as
part of that process, we have to discover the best conceptual
language for formulating its cause. The two processes must
proceed together, success in one establishing and validating
the other. This is not pseudoscience, as the analogy with
alchemy might suggest: It is really fundamental science,
more difficult perhaps, but also far more challenging than the
routine application and extension of an established language
within a well-developed area of scientific enquiry.
1.9.
Provisional definition of “schizophrenia
and related disorders”.
We may accept the conclusion of section 1.8. that, for
complex illnesses such as schizophrenia “definition follows
rather than precedes explanation”. Nevertheless, we must
have a provisional, rather loose definition of the subject
matter of concern to us before we tread the road towards
explanation. The provisional definition adopted here for
schizophrenia is as follows: Our primary concern is to
explain those illnesses which have three characteristics:
(i) They exhibit characteristic periods of severe mental
turmoil, which we refer to as “psychosis”. In broad terms
psychosis involves a break with a patient’s grasp of reality,
as generally understood, and can be resolved to greater or
less extent with appropriate medication. Psychosis is
discussed in detail in a later chapter.
(ii) They also have longer standing symptoms, mainly
impairments, of a less distinctive kind, which are associated
with psychological and social impairment seen before and
after these psychotic episodes, and which also tend to occur
in relatives of those who are prone to the episodes of
psychosis mentioned above.
(iii) Illnesses included in this provisional definition are
usually long-lasting, with onset in late adolescence or early
adulthood.
For this broad area of illness we could systematically
use the phrase “schizophrenia, and related disorders”. This
usage would then not be applied for more specific
subdivisions within the broad category designated by this
phrase. However, it would be cumbersome and pedantic to
add “and related disorders” whenever this meaning is
intended. Since the distinction between the two usages is
generally implied by the context, the word “schizophrenia” is
used mainly, in what follows, and more specific diagnoses
other than schizophrenia are specified only when necessary.
It needs also to be emphasized that both the symptoms of
psychosis and the longer-standing but less distinctive
abnormalities which are the twin elements of this provisional
definition, are themselves complex, each requiring a great
deal of analysis. It is emphasized at the outset that it is not
assumed a priori that schizophrenia is a totally different
category of illness from affective illness. Nevertheless the
widespread feeling amongst psychiatrists that they are
distinct is respected, if not adopted unequivocally
21
Synopsis of the Theory
Chapter 2.
Synopsis of the Theory
2.1.
illness.
Life-time
trajectory
of
schizophrenic
A complicating factor in any attempt to understand
schizophrenia is that the disorder has different
manifestations at different stages of a person’s life. The
most dramatic and severe expression of the disorder, seen as
episodes of active psychosis is evident in late adolescence or
early adulthood. The assumption that psychosis at this stage
of life is the “age of onset”, was the fact which led
Kraepelin to call the disorder “dementia praecox”. The same
assumption is made, as the third of the criteria (end of
Chapter 1) used for “provisional definition” of the disorder
dealt with here. Only rarely does this apparent onset occur
in early adolescence, and the existence of “childhood
schizophrenia” is an unresolved controversy (see Footnote,
Sect 13.7.). However, by no means does this exclude that
there be impairments earlier in life than this designated time
of “onset”. A number of studies have documented lesser
degrees of impairment during childhood and early
adolescence. Clinically these impairments include poor
social competence and emotional adjustment, poor motor
coordination and poor development of visual abilities (Roff
et al, 1976; Done et al, 1994; Crow et al, 1995). Children
who later develop schizophrenia present to child guidance
clinics more commonly than normal (Roff et al, 1976).
From study of home movies, an excess occurrence of
neuromotor abnormalities in those who later develop
schizophrenia, is detectable as early as 2 years of age
(Walker et al, 1994). More detail on these early
impairments, as documented in specific psychological tests,
is discussed in some of the later sections, dealing with
children at elevated genetic risk, but before the usual age of
greatest risk of onset (e.g. Sects 7.3.3, 9.2.2.3., 9.2.4.3.,
9.3.5.2., 10.2.2.2., 10.3.7.2.).
Later in adolescence, in the lead-up to the first psychotic
episode, a distinct “prodromal syndrome” has been described,
associated with overall fall-off in school performance, which
has been correlated with increasing impairment in specific
cognitive tests (Niendam et al, 2006), fluctuating mood,
negative symptoms and attenuated positive ones (Yung and
McGorry, 1996; Cornblatt et al, 2003). This period is of great
importance for early intervention programs. In the present
work it features in the discussion in Chapter 12 (Sect. 12.7.3.),
in relation to change in brain morphology.
The symptoms and mechanisms of the psychotic episodes
themselves are discussed in detail in Chapter 5. Of particular
importance for the present work is the time-course, and
process of recovery from psychosis. Later on in the course of
an established schizophrenic illness a variety of trajectories
have been described (Ciompi, 1980). The particular emphasis
for the present work is that non-psychotic traits may often be
seen without the confounds of concomitant psychosis,
17
especially if recovery from psychosis is relatively good. For
long-established illness, a group of patients on whom research
efforts have been specially focused are those with severe and
lasting impairments, corresponding to what is sometimes
called the “defect” state or “Kraepelinian” schizophrenia
(mentioned in Sects. 4.1, 8.7.1., 9.6.2., 12.1., 12.5.4.2,
12.7.4.0., 12.11.3.) These patients have tended to become
long-stay institutionalized in-patients, and many of them
spend their last years in institutional care. In
neuropathological studies, the brains of these patients are
likely to be overrepresented. The substantial proportion of
cases who recover completely (or nearly so), or who show
only mild impairment, with or without the need for continuing
medication, are often seldom seen in psychiatric practice, and
are not well researched.
The emphasis of the present work is to develop a theory of
the fundamental causes of schizophrenia. The focus is then on
psychosis, and (especially) on the enduring traits seen in the
more typical cases, before during and after resolution of
psychosis. In patients with illness of long standing, especially
if the impairment is severe, factors in addition to these
fundamental causes are likely to complicate the profile of
functional impairments. These factors include prolonged
under-activity of the nervous system, associated with
profound, long-lasting negative symptoms, under-stimulation,
and other effects of institutionalization, as well as the effects
of prolonged high-dose medication, or (for patients
hospitalized before the neuroleptic era), the effects of insulin
coma therapy, as well as ECT.
2.2.
Contributions
of
inheritance
schizophrenia and related disorders.
to
If we sidestep the complications arising from the many
stages of illness and concentrate on schizophrenia as a whole,
one of the immediate issues to consider is its genetics. Studies
of inheritance of schizophrenia leave no room for doubt that
genetic influences play an important role in its causation. The
evidence includes studies in first, second and third degree
relatives of probands with schizophrenia, twin studies and
adoption studies (3.2.). Adoption studies indicate that genetic
factors have an influence which prevails over family
environmental ones. However, strong evidence for inheritance
is not the same as evidence for strong inheritance: The genetic
influence is important, but by no means overwhelming. There
is plenty of room for environmental or other non-genetic
factors. The pattern of inheritance is not of a simple
unifactorial Mendelian nature, nor does it suggest that
different genetic factors are widely involved in different
pedigrees (genetic heterogeneity), although rarer conditions
similar to schizophrenia may be genetically distinct. The
evidence fits better a polygenic manner of inheritance (3.3.).
The fact that the heritability of schizophrenia is a graded
function of illness severity (measured in several ways) in a
Synopsis of the Theory
proband (3.3.4.) also suggests polyfactorial inheritance. Since
schizophrenia is associated with a substantial fertility
disadvantage (3.3.5.), it is unlikely that there is any one (or
few) genes of dominating importance. If there were, they
would be selected out, and schizophrenia would not be the
common disease that it is. Several arguments based on
classical evidence converge to suggest that multiple genetic
factors are involved, probably involving the collaboration of
many common genes, all with small effects, none of which is,
by itself, pathological.
Studies of cross-prevalence (the prevalence of one disorder
in first degree relatives (FDR) of probands with another
disorder) show a complex variety of interrelations (3.4.1. and
3.4.2.): The classical subtypes of schizophrenia are not
genetically distinct, and “simple schizophrenia” (Bleuler’s
addition to the Kraepelinian subtypes) is genetically linked to
the other subtypes (3.4.1.). The major conventionally-defined
entities in the broader spectrum of disorders do not “breed
true” (3.4.2.), but a few less-common phenotypic variants do
so. Schizophrenia has a puzzling asymmetric genetic relation
with affective disorder, especially with major depression
(3.4.2.3.). In other words, schizophrenia in probands does not
increase the prevalence of affective disorder in FDR, but
presence of affective disorder in probands does increase the
prevalence of schizophrenia in FDR. This is probably
explained by the fact that major depression is heterogeneous,
schizophrenia sharing genetic factors with psychotic
depression, and to a much lesser degree with non-psychotic
depression (3.4.2.4.). Bipolar disorder appears to be closely
related to unipolar affective disorder, but the genetic relation
between the two is again asymmetric (3.4.2.4.). In other
words, FDR of bipolar subjects have an elevated risk of
unipolar depression, but FDR of unipolar subjects have only a
slightly elevated risk of bipolar disorder. This may be because
bipolar disorder has genetic factors in addition to those
needed for the appearance of unipolar disorder. Bipolar
disorder has the best claim of those considered here to be
genetically distinct, but nevertheless has some genetic kinship
with schizophrenia, which requires to be clarified (3.4.2.3.,
3.4.2.4.). Schizoaffective disorder is a hybrid, with greater
genetic relation to either schizophrenia or affective disorders
(both unipolar and bipolar) than to itself in FDR (3.4.2.3.,
3.4.2.4.). Brief periods of schizophrenia-like illness
(schizophreniform disorder or “reactive psychosis”) do not
carry the same risk to relatives as schizophrenia fulfilling the
“six-month criterion” of DSM-III, though they may
predispose to affective illness, and perhaps to similar shortlived illness in FDR (3.4.2.5.). Post-partum psychosis
probably falls in the same category. Various personality
variants (“schizotypal personality” defined in several ways,
and “paranoid personality”) have a genetic kinship with
schizophrenia (3.4.2.6.). Opinion is divided on whether lateonset schizophrenia-like illness (“late paraphrenia”) is
genetically part of the schizophrenia spectrum (3.4.2.7.).
Overall, the inheritance evidence better fits a dimensional
than a categorical conceptualization of most of these disease
entities, according to any definitions in current use: Many
genetic factors confer graded vulnerability to the illness.
However, in the broad schizophrenia/affective disorder
spectrum, more than one dimension is needed to capture the
genetic relations (3.4.2.8.). It is likely that more than one
underlying disease process, as well as different thresholds are
required to meet diagnostic criteria for the different
conditions. The different disease processes cannot be
distinguished categorically on the basis of symptoms alone.
In the last twenty years attention has been drawn to a
variety of possible anomalies in inheritance of schizophrenia,
not predicted by classical genetic models. Attempts have been
made to relate these to recently-discovered information about
behavior of chromosomes. They include: stronger genetic
transmission of schizophrenia from female than male
probands (3.5.1.) possibly indicating sex-linkage; increasing
severity or decreasing age of onset of schizophrenia-spectrum
disorders over generations in a multi-affected pedigree
(3.5.2.) possibly indicating accumulation of dynamic
mutations in the form of trinucleotide repeats; an excess of
same-sex concordance in schizophrenia (3.5.3), perhaps
implying a pseudoautosomal factor predisposing to
schizophrenia; and an excess of schizophrenia in people of
consanguineous parentage (3.5.4.) which would suggest
recessive Mendelian factors. Many biases confound the
collection of reliable statistics to establish these anomalous
patterns of inheritance. They have not withstood close
scrutiny.
Molecular genetic studies of schizophrenia have been
pursued with great energy especially in the last ten years
(Sect. 3.6.), but have not yet fulfilled their promise. It is
possible that, by combining methods of genetic analysis with
those of gene expression in specific tissues (notably brain),
specific genetic factors can be identified. However, it is clear
from work carried out to date that no genetic factor of major
effect (conferring an “odds ratio” for the disorder >2.5) is
present in most cases (though such factors may be present in
particular pedigrees). Identifying multiple genetic factors each
of rather weak effect is very expensive, and may still elude
the best efforts of molecular geneticists. Identification of
specific genes would be aided if there was more deliberate
work on theory construction. In this context the finding that
genes related to myelin formation and oligodendrocyte
function are abnormally expressed in brain tissue obtained
post-mortem from persons with schizophrenia. This finding
may be important, since it corresponds well with the central
premise of the theory to be developed in later chapters of the
present work.
2.3.
Synopsis of contributory environmental
causes for schizophrenia and related disorders.
Various aspects of life and environment have been shown
to correlate with the occurrence of schizophrenia, and have
been taken as indicators of contributory causes of the
condition, which are environmental in nature. Both biological
and psychosocial factors are implicated. However,
interpretation of the evidence is not straightforward, there
being uncertainties sometimes on whether the observed
correlations do indeed indicate causal effects, and if so,
whether they arise from genetic or environmental causes, and
sometimes whether an environmental cause is in the
biological or the psychosocial realm.
18
Synopsis of the Theory
2.3.1.
Contributory causes from the biological
environment.
It has often been observed that there is an excess of
roughly 8-10% in incidence of schizophrenia in people born
in winter months, especially where there are seasonal
variations in climate (4.1.). It has been proposed that some
seasonal environmental factor (such as common infections)
acting during pregnancy increases the risk for the disorder.
However, predictions from this proposal, that familiality
should be less in winter-born cases, or that winter-born cases
have distinctive features not shared by cases born at other
times of the year are not consistently supported by available
evidence. An alternative possibility is plausible, and is
supported by some evidence, namely that seasonal patterns of
conception differ between those who, for genetic reasons are
likely to have offspring with schizophrenia, compared to the
rest of the population.
Direct evidence has been sought that prenatal infections,
especially influenza, predispose offspring to schizophrenia
later in their life (4.2.). Any such effect is, at most, quite a
small one, demonstrable to a significant degree only in studies
of large populations, and accounting for no more than 1-2% of
all cases of the disorder. The smallness of the effect means
that prenatal infections can contribute to the season of birth
effect only in a small way, if at all. Nevertheless, there is
some consistency in the evidence, in that the middle third of
pregnancy is usually identified as the period of risk for
prenatal infections. This period of vulnerability is also
identified by studies of prenatal famine, and of some minor
physical anomalies which occur with increased frequency in
schizophrenia, and have their origin in this period of fetal
development (4.3.). These developmental anomalies need not
represent definite deviations in genetic programming, nor
environmental causes: They might reflect quasi-random
instabilities in the developmental program. Nevertheless, in
Sect. 12.3.3., evidence on cellular development is mentioned
suggesting reasons why the mid-trimester may be critical in
the developmental processes which lead to schizophrenia in
young adults.
There is a clear statistical association between obstetric
complications (OC) and later development of schizophrenia.
This does not necessarily reflect a causative role for OC.
Nevertheless, in several studies the evidence has withstood
attempts to explain away the statistical association in terms
other than those of a direct (contributory) cause. OC as a
whole are elevated for schizophrenia births even when
siblings are the controls, so the association is not simply a
reflection of a general tendency to OC in the mothers of
schizophrenia patients. There are also a few studies
demonstrating an excess of OC in schizophrenia births when
unaffected co-twins are controls, so the association is
probably not due entirely to aspects of maternal lifestyle at the
time of that pregnancy (which would affect both co-twins).
When a schizophrenia birth is accompanied by OC the illness
tends to be one of the more severe forms of schizophrenia, or
there is an increased incidence of schizophrenia compared to
other less severe diagnoses. In such cases, schizophrenia tends
to occur with earlier age of onset, less responsiveness to
antipsychotic medication, and possibly with more abnormality
of brain morphology. Familiality does not differ reliably
19
between patients with and without OCs, but familiality is a
poor guide to genetic loading (see introduction to Chapter 4).
Complications both before birth, and during delivery and the
immediate post-natal period have been found to increase the
risk of schizophrenia. Specific OCs which have been linked to
later emergence of the disorder include aspects of maternal
lifestyle, reduced birth weight and/or prematurity, and
asphyxia/hypoxia (both during pregnancy and during the
perinatal period). Some studies have shown that the excess of
perinatal asphyxia/hypoxia in schizophrenia births applies
even when unaffected siblings or twins are used as controls,
although this does not exclude the possibility that at least
some of the excess is due to lifestyle variables, applying to the
particular pregnancy. Several studies show that perinatal
asphyxia is associated with more severe types of
schizophrenia, or cases with early onset. The association with
early onset illness remains significant even after co-variation
for several other possibly-confounding factors. This suggests
that perinatal asphyxia is a contributory cause, not just a
correlation arising less directly. However, in the total picture
the contribution of direct causal influences to the observed
correlation between schizophrenia and OC has not been
resolved. Relative risk of schizophrenia for those with OCs as
a whole vs those without, has been estimated as ~2, and for
some specific OCs the relative risk can be much higher (7 for
diabetes during pregnancy; 4.5 for total fetal/perinatal
hypoxia scores). However, in translating such values to give
the fraction of cases in the population attributable to OCs (or
to specific OCs), one has to bear in mind also the relative
frequency of the latter, which may be quite low for specific
OCs. Estimates that as many as 20% of cases are due to OCs
are, for various reasons, likely to be exaggerations.
Nevertheless, OCs are significant contributory causes, more
important than pre-natal infections. They are not primary
causes, but may “tip the balance” or increase the severity of
an underlying problem, so that the diagnostic criteria for
schizophrenia are met, when otherwise they might not be.
They are in operation over a longer stage of gestation than
(apparently) is the influence of prenatal infection. Whether the
effect of OCs can be incorporated in any specific and detailed
way into an overall theory of schizophrenia, depends on the
form such a theory takes, based on much other evidence (see
also 12.3.3. and 12.9.4.).
Of the risks during childhood and adolescence, head injury
probably has a negligible influence, although CNS infections
may have a larger effect (4.5.). The relevance of cannabis has
been much debated. Recent evidence clarifies its role: It
appears to be not only a precipitator of schizophrenia-like
illnesses in persons who are already vulnerable, but also a
significant contributory cause, producing illness in persons
who would otherwise not be affected (4.6.). The effect of
other street drugs is mentioned in Chapter 5.
2.3.2.
Contributory causes in the psychosocial domain.
It is well known that increased prevalence of
schizophrenia occurs in association with low socio-economic
status (4.7.). In large measure this is due to downward drift in
social status and failure of upward mobility, not only in
people who already have the illness but also in the years
before onset of illness. Some degree of actual causation by
Synopsis of the Theory
social factors cannot be excluded. Urban birth and upbringing,
produce substantial increases in risk of schizophrenia, a risk
which increases with the duration of life during adolescence
spent in an urban environment (4.8.). This suggests that a
definite environmental factor, either in the biological or social
realm, associated with urban life increases the risk of
schizophrenia. Most important, immigration produces a very
variable, but sometimes very large increase in incidence of
schizophrenia (4.9.). Rather than being a biological effect, this
seems to be a psychosocial one, acting over a long period,
probably during a child’s formative years. However, it is most
pronounced in those who also have a genetic predisposition.
This effect can be so large, that it overshadows completely the
small effects of prenatal infections, obstetric complications or
CNS infections during childhood, which can presumably be
detected only when psychosocial factors are relatively
constant or slowly changing. Some modern evidence suggests
that adverse family social factors may predispose to
schizophrenia, especially in those who are at genetic risk
(4.10). This evidence includes an adoption study where
disturbed dynamics in the adoptive family, as well as genetic
risk are identified as risk factors. Shared environmental
factors within families (probably psychosocial in nature) have
also been identified in family studies as contributors to
schizophrenia, although only in a small way. Some evidence
also implicates the number and relative age of siblings. There
is however, little evidence that divorce and family separation
predispose children to schizophrenia.
The evidence of major contributory causes in the
psychosocial domain (especially the effect of immigration)
has wide impact on schizophrenia research (4.11.). It implies
that the proportion of the population who carry the genetic
diathesis for schizophrenia is much larger than otherwise
suspected – of the order of 10-20% - and for many people
with this diathesis it is only the combination with
psychosocial adversity which brings this genetic loading out
into the open. If this is true, it makes more difficult the task of
molecular geneticists in their search for the exact genetic
factors underlying schizophrenia. This evidence also has
impact on one’s interpretation of the relation between druginduced psychoses and schizophrenia, as well as the
international studies comparing prevalence of schizophrenia
in different countries and cultures. Most important for the
present work, this evidence defines one of the criteria by
which any comprehensive theory of schizophrenia should be
judged: If a neurodynamic theory of schizophrenia is to be
upheld, it will need to encompass psychosocial influences as
well as underlying biological substrates for the disorder (see
Chapter 13).
2.3.3.
Genetic liability, environmental influences and
concepts of schizophrenia.
The range of causative factors, genetic and environmental,
which contribute to schizophrenia is very broad. Their sheer
diversity raises uncomfortable questions about the very
concept of schizophrenia. It could be said that the concept is
fundamentally unsound, an arbitrary human creation with a
shaky foundation in a motley collection of antecedent
correlations, rather than a real disease entity. Alternatively,
“schizophrenia” might be conceptualized as a very non-
specific result of multiple hazards, including diverse genetic
liabilities, biological insults and psychosocial adversity. To
this author, such viewpoints are unduly cynical. Nevertheless,
a challenge is posed for the rest of this book, namely to re-cast
the definition of schizophrenia in terms of a theory which
encompasses all these factors. A few guidelines can be
suggested for such a reformulation:
Genetic contributions can presumably produce a brain
which has certain propensities biasing it towards
schizophrenia. It might then be possible to define a causal
hypothesis, based on innate brain mechanisms, applying in the
first instance just to those cases where the environmental
insults to the brain and the psychosocial influences on its
functioning in childhood and adolesence are not important. To
these are then added non-genetic biological factors acting at
an early stage of development. Although these are of small
overall impact, they help to demarcate the time during
development at which the brain becomes committed to the
developmental program leading to schizophrenia. This
appears to be the mid-trimester of pregnancy. Factors such as
obstetric complications acting at this and later stages of
pregnancy and later in biological development can be seen as
complicating factors, sometimes substantial, but not the core
of the problem. Then, added to this, one should consider, how
adverse psychosocial factors might interact with genetic and
developmental ones to produce the manifest illness. In this
regard, it is clear that in post-natal life, the dynamic potential
of the brain is determined not only by early biological
development: It is also “shaped” by the information patterns
to which it is exposed in post-natal experience. Current
knowledge establishes this best for the sensory and motor
systems. However, there is no reason why it should not also
apply to the higher functions of the brain, which are
particularly implicated in schizophrenia. These are more
closely linked to the social environment than to immediate
sensory input. There is thus the possibility that the
psychosocial environment plays a part in determining the
dynamic functioning of the adult brain: Adverse psychosocial
influences could contribute to producing the disturbed brain
dynamics shown in schizophrenia. These influences include
those encompassed by the concepts of “reward”,
“punishment” and “positive or negative reinforcement”. There
is a variety of terminology to chose from (as discussed in
Chapter 5.), and these terms are used in a very broad sense.
Whichever terminology is chosen, these concepts bridge not
only between biology and psychology, but also, in humans,
between biology and factors in the social environment.
Development of normal brain dynamics and normal
information processing in humans might depend at least in
part on the long-term history of such influences. Prolonged
absence of reward, presence of punishment or negative
reinforcement, might well change the overall dynamics of the
brain.
These conceptualizations are quite compatible with
previous models put forward for schizophrenia. The genetic
and developmental evidence is compatible with the
“neurodevelopmental model”. The psychosocial influences fit
well within the “stress-diathesis model”. However, in Chapter
1, it was suggested that schizophrenia might be conceived
more exactly as a “neurodynamic” disorder. Such a model of
20
Synopsis of the Theory
disease can hold together all the strands of causation, within a
single set of causal premises. In this formulation abnormal
brain dynamics in the adult determine abnormal patterns of
information processing, reflected in symptoms. Abnormal
adult brain dynamics could themselves be determined by
abnormal cellular architecture in brain tissue. This in turn
would be mainly under genetic control, unfolding during the
expression of a complex developmental program. During this
unfolding, harmful biological influences, especially those
acting in the prenatal period could modify the developmental
process to increase the likelihood of the adult brain’s dynamic
capabilities becoming abnormal. Regardless of this however,
the dynamic capabilities of the brain develop post-natally,
under the influence of the information patterns to which the
brain is exposed, and the rewards, punishments, meanings,
purposes, and contexts which determine our social life. In this
way one can conceive of psychosocial influences shaping the
dynamic brain functions underlying higher cognitive function,
in a way similar to the influences at the sensorimotor level
which create plastic changes in sensory or motor systems at
an earlier stage of postnatal life.
Most epidemiological studies of causal effects on
schizophrenia are committed in advance to genetic causation,
or if environmental, to either biological or psychosocial
causation. Few studies have attempted to compare
quantitatively the relative influence of these two. One such is
that of Mortensen et al (1999): Relative risk, if there was an
affected FDR, ranged from 7—9.3 (varying with the class of
FDR), 2.4 if there was urban birth, but only around 1.1 (i.e.
10% increase) if there was a winter birth. The overall
proportion of cases attributable to each of these risk factors
was 5.5% for affected FDR, 34.6% for urban birth, and 10.5%
for winter birth. The total contribution of genetic factors to
schizophrenia is however likely to be larger than 5.5%,
because, given that genetic factors are often not expressed,
overt family history is an underestimate of true genetic
contribution.
With a formulation such as that presented above, there is
no need for biological and psychosocial concepts of
schizophrenia to be pitted in opposition to each other.
However, much work is needed to develop such a general
shape of a theory into a theory providing detailed
explanations.
2.4.
Dopamine and the theory of psychosis.
Psychosis is defined here as a state where a patient loses
contact with everyday reality, this state being characterized by
delusions, hallucinations, Schneiderian symptoms and other
signs of severely disturbed cognitive processes. It is the most
obvious and dramatic departure from normality in
schizophrenia, but it is not synonymous with schizophrenia:
Psychosis can arise in many other ways, and schizophrenia
includes many other less dramatic but enduring abnormalities.
However, as the most obvious surface indication of
schizophrenia, it is important to develop a theory for
psychosis, so that the underlying core of abnormality can, in
turn, be better understood.
At a biological level, a theory of psychosis based on overactivity of the forebrain transmitter dopamine is compelling
(5.2.). This theory develops from the well-documented actions
21
of antipsychotic drugs as dopamine antagonists, the similarity
of their motor side effects in humans to the symptoms of
parkinsonism, the psychosis-producing effects of stimulant
drugs, which release dopamine in active form, and the
similarity between stimulant-sensitization in animals and
psychosis-proneness in humans. Recent evidence obtained
using various PET methods has demonstrated that forebrain
dopamine systems are overactive (that is, they release an
excess amount of transmitter). Indirect evidence suggests that
such excess release of dopamine is a consequence of excess
impulse traffic in the midbrain dopamine neurons and their
pathways. The cause of this excess impulse traffic is one of
the deeper questions about the pathophysiology of
schizophrenia, dealt with at a later stage of exposition of the
present theory (9.6.9.3., 11.2.2.6.).
2.4.1.
The long time-course of therapy with dopamineblocking drugs.
At the psychological level, it is suggested that a key
feature of psychotic states of schizophrenia, critical for
shaping an explanation, is the relatively slow pace of recovery
from psychosis when a patient is treated with antipsychotic
medications (5.3.1.1). The slow recovery is particularly
notable for the symptom of delusions. Various clinical
features of the recovery process (the phenomenology of
recovery, and the fact that the completeness and speed of
recovery may depend on baseline personality, or duration of
prior untreated psychosis) suggest that complex psychological
processes intervene between reduction of dopamine’s activity
and eventual abatement of symptoms. Attempts to explain this
in purely biological terms have been made by Grace and
Bunney (1985)(5.3.1.2.). They base their account on the fact
that chronic regimes of neuroleptic drugs in animals silence
the impulse firing of midbrain dopamine neurons, by a
process identified as “depolarization block”. This finding, and
its interpretation as depolarization block are not challenged
here. However, depolarization block appears to be dependent
on the effect of chronic regimes of neuroleptic drugs as
revealed in anesthetized animals. It does not occur in freemoving ones (as demonstrated by a number of different
methods). Thus, depolarization block cannot apply to the
circumstances of therapy with antipsychotic drugs in humans,
and is inadequate as an explanation of the long time course of
antipsychotic therapy. What is needed for a satisfactory
explanation is a form of reasoning which crosses levels
between the biological and the psychological descriptions of
psychosis.
2.4.2.
Psychobiology of dopamine.
To develop such reasoning, it is necessary to understand
the psychobiology of what is termed the “reward/incentive
function” (5.3.2.). Starting from Thorndike’s celebrated “law
of effect” many studies have analyzed the behavioral aspects
of reward-related learning (5.3.2.1.). Events which are
“rewarding” in relation to an animal’s motivational systems
can enhance the attractiveness of stimuli with which they are
associated, or can enhance the vigor of responses when those
responses lead to the rewarding stimulus. Under appropriate
circumstances these two can be combined, so that a rewarding
event strengthens specific stimulus-response links. These
Synopsis of the Theory
relationships are defined in relation to overt behavior in
experimental animals. However, it is very likely that formally
similar processing of information occurs in humans, serving
covert mental processing (“thoughts”), such as those which
are disturbed during periods of active psychosis. Both in
animals and humans, the rubric of reward-related learning
implies that there be an internal signal in the brain which acts
as a reinforcer. This signal mediates the effects of rewarding
events on behavior or thought.
A large weight of evidence contributes to the conclusion
that forebrain dopamine (especially that in the pathway from
midbrain dopamine cells to the striatum) is a major
component of the internal reinforcement signal implicit in
reward-related learning (5.3.2.2.). Intensive investigation of
the role of dopamine in reinforcement enriches the
psychological descriptions of reward-related learning. In some
experimental designs dopamine over-activity not only
exaggerates the reinforcement effects mentioned above, but
can broaden the “span of attention”. Thus in terms of
psychobiological theory, selective attention is not totally
separate from the reward/incentive function. In addition, in
the inputs to the internal reinforcement system (i.e. afferent
pathways of the midbrain dopamine neurons), information
processing occurs such that the dopamine neurons respond not
so much to the absolute magnitude of a rewarding event, but
to the differential between that, and what is expected on the
basis of other recent events.
At a more fundamental level, recent evidence indicates
that the reinforcing actions of dopamine depend on a type of
synaptic modification, which strengthens selected excitatory
synapses in the striatum, and for which dopamine is an
essential co-factor (5.3.2.3.). The abnormalities of selective
attention occurring in high-dopamine states appear to arise
because principal neurons in the striatum are engaged in
mutual inhibition at a population level. When dopaminemediated synaptic strengthening is excessive, excitatory
inputs to these striatal neurons overwhelm the inhibitory
interactions between them which normally limit the number
of simultaneously active cells. The sensitivity of the
dopaminergic reinforcement mechanism to the differential
between actual and expected size of rewarding stimuli appears
to be a function of neural processing in the input to the
dopamine cells, notably in the amygdala. For the cognitive
equivalent of reward-related learning, likely to be important in
humans, control of midbrain dopamine neurons probably
depends more on afferent pathways from the cortex, which
may be direct, or indirect via the amygdala, superior
colliculus or subthalamus. Dyscontrol of dopamine neurons in
psychosis is likely to depend on abnormal activity in these
pathways from the cortex.
normal beliefs, are strongly reinforced, and, at least
temporarily, become incorrigible delusions. When the
medications take effect, they stop further accumulation of
such distorted and exaggerated beliefs, but do not of
themselves eradicate those already stored in memory banks.
However, by “taking the pressure off” a person’s total
cognitive apparatus, it is possible for the person to start to
“work through” the conflicts of belief set up during the period
of active psychosis. An equivalent description, using the
language of learning theory, is that delusional beliefs are
gradually “extinguished”. To complete this process takes
some time (weeks or months). It is to be expected that this
process takes longer if there has been a long duration of
untreated psychosis. In addition, persons with a general
tendency to rigid retention of belief structures may have
slower and less complete elimination of psychotic beliefs than
those who, inherently, can change beliefs in a more flexible
fashion.
2.4.3.
Hypothesis to explain the slow action of
antipsychotic drugs.
This account of the psychology and physiology of
forebrain dopamine forms a basis for explaining the slow
time-course of recovery of psychosis (especially of the
symptom of delusions) during therapy with antipsychotic
drugs (5.3.2.4.). In the active phase of psychosis, when
dopamine systems are overactive, patterns of cognitive
information, which are distortions and exaggerations of
2.4.5.
Therapy with antipsychotic drugs and dopamine
receptors.
The theory of psychosis based on the reinforcing actions of
dopamine contains a major discrepancy, related to the
pharmacological receptor type upon which the actions of
antipsychotic drugs depend (5.4.1.). The therapeutic effects of
these drugs is proportional to their blockade of dopamine D2
receptors. However, the psychological function of
reinforcement, identified as that which mediates the
2.4.4.
Explanation of phenomenology of psychosis.
The account of dopamine as a reinforcing agent also
makes possible a wider explanation of the phenomenology of
psychosis in schizophrenia (5.3.2.5.). Excessively vivid
perceptual experiences (common at the start of a psychotic
episode) probably signify exaggeration of the incentive
functions of dopamine. Many hallucinations probably
represent, in part, an exaggeration of normally-subliminal
perceptual experiences associated with cognitive processes, to
the point where they seem like perceptions of external origin.
Abnormalities of attention may play a part in generating
psychotic symptoms (including Schneiderian symptoms) both
by blocking attentional focus on the desired items and by
generating intrusions of unwanted material. The specific
content of delusions can be explained as exaggeration of the
motivational significance of events. This applies to “visceral”
motives, leading to delusions on themes of wealth, power,
love, sex etc. It also applies to “cognitive motives”. In the
latter case, ideas which provide all-encompassing, but
spurious “explanations” of everyday events are a particular
focus of delusions, because reinforcement normally provided
by an apparent explanation is exaggerated. This may explain
why psychotic delusions often focus on topics rich in
associations, or “explanatory power” (such as the paranormal,
the occult, and ideas of philosophy, religion etc). The
principle that dopamine systems are controlled by the
differential between actual and expected value of
motivationally-significant events, rather than their absolute
value can provide an account of why psychotic delusions
exaggerate the negative as well as the positive motivational
valence of mental images.
22
Synopsis of the Theory
therapeutic effects is known (on the basis both of
psychopharmacological evidence and recent physiological
experiments on synaptic change) to depend on the actions of
dopamine at D1 receptors. This apparent paradox could be
explained if actions at D2 receptors achieve their effects
indirectly, with reduction of the effects of D1 receptors being
the ultimate target. Such an indirect effect could be produced
via cholinergic mechanisms in the striatum. Cholinergic
neurons in the striatum are normally inhibited by dopamine
acting at D2 receptors, so that blockade of D2 receptors leads
to these neurons becoming overactive. Activation of the socalled M4 muscarinic receptors in the striatum has effects
similar to and synergistic with those of blockade of dopamine
D1-receptors (vis: reduction of cAMP formation, known to be
involved in dopamine-mediated synaptic change). In
antipsychotic treatment in normally-responsive patients, D2
blockade will enhance acetylcholine release in the striatum,
increasing activation of M4 receptors, and producing effects
equivalent to those of D1 blockade. Support for this comes
from evidence on the special effects of clozapine in psychotic
patients refractory to treatment with other medications. Such
refractoriness probably arises because of a relative scarcity of
cholinergic neurons in the striatum. However, clozapine itself,
amongst other effects, probably has an agonist action at
muscarinic M4 receptors, and thus can reproduce the effects
of natural cholinergic activation even when there are few
cholinergic neurons in the striatum to release acetylcholine
after D2 blockade. One of the critical tests of the hypothesis
that D1 blockade and/or reduced cAMP formation are the
final target of antipsychotic mediations of all classes is that
D1-blocking agents should have antipsychotic effects.
Clinical trials of D1-antagonists conducted so far have failed
to show this, but have a number of methodological
shortcomings. More rigorous clinical trials are needed.
2.4.6.
Psychosis and the “limbic striatum”.
There is a widespread belief that dopamine blockade in the
so-called “limbic striatum” is critical for the actions of
antipsychotic drugs (5.4.2.). This belief is based almost
entirely on studies in animals. Such evidence has suggested
regional differences in behavioral effects of dopamine
blockade (motor side effects in the neostriatum/substantia
nigra; cognitive/motivational effects in ventral tegmental
area/limbic striatum). Attention has also been drawn to
region-selective patterns of development of tolerance to
neuroleptic drugs, which is relevant to the fact that tolerance
does not develop in human therapy. Regionally-selective
production of depolarization blockade of dopamine neurons
with chronic regimes of antipsychotic drugs has also been
thought to indicate a special role for the limbic striatum. Apart
from some weaknesses in the detail of each of these
arguments, they all draw uncertain parallels between the
striatal complex of laboratory animals (especially rats), and
humans (where the “limbic striatum”, or the “nucleus
accumbens” has rarely been properly defined in clinical
studies). The conceptual status of the “limbic system” itself
has also come under recent criticism. It is more likely that
over-activity of dopamine anywhere in the striatal complex
can lead to psychotic symptoms. The details of the psychotic
23
symptoms then depend on the locations at which dopamine
exerts its excessive influence.
2.4.7.
Psychosis, schizophrenia and transmitter
glutamate.
Much recent theorizing about psychosis and schizophrenia
has implicated transmitter glutamate and its receptors. It has
been claimed that NMDA-receptor antagonists (PCP,
ketamine) produce a psychosis resembling that of
schizophrenia more closely than that produced by stimulants,
in that they reproduce negative as well as positive symptoms
(5.4.3.). Scrutiny of the evidence does indeed support the
view that these agents can mimic negative symptoms.
However, in the few studies where they have been
administered to healthy volunteers, they do not reproduce the
positive psychotic symptoms as well as do the stimulant
drugs. Studies where positive symptoms are reported are
generally those of subjects hospitalized after an adverse
reaction (a “bad trip”), and are probably not representative of
the effects of these agents generally.
Some of the recent theorizing about schizophrenia draws
on evidence of interactions in the striatum between transmitter
glutamate and dopamine (5.4.4.). Grace (1991) uses evidence
that glutamate in the striatum enhances dopamine release. He
has proposed that reduction of glutamate release there leads to
reduction of tonic dopamine release (unrelated to impulses)
which sets into action compensatory processes which enhance
phasic (impulse-associated) dopamine release. This
hypothesis is proposed as an explanation of both the negative
symptoms and cognitive impairments (due to reduced
glutamate activity) and the positive symptoms (due to
increased phasic dopamine activity). While some evidence
supports these ideas, there are many discrepant findings. The
interaction between glutamate and dopamine in the striatum is
probably mediated indirectly in a variety of ways, which
undermines the plausibility of this hypothesis.
2.4.8.
Relations between cortex and subcortex and
theories of psychosis and schizophrenia.
Another proposed explanation of the relation between
positive and negative symptoms in schizophrenia is based on
levels of neural activity in cortex and subcortex, rather than
on interaction between transmitter systems (5.4.5.1.). It is
based on evidence that the prefrontal cortex normally exerts
inhibitory control over subcortical dopaminergic activity.
From this, it is proposed that, in schizophrenia, cortical underactivity (especially in prefrontal regions, and perhaps specific
to dopamine systems there) is associated with, and leads to,
dopaminergic over-activity in the striatal complex. This
hypothesis gives a consistent account of the relation between
positive symptoms and cognitive impairment/negative
symptoms, and has much evidence in its support. However,
one body of evidence is difficult to reconcile with this
hypothesis, namely that in schizophrenia, measures of neural
activity in the cortex, though generally below normal, are
usually found to be positively correlated with positive
(psychotic) symptoms. The hypothesis would have predicted a
negative correlation. In addition, there is a great deal of
evidence about trait impairments in schizophrenia (reviewed
in Part IV), which has not been incorporated into this
Synopsis of the Theory
hypothesis. Furthermore, cognitive trait impairments and
negative symptoms may occur at different times from positive
symptoms, and may be present in subjects (for instance in
relatives) who never show positive symptoms. Thus, although
this hypothesis is plausible, one is left searching for a better
one.
Following from Weinberger’s neurodevelopmental
hypothesis, a number of studies in animals have shown that a
lesion in the hippocampus or other regions, sustained early in
life, can lead, when the animal becomes mature, to signs of
dopamine over-activity (5.4.5.2.). In a general way this may
be relevant to the fact that schizophrenia in humans emerges
only in late adolescence or early adulthood. However, this
work leaves unanswered a major question about the nature of
the “lesion” in humans, which could be the equivalent of the
lesions produced in animals. There is no clear evidence of
such a focal lesion in human neuropathological studies of
schizophrenia.
Of particular relevance to the theory developed in this
book, a number of studies has shown that lesions in animals
may have different effects on dopaminergic and noradrenergic
activity according to the side of the lesion (5.4.5.3.). Rightsided cortical lesions have a greater effect in amplifying
behavioral activity related to these transmitters than left-sided
ones. This intriguing evidence is referred to later as the theory
of this book unfolds.
2.4.9.
General comments on the theory of psychosis.
While the actions of dopamine can provide a good
explanation of many of the key features of the psychoses of
schizophrenia, they cannot account for the whole of this
disorder, including the enduring trait abnormalities. Attempts
made so far to provide more complete accounts including the
negative symptoms and cognitive trait abnormalities, as well
as positive symptoms have some merit. However, they do not
incorporate the large bodies of evidence, on abnormal
psychological traits, and electrophysiological or brain
morphological abnormalities, into a coherent theory.
The evidence covered in Chapter 5 reveals several sources
of confusion. “Psychosis” has often been equated with the
whole clinical picture of schizophrenia. Several blind alleys,
have grown to prominence because the research has been
guided by findings in animals, rather than those in humans.
Animal research certainly is relevant to understanding
psychosis, but requires careful consideration of the conceptual
shifts involved in making the leap from laboratory animals to
human psychopathology. Some of the blind alleys have arisen
because correlation has taken the place of true scientific
reasoning. Others have arisen because the disease model
adopted for schizophrenia assumed that there are qualitative
or categorical differences between normality and
schizophrenia (e.g. hypotheses of abnormal receptors, or other
molecules or genetic factors). In so far as we understand the
basis of the psychotic episodes of schizophrenia – that is, in
terms of excessive neural traffic in the midbrain dopamine
neurons – the abnormality is not fundamentally qualitative or
categorical in nature. Rather it is a quantitative extension of
the normal psychobiology of dopamine. Admittedly there
comes a point in the transition to active psychosis where, in
psychological and social terms, there is a true categorical
“break with reality”. Such a categorical break probably does
not apply when considering the whole picture of
schizophrenia, although some symptoms involving such a
“break with reality” may be enduring traits rather than linked
just to transient episodes. A general issue is whether theories
based on relative excess or deficit of neurochemical factors
such as transmitters or their receptors can be adequate. They
may be very useful to explain the psychotic state, but less so
for the enduring abnormal traits. In any case, from the point of
view of humane understanding of schizophrenia, it is wise to
emphasize the psychological features in common between the
psychoses of schizophrenia and normality – to understand
abnormality in relation to normal function. The account of
psychosis given in Chapter 5 attempts to do this.
2.5.
Introduction to the survey of trait
abnormalities
in
psychological
and
psychophysiological functions, and in brain
morphology.
A major component of the theory developed in this book is
that, in so far as brain mechanisms are concerned, the
fundamental basis of schizophrenia is an abnormal variant of
the cerebral asymmetry present in the normal human brain.
Cerebral asymmetry of function has been documented for 150
years, and before that could be inferred from the phenomenon
of handedness. The idea that there is something unusual about
cerebral asymmetry in the functional psychoses has developed
over the last 35 years, starting with studies of Flor-Henry
(1969, 1972). These showed that temporal lobe epilepsy was
associated with schizophrenia-like psychoses with paranoia if
the focus was in the left hemisphere, and with affective
psychosis or depression if it was in the right hemisphere. In
the following 15-20 years a few studies pursued the relation
between laterality and schizophrenia, and three books
(Gruzelier and Flor-Henry, 1979; Flor-Henry and Gruzelier,
1983; Takahashi et al, 1987) reviewed the topic. Subsequently
very many papers have reported both functional and brain
morphological data about differences from normal cerebral
asymmetry in schizophrenia.
Several specific suggestions have been made about the
nature of the abnormalities of asymmetry in schizophrenia
(see Cutting, 1985 [pp 151-160], 1992), including left
hemisphere over-activity (Gur et al, 1983), left hemisphere
impairment (Guenther et al, 1985), loss of normal asymmetry
(DeLisi et al, 1997b), and right hemisphere impairment
(Cutting, 1992). However, none of these ideas has been
developed into a coherent theory encompassing a wide range
of evidence. In the view of the present author, this failure has
been a consequence of two other inadequacies in research in
this field. First, it has not been realized that different
theoretical frameworks are needed for active psychosis and
for the enduring functional trait abnormalities in
schizophrenia. However, if this is so, it would permit the
possibility that different laterality effects are seen in these two
situations. In the present work, an attempt is made to separate
evidence pertaining to the active psychotic state from that
reflecting enduring traits. As discussed in Chapter 5, there are
theoretical grounds for suggesting that these two are largely
separate, although not all psychotic manifestations are limited
24
Synopsis of the Theory
to acute episodes. The methods for separating empirically
between active psychosis and enduring traits are also not
entirely clear-cut, and are discussed below.
2.5.1.
Axonal conduction time as a critical variable for
the theory of normal cerebral asymmetry.
The second reason why a coherent explanatory theory of
schizophrenia, based on the idea of an abnormality of cerebral
asymmetry, has not been constructed hitherto is that a
prerequisite for such a theory is that a similar theory should be
available for normal asymmetry, perhaps in terms of cellular
or biochemical differences between the hemispheres. Until
recently, there has been no such theory. However, Miller
(1996a) published such a theory. This attempts to explain
normal cerebral asymmetry of function in terms of a “central
hypothesis” about conduction time in cortico-cortical axons.
Axons are of two morphological types, unmyelinated and
myelinated. The former are basically a long cylinder of
.
axoplasm surrounded by a cell membrane. In the latter type,
the axon is surrounded by a myelin sheath, made mainly of
lipids (multiple cell membranes). The myelin sheath increases
the conduction velocity for impulses, by the process called
“saltatory conduction”. Even discounting the myelin sheath,
myelinated axons are of larger caliber than unmyelinated
ones. However, for our cortico-cortical axons of both
morphological types, caliber varies greatly, by more than tenfold, within a population of axons. The two types, and their
wide range of calibers are shown in an electron micrograph of
subcortical white matter from the rat (Figure 2.1.). It is
seldom possible to do electron microscopy of the human
brain, for a combination of ethical and technical reasons, but
there is little reason to doubt that hemispheric white matter in
humans also consists of axons of both types, of widely
varying caliber.
Figure 2.1. Electron micrograph of a portion of white matter under the cerebral cortex in rat. This shows the difference between
umyelinated and myelinated axons (running in different directions, but mainly cut in tranverse section), and for each type shows the
wide range in caliber. Myelinated axons have prominent sheaths (ring-like in transverse section). Unmyelinated axons (e.g. cluster
indicated by arrow) are smaller, less prominemt, but (in rats) more numerous (making up 75-90 % of all axons, according to
Partadiredja et al [2003]). Their numerical proportion in humans is not known. Most of the axons shown are probably cortico-cortical
ones (Electron micrograph prepared by G. Partadiredja, reproduced here with thanks).
Since the basic facts about conduction time in corticocortical axons are central for all the theory that follows in this
book, it is necessary to present some detail. Conduction time
in single axons of the CNS cannot be studied in humans, for
clear ethical reasons. In experimental animals, the most direct
25
method available is to conduct single cell recording, and
activate each neuron’s axon at a distance from the cell body.
An impulse is then conducted in a direction opposite to that
occurring in normal physiological circumstances (antidromic
conduction). The advantage of this is that it allows direct
Synopsis of the Theory
measurement of the latency of conduction in a manner not
confounded by the complications of synaptic transmission.
Antidromic responses after stimulation generally have a very
constant latency (varying by no more than a tiny fraction of a
millisecond on successive stimulations). Study of a population
of neuronal responses in this way gives information about
conduction times in a population of axons. Experiments
conducted in the 1970s in anesthetized cats (Miller, 1976),
and later in rabbits (Swadlow and Weyand, 1981; Swadlow,
1989, 1990, 1991, 1994) showed that cortico-cortical axons
have conduction times (for distances ranging from a few mm
[Swadlow] to about 1 cm [Miller]) which vary greatly
between axons, ranging from less than 10 msec to several tens
of milliseconds (Figure 2.2.).
QuickTime™ and a
TIFF (U ncompressed) decompressor
are needed to see this picture.
Figure 2.2. Composite diagram showing latency histograms for antidromic responses in ipsilateral and callosally-projecting long
cortico-cortical axons. Upper left: Callosal neurons in cat primary somatosensory cortex (from Miller, 1976). Upper right: Neurons in
cat primary somatosensory cortex projecting to second somatosensory area (from Miller, 1976). Lower left: Callosal neurons in rabbit
visual cortex (from Swadlow, 1974). Lower right: Neurons in rabbit visual area V-1 projecting to ipsilateral area V-II (above) and
across the callosum (below)(from Swadlow and Weyand, 1981). Redrawn from originals: lower left: Reprinted from Experimental
Neurology, vol 43, no 2, H.A.Swadlow; Properties of antidromically activated callosal neurons and neurons responsive to callosal input
in rabbit binocular cortex, pp. 424-444, Copyright Elsevier Ltd., © 1974, with permission from Elsevier. lower right: H.A.Swadlow and
T.C.Weyand, 1981, with permission from John Wiley & Sons Inc.).
Conduction time for a given length of axon is the
reciprocal of conduction velocity, and this depends on axonal
morphology. From studies based on the peripheral axons,
Rushton (1951) concluded that conduction velocity was
directly proportional to axon caliber for myelinated axons, but
to the square root of caliber for unmyelinated ones (see also:
Goldman and Albus, 1968; Matsumoto and Tasaki, 1977).
While the scaling factors are different in the central nervous
system, the basic relationships appear to be similar (Waxman
and Bennett, 1972). In cortico-cortical axons, the wide
variation between axons in conduction times, for similar
conduction distances (matching the wide variation in
conduction velocity, over a more-than-tenfold range), is well
accounted for by variation in caliber and type of these axons.
There is a variety of sampling and other biases on the data
presented in Fig. 2.2. (Miller, 1994; Swadlow, 2000), all of
26
Synopsis of the Theory
which favor recording from neurons with more rapidlyconducting axons, or which underestimate the true conduction
time from soma to synapse. Thus the proportion of corticocortical axons with the longer conduction times are certainly
under-represented in the histograms of figure 2.2. In addition,
the experiments on which those results are based were
conducted in animals with small brains, where conduction
distances are not much more than 1 cm. In humans, the length
of cortico-cortical axons may often be 10 cm or more. No
empirical data exist on their conduction times or velocities.
However, a simple extension from these animal data to the
situation in humans, suggests an important conclusion: There
is a major proportion of cortico-cortical axons with
conduction times from soma to synapse of 100 msec, 200
msec, or even more (Swadlow et al, 1979; Miller, 1994).
In Chapter 1, it was suggested that a truly explanatory
theory of schizophrenia needs to be based on cross-level
reasoning, explaining the psychological manifestations of the
disorder in terms of neuronal dynamics. In basic neuroscience
there already exist some such explanations. Perhaps the most
influential concept is Hebb’s (1949) notion of the cell
assembly, which constitutes a “strategic bridge” between
brain function studied at the behavioral and at the neuronal
levels. However, at the time Hebb’s ideas were formulated,
little was known of the detailed functioning of neurons. Since
then, the physical basis of action potentials, synaptic
potentials, and other aspects of neuronal biophysics has been
revealed in elaborate detail. We therefore should be in a much
better position to “put flesh on the bones” of Hebb’s theory.
This should be of immense value in our task, that of creating a
psychobiological theory of schizophrenia. However, the one
neuronal variable which has been
severely neglected in basic neuroscience is that just
emphasized, namely axonal conduction time. The author of
this work believes that, if this variable is included along with
other neuronal variables, many new avenues of theoretical
research will become possible, in the attempts to explain
psychological findings in neuronal terms. This applies not
only in the basic neurosciences, but also, as here, in the theory
of mental disorders.
With regard to normal cerebral asymmetry in humans, the
“central hypothesis” of Miller (1996a) proposes that these
axons differ between hemispheres in their range of conduction
velocities. Specifically, it was proposed that a typical
population of axons in the normal right hemisphere has a
relative preponderance of rapidly conducting axons, whereas a
similar population of axons in the left hemisphere has a
relative preponderance of slowly-conducting axons. As far as
the cybernetics of nervous tissue goes, the implication from
this hypothesis is related to axonal conduction time: In the
right hemisphere it is envisaged that a high proportion of
cortico-cortical axons have conduction times from soma to
synapse less than the integration time in a typical cortical
pyramidal cell (~10 msec). Activity in such axons converging
on a pyramidal cell would then encode no information about
27
temporal patterning of the converging signals, since, as far as
the post-synaptic neuron goes, they indicate nearsimultaneous firing of the various presynaptic neurons (see
Figure 2.3A). In the left hemisphere, it is envisaged that a
high proportion of connecting axons have conduction times
substantially longer than the neuronal integration time, and
(in absolute terms), have widely varying conduction times.
Activity in such axons converging on a pyramidal cell would
then still activate the postsynaptic neuron only if they all
arrive within a single integration time. However, this implies
that the activation of the presynaptic neurons was at
substantially different times (Figure 2.3B). While this central
hypothesis is framed in terms of axonal conduction time (or
velocity), it also has clear implications for morphology, since
slowly-conducting axons are of finer caliber, are more
commonly unmyelinated, or, if myelinated, have thinner
myelin sheaths than rapidly-conducting ones.
This “central hypothesis” originated by inference from
indirect evidence, about lateral specializations for perceiving
different sorts of stimuli in humans. The right hemisphere (in
typical right-handers) is known to be superior for perceiving
visual patterns (e.g. faces), all of whose components are
present in the same instant of time. The left hemisphere
however (for right-handers) is superior for perceiving stimuli
(such as basic speech sounds) whose components occur nonsynchronously in accurately-timed sequence within a duration
of the order of 100 msec.
From a strictly scientific point of view, it is, of course
highly desirable that direct evidence be provided to evaluate
this central hypothesis. This would involve either single unit
electrophysiological experiments (such as those conducted in
cats or rabbits) or electron microscopy to discover the range
of calibres and proportion of myelinated to unmyelinated
axons. Overwhelming ethical considerations preclude such
electrophysiological experiments in humans. In addition,
electron microscopy of brain tissue is very difficult in
humans, for a combination of ethical and technical reasons.
Tissue can seldom be obtained in humans soon enough after
death, or in a state of adequate fixation for good quality
electron micrographs to be prepared. In rare circumstances
they can be prepared (e.g. Uranova et al, 2001) but the
methodological limitations then still preclude systematic and
quantitative electron microscopy in humans (including
stereology), such as is possible in laboratory animals. Hence
evaluation of the central hypothesis of Miller (1996a) must
rest on accumulation of evidence more-or-less indirectly
related to the basic postulate, mainly examples of what the
central hypothesis will explain. In such circumstances, the
greater the number of indirect tests which turn out to be
consistent with the hypothesis, the more firmly is it supported.
This strategy has many parallels in earlier scientific history
(e.g. Dalton’s “atoms”; Gregor Mendel’s genetic “factors”),
where a postulate is initially justified in terms of what it will
explain, and only later, as adequate techniques become
available, is the postulate confirmed by direct evidence.
Synopsis of the Theory
Figure 2.3: Principles linking axonal conduction time to neurocybernetics. These are “space-time” diagrams with time elapsing
from left to right, and “neuronal integration time (~10 msec) indicated by pairs of vertical parallel lines with shading. A:- Hypothetical
pathway in right hemisphere, where conduction time is short, and temporal dispersion does not exceed a single neuronal integration
time. B:- Hypothetical pathway in left hemisphere, where mean conduction time is slower, and temporal dispersion in the population is
greater than the neuronal integration time. If signals in different axons are initiated at the same time, only limited post-synaptic
convergence occurs within a single integration interval (left). If optimal post-synaptic convergence is to occur, signals must be initiated
at different times (right), so that the post-synaptic neuron responds to a specific temporal pattern.
In the monograph of Miller (1996a) indirect evidence was
reviewed of morphological, electrophysiological, and
especially psychological nature. The morphological evidence
included data that the volume ratio of white matter to grey
matter was lower in the left hemisphere than the right, this
being the same for all four lobes of the hemispheres. In
quantitative terms, the differences between right and left often
failed to reach statistical significance, but nevertheless almost
always pointed in the same direction. The methods used in
different studies were quite varied, so pooling of data across
studies, followed by quantitative meta-analysis was not
possible. However, recent studies tend to confirm the
conclusions made in 1996 (Gur,R.C. et al, 1999; Carne et al,
2006). Electrophysiological studies using EEG methods
provided some support for the central hypothesis in that EEG
coherence between electrode pairs was generally higher, and
phase delays less in the right than the left hemisphere
(although these approaches need to be used much more
extensively
to
make
a
convincing
case).
A
psychophysiological measure (simple reaction time: RT)
provided strong, and fairly direct confirmation of the central
hypothesis. The experiment here involves comparing
“crossed” reactions (e.g. right visual fields and left hand) with
“uncrossed” ones (e.g. right fields and right hand), the former
situation giving longer RTs because it involves an additional
relay across the corpus callosum. This experiment can be
carried out for either right-to-left or left-to-right transmission
across the corpus callosum. Strikingly, the reported
transmission times are longer for left-to-right than for right-toleft callosal transmission. Since callosal axons originating in
one hemisphere are really a subset of all the long corticocortical axons of that hemisphere, this result shows a
significant tendency for transmission to be faster for right than
for left hemisphere axons, as predicted by Miller (1996a). The
largest and most complex body of evidence reviewed by
Miller (1996a) was related to psychological predictions from
the central hypothesis. Evidence consistent with the
hypothesis included the facts on perceptual processes, namely
that perceptual integration occurs more rapidly in the right
than the left hemisphere; on motor control, where control by
sensory guidance is faster and more accurate if the right
hemisphere is involved than the left; on semantic decoding of
incoming language, which is accomplished better by the right
than the left hemisphere; and on sustained attention/vigilance,
where the right hemisphere is superior to the left.
This survey does not by any means exhaust the evidence
relevant to Miller’s “central hypothesis”, there being many
other paradigms where the hypothesis is accessible to test, and
much relevant evidence published since 1996. The measure
which is centrally placed between neurocybernetics and
psychology on the one hand, and axonal properties and
microscopic or gross morphology on the other is axonal
conduction time. The evidence on this surveyed by Miller
(1996a) can be supplemented by a number of
28
Synopsis of the Theory
electrophysiological studies showing, as does the RT data,
that transmission across the corpus callosum is faster from
right-to-left than from left-to-right (11.3.3.). One would also
expect that the latency of evoked potential components in the
right hemisphere should be less than that in the left
hemisphere. Since increased conduction time means increased
temporal dispersion amongst a population of axons, and
therefore less opportunity for temporal summation in postsynaptic neurons, one would also expect lower amplitude for
evoked potentials in left compared to right hemispheres.
There have been few attempts at accurate comparison between
hemisphere on these measures, but there is a little evidence for
these predictions (see for example, 11.4.2.1., on mismatch
negativity).
2.5.2.
Axonal conduction time and the origin of the
“central hypothesis” for the trait abnormalities in
schizophrenia.
The “central hypothesis” for normal cerebral asymmetry
becomes relevant to understanding trait abnormalities in
schizophrenia in the following way: A number of the enduring
traits in schizophrenia appear to be impairments of functions
normally preferred by the right hemisphere. These include the
following: impairment compared to normal in perceiving
visual patterns such as faces; impairment in motor control by
sensory guidance (shown most often with respect to smooth
pursuit eye tracking); a marked tendency to lapses in
vigilance; impairment in higher-level aspects of language
(semantic decoding). In addition, one of the classical
symptoms of schizophrenia - referred to as “flattened affect” –
can be analyzed in terms of three neuropsychological deficits reduced facial expressiveness, reduced communication by
gesture, and reduced “prosody” in vocal expression - all of
which are normal functions accomplished better by the right
hemisphere.
These pieces of evidence are, at this stage, no more than
clues linking schizophrenia traits to an abnormality of cerebral
asymmetry. However, taken at face value, they allow us to
frame an initial hypothesis for the broader range of abnormal
traits. As such they have the potential to be truly explanatory
– explaining psychological dysfunctions in terms of
fundamental biological (i.e. cellular) differences between
normal and schizophrenia, just as Miller’s (1996a) central
hypothesis allowed explanatory arguments to be constructed
linking axonal properties to differences between left and right
sides in normal subjects. The “central hypothesis” for
schizophrenia-related traits can then be stated as follows, that
there is a relative absence of rapidly-conducting corticocortical axons in schizophrenia, compared to normal. Since
rapidly-conducting axons are likely to give the normal right
hemisphere its special functional properties, one may expect
that the enduring trait impairments of schizophrenia will be
largely in functions preferred by the normal right hemisphere,
although they may not be exclusively covered by this concept.
As a broad slogan, one might then capture the trait
impairments of schizophrenia in the phrase “two left
hemispheres”. This has the additional implication that
sometimes there may be an exaggeration of functions
normally attributed to the left hemisphere. To introduce the
full exposition of the theory of schizophrenia traits, a list of
these traits is given in Table 2.1. Two points are worth noting:
First, they are not all impairments: For instance, under some
circumstances, the excessive awareness of associations may
be an advantage. Second, the last in the list of traits
(“vulnerability to psychotic breakdowns”) raises what has
already been identified as one of the deepest problems for a
comprehensive theory of schizophrenia. Added to this list,
there is much other evidence to be explained by a
comprehensive theory, including psychophysiological
evidence (notably that using methods of clinical
electrophysiology), and much morphological evidence. The
whole range of topics is explored step-by-step in Chapters 612.
Table 2.1.
List of Schizophrenia Traits
Impairment in perception of Gestalts (in visual, auditory and somesthetic modalities)
Impairment in motor control by sensory guidance
Impairment in simultaneous motor coordination of many effectors
Impairment in rapid coordination between the two hemispheres
Impairment in sustained attention/vigilance
Impairment in semantic decoding of incoming language (sentences and longer)
Impairment in planning of semantically-coherent outgoing discourse (part of “thought disorder”)
Super-normal awareness of semantic and other associations
Excessive vulnerability to distractions in various sensory modalities, and to “sensory overload”
Impairment in tasks where multiple sources of information have to be dealt with
Impairment in tasks involving shift of attentional focus
Impairment in acquisition of information from lists, etc (“rote learning”)
Vulnerability to psychotic breakdowns
29
Conclusions: The Concept of Schizophrenia
It should be stated here that the two “central hypotheses”
(respectively for normal cerebral asymmetry and for
schizophrenia), carry the assumption that axonal conduction
time, in the adult, is a stable “structural” aspect of brain
organization.
However, there is evidence that the degree of myelination
in hemispheric white matter, is influenced by the prevailing
environment. For instance, environmental enrichment leads to
increase in myelination or calibre of axons in the corpus
callosum in rats (Juraska and Kopcik, 1988) and increased
size of the callosum in monkeys (Sánchez et al, 1998). In
humans, diffusion tensor imaging (see Chapt. 12), has shown
that the degree of myelination inferred in hemispheric white
matter tracts in pianists is positively correlated with the
number of hours spent practicing in previous years (Bengtsson
et al, 2005). These findings suggest that adaptive plasticity
affects not only synapses but also the degree of myelination of
axons. Evidence currently available suggests that such
processes influence the degree of myelination during
development when myelination is not yet complete. It has not
yet shown that such processes in mature adults lead either to
further myelination or to demyelination, in an adaptive sense.
Therefore, there is as yet no basis for questioning the
assumption that axonal conduction time in adults is a stable
“structural”
feature
of
hemispheric
organization.
Developmental aspects of myelination in relation to
schizophrenia are discussed in Chapter 12.
2.5.3.
System adopted for presenting theory and
reviewing evidence about trait abnormalities (Chapters 612).
With such a large amount of evidence to be reviewed, it is
necessary to bring some system to its presentation. The series
of detailed reviews of empirical evidence on trait aspects of
schizophrenia is covered in Chapters 6-12. In the remaining
subsections of the present chapter, summaries of each block of
empirical data will be presented, but without detailed
referencing except to the later chapters where each detailed
review appears. Thus, the remaining sections of the present
chapter should allow the reader to get a synoptic overview of
the complete theory of the trait aspects.
In Chapters 6-12 evidence of psychological abnormality
will be dealt with before that on brain function and
morphology. This is because the primary way in which the
concept of schizophrenia has arisen is from psychological
rather than biological brain abnormalities. The morphological
evidence, taken by itself, is difficult to interpret without
ambiguity and so is left to a later stage of the argument, when
some of the emerging picture has already been clarified.
However, with that emerging picture as a context, the
morphological evidence includes more direct tests of the
“central hypothesis” than does much of the functional
evidence.
The functional evidence to be considered includes both
purely psychological data and psychophysiological data (such
as studies using electroencephalography). Some areas of
evidence (such as the detailed study of eye movements) cross
between these two disciplines. The main functional
subdivisions to be covered are as follows: Perception (in
major sensory modalities, and also including subsections
dealing with inter-hemispheric and inter-modal interactions
with sensory stimuli)(Chapter 7); Motor control (Chapter 8);
Vigilance, mental association, selective attention, short-term
memory, rote learning, and shift of attention (Chapter 9);
Language and Communication (Chapter 10). Chapter 11 deals
with findings using EEG, evoked potential and some
metabolic/blood-flow scanning methodologies. Chapter 12 is
a long and complex one, in which brain morphology is
discussed from various aspects. In introducing most sections
within Chapters 6-12, aspects of normal function or structure
need to be reviewed, before discussing the abnormalities in
schizophrenia. These introductory sections often include some
expansion of the theory already published about normal
cerebral asymmetry, in the case of paradigms not already
considered by Miller (1996a). In some cases this discussion
also shows that the “central hypothesis” for schizophrenia
traits needs elaboration. Results inconsistent with the
hypothesis are not ignored in presenting the theory. Chapter
13 is a final summary chapter, using the whole body of
information to give a synoptic view of the overall concept of
schizophrenia which emerges. It makes explicit the
implications of the theory for classification of disorders in the
schizophrenia spectrum, and concludes with some of the
implications of the theory for individual healthcare and public
health measures related to schizophrenia.
Many data are reported in empirical studies about
correlations between different trait measures used to
differentiate normal subjects and those with schizophrenia.
However, correlations can arise as a result of causal relations
which may range from being quite direct to very indirect.
Specifically, in relating functional abnormalities to the theory
based on the relative absence of rapidly-conducting corticocortical axons, correlations between trait measures may arise
because they are different manifestations of abnormality in the
same axonal pathway, or because the conduction properties of
different cortico-cortical pathways are themselves correlated
(due perhaps to a common genetic influence). As a result of
these uncertainties comprehensive review of all reported
correlations is not attempted here. Correlative data will be
drawn upon when specific questions need to be resolved (e.g.
about whether two aspects of functional abnormality arise
from the same or from different mechanisms). Nevertheless,
because of the problem of interpreting correlative data, they
will not be called upon to bear the whole burden of proving a
particular point in the theory. Moreover, the strength of an
argument based on correlation depends on the value of the
correlation coefficient in individual studies, and the
consistency of correlation across studies. Therefore,
arguments from correlations become more relevant, and are
given more attention, when a number of studies have assessed
correlation between similar pairs of variables, and give similar
results across studies.
In this context, an important focal point for discussion of
trait abnormalities is the association and dissociation of
symptoms of schizophrenia as encountered in the clinic, and
as revealed by the statistical method called factor analysis.
This topic is covered prior to discussion of evidence obtained
with experimental methods, in the short Chapter 6. The
important conclusion emerging from this chapter is that the
symptoms of chronic schizophrenia fall into three groups,
30
Conclusions: The Concept of Schizophrenia
statistically independent each other. Following Liddle (1987)
these three factors are referred to here as Psychomotor poverty
(a collective term for negative symptoms), Disorganization (a
symptom group dominated by thought disorder) and Reality
distortion (a collective term for symptoms related to actual
psychosis).
Obviously a major conceptual distinction for the present
book is that between “active psychosis” and the enduring
traits. While this distinction is based on theory, in reviewing
evidence by which the theory is to be evaluated, it is
necessary to have other independent methods of making the
distinction empirically. Clearly “trait abnormalities” should be
present in well-stabilized patients who do not show psychotic
symptoms. However, as discussed in Chapter 5 (see also 2.4.),
psychotic symptoms may be sustained in attenuated form as
“cognitive habits” by memory processes. Therefore the
presence of psychotic symptoms is not in itself a sure criterion
for recognizing “active psychosis”. Ideally, the distinction
should be made by closer assessment of the dynamic aspects
of the psychotic symptoms (e.g. the time course of their
formation, persistence and extinction). A recently-devised
rating scale allows such assessment to be made on individual
patients (Chouinard and Miller, 1999a,b). Since this has been
introduced only recently, a less rigorous distinction must be
made pragmatically to make sense of the existing literature: In
classifying the state and stage of illness of patient groups, it is
likely that one is dealing with an active psychotic process if
there is a specific statement that patients are “floridly
psychotic” or in “acute exacerbation” or are “recent
admissions”. When patients are described as suffering from
“acute schizophrenia”, this does not clearly indicate “active
psychosis”, because the usual definition of this term,
especially in older papers, has been “duration of illness two
years or less”. Likewise a phrase such as “acute illness,
attending day hospital” does not identify “active psychosis”.
In some chronic cases of schizophrenia, especially in patients
in long-term institutional care, psychotic symptoms may not
have responded to drug treatment, this being the reason for
continuing in-patient care. In such cases, if psychotic
symptoms are present it is likely that they do represent an
active and persisting process of psychosis, rather than a
“memory effect” lasting from previous periods of active
psychosis. However, it is acknowledged that rigorous
separation between chronic cases where active psychosis
persists, and other chronic cases where psychotic symptoms
endure merely as a memory effect is not possible in many
published reports. Apart from exclusion of active psychosis in
schizophrenia patients there are other ways in which particular
impairments can be identified as enduring traits: The trait
abnormalities found in stabilized patients should also be
present (perhaps less severely) in subjects identified as having
personality variants related to schizophrenia (“schizotypy”, or
“schizotypal personality disorder”), without clear evidence of
active psychosis. Similarly, the same traits should be present
in high-risk adolescents (offspring of those with the
schizophrenia diagnosis), or other FDR of schizophrenia
probands.
In each section reviewing empirical data in Chapters 6-12,
material will be covered in approximately the same sequence.
First, before considering comparisons between normal and
31
schizophrenia, it will usually be necessary to consider normal
aspects of function or morphology by themselves, including
evidence on normal lateralization. In addition, in dealing with
each aspect of function or morphology a preliminary account
may be needed of the methodologies used in that context.
After these preliminaries, the basic findings comparing
normal with schizophrenia will be presented, including details
of right- vs left-sided effects, where relevant. To clarify the
status of these basic findings, evidence will then be
considered on possible confounds from the immediate effects
of medication, or of psychotic exacerbation. The extent to
which each functional abnormality is present in stablymaintained patients can thus be ascertained. Further evidence
that one is considering true traits comes from considering the
extent to which the relevant impairment is present in different
subtypes of schizophrenia, in later stages or more severe
variants of the illness, in, subtypes defined by prognosis, in
schizophrenia-related personality variants, and in FDR. In
addition available evidence of functional impairment or
morphological abnormality in disorders other than, but related
to schizophrenia (including the overlap with affective
disorders) is considered. In those areas of abnormality which
have been most intensively investigated, there is often
evidence on all the above topics. However, for some of the
less-well studied aspects of function and morphology the
limited evidence available document only the basic findings in
schizophrenia.
2.6.
Factor structure of enduring symptoms of
schizophrenia.
From around 1980 it became common to divide the
symptoms of schizophrenia into “positive” and “negative”
groups, the former abnormal by the presence of psychological
features not normally present, the latter being abnormal
because normal psychological features were absent. However,
factor analysis of the symptoms of chronic schizophrenia
revealed a more complex subdivision of symptoms (Chapter
6). There are at least three, and perhaps more symptom
factors, each statistically independent of each other. The first
two of these were given the names “Reality distortion” and
“Psychomotor Poverty” by Liddle (1987), the former
including many positive symptoms the latter most negative
symptoms. The third factor was called “Disorganization”
whose most characteristic symptoms were some of those
included in the rather imprecise term “thought disorder”. This
three-factor analysis of the symptoms of chronic
schizophrenia has been widely replicated, although more
complex factorizations sometimes emerge, especially when a
wider body of symptoms is used than in Liddle’s analysis. It is
found regardless of the stage of illness, or the
presence/absence of medication, although scores on the three
factors are affected by these influences. These factor analyses
have been used to subdivide schizophrenia into mutually
exclusive subtypes. However, more properly, factor analysis
defines statistically independent or “orthogonal” dimensions
for description of symptoms, without inferences necessarily
being made about how patients fall into discrete subgroups.
Given this, the results of factor analyses raise important
theoretical issues, serving as pointers to separate mechanisms
Conclusions: The Concept of Schizophrenia
underlying each of the independent factors. The component
symptoms of the Reality Distortion factor are most (but not
all) of those recognized as aspects of active psychosis. That
they make up a coherent factor in chronic schizophrenia can
easily be understood from the theory of psychosis developed
in Chapter 5, since many psychotic symptoms (especially
delusions of various sorts) persist as a “cognitive habit” or
“memory effect” long after the most acute aspects of
psychosis have remitted. This factor may also have its origin
(in part) in active psychotic symptoms shown by patients who
are refractory to treatment with antipsychotic medication. The
other two major factors (Psychomotor poverty and
Disorganization), are enduring traits in a more fundamental
sense than is the Reality distortion factor. The underlying
neurodynamic processes, and the reasons why they are
statistically independent, emerge as the evidence and theory of
these traits is discussed (Chapters 7-10).
2.7.
Abnormalities of sensory perception in
schizophrenia.
Chapter 7 deals with perception in schizophrenia in the
three main modalities - vision, hearing and somatic sensation
(including proprioception). Olfactory sense is dealt with in a
different Sect. (9.4.2.4.). There is almost no evidence
comparing normal subjects and those with schizophrenia on
taste or vestibular sense.
In the three main sensory modalities, any abnormalities in
schizophrenia are set against the background of normal
perceptual processes. These include the integration of
intensity over time (for short stimuli - up to a few 100 msec)
and lateral differences in perceptual capability. In general the
right hemisphere is superior for integration of Gestalts or
spatial patterns, all of whose components are present together
in the same moment, while the left is better for sensory
patterns extended briefly in time. In the visual sense two
additional normal aspects of perception need to be borne in
mind - the distinction at the subcortical level between
transient and sustained channels, and that within the cortical
visual areas between the so-called dorsal and ventral streams
of processing.
2.7.1.
Visual perception in schizophrenia.
In the visual sense, many of the most precise tests of
perception use very brief (tachistoscopic) stimuli. In nonlateralized tests of this sort (7.2.2.), there is abundant evidence
in schizophrenia of impairment in functions normally giving a
right hemisphere advantage. In particular, in schizophrenia a
stimulus needs to be of longer duration than normal to be
recognized (lengthened “critical stimulus duration”), and,
once a perceptual trace is formed, it appears to persist longer
than normal. As a result, masking stimuli can prevent
assimilation of perception for a longer-than-normal period
post-stimulus in schizophrenia. The contrast in this respect
between schizophrenia and normal is similar to that between
the left and right hemispheres (respectively) within normal
subjects. These abnormalities indicate a relative sluggishness
of visual processing in schizophrenia, which can be explained
on the assumption that axonal pathways conduct more slowly
than normal and so produce greater-than-normal temporal
dispersion of visual signals as they are distributed in the
cortical pathways. In some tests, such as those of subliminal
perception, subjects with schizophrenia appear to be better
than normal. There is also differential preservation, despite
overall impairment, for some functions, such as perception of
local as opposed to global visual patterns. Likewise when
much information needs to be derived from a brieflypresented stimulus array, patients with schizophrenia are
minimally impaired, or even supernormal, because the
perceptual trace lasts longer than normal, allowing more
extensive processing than normal before the trace fades. It is
also be predicted that when components of a stimulus
presented at slightly different times need to be integrated,
schizophrenia patients would be able to accomplish this for
greater temporal separations than normal subjects. Evidence
presented to date does not support this prediction.
Nevertheless, overall, the functions which are relatively
preserved or supernormal are those normally accomplished
better by the left hemisphere, specializations which are
favored by temporal dispersion of visual signals. There is
some indication that functions normally performed by the
dorsal cortical stream, such as rapid visual location of a
stimulus, are impaired more than those preferred by the
ventral stream of cortical visual processing.
While some of this evidence could be interpreted as
indicating impairment of the transient visual system at a
subcortical level, the evidence is more parsimoniously viewed
as showing a relative loss of rapidly-conducting axons within
cortical pathways. This idea fits the tendency for particular
impairment in functions mediated both in the right hemisphere
and in the dorsal visual stream. Indeed, for one function of the
dorsal stream - detection of motion in slowly-moving stimuli the evidence fits well the idea that there is loss of rapidlyconducting axons in a specific pathway, that from area V1 to
area MT (V5), which is normally specialized as rapidly
conducting. Some of the above impairments (lengthened
critical stimulus duration for detection, prolonged visual
backward masking) are documented as being correlated with
the negative symptom group. However, there is no direct
correspondence between these symptoms and the laboratory
measures, since negative symptoms are expressions more of
behavior than of perception.
When lateralized visual tests are performed (7.2.3.), with
right-hemisphere-preferred material it is generally found that
right hemisphere (left field) performance is impaired, while
left hemisphere (right field) performance remains more intact.
As a result, there is a loss of the normal asymmetry. With
lateralized presentation of left-hemisphere-preferred material,
there is often no major impairment in schizophrenia. When
there is, left hemisphere impairment is usually accompanied
by right hemisphere impairment for the same material. This
may reflect that fact that, normally, optimal function of the
left hemisphere depends on “boosting” from the more easilyactivated right hemisphere. In schizophrenia, along with
impairment of the right hemisphere, this boosting of the left
hemisphere appears to be lost (7.2.5.). In non-tachistoscopic
visual tests (e.g. in perception of facial identity or facial
emotion) subjects with schizophrenia are generally impaired
(7.2.4.). Such tests also assess functions normally preferred by
the right hemisphere, but exact interpretation is confounded
32
Conclusions: The Concept of Schizophrenia
by several factors other than perception. Overall, there is
compelling evidence from visual studies that functions
normally preferred by the right hemisphere are impaired in
schizophrenia.
2.7.2.
Auditory perception in schizophrenia.
Detection thresholds for maintained auditory stimuli are
generally higher than normal in schizophrenia, more
consistently so for left ear/right hemisphere stimuli than for
right ear/left hemisphere ones (7.3.1.). The left hemisphere is
more variable than the right, with impairment in the former
perhaps being related to active psychosis. In schizophrenia
integration of auditory perception takes longer to be complete
than in normal subjects, this being reflected in a steeper-thannormal fall of threshold intensity as stimulus duration is
increased. As with visual perception, this suggests that
convergence of signals can occur across a wider-than-normal
time interval, as expected when rapidly-conducting axons are
substituted by a range of more slowly-conducting ones.
Auditory stimuli with relatively slow acoustic transients
(similar to the prosody in speech) are normally preferred by
the right hemisphere, and the evidence is consistent that
perception of such stimuli is impaired in schizophrenia
(7.3.2.). Perception of sounds with faster transients (such as
the rapid sequence of acoustic events which makes up a
consonant speech sound) are normally preferred by the left
hemisphere. Contrary to expectation from the slogan “two left
hemispheres”, perception of such sounds is also sometimes
found to be impaired in schizophrenia. However, this
impairment is limited to subjects experiencing auditory
hallucinations (7.3.2.).
In dichotic listening tasks (competing CV stimuli to the
two ears), studies of schizophrenia generally report loss of
normal asymmetry, if the experimental design limits auditory
processing to purely perceptual factors. This result is
ambiguous since it could reflect either relative impairment of
the left hemisphere or relative lack of impairment in the right.
A single lateralized study using monaural stimuli favors the
latter idea, suggesting that the right hemisphere in
schizophrenia may have some of the specialization of the
normal left. However, this may not be the whole explanation
of abnormalities of auditory perception in schizophrenia, since
the loss of right ear advantage has been associated in several
studies with presence of auditory hallucinations. In dichotic
tasks with a working memory/vigilance component, an
increased right ear advantage is commonly seen, especially if
subjects are actively psychotic. This may reflect the fact that,
despite a general trend to impairment, the left hemisphere can
function normally if overall levels of activation are high.
The impairment in auditory perception for lefthemisphere-preferred stimuli, the loss of right-ear advantage
in dichotic listening tasks, and (especially) the association
between each of these and the presence of auditory verbal
hallucinations, leads one to consider the mechanisms behind
such symptoms. Unlike other hallucinations, auditory verbal
ones (“hearing voices”) are in part an enduring trait, not
entirely eliminated by antipsychotic medications (5.5.).
Theory is developed in Sect. 7.3.4. based on the supposition
that normal perception of speech sounds depends on
integration of representations of the acoustic aspect of a
33
speech sound with that of the vocal motor program required to
produce the same sound. This in turn requires rapid
coordination of cell assemblies spread over relatively distant
regions of cortex (including both Wernicke’s and Broca’s
areas). If there is a relative absence of rapidly conducting
cortico-cortical axons (our “central hypothesis” for
schizophrenia), this widespread integration of cell assemblies
may fail. As a result, internal speech (“verbal thoughts”) can
no longer make up integrated perceptuo-motor abstractions,
but may be experienced as more similar to sensory
perceptions, that is, ones originating from an external source.
This hypothesis for verbal auditory hallucinations has definite
morphological implications, which are considered in Sect.
7.3.4., summarized also in Sect. 12.8. and Sect. 2.13.6. of the
present chapter.
2.7.3.
Somatic perception in schizophrenia.
In schizophrenia, a number of tests of somatosensory
perception show impairment (Sect. 7.4.). In lateralized tests
(such as the “quality extinction test”) an excess of left-sided
extinction has been reported several times. Since this
abnormal asymmetry correlates with impairment in other tests
of right hemisphere function, and since another right
hemisphere function - stereognosis - is often found to be
impaired in schizophrenia, it probably reflects impaired right
hemisphere rather than enhanced left hemisphere perceptual
abilities. Studies of tactile discrimination during active
psychotic states tend to find left rather than right hemisphere
impairment, and this normalizes as treatment takes effect. The
lateralization of abnormality in active psychotic states thus
seems to be in different directions comparing auditory and
somesthetic modalities.
2.8.
Interhemispheric
transfer.
and
cross-modal
In each of the three major sensory modalities there is
evidence for reduced or impaired coordination between the
two hemispheres, although there is also a number of studies
which fail to find this. In the visual sense this has been
detected as impairment in matching stimuli presented in
opposite visual fields, in loss of bilateral advantage when the
same stimulus is present in both fields, in reduced interference
when different stimuli are presented in opposite fields, and in
reduced right-to-left transfer involved in rapid naming of
color stimuli presented in left fields. In the auditory sense,
loss of bilateral advantage in comprehension of speech is well
documented. In the somesthetic sense, studies involving
matching of shapes presented to each hand is impaired in
schizophrenia, especially when “nonsense” shapes are used
which cannot be recoded in linguistic form. There are many
studies which do not show such impairments. However,
overall, when impaired inter-hemispheric coordination is seen,
it is in circumstances where rapid coordination is required.
The impairment in inter-hemispheric coordination can thus
best be interpreted as due to slower-than-normal callosal
conduction, a probable reflection of a relative absence of
rapidly-conducting callosal axons. A single study in the visual
sense directly demonstrates increased callosal conduction time
in schizophrenia.
Conclusions: The Concept of Schizophrenia
Slower-than-normal cortico-cortical transmission should
also lead to impairment in coordination between different
sensory modalities, since the cortical regions for the different
modalities are relatively distant from each other. There is
some evidence for this, mainly concerning coordination
between the visual and the vestibular or proprioceptive senses.
There are many predictions about other combinations of
sensory systems awaiting evaluation in this area.
2.9.
Abnormalities of motor coordination in
schizophrenia.
The best-known normal aspect of cerebral asymmetry in
the domain of motor control is handedness. There is
considerable evidence that in schizophrenia non-righthandedness is more common than normal, and there also
appears to be a shift away from right-eyedness and footedness. However, many people with the diagnosis are
clearly right-handed. There are many problems with obtaining
estimates of anomalous handedness which are precise and
objective. Thus the evidence of an excess of anomalous
handedness in schizophrenia is not robust enough to become a
major consideration for theory development.
In more detail, motor control can be subdivided into two
varieties, closed-loop control, under moment-by-moment
sensory guidance, and open-loop control, preplanned a few
hundred msec in advance. In normal subjects the former is
carried out better in the right hemisphere, presumably because
of more rapid sensory-motor feedback, the latter by the left
hemisphere, presumably because of a richer repertoire of long
axonal delay lines, used for coding delays in the “plan”. A
number of studies of sensory-motor closed-loop control have
been conducted in subjects with schizophrenia. In the form of
visuo-manual control it is clear that schizophrenia patients are
impaired, suggesting sluggish sensory-motor feedback, while
there is little evidence of impairment in preplanned open-loop
manual control. In addition, the synergy of several parts of the
motor apparatus in simultaneous action (a motor “Gestalt”),
normally coordinated by the right hemisphere, shows
impairment in schizophrenia. These results support the central
hypothesis for schizophrenia of a relative absence of rapidlyconducting cortico-cortical axons, hypothetically typical of
the normal right hemisphere. With these results as a
background, it is likely that the loss of asymmetry in
handedness in schizophrenia arises because the right
hemisphere comes to have characteristics normally typical of
the normal left hemisphere. There is some direct evidence that
the left hand in schizophrenia is superior to that in normal
subjects in tasks normally preferred by the left hemisphere
(right hand).
2.9.1.
Eye tracking.
In the first half of the twentieth century, abnormalities of
eye tracking were reported several times in schizophrenia
(a.k.a. “dementia praecox”)(7.4.1.). Systematic study of this
did not start until a seminal paper of Holzman et al (1973)
who reported an excess of velocity arrests and of “catch-up
saccades” during tracking of continuously-moving targets. A
large literature on eye tracking in schizophrenia has
accumulated since then. To interpret such evidence,
mechanisms underlying eye tracking in normal subjects must
first be considered.
2.9.1.1.
Physiology of normal eye tracking.
Eye movements can be divided into two main types
(7.4.4.1.). Saccades are rapid step-like movements which
succeed in “catching” on the fovea the image of an object
moving in a similar step-like fashion. In contrast, smooth
pursuit eye movements (SPEM) succeed in matching eye
movement to continuous movement of the target. SPEM is
found only in primates. Saccades are of several types. Those
which occur to supplement SPEM (mainly catch-up saccades
[CUSs]) are of most interest in relation to schizophrenia.
SPEM reflects sensory guidance of eye movement by visual
stimuli. However, unlike visuo-manual control (considered
above) the control is exerted largely by disparity in the
respective velocities of eye and target, with lesser effects
achieved as a result of position disparity. Steady eye fixation
also involves feedback control by visual stimuli, but in this
case, control is entirely by position disparity. In addition to
control of eye movement by sensory guidance, there are
mechanisms (referred to as “velocity memory”) which tend to
sustain eye movement at the current velocity, at least for a few
100 msec. Furthermore, predictive or anticipatory control is
possible, and has an influence on both SPEM and saccades.
CUSs occur when the current velocity and position disparity
predict that eye and target trajectories will not intersect in the
next 180 msec. The combination of SPEM and CUSs, guided
either by sensory feedback or by prediction ensures that
normally both velocity and position of the eyes match those of
the target quite well.
Movement of a visual image with respect to the retina is
detected in cortical area MT, and more complex whole-field
patterns of image movement are represented in area MST
(7.4.4.3.). These areas are involved in control of SPEM, the
former in the initial phase of movement, the latter during
SPEM maintenance. However, the cortical area most directly
involved in generating the signals for change of eye velocity
is the frontal eye field (FEF)(7.4.4.3.). Damage to this area
impairs SPEM gain as well as predictive and anticipatory
control of eye tracking. Lesions to any of the above three
areas fail to prevent corrective (catch-up) saccades. Hence, the
impairment of SPEM gain after lesions in FEF is compensated
by increased CUS frequency. Since these CUSs are usually
accurate, the predictive computations in themselves are
probably intact after such lesions. The “velocity memory”
referred to above depends on mechanisms in cerebellum and
brainstem.
Since both SPEM and CUS involve feedback control by
visual signals, cortico-cortical pathways are likely to be
involved, whose conduction time will influence the speed and
accuracy of eye tracking. A variety of such pathways could be
suggested, that from MST to FEF being probably most
important for feedback control by velocity disparity. The fact
that feedback control of the eyes tracking a moving stimulus
is faster than that of eye fixation may be explained by the
unusual rapidity of conduction in the pathway from V1 to MT
(the area primarily responsible for detecting velocity of image
movement over the retina)(7.4.4.4.).
34
Conclusions: The Concept of Schizophrenia
2.9.1.2.
Eye tracking in schizophrenia.
From the central hypothesis of relative absence of rapidlyconducting cortico-cortical axons, a number of predictions can
be made (8.4.5.1.). The different predictions interact with one
another, so it is difficult to evaluate them individually.
Overall, however, it is predicted from theory that eye tracking
and visual fixation in schizophrenia will be less accurate than
normal, gain for tracking constant-velocity targets will be
below normal, and latency for eyes to reach target velocity at
the start of movement (and when velocity changes) will be
greater than normal. In addition catch-up saccades, though
normal in themselves, should occur with excessive frequency
as a corrective response to the primary abnormality.
Considerable evidence (8.4.5.2-8.2.5.4) supports each of these
predictions. Abnormalities in SPEM tend to be associated
with negative symptoms, although this is clearer for
schizotypal personality disorder (SPD) than for schizophrenia
itself (8.8.). Correlations with positive symptoms or
symptoms of the Disorganization factor are inconsistent
between studies. CUSs compensating for low pursuit gain use
a variety of strategies (different combinations of increased
frequency and amplitude), but the mechanisms generating
CUSs appear to be normal.
The theory developed relating normal cerebral asymmetry
to motor control (Miller 1996a [Chapts 8 and 9]) suggests that
the left hemisphere is superior to the right in predictive or
anticipatory control. Similar reasoning suggests that in
schizophrenia such control should be better than normal. In
investigations of eye movement there is indeed substantial
evidence for this: Programming of eye movements appears to
be planned further ahead (by ~60 msec) than in normal
subjects, a difference readily explained in terms of a richer
repertoire of cortico-cortical delay lines. There is also a
suggestion that anticipatory saccades are more frequent than
normal in some schizophrenia patients. However, not all
evidence fits the prediction, and the circumstances in which
supernormal predictive control of eye movements occurs is
not yet well defined. Nevertheless this evidence is important,
because, like some of the evidence on perception, it refutes
the idea that abnormality in schizophrenia is merely a nonspecific deficit.
From theory it is predicted that impairment in normal
functions in schizophrenia should apply more to right than left
hemisphere, since the functions showing impairment are held
to depend on the rapidly-conducting pathways typical of the
normal right hemisphere. Specifically it would be expected
that right hemisphere control of SPEM (vis: in rightward
tracking) would be more severely abnormal than left
hemisphere control (in leftward tracking)(8.4.7.). This
prediction is not well supported by available evidence: What
evidence there is finds either no asymmetry of the impairment
in tracking in schizophrenia, or greater impairment for
leftward than rightward tracking. However, in accord with
theory, several studies find that for control of predictive eye
movements in schizophrenia, the right hemisphere acquires
some of the special ability of the normal left hemisphere. One
further abnormal aspect of asymmetrical eye movements
remains unexplained. Some saccades have unusually short
latency (“express saccades”), and are thought to arise from
loss of inhibitory control of the prefrontal cortex over the
35
superior colliculus. These are more common than normal in
schizophrenia, especially when targets are presented in the
right rather than the left visual fields.
Despite the abnormal features, many aspects of eye
movement are normal in schizophrenia (8.4.8.). Brainstem
reflexes controlling eye movement (vestibulo-ocular, oculocephalic, optokinetic) are normal. Refixation saccades
(locating the image on the fovea after a step target movement)
sometimes show abnormalities in amplitude or velocity, but
the correlation of these two remains normal, suggesting that
saccadic control is basically normal.
SPEM impairment in schizophrenia can be reduced
somewhat by strategies to focus attention on the target, but
significant impairment remains even after these strategies
have been employed. In normal subjects, distraction by
irrelevant stimuli does not accurately reproduce the
impairment in schizophrenia. Thus this impairment is not
simply a byproduct of impairment of focused attention
(8.4.9.1.).
Many studies have concluded that the SPEM abnormality
in schizophrenia is not a consequence of neuroleptic
medication (8.4.9.2.). The pursuit abnormality is also not
reproduced in normal subjects by stimulants, even in cases of
stimulant-induced psychosis. SPEM abnormality is not
associated with active psychosis, and may even be reduced in
this state (8.4.9.3.). A number of studies have examined the
effects of anesthetics, especially ethanol (8.4.9.2.). These
produce impairments somewhat similar to those in
schizophrenia. Dissociative anesthetics (NMDA antagonists)
reduce SPEM gain and open-loop acceleration, and increase
the frequency of CUSs in normal subjects. They also make
eye fixation unsteady. These impairments are similar to those
in schizophrenia. However, the slowed latency characteristic
of schizophrenia is not reproduced by NMDA antagonists.
Tardive dyskinesia is associated with irregularities of eye
movements which are distinguishable from the tracking
impairment of schizophrenia.
The eye tracking abnormality and the unsteadiness of
fixation in schizophrenia (like that for visuo-manual control)
fit well the predictions based on the relative absence of
rapidly conducting axons (8.5.). Likewise the relative
intactness (or even super-normality) of predictive tracking
accords well with theory. The tracking abnormality is not the
same as that produced by lesions in any of a number of
relevant cortical areas, and is not exactly reproduced by
blockade of glutamate receptors involved in cortico-cortical
transmission. The best parallel to the abnormality in
schizophrenia may be eye tracking in normal children, where
it is also likely to be explained in terms of a relative absence
of rapidly-conducting cortico-cortical axons. Alternative
hypotheses have been proposed for the abnormalities in
schizophrenia, including the idea that there is a loss of
inhibitory control over a variety of eye movements. However,
these hypotheses do not give such a comprehensive account of
the relevant phenomena, and are not framed in terms of
fundamental (e.g. axonal) differences between normal
subjects and those with schizophrenia.
Conclusions: The Concept of Schizophrenia
2.9.1.3.
Eye tracking and inheritance of schizophrenia.
Eye tracking is under substantial genetic control: Studies
of normal twins show strong concordance between members
of MZ but not DZ twin pairs. In MZ twins discordant for
schizophrenia abnormal eye tracking shows strong
concordance, stronger in most studies than the schizophrenia
itself. Thus SPEM disorder may be a more certain guide to the
genetic diathesis underlying schizophrenia than the manifest
disorder. Many (but not all) studies of FDR of schizophrenia
probands show SPEM dysfunction, although it may be less
severe than in the probands, and minor qualitative differences
from the probands have been described. No clear picture is
currently discernible on whether different classes of FDR are
more prone to SPEM dysfunction. Several studies, in
populations of either schizophrenia probands or their FDR
have shown bimodal distributions in SPEM measures, and this
has been suggested as indicating a sharply-categorical genetic
factor underlying this abnormality. However, there are serious
flaws in this inference. It has nevertheless led to the postulate
that the SPEM disorder is controlled by a single dominant
gene. Formal genetic models have been developed, combining
this idea with that of different penetrances for the SPEM
disorder and schizophrenia itself (higher for the former than
the latter). While these could account for several aspects of
inheritance of these two related traits, they fail to account for
the near-50% MZ twin concordance of schizophrenia itself.
The idea of a single gene, or a single gene of major
importance is not consistent with whole-genome studies
(3.6.2.).
presented amongst distracters. This is the case whether the
distracters are presented simultaneously (e.g. on a sheet of
paper; 9.2.1.), or sequentially in an extended series, usually of
visual stimuli (9.2.2.). Many studies of target detection in
extended series have been reported in the various versions of
the Continuous Performance Test (CPT). Some of these
versions also involve a degree of manipulation of stimuli
within working memory (WM), but the basic findings in
schizophrenia are similar whether or not WM is involved.
Performance may be impaired in the short term by neuroleptic
administration, but tends to improve with prolonged
treatment. Even in well-stabilized medicated patients,
performance is impaired compared to normal subjects. This
impairment correlates with presence of negative symptoms or
scores on the Psychomotor poverty factor, but not with scores
on the Reality distortion factor, and inconsistently with
Disorganization factor scores. A lesser degree of impairment
is present in FDR of schizophrenia probands. Impairment is
also found in affective disorder including both mania and
depression, more so in psychotic depression, but even during
remission. Impairment is also found in schizophreniaspectrum
personality
disorder
(as
defined
both
psychometrically and clinically). The impairment in target
detection tasks implies a reduction of the ability to selectively
bring particular cell assemblies close to ignition threshold,
and to sustained them above threshold. This in turn is
predictable if there is a relative absence of rapidly conducting
cortico-cortical axons, with increased temporal dispersion of
signals and a reduced degree of post-synaptic summation.
2.9.1.4.
Eye tracking impairment in conditions related to
schizophrenia.
SPEM abnormality does not differ between clinical
subtypes of schizophrenia, though it may be more prevalent in
illnesses which, clinically, are more severe. It occurs more
commonly than normal in subjects with personality
characteristics related to schizophrenia. This is clearer for the
clinically-determined schizotypal personality disorder (SPD)
than for psychometrically-determined schizotypy. Sometimes
the SPEM impairment in SPD is found to be limited to
subjects who also have a positive family history for
schizophrenia, or who are impaired sufficiently to merit
treatment. SPEM abnormality occurs in affective disorder,
including both bipolar and unipolar disorder. It is difficult to
compare the severity or prevalence of the SPEM disorder
between schizophrenia, and bipolar or unipolar affective
disorders because of confounding state variables. Lithium
treatment impairs SPEM, but affective patients have an
impairment regardless of this. FDR of affective probands, like
those of schizophrenia probands probably do have increased
SPEM abnormality, although quantitative measures rather
than the less sensitive categorical ratings are needed to show
this.
2.10.2.
Reaction-time crossover.
In reaction time (RT) tests, normal subjects benefit from
an advance warning signal if it occurs at a regular time, up to
20 sec ahead of the imperative signal. Subjects with
schizophrenia do so too, but only for shorter preparatory
intervals. As preparatory interval is lengthened, RT with
irregular warning stimuli may actually become less than that
with regular warning stimuli, giving a “cross-over” in the plot
of preparatory interval vs RT (9.2.4.). This commonly occurs
at shorter preparatory intervals in schizophrenia than in
normal subjects (9.2.4.2.).
Two processes appear to contribute to the RT cross-over
effect (9.2.4.2.). The benefit from a warning stimulus if it is
regularly timed is presumably an indication that activity in a
cell assembly activated by the warning stimulus can be
transferred to that activated by the imperative stimulus, so
speeding RT. In schizophrenia, relative absence of rapidlyconducting axons, with consequent temporal dispersion of
signals, impairs the sustaining of activity in the first cell
assembly, so that the RT benefit from regularly-timed
warning signals disappears at shorter-than-normal preparatory
intervals.
In addition to this, when preparatory interval is lengthened
over successive trials, RT is speeded. This effect occurs to
more-than-normal degree in schizophrenia. In the usual
designs of RT cross-over experiments, long preparatory
intervals in irregular series are, on average, longer than in
preceding trials. This results in RT speeding. This occurs to
more-than-normal extent in subjects with schizophrenia, so
that, at the longer preparatory intervals, RT in irregular series
2.10.
Abnormalities in schizophrenia in the
realm of cognitive psychology.
2.10.1.
Target detection and vigilance.
Persons with schizophrenia are impaired in tasks requiring
focused or sustained attention for detection of target stimuli
36
Conclusions: The Concept of Schizophrenia
becomes less than that for regular series. In terms of
neurodynamics, the tentative explanation of this is related to
one of the conclusions derived from the evidence on SPEM,
namely that anticipatory eye movements can be planned
further in advance in schizophrenia than is normally the case
(2.8.1.2.). In the RT cross-over paradigm, this could mean that
in schizophrenia, better advantage can be taken than in normal
subjects of the imperative signal occurring later than expected.
In either case, the supernormal preparatory planning can be
explained by there being a richer repertoire than normal of
long axonal delay lines.
Evidence on abnormalities in the RT cross-over paradigm
in FDR and disorders related to schizophrenia is not abundant
(9.2.4.3.). Available studies show that FDR sometimes show
abnormalities similar to, but smaller, than those in
schizophrenia. In affective disorder, abnormalities are slight,
whether patients are currently depressed, manic or stabilized.
Normal subjects scoring high on schizotypy scales show
abnormalities of lesser degree than those with schizophrenia.
2.10.3.
Associative processes, cognitive inhibition and
processing resources in schizophrenia.
2.10.3.1. Associative processes.
The idea that people with schizophrenia have an
abnormality in the process of mental association has a long
history (9.3.1.) and figured prominently in Bleuler’s writings.
It has been a matter of debate whether this abnormality
consists of disorganization of association, or rather
heightened awareness of associations, especially of the more
remote ones. For the pioneers, the issue was clouded by their
inability to separate aspects of psychosis from true traits.
More recently it has become clear that heightened awareness
of associations is indeed an enduring trait in schizophrenia,
shown in sorting tasks, word association tests and non-verbal
assessments of generalization gradients (9.3.2.). Hyperactive
processes of association are shown most precisely in modern
work on semantic priming (9.3.3.), using tachistoscopic
stimuli, where semantically-related primes accelerate RT to
target stimuli in lexical decision tasks. At first sight the
literature on this has many contradictions, but these are
mainly resolved when account is taken of the fact that shortduration primes (less than ~150 msec) are not properly
encoded in schizophrenia (see analysis of perceptual
processes, in Chapter 7). Therefore, the semantic priming
design is a valid test of associative processes only when prime
duration is longer than this. Given this complication, semantic
hyper-priming is associated with the clinical symptom of
thought disorder. Evidence is insufficient to reach conclusions
about whether the heightening of associations applies to FDR
of schizophrenia probands. Most studies of affective disorder
find only a small degree of abnormality, and evidence on
schizotypy is too scanty to reach firm conclusions.
2.10.3.2. Cognitive inhibition and reduced “processing
resources” in schizophrenia.
The mirror image of heightened associative processes in
schizophrenia is increased difficulty in shutting out mental
images irrelevant to the task requirement (9.3.4.). The
pioneers were well aware of this impairment (9.3.4.1.). More
recently the impairment has been shown in many studies of
37
distractibility, which is increased in states of active psychosis,
and also, but to a lesser extent, in stabilized patients with
schizophrenia (9.3.4.2.). Experiments attempting to show
impairment in shutting out distracters using tachistoscopic
methods (“negative priming”) are not very conclusive,
because the predicted lack of negative priming can often be
given an alternative explanation: Priming stimuli, with
durations less than 150 msec, are not long enough to be
properly encoded in subjects with schizophrenia, and may fail
to show negative priming for this reason alone (9.3.4.3.).
A likely corollary of the increased vulnerability to
distraction in schizophrenia is that fewer test items can be
handled independently than is normally the case. This
corresponds to the psychological finding of reduced
“processing resources” for cognitive operations. There is
abundant evidence for this in schizophrenia, including a
steeper-than-normal gradient for RT as a function of
increasing task complexity, and differential impairment in
target detection as the complexity of a stimulus array
increases. In formal dual task paradigms, subjects with
schizophrenia are also differentially impaired, compared to
their performance in the various tasks considered singly.
Distractibility, reduction of negative priming, or reduction
of processing resources tend to be associated with increased
scores on the Disorganization factor, or on thought disorder,
but not with scores on the Negative symptom factor.
2.10.3.3. Theory: Axonal conduction time in relation to
associative processes, cognitive inhibition and processing
resources.
The three abnormalities considered above - excessive ease
of mental association, increased vulnerability to distraction
and reduced processing resources - are closely related in that
they can all be derived from the same theory based on a
relative absence of rapidly conducting cortico-cortical axons,
Consider first a cortical network with the normal complement
of rapidly conducting axons. When a focus of activity appears
in the cortex, it may transmit activity to other sites, and this
will occur rapidly and with minimal temporal dispersion.
There will then be enough post-synaptic summation for
activation of the neurons in the recipient site, followed by
strong rebound inhibition. However, in networks where the
rapidly conducting axons are fewer in number, replaced by
slowly conducting ones, there will be considerable temporal
dispersion before signals reach their destination, and
consequently less post-synaptic summation, less suprathreshold activation, and less rebound inhibition. Instead there
will be a large “subliminal fringe” of subthreshold activation
of axons (but not of the post-synaptic neurons). The
subliminal fringe, little diminished by rebound inhibition, will
be available for summation with subliminal activity from
other sources. It therefore represents the capacity of the
cortical network for associative processes, as detected, for
instance, in semantic priming experiments. In addition stimuli
irrelevant to the task in hand cannot be shut out as easily as
normal. This is because the cell assemblies representing the
target stimuli do not generate such a large surround of
inhibition, to suppress awareness of potential distracters.
Similarly, if, in schizophrenia, cell assemblies can associate
more freely and interfere with one another more than normal,
Conclusions: The Concept of Schizophrenia
the number of cell assemblies which can function
independently will, by the same token, be reduced. This
reduction corresponds at the psychological level to the
observed reduction in “processing resources” in
schizophrenia.
The explanation of the ease of association, and
vulnerability to distraction is based on an assumption which
should not be overlooked: Interactions between cell
assemblies will occur only if the cortical network as a whole
is in a state of relatively high activation, with the membrane
potential of member neurons poised not far below threshold
for firing. This assumption is not needed to explain
impairments in schizophrenia in other experimental paradigms
considered so far: In these cases it is implicit that membrane
potential in member neurons is a long way negative of
threshold, so that convergent activation of many afferent
synapses is needed to fire them. The impairment in
schizophrenia then arises because temporal dispersion of the
activation in these synapses reduces the degree of postsynaptic summation. This distinction between two classes of
impairment follows from a basic bimodality in the operation
of the cortex, discussed more fully in Chapter 11, in the
context of electroencephalography. The expression of this
bimodality as two types of abnormality in experimental
studies of schizophrenia may indeed have a counterpart in the
symptoms of schizophrenia as documented in the clinic:
Negative symptoms (or scores for the Psychomotor poverty
factor) correlate with and are probably another expression of
the impairments in the cortex when it is at a low level of
activation. Thought disorder (or scores for the Disorganization
factor) correlate with abnormality in the semantic priming
task, and is probably another expression of the abnormal
dynamics of the cortex in schizophrenia when activation level
is relatively high.
2.10.4.
“Short term memory” and “working memory” in
schizophrenia.
The phrases “short term memory” (STM) and “working
memory” (WM) are often used rather inconsistently. In this
book the former term is used to emphasize the holding of
information “on-line”, and available for further processing for
periods of up to one minute. The term “working memory”
requires this, but also places emphasis on the manipulation of
information held in such an activated form. Given these
definitions psychological analysis of STM (following
Baddeley9) has revealed two components, the “phonological
loop” which copes well with lists of (usually auditory)
material, and the “visuospatial sketch pad” which prefers
spatial patterns of visual material. Tentatively these
correspond respectively to STM functions preferred by the left
and right hemispheres. In schizophrenia there is little evidence
of impairment in the use of the “phonological loop”, except
when distraction tasks are employed during the retention
interval (9.4.2.1.). Vulnerability to distraction alone can
account for observed impairments. In contrast, impairment in
holding visuospatial material “on line”, in the “sketch pad” for
STM intervals is impaired in a wider variety of conditions,
and is not just a function of vulnerability to distraction
9
Baddeley actually uses the term “working memory”.
(9.4.2.2.). These results can be accounted for in terms of the
central hypothesis for schizophrenia, that there is a relative
absence of rapidly-conducting cortico-cortical axons. The
relative intactness of the “phonological loop” indicates that
the special functions normally performed by the left
hemisphere, such as a preference for verbatim recall of
temporal sequences, are not fundamentally affected.
Impairment in the “visuospatial sketch pad” indicates that the
special function of the normal right hemisphere are
compromised, as expected from the hypothesis, assuming that
the right hemisphere normally owes its special properties to
an abundance of rapidly conducting axons. Under normal
circumstances this allows cell assemblies to “ignite” easily
and remain for a while in active state without decrement. In
schizophrenia these functions are impaired.
In this context it is relevant that identification of odors is
often impaired in schizophrenia (9.4.2.4.), a fact which cannot
be attributed either to the effect of neuroleptics or smoking on
olfactory perception. The olfactory sense is unique in that its
pathways do not involved relay through the thalamus, and,
related to this, do not permit analysis of patterns with fine
resolution in time. Representing a particular odor is thus, in
neurocybernetic terms, closely similar to representing
visuospatial patterns (or a variety of other types of pattern
without temporal structure). What evidence there is suggests
that olfactory identification is preferred by the right
hemisphere in normal subjects. The impairment in
schizophrenia thus fits the generalization that righthemisphere-preferred functions are most affected.
In tasks involving organization or manipulation of material
within STM (the “work” of working memory), people with
schizophrenia are substantially impaired, under a wide variety
of conditions, and whether the material used is preferred
normally by right or left hemispheres (9.4.3.). WM tasks often
involve a number of “hidden” steps, and so place great
demands on processing resources. That this is the real reason
why people with schizophrenia are impaired on WM tasks is
shown in a number of studies where performance declines
more steeply than normal as the complexity of the WM task
increases. Although WM impairment is held by some
researchers to be a central feature of schizophrenia, it does not
have such importance in the present work, because it is seen
to be a compound of several more fundamental impairments,
dealt with in earlier chapters. “Working memory” in itself, is
not a sufficiently unified concept to be directly related to the
basic abnormality proposed here as fundamental to
schizophrenia. However, it is a very useful concept in
accounting for psychological dysfunction at a higher cognitive
level (especially in higher levels of language processing - see
Chapter 10).
2.10.5.
“Rote” learning in schizophrenia.
Learning of material presented without reinforcement
(“rote” learning of lists of words, sentences, patterns, or
pictures) involves fundamental processes of “learning by
stimulus contiguity”. In modern views, this is thought to be
mediated in part by Hebbian processes of synaptic
modification. However, it is a large jump from the synaptic
level to the level of learning experiments conducted in intact
humans. To make inferences about fundamental Hebbian
38
Conclusions: The Concept of Schizophrenia
processes from such experiments, many confounds, at higher
levels of organization need to be eliminated or controlled. In
learning experiments in humans an important confounding
factor is the subject’s ability to organize memoranda in a way
which aids retrieval. This is certainly impaired in
schizophrenia, presumably as a result of impairment in WM at
the time of encoding. However a variety of experimental
designs indicate that there is impairment beyond that due to
failure of organization (9.5.). These designs include use of
learning tasks where there is minimal possibility for
organization of memoranda, measurement of retention under
conditions where this plays little part (recognition, or cued
recall, rather than uncued recall), or co-variation of recall
scores for scores on independent tests of organization within
WM. Furthermore, when learning curves are plotted, it is
usually found that schizophrenia patients require more trials to
criterion than normal subjects, a finding not usually explained
by impaired organization of material. Apart from the process
of learning, there is no evidence that long-term retention is
impaired in schizophrenia, except in severely disabled longterm inpatients. Overall, there is a substantial case to be made
that there is an impairment in the fundamental Hebbian
process of learning. The theoretical significance of this arises
from the fact that recruitment of Hebbian processes of
synaptic modification depends on convergence of the
influence of several synapses within a single neuron, much as
does the actual firing of the post-synaptic neuron, and the
“integration time” appears to be similar. Therefore, when
there is a relative absence of rapidly-conducting corticocortical neurons, with resultant increase of temporal
dispersion of signals generated by a phasic stimulus, the
summation needed to trigger Hebbian processes will be
reduced. Full synaptic strengthening will then require a larger
number of repetitions than in a network with a higher
proportion of rapidly-conducting axons.
2.10.6.
Shift of attention in schizophrenia.
People with schizophrenia sometimes have difficulty in
shifting the focus of their of attention: Their attentional “set”
may persist when it is no longer appropriate, that is, they
perseverate. Early indications of this came from a variety of
tasks, especially from study of the sequence of subjects’
choices in guessing tasks (9.6.2.).
2.10.6.1
The Wisconsin Card Sort Test.
The largest body of evidence pointing to an abnormal
persistence of attentional “set” uses the Wisconsin Card Sort
Task (WCST)(9.6.3.). In this task, cards can be sorted
according to one of several principles (number, color or shape
of the designs on each card). Which principle is in operation
for correct sorting is not stated explicitly: Subjects have to
discover this from the investigator’s responses after each of
the subject’s choices (“correct” or “incorrect”). Periodically
the principle for sorting is changed, and subjects have to
recognize that a change has occurred and discover the new
principle for correct sorting. This is a complex task recruiting
several psychological faculties. Performance is determined
partly by the subject’s IQ and level of education. A variety of
impairments are seen in schizophrenia (9.6.3.2.), some of
which can be remedied by training, although persisting
39
improvement has not been shown as a result of training.
Perseveration (“persistence of set”) after change of the
principle for sorting is a prominent aspect of this impairment.
In factor analyses of the various measures of WCST
performance, perseveration emerges as a major component of
the dominant factor. This impairment occurs in all states and
stages of schizophrenia, and is not a function of medication
status.
Part of the WCST impairment in schizophrenia arises from
deficits in WM, and especially from a difficulty in keeping
track of the relation between responses and outcomes for a
sufficient number of trials to recognize shifts of sorting
principle (9.6.3.3.). However, several analytic studies using
tasks related to WCST have shown that perseveration in
schizophrenia also depends on a relative difficulty in shift of
attention (“persistence of set”)(9.6.3.4.).
Performance in the WCST, unlike that in several other
experimental paradigms correlates with scores on the
Disorganization factor scores more consistently than with
negative symptoms or Psychomotor poverty factor scores
(9.6.3.6.). When WCST impairment does correlate with
negative symptoms, it may reflect relatively mild symptom
scores while more intense negative symptoms are independent
of WCST performance. WCST performance does not
correlate with Reality distortion factor scores.
Impairment in the WCST is also found in FDR of
schizophrenia probands (9.6.3.7.), but nevertheless appears to
transmit to FDR significantly less strongly than do some other
trait features of schizophrenia (notably the CPT and - at trend
level - SPEM). The WCST thus appears to identify people
who not only have non-psychotic trait characteristics of
schizophrenia but also are vulnerable to psychotic
decompensation. In affective disorder there are too few
studies using the WCST to draw strong conclusions, but it is
probable that bipolar or unipolar patients, especially when
studied in remission are much less impaired than those with
schizophrenia (9.6.3.8.). Actively manic or depressed patients
may have more definite impairment. Impairment for
schizophrenia-related personality variants has been shown
more consistently than for affective disorders.
2.10.6.2. The Stroop test and other set-shift tasks.
In the Stroop task (9.6.4.), subjects are presented with a
word which may designate a color, and which may also be
printed in colored ink. The critical measure of set shifting is
the ability to suppress the dominant tendency to read a color
word, and instead to name the ink color. Here a color word
interferes with hue naming. The test may be presented as a list
of items presented on paper, when total time for the list is the
dependent measure, or in computerized form, when RT on
each trial is the dependent measure. In schizophrenia,
interference effects appear to be greater than normal, but this
has been shown more consistently with the list than with the
computerized version (where confounds in the usual design
have seldom been eliminated). As with WCST perseveration,
interference measures correlate more consistently with
Disorganization factor scores than with scores on the
Psychomotor poverty or Reality distortion factors. Several
studies with the Stroop task have been reported in FDR of
schizophrenia probands, but too few report true interference
Conclusions: The Concept of Schizophrenia
measures to permit firm conclusions to be made. However
Stroop interference is elevated in subjects with
psychometrically-defined schizotypy.
In the antisaccade task (9.6.5.), subjects have to suppress a
dominant tendency to produce a saccadic eye movement
towards an object appearing off-centre in the visual field.
Instead they have to produce an eye movement away from the
newly introduced object. Since vision is the dominant sensory
modality, and given that motor control of saccadic eye
movements is unimpaired, it follows that saccades are an
indication of attentional focus, and antisaccades reflect ability
to switch attention. People with schizophrenia are impaired on
the antisaccade task, producing more errors (saccades rather
than antisaccades). This is not a side effect of medication. It is
under some degree of genetic control, as shown in studies of
twins and FDR. In affective disorder, similar though milder
impairment is seen, which may be more obvious in psychotic
depression and bipolar disorder than non-psychotic unipolar
depression.
Subjects
with
psychometrically-defined
schizotypy are also usually found to be impaired, more
consistently than those with the clinically-defined SPD. Of the
various symptom groups, antisaccade errors correlate most
consistently with Disorganization or thought disorder rather
than with other positive symptoms or with negative
symptoms.
In RT studies, shift of the stimulus modality slows RT,
more conspicuously in subjects with schizophrenia than in
control subjects (9.6.6.). The differential impairment in
schizophrenia is seen more consistently for shift from the
visual to auditory modality than in the reverse direction. This
is not due to medication effects. What little evidence there is
fails to show transmission of this effect to relatives of
schizophrenia probands, but does show similar impairment in
patients with mood disorder. Correlations with symptom
groups are reported too rarely to reach any conclusion.
Another attention shift paradigm, involving shift of focus
from one visual field (i.e. hemisphere), originally developed
by Posner, is beset with too many problems of interpretation
to allow any definite conclusion to be reached (9.6.7.). The
Trails test (notably the impairment specific to the Trails “B”
version) provides further evidence of impairment in
attentional shift in schizophrenia. A seldom-used test of
alternation of semantic categories in word generation also
provides suggestion of similar impairment in schizophrenia.
2.10.6.3. Theory of excessive “persistence of set” in
schizophrenia in attention-shift paradigms.
The evidence showing problems in “set shifting” in
schizophrenia in the various paradigms discussed in Sect. 9.6.
reveals impairment of a nature different from that for many of
the other paradigms discussed in Chapters 7-9. Impairment in
these tasks tends to correlate with scores on the
Disorganization factor or with thought disorder. This is a
contrast with impairments such as the lengthening of CSD,
extended vulnerability to backward masking, as well as
impairments in SPEM, the CPT and visuo-spatial WM, all of
which are associated with negative symptoms or Psychomotor
poverty factor scores. However, one other experimental
measure - semantic hyperpriming - also shows an association
with thought disorder. Further indications that attention shift
impairment in schizophrenia has an origin different from
some other trait impairments is that it transmits less strongly
to FDR than does impairment in CPT measures, and, possibly
than that for SPEM
Can the impairment in attentional shifting in schizophrenia
be encompassed within the same theoretical framework used
to account for other trait impairments, despite the fact that
scores on the Disorganization and Psychomotor poverty
factors are, by definition, statistically independent?
Specifically can both sorts of impairment be derived from the
central hypothesis developed here, that, in schizophrenia,
there is a relative absence of rapidly-conducting corticocortical axons? These questions are addressed in 9.6.9.2., and
as follows.
The normal cortex, in the waking state, exhibits two
overall regimes of dynamic activity. This is shown on the
large scale in EEG recording, where there appears to be a
bistability between a state where the classic alpha rhythm
dominates, and another state characterized by “low voltage
fast”, “desynchronized” or “beta/gamma” activity. At the level
of single neurons this bistability corresponds to a “down
state” where membrane potential of the principal neurons is
held far negative of threshold for firing, and an “up state”,
when membrane potential appears to be stabilized and poised
just a few millivolts below firing threshold. More detail on
these two dynamic regimes is presented in Chapter 11
(dealing with clinical electrophysiology of schizophrenia).
Here it is necessary to point out that in the “down state”,
coincidence of many co-active synapses on a neuron is needed
to produce impulses which will transmit to other cortical sites.
In the normal brain, where, hypothetically, there is an
abundance of rapidly conducting cortico-cortical axons, the
population of axons transmitting from one locus to another
will produce relatively little temporal dispersion of a signal
generated by a phasic event (such as a tachistoscopic visual
stimulus). Summation of effects within a single neuronal
integration time sufficient to fire the neurons is thus not
compromised. However, in schizophrenia, when the “down
state” prevails, temporal dispersion is envisaged to be greater,
due to the repertoire of axonal conduction delays being shifted
to slower conduction. There will then be a significant problem
in activating post-synaptic neurons, especially when
transmission over long distances is involved (which would
increase temporal dispersion). This, it is envisaged, leads to
many of the abnormalities in experimental measures in
schizophrenia which clearly are impairments (loss of normal
abilities), and is also likely to be the basis for most negative
symptoms.
Consider what happens in the alternative modus operandi
for the cortex, the “up state” as seen in single unit recording in
animals. A cortical locus activated by a phasic stimulus will
transmit signals to other loci. Again the signals will be
temporally dispersed more than normal in schizophrenia, and
will therefore be incapable of such a high degree of
summation at their destination. Since membrane potential is
close to threshold, such a high degree of summation is not
required, and, in schizophrenia many recipient neurons will
still be activated above threshold. However, in schizophrenia,
in any one locus, if several neurons are activated, their
activations will not be confined to the same integration
40
Conclusions: The Concept of Schizophrenia
interval. Synchronized rebound inhibition will therefore be
relatively weak compared to normal. Since the up-state
prevails widely across the cortex, it will be possible for
activity to pass from one locus to others, as a network of
reverberatory activity. There may be sequences of persisting
activity, corresponding subjectively to “long trains of
thought”, and to perseveration in experiments designed to
assess shift of attention. In addition, foci of activity may arise
from combination of subthreshold activation from more than
one source. In psychological terms this corresponds to
hyperpriming in semantic priming experiments, or to some
aspects of thought disorder (although in this case the items
being associated cannot be identified).
This account of the dynamics of the hemispheres in
schizophrenia when the “up state” prevails suggests a way of
answering what is referred to above (2.5.2.) as the “deepest
question” about schizophrenia (9.6.9.3.): Why are people with
all the trait characteristics of the disorder also vulnerable to
episodes of psychosis? Since the transition to psychosis
involves over-activity of the midbrain dopamine neurons, this
question can be transformed into another: How can it be that
hemispheres with a relative abundance of slowly conducting
axons are prone, periodically, to over-activity of the midbrain
dopamine neurons? There is a variety of animal evidence,
both anatomical and functional, that the cortex can exert
control over the midbrain dopamine neurons. One can
therefore suggest that, in the up state, when persisting activity
tends to reverberate around the cortex, an unusual degree of
excitation is transmitted from the cortex to the midbrain
dopamine neurons. This, it is suggested, is the condition under
which transition to psychosis occur. This suggestion fits
several other pieces of information: First, the conclusion that
impairment in the WCST identifies people who are vulnerable
to actual episodes of psychosis fits the reasoning just
presented, since WCST perseveration, and scores on the
Disorganization factor or thought disorder with which it is
associated are also linked theoretically with the activated “up
state” of the cortex. Second, the activated state of the cortex is
likely to be generated in part in response to environmental
circumstances - major life events or psychological traumata and these are known to be significant predictors in
schizophrenia of episodes of psychotic relapse. Third,
referring again to evidence from animals, it is mentioned in
Sect. 5.4.2.3. that lesions of the right, but not the left
hemisphere in rats leads to behavioral and neurochemical
signs of overactivity of forebrain dopamine systems.
Assuming that cerebral asymmetry in rats has some similarity
to that in humans (for which there is some evidence), the
right-hemisphere-lesioned rat may be dominated by lefthemisphere-type cortical dynamics, which would favor
periods of dopaminergic over-activity.
Several lines of evidence indicate that WCST performance
in normal subjects depends strongly on intactness of the
frontal lobes (9.6.3.5.), probably with right side dominance,
and perseveration in schizophrenia also probably depends on
impaired function of the frontal lobe. Likewise the frontal
lobe is implicated in performance in the Stroop task (9.6.4.),
and in the impairment in schizophrenia in this task, shown as
excess interference scores. However, in view of the complex
and rather global requirements for adequate performance in
41
these tasks, it is likely that the impairments in schizophrenia
arise from widespread loss of rapidly-conducting axons rather
than loss in discrete definable pathways.
2.11.
Language and schizophrenia.
Language
functions
can
be
subdivided
into
syntax/grammar and semantics. Both of these can be
considered in relation either to decoding of incoming
language (10.2.) or to planning language output (10.3.).
Syntax and grammar are concerned with the exact sequencing
of words and word endings, and on a larger scale, the
embedding of clauses, to define the meaning inherent in a
sentence. Semantics is concerned with the representation of
meaning itself, regardless of its coding in exact word
sequences. Small scale aspects of semantics (meaning of
individual words) have been considered already (9.3.3.;
synopsis in 2.10.3.1.). Larger-scale semantics, as well as
syntax and grammar raise issues of laterality, for the normal
brain. Syntax and grammar, involving timing and exact
sequence, are preferentially dealt with by the left hemisphere,
while higher-level semantics appears to be right hemispherepreferred. In schizophrenia, a major issue is whether the
disturbance of higher aspects of language function arises
fundamentally from impairment in larger-scale aspects of
semantics, or in the domain of syntax and grammar. The issue
is not straightforward, because primary impairment in one is
likely to have secondary impact on the other. An additional
high-level aspect of language function is its “pragmatics”, that
is the adjustment of language output to meet the needs of
listeners (10.3.8.). For all the above functions, a proper
theoretical account needs to place linguistic functions in the
context of broader concepts for cognitive psychology.
Potentially this can allow language dysfunction in
schizophrenia to be related to the “central hypothesis”
concerning axonal conduction properties.
2.11.1.
Decoding of language input in schizophrenia.
A variety of methods are available to assess subjects’
awareness of syntactic structure. In schizophrenia there is no
deficit in this, provided the measure is truly of this, rather than
of the meaning derived from that syntactic structure (10.2.1.).
However, there may be a deficit in comprehending
syntactically-complex sentences, due to information overload
in WM. In contrast, there is considerable evidence that
decoding of semantic aspects of sentences is impaired in
schizophrenia (10.2.2.). This has been shown by the failure to
benefit from semantic organization in word- or sentence-recall
tests, and by reduced semantic organization of the recalled
material (10.2.2.1., 10.2.2.2.). In the “cloze” procedure
(10.2.2.3.), subjects are presented with written sentences, and
are required to guess deleted words from the surrounding
context. Subjects with schizophrenia are less efficient at
guessing than control subjects, and use a smaller context of
surrounding words. In other tests it is shown that such
subjects are often impaired in interpreting indirect inferences,
metaphorical usages of language, or proverbs (10.2.2.4.). In
reading aloud, their fluency is impaired, probably because
they gain less than normal benefit from comprehension of the
passage to be read (10.2.2.6.). Overall, subjects with
schizophrenia appear to have difficulty in assimilating
Conclusions: The Concept of Schizophrenia
meaning across the span of a sentence or longer passage. In
addition, it has been suggested that such subjects have
difficulty
with
comprehending
abstract
meanings
(“concretism”: 10.2.2.5.), and in inferring mental states in
another person (“Theory of Mind” deficit: 10.2.2.7.). The
evidence on these topics is not convincing, although theory of
mind deficits may be present in states of active psychosis.
2.11.2.
Organization
of
language
output
in
schizophrenia.
Disorder of language output in schizophrenia has been
noted since the earliest studies (10.3.1.). There has been a
debate whether this is to be understood using models of
aphasia derived from neurology, or has a quite different basis.
Many blind alleys have been investigated, some based on
psychoanalytic reasoning. There appear to be problems in
articulation in some patients (10.3.2.), including restriction in
prosodic modulation, but these are not primarily linguistic.
“Delayed auditory feedback” which disturbs speech in normal
subjects does so more severely in schizophrenia, in some
studies, and the delay producing maximum effect is longer
than normal (10.3.3.). This suggests that advance planning of
words-to-be-uttered occurs in longer segments in
schizophrenia than in normal subjects, although more work is
needed to corroborate this, and it is not clear whether the
disruption is of syntactic or semantic planning (or both).
Pauses within utterances have been taken as another measure
of speech planning, and tend to be more frequent and longer
in schizophrenia (10.3.4.). Probably they are an index of WM
processing limitations during discourse planning. Modern
studies comparing disordered speech in schizophrenia with
that in aphasia (10.3.5.) find important differences. In
particular, speech from subjects with schizophrenia does not
show the prominent word-finding difficulty typical of Broca’s
aphasia, or the problem with syntactic organization, typical of
Wernicke’s aphasia. The abnormality seems to be at a level
beyond that of individual words, in aspects of meaning.
Moreover, “thought disorder” in schizophrenia tends to be
less when subjects are not under time pressure, or
communicate in writing rather than vocally. The problem may
therefore not be fundamental to forming semantic
representation in sentences per se, but in doing so at the speed
at which speech normally has to be uttered.
Direct studies of syntax in speech from schizophrenia
patients have reported abnormalities, consisting of syntactic
simplification (10.3.6.), but since these are related to age of
onset of the disorder, they are probably an indication of
arrested development of adult language capability, rather than
a fundamental characteristic of the disorder. In contrast, direct
studies of semantics of speech in schizophrenia have revealed
a number of problems which are probably more basic. When
such speech is submitted to the “cloze” procedure with normal
raters (10.3.7.1.), it is often found to be more difficult than for
normal speech to guess the deleted words. Guessing the
deleted words relies on more closely neighboring words than
for normal speech. When sentence order in a paragraph is
randomized, and normal raters have to reconstitute the
original order, it is found that speech from subjects with
schizophrenia loses its organization across sentences more
than within them. The most interesting evidence on this topic
uses a method assessing links within and between sentences,
which tie together ideas in the discourse (10.3.7.2.). In
schizophrenia, the use of such ties are looser and weaker than
normal, and, although the abnormalities are not common,
when they occurred, they are very disruptive for the listener.
Occurrences of these abnormalities are associated with
clinically-rated thought disorder, and probably are a major
component of this symptom. This abnormality is more severe
in acutely ill patients, but is also present to lesser degree as an
enduring trait. The abnormality is also present to some extent
in FDR of schizophrenia probands. Another way in which
high-level discourse planning has been analyzed is in terms of
the “hierarchy” in which ideas are delivered. It is suggested
that discourse from normal subjects has a strong hierarchy,
which breaks down in schizophrenia (10.3.7.3.). However, it
is very difficult to reduce these proposals to an objective
method of analysis, and so they remain unsubstantiated.
In the “pragmatics” of language output (or “effectiveness”
in communication) the speaker “puts himself in the listener’s
shoes” in planning discourse (10.3.8.). This overlaps with the
use of cohesive ties and other planning devices for integrating
discourse. It is also closely related to deployment of “theory
of mind” in understanding the more complex aspects of
incoming speech. There is evidence (mainly quite old) that
this function is impaired in schizophrenia.
These various impairments in discourse planning in
schizophrenia are likely to derive from more basic
abnormalities in cognitive processes (10.3.9.). Many of them
reflect limits on “working memory”. However, the real limit
is in processing resources, in the complex operations of
linguistic planning. This is likely to account for the
impairments both in decoding incoming semantics and in
planning semantic aspects of speech output (discussed in
10.4.).
2.11.3.
Language dysfunctions in schizophrenia and the
“central hypothesis”.
How do the various language abnormalities in
schizophrenia relate to the abnormality in cerebral asymmetry,
and the “central hypothesis” proposed as the essential basis of
schizophrenia? Normal language processing, whether of input
or output, requires two separate processes, and requires them
to be exactly coordinated. First, speech must be planned
syllable-by-syllable and word-by-word, with attention to
syntax and grammar. These are matters of exact timing and
sequence of word endings, words, and clauses. They are
presumably left hemisphere functions. On the other hand,
such time-structured output needs to be guided on a longer
time scale, phrase-by-phrase, sentence-by-sentence, and
paragraph-by-paragraph, according to the intended meaning.
It is likely that the slow-moving blocks of meaning (“semantic
Gestalts”) which constitute “deep semantic structure” are
embodied by right hemisphere-type assemblies, held in a state
of heightened activation for STM intervals. Interpretation of
long segments of incoming speech requires coordination of a
variety of such right-hemisphere-type assemblies. Likewise
production of comprehensible emitted discourse requires
coordinated deployment of such assemblies, activated in
planned sequence.
42
Conclusions: The Concept of Schizophrenia
These two high-level aspects of language - involving finegrained temporal structure, and slower longer-term semantic
representations - need to be well coordinated in an intimate
synergy if incoming speech is to be understood, and fluent
and meaningful speech is to be produced. In comprehending
incoming speech, the detailed syntactic structure needs to be
translated into slower-moving semantic representation.
Likewise, in planning speech output, deep semantic structure
must be translated into a well-organized utterances, involving
transformations to form verbal, phonetic and syntactic
sequences. Since a particular deep structure can be expressed
in a variety of superficial structures, these transformations
must be more complex than simple one-to-one
correspondence. In normal subjects, it is likely to involve
complex collaboration between the two hemispheres, across
the corpus callosum. In schizophrenia this collaboration
breaks down, either because the right hemisphere aspect of
decoding or discourse planning is impaired, or because the
exactly-timed coordination between the two hemispheres is
lost (or both may occur). In either case, the impairment can be
explained in more fundamental terms by our central
hypothesis, a relative absence of rapidly conducting corticalcortical axons.
2.11.4.
Comment
on
author’s
presentation
of
psychological evidence.
The reader may notice a strategy, used throughout the
discussion of psychological evidence on schizophrenia, in
Chapters 7-10, to avoid strong emphasis on some of the highlevel psychological concepts used to “explain” psychological
findings. These concepts include the distinction between
automatic and controlled processing (often used in
considerations of semantic priming and negative priming), the
“central executive” (envisaged to be in charge of attentional
shift), and to some extent the broad concept of “working
memory”. This strategy is deliberate: The most powerful
scientific explanations are “cross-level”, not “within-level”
ones. Psychological evidence is crucial to understanding
schizophrenia, but it should be explained in terms of neural
dynamics, not in terms of psychological concepts which,
through constant use become familiar, and appear “solid” and
“reified”. Such concepts become really solid, not by constant
use, but by their being translated, accurately and in detail into
neurobiological terms. At this point, rigorous cross-level
explanations will have been constructed.
2.12.
Axonal
electrophysiology
schizophrenia.
conduction
time,
and
and functional imaging in
The strategy adopted in presenting psychological evidence
in Chapters 7-10 was mainly to present evidence, and then to
show how it fitted (or failed to fit) the central hypothesis for
traits of schizophrenia. However, since that lengthy discussion
was fairly successful in supporting that hypothesis, a change
of strategy is adopted in presenting the biological evidence in
Chapters 11 and 12: Predictions from the hypothesis are
usually made first, to be explicitly tested as the empirical
evidence is reviewed.
43
2.12.1.
The spontaneous EEG in schizophrenia.
In the theoretical introduction to the topic of the EEG in
schizophrenia, two themes underlying the normal waking
EEG are described. First, the cortex is bistable: There are
periods of “idling activity”(classic alpha rhythm), when
neurons are hyperpolarized for most of the time, and when
little active information processing is occurring. At other
times the cortex is “desynchronized”, when many neurons
have their membrane potential poised just below threshold for
firing, cell assemblies are easily ignited, and active chains of
neuronal firing may occur. Axonal conduction time in corticocortical axons has little relevance for the classic alpha rhythm,
but the transition to the desynchronized state and the dynamic
interactions in that state are influenced by conduction times.
Specifically, in a cortex with a rich repertoire of delays lines,
and hence with wide temporal dispersion of any phasic signal,
it is difficult, in the idling state, to activate the cortex to the
point where reverberatory activity occurs; but when this level
of activity is reached, in the desynchronized state,
reverberatory activity is sustained longer than in a cortex with
more rapid axonal conduction, and less temporal dispersion.
Metaphorically one could say that the hemispheres in
schizophrenia have greater “inertia” than in the normal case,
but once activated have greater “momentum”. From this it is
predicted that in schizophrenia, especially when the cortex is
in a state of arousal, the proportion of time spent in the
desynchronized state will be higher than in the normal
hemispheres. In power spectral analyses, this would
correspond to reduced alpha power and increased beta power.
The
arguments
here,
framed
in
terms
of
electrophysiological variables, are a close counterpart of those
framed in Sect. 9.6.9.6. (summary in 2.10.6.3.), to account for
“persistence of set” in attention-shift paradigms. Moreover, it
is important for understanding the transition to psychosis to
remember that the midbrain dopamine neurons are under
cortical control. Whether expressed in terms of physiological
or psychological measures, periods of reverberatory activity in
the cortex which are more prolonged than normal are the
necessary precursor for the acceleration of firing of midbrain
dopamine neurons. This in turn is the immediate trigger for
destabilization to episodes of active psychosis. The additional
prediction is therefore made that the increased duration of
periods of EEG desynchronization (and, as a less direct
measure, the increase in beta power in power spectral
analyses) should be associated with the unmedicated state and
states of active psychosis.
The second theme refers to the details of the
“desynchronized” state: This is not strictly desynchronized
because it contains low amplitude activity in the beta and
gamma bands. In addition, accumulating evidence has
recently shown that the active cortex generates activity in the
alpha band, related to concurrent information processing,
though this is very different from the classic alpha rhythm.
There is also evidence that there is an inverse relation between
the frequency of EEG activity (ranging from gamma to alpha)
during information processing, and the distance over which
inter-cortical interactions are occurring. This is plausibly
explained in terms of the conduction delays in cortico-cortical
axons during inter-cortical interactions over various distances.
Given this, and assuming that in schizophrenia there is a shift
Conclusions: The Concept of Schizophrenia
to slower transcortical transmission, the prediction for
schizophrenia is clear: Gamma activity should occur more
rarely and be more difficult to detect with scalp electrodes
than in the normal case. At the slower end of the range of
frequencies generated by the active cortex, activity should
appear not only at alpha frequencies but also in the theta band,
or even at lower frequencies.
Empirical evidence supports all the above predictions.
Alpha power in power spectral analyses is generally reduced
in schizophrenia (11.2.3.1.), and beta power is increased
(11.2.3.2.). The latter increase is particularly associated with
the unmedicated condition, shown both in group comparisons
and longitudinal ones. While most recent studies on this are
based solely on power spectra, a number of studies (mainly
from before the era when automated analysis was routine)
report the more specific finding that periods of
desynchronization are longer than normal in schizophrenia, or
occupy a larger proportion of recording time (11.2.3.6.).
It is also reported that gamma activity is more difficult to
detect in subjects with schizophrenia than in controls,
although such comparisons are based on EEG reactivity to
various task situations, rather than the spontaneous EEG
(11.2.3.5.). Theta and delta activity are more prominent than
in the normal case (11.2.3.3.), where these slow rhythms are
seldom seen in the waking EEG. These findings fit the
predictions made on the basis of neurodynamic theory.
A finding not predicted from the central hypothesis is that
the elevation of beta power in schizophrenia often occurs most
prominently in the left hemisphere (11.2.3.4.) although the
exact regions identified in this hemisphere differ between
studies. This evidence forms part of a small body of evidence
using other methods which does not fit with the simplified
version of the central hypothesis, captured by the phrase “two
left hemispheres”. Such evidence suggests that not all the
abnormalities in schizophrenia amount to loss of right
hemisphere-type functions.
Predictions from theory can also be made about the
coherence and phase relations between waveforms at
particular frequencies recorded simultaneously in different
hemispheric locations: Coherence should be lower than
normal in schizophrenia, and phase delays should be larger
(11.2.4.1). The available evidence (11.2.4.2.) does not provide
strong support for the prediction about coherence, although a
few recent studies provide promising hints, and the validity of
the reasoning is supported by the fact that the normal left
hemisphere has lower EEG coherence than the normal right
hemisphere. Evidence on EEG phase delays in schizophrenia
is very scanty, and does not yet permit any clear statement
about the predicted differences from normal.
2.12.2.
Levels of neural activity assessed by functional
imaging (rCBF, rCGU or BOLD).
Amongst psychophysiological indicators of cerebral
activity, much recent work has used the methods of functional
imaging, based on local measurement of regional cerebral
blood flow (rCBF), glucose utilization (rCGU) or blood
oxygen level differences (BOLD). These methods have
produced much new information, in both normal subjects and
a wide variety of clinical populations, establishing
correlations between these measures of cerebral activity and
many psychological variables. However, these methods, while
providing high spatial resolution, have much coarser temporal
resolution than the EEG. Moreover, elucidation of the exact
neural basis of the signals used in such functional imaging is
at an early stage, so that the relative role of excitation vs
inhibition is unclear. It is also unclear if large signals in a
particular region indicate that this region is performing its
special function well, or, alternatively is over-activated
because it is forced to perform a task for which it is ill suited.
Given these limitations, it is difficult to use the correlative
data obtained with these methods for true explanations in
neurodynamic terms. Therefore not much of the evidence
using functional imaging methods in schizophrenia is dealt
with in this book. However, in one area, where predictions for
functional imaging measures in the resting cortex are a close
parallel to those in the spontaneous EEG, a brief review is
included,
The coverage of this evidence is limited to studies which
report actual resting blood flow or glucose utilization
measures (rather than measures normalized in various ways).
A variety of results are reported, including both increases and
decreases above normal levels of resting cerebral activity. The
evidence becomes more comprehensible when medication
status and symptom profile are taken into account.
Unmedicated patients have higher levels of cerebral activation
than medicated ones, the former usually above normal levels
the latter usually below normal. In addition, these measures of
cerebral activation are usually positively correlated with
positive symptoms and negatively correlated with negative
ones. These findings are similar to those obtained with EEG
measures, where increased EEG desynchronization is
correlated with positive symptoms or the unmedicated state.
Therefore the functional imaging studies broadly support the
theory developed in this book. Another popular hypothesis
has suggested that schizophrenia is characterized by
“hypofrontality” - a relatively low level of cerebral activation
in the frontal lobes. However, this is not supported in the
foregoing meta-analysis, for either medicated or unmedicated
patients: Group differences, when found, are found equally in
all regions of the hemispheres, although the large number of
studies in frontal regions obscures this conclusion.
2.12.3.
Evoked
schizophrenia.
and
event-related
potentials
in
2.12.3.1. Latency and amplitude.
When brief stimuli are given in major sensory modalities,
a regular series of electrical waveforms - evoked potentials, or
EPs - are produced. Those with latencies more than ~30 msec
are of cortical origin. Because these waveforms tend to be
obscured by spontaneous EEG waveforms in single traces,
they are often studied after stimulus-locked averaging of
many traces. However, this method of analysis makes it
impossible to explore an alternative interpretation of EPs,
namely that they are themselves a manifestation of the
spontaneous EEG, emerging as distinct waveforms in
averaged traces because their phase is reset by the stimulus, to
give stimulus-locked waveforms. Hence other methods of
analysis have been devised, including frequency-filtering of
individual traces followed by frequency-selective averaging.
44
Conclusions: The Concept of Schizophrenia
These two approaches to analysis of EPs may be
complementary, so that predictions from neurodynamic
principles using either approach do not contradict one another.
These predictions concern latency and amplitude of the EP
components. Assuming that the response components
revealed by averaging are substantial realities, their latency is
determined in part by conduction time in cortico-cortical
axons. It would then be predicted from the central hypothesis
about schizophrenia that latency should generally be longer
than normal. If one makes the alternative assumption that EPs
arise from phase resetting of the spontaneous EEG, there is a
delay between the stimulus and the time of phase-resetting,
again determined in part by conduction time in corticocortical axons. Thus the same prediction would be reached
that, in schizophrenia, the potential emerging from averaging
would have a longer than normal latency. However, the
latency of EP components in averaged traces varies
considerably between subjects. If EP components are defined
using latency criteria, this may prevent group differences in
latency being detected. The prediction can be better tested if
EP components are defined by their intrinsic morphology
rather than by latency criteria.
Predictions about amplitude are as follows: If conduction
times in cortico-cortical axons are extended, and signal
transmission in a population of axons is therefore subject to
greater temporal dispersion, post-synaptic summation at the
site of EP generation would be reduced and so the EP
components should be reduced in amplitude. If one adopts the
assumption that EP components arise from phase-resetting,
the impact of the stimulus would still undergo temporal
dispersion in schizophrenia. Its influence on spontaneous EEG
rhythms would then be less than in the normal case, so that
the degree of phase-resetting would be reduced. Again one
reaches the conclusion that amplitude should be reduced in
schizophrenia.
There is a complications to these predictions. Within 100
msec of a stimulus, direct transmission can spread its
influence to any part of the hemispheres. Thus EP components
longer than this probably reflect back-and-forth interplay,
rather than direct transmission. Therefore the predictions are
limited to EP components between ~30 and ~100 msec (“midlatency EPs”).
Does the empirical evidence support these predictions?
Most studies on mid-latency EPs (notably auditory P50 and
N100 potentials) fail to document a latency prolongation in
schizophrenia. However, this result is suspect, since latency
criteria are used to define the EP components in most studies.
In a single study where these EP components are defined by
criteria independent of latency, the measured latency is found
to be substantially prolonged in schizophrenia. More such
studies are needed. The predicted amplitude reduction is
however supported by many studies of both the auditory P50
and auditory N100 potentials.
2.12.3.2. Interhemispheric transmission time.
There is one electrophysiological test of the central
hypothesis for schizophrenia based on latency measures,
which is not confounded by the use of latency criteria to
define the response component. This is the measure of interhemispheric transmission time (IHTT). The central hypothesis
45
for schizophrenia predicts that this should be longer than
normal. The corresponding hypothesis for normal cerebral
asymmetry also has a clear prediction: Since callosal fibres
are really a subset of the long cortico-cortical axonal
projections arising in one or other hemisphere, one would
predict that transmission from right to left would be faster
than that from left to right. This prediction for directional
asymmetry of callosal transmission in the normal brain is now
well supported. Earlier estimates of callosal transmission
times were based on RT measures, comparing crossed with
uncrossed reactions. Although the data available with this
method are rather variable, it is clear that when directional
asymmetry is present, it always points to faster right-to-left
than left-to-right transmission. Use of EP components
provides a more reliable test of our hypotheses. Comparing
the peak latency of EP components contralateral to a stimulus
(the direct response) and ipsilateral to it (the indirect or
transcallosal response) it is shown consistently in normal
subjects, that transmission from right-to-left is significantly
faster than from left-to-right. Two studies compare IHTT
between normal subjects and those with schizophrenia, using
EP components. Both find longer IHTT in the patient groups.
One of these studies shows that left-to-right transmission (the
slower direction in normal subjects) differs little between
groups, but right-to-left transmission is slowed in
schizophrenia. This fits well the concept that in schizophrenia
the right hemisphere becomes more like the normal left
hemisphere. This study also illustrates (but does not
systematically analyze) another effect predictable from
theory: The decrement in amplitude in transmission from
contralateral to ipsilateral appears to be greater in
schizophrenia than normal. This is predicted on the basis of
greater-than-normal temporal dispersion of signals during
transcallosal relay in schizophrenia. This method of analysis
has rarely been applied, and might provide further critical
tests of the central hypothesis for schizophrenia.
2.12.3.3. Paired-stimulus paradigms.
Another way in which electrophysiological evidence can
be used to evaluate the central hypothesis for schizophrenia is
in the patterns of response to pairs of stimuli closely spaced in
time. In principle the response to a second stimulus can differ
from that to the first, or to a single isolated stimulus in either
of two ways: It may be smaller than the first (suppression) or
it may be larger (potentiation). Either effect is a function of
the repertoire of delays in cortico-cortical axons (11.3.4.1.). If
cortical relays leading to generation of the EP to the first
stimulus are rapidly conducting, with little temporal
dispersion, rebound inhibition will be strong. While that
inhibition lasts, the response to a second stimulus will be
suppressed. For cortical relays which are slower conducting,
with substantial temporal dispersion, the late subthreshold
influence of the first stimulus, relayed along the slowestconducting members of the axonal population may summate
with the early response to the second stimulus, relayed along
the most rapidly-conducting axons. Provided the two stimuli
are close enough in time for such summation to occur, it will
be manifest as paired stimulus potentiation. Which of these
two effects occurs depends not only on conduction velocity,
but also on conduction distance. For short distances, where
Conclusions: The Concept of Schizophrenia
there is little opportunity for temporal dispersion of signals,
paired-stimulus suppression will tend to occur (ceteris
paribus), while for longer distance, paired stimulus
potentiation will be favored.
The predictions for schizophrenia (11.3.4.1.), based on the
central premise (a relative absence of rapidly conducting
cortico-cortical axons) are as follows: Under conditions where
normal subjects show strong suppression, subjects with
schizophrenia will show reduced suppression. This follows
since there will be greater temporal dispersion in the relays
generating the response to the first stimulus, with the result
that its amplitude will be below normal and rebound
inhibition less potent than in the normal case. Under
conditions where normal subjects show potentiation, there
may appear greater than normal potentiation. This would
occur if, amongst the population of axons carrying the signal
from the first stimulus, the proportion with exceedingly slow
velocity was larger than normal. There would then be greater
than normal summation of the effects of signals in these axons
with those produced by the second stimulus.
Empirically, in normal subjects, paired stimulus
suppression is well documented, most commonly for the
auditory P50 potential, but also for the auditory N100
potential. In agreement with predictions, in schizophrenia the
amplitude of the response to the first stimulus is below
normal, and the degree of suppression of the response to the
second is substantially reduced (11.3.4.2.). Paired stimulus
potentiation has also been described, for the N100 potential
(11.3.4.5.), though it requires special settings of stimulus
duration and interstimulus interval. Also in agreement with
predictions, for the longer interstimulus intervals where
potentiation can be detected in normal subjects, it can be
greater than normal in schizophrenia. It is also notable, and in
accord with the model just described, that the reduction of
suppression is best documented for the P50 potential which is
generated after relatively short-distance relay from the
primary auditory cortex, whereas the potentiation effect is
seen for the N100 potential, where longer distances are
involved in relay from the primary auditory cortex.
2.12.3.4. Event-related potentials in oddball paradigms.
A simple, but much-used paradigm in clinical
electrophysiology involves comparison of averaged potential
responses to “standard” stimuli in a series, with those to
stimuli which are “deviant” in some way, interspersed among
the “standards”. Some electrographic responses to the deviant
(“oddball”) stimuli are larger than those to the standards.
Early potential components showing such behavior in oddball
designs exhibit enhanced negativity (“mismatch negativity” or
MMN), which is found regardless of focused attention on the
stimuli. A longer latency component - the P300 potential - is
manifest as enhanced positivity to oddballs, this being found
only with attentional focus on the stimuli.
The latency of MMN potentials varies in differing
circumstances, but, the shortest latency examples (seen in
animal experiments with indwelling electrodes) are too early
to involve interaction between different cortical regions.
Longer-latency examples (typically studied in humans) do
implicate relay between distant cortical regions. It is likely
that there are local circuits at every locality in the cerebral
cortex which detect deviant stimuli in that locus, by
comparison with a “template” of familiar “standard” stimuli.
This comparison is probably achieved by inhibitory feedback
in each locus, from the representation of the template to
earlier stages of cortical processing. Deviant stimuli are not
recognized by this template, produce less feedback inhibition,
and therefore produce larger responses. As a result, impulse
traffic around the cortex generally gives emphasis to signal
patterns which are novel or unusual.
While there is no reason to suppose that the local processes
of oddball detection are influenced much by conduction time
in cortico-cortical pathways, the relay between distant regions
will be. If rapidly conducting axons are replaced by more
slowly-conducting ones, there will be greater-than-normal
temporal dispersion of signals in a pathway, with loss of
temporal summation at the destination. The result is that the
strength of the “template”, representing what is familiar,
formed in a non-primary area, will be reduced. Hence the
feedback inhibition associated with standard stimuli would be
attenuated. The consequence is that the difference between
responses to standard stimuli (where feedback inhibition is
recruited) and that to deviant ones (where it is not) would be
smaller than normal. This difference - the MMN potential should thus be smaller than normal in schizophrenia. It is also
predicted that the latency of this potential should be greater
than normal. These predictions are largely supported by
empirical evidence, although the predicted increase of latency
is found only when a wide latency range is used as the
defining criterion for the MMN. The reduction in amplitude is
found in both medicated and unmedicated patients, and
appears to be a trait characteristic, rather than an aspect of the
psychotic state.
The P300 potential, as expected from its long latency,
arises from generators widespread throughout the neocortex.
In addition. similar enhancement of averaged potentials to
oddball stimuli in attended conditions are produced in the
hippocampal formation. The latter contribute little to scalprecorded potentials, but nevertheless may control, or be
controlled by, the generators of scalp potentials. While P300
potentials are generally studied in humans, the circumstances
in which they are produced are rather similar to those which
elicit the hippocampal theta rhythm in experimental animals.
In such animals, the P300-like potential recorded in the
hippocampus is in fact a single waveform at the theta
frequency. Accumulating evidence shows that the
hippocampus can engage in rhythmic interplay at the theta
frequency with the neocortex, employing long axonal delay
lines between the two structures. The neocortex itself shows
little evidence of rhythmic theta activity, presumably because
of temporal dispersion of signals generated in the
hippocampus, as they influence the neocortex. There is only a
little evidence on hippocampal theta activity in humans, but
what there is indicates that, in the circumstances in which
P300 potentials are elicited, the hippocampus produces only a
short burst of two or three theta-frequency waveforms,
dominated by just a single such waveform. It is suggested that
temporal dispersion in hippocampo-neocortical relays would
“smear” this waveform in the time dimension, the result being
the broad waveform obtained with scalp electrodes, otherwise
known as the P300 potential. With this as a basis, three
46
Conclusions: The Concept of Schizophrenia
predictions about P300 potentials can be made for
schizophrenia, based on the hypothesized replacement of
rapidly conducting axons by more slowly-conducting ones in
hippocampo-neocortical relays: First, the latency should be
longer than normal. Second, the amplitude should be reduced,
this being evident even in single traces (i.e. not simply a
byproduct of averaging of waveforms which are less-thannormally synchronized). Third, because there would be
greater-than-normal temporal “smearing” in schizophrenia,
the P300 waveform should be extended more broadly in time
than in normal subjects.
The first two predictions are supported by abundant
empirical evidence. The reduction in amplitude is seen in both
averaged and single traces. In averaged traces the reduction is
due partly to greater latency variability, but the reduction in
single traces corresponds well to predictions. Medication
status, whether studied in cross-sectional or longitudinal
designs, has little effect on the differences between
schizophrenia and control groups. The reductions in amplitude
and prolongation of latency appear to be true traits. These
abnormalities are not related to other prevailing cognitive
abnormalities, such as increased RT variability, or decreased
vigilance, and so probably derive from more fundamental
aspects of schizophrenia. No published data are available with
which to evaluate the third prediction, that the P300 waveform
should be more extended in time. A further finding, made in
several studies, which goes beyond the immediate predictions
of the “central hypothesis”, is that P300 amplitude reduction
in schizophrenia is more marked on the left than the right side,
especially in the posterior temporal region. In Sect. 2.7.2. (and
7.3.4.) theoretical arguments were developed to show how
loss of rapidly conducting axons in projections passing
between Wernicke’s and Broca’s area could produce a
tendency to verbal auditory hallucinations. It would therefore
be interesting to know whether this unexpected abnormal
asymmetry of P300 potentials correlates with such symptoms.
This question has not yet been adequately explored.
Various symptom correlates of P300 potentials have been
documented: Significant associations with positive symptoms
are rarely reported, while the majority of reports on negative
symptoms do find an association. Strikingly, almost all studies
reporting on the relation between P300 abnormalities and
thought disorder find a positive correlation. This is to be
expected from theory developed here, since the P300 potential
is produced in conditions of focused attention, during which
overall cortical activity levels will be high. Following the
same reasoning, one would expected the reduction in MMN
amplitude to correlate mainly with negative symptoms, since
this ERP is produced regardless of focused attention. The few
studies reporting on symptom correlates of reduced MMN do
show this, although the subject has not been studied
sufficiently to exclude a correlation with thought disorder (not
expected from the same reasoning).
2.13.
Schizophrenia and brain morphology.
The earliest investigations of brain morphology in
schizophrenia date from a time shortly after Kraepelin defined
the concept of “dementia praecox” (12.1.). These studies
made several findings which have been greatly amplified by
more recent work. In the middle years of the twentieth century
47
studies using post-mortem brain produced quite inconsistent
results. They were however supplemented by the technique
called pneumo-encephalography (PEG) which allowed in vivo
visualization of cerebral ventricles. This has now been
superceded by brain scanning using computerized tomography
(CT) and magnetic resonance imaging (MRI)(12.2.1.),
although several findings on gross brain morphology were
first made using PEG. Modern uses of MRI allow estimates of
the volume of the brain and its several regions to be made.
The success of these methods has led to a renewal of interest
in studies of post-mortem brain, which have produced more
reliable findings than in early work, at the level of both gross
and microscopic morphology. An additional approach
involves use of signal characteristics in CT and MRI to infer
tissue characteristics. All these approaches to study of brain
morphology in schizophrenia are surveyed in Chapter 12.
2.13.1.
Volumes of cerebral and cranial structures.
The volumes of the lateral and third ventricles and the
external fluid spaces are all increased in schizophrenia
(12.2.2.). Volume increase of the lateral ventricles is best
documented, but is small quantitatively compared to the
volume increase in external fluid spaces.
Whole brain volume (WBV)(and combined hemispheric
volume)(12.2.3.) is decreased in schizophrenia by ~3% (~35
cc), the effect being very similar in male and female patients,
although in both control and schizophrenia groups volume is
larger in male than female by 13-15%. These volume
reductions are similar in left and right hemispheres, taking the
hemispheres as a whole. However there are hints from the size
and shape of the hemispheres that, in normal subjects,
individual lobes are asymmetrical, the right side being larger
in frontal and temporal lobes, the left being larger in parietooccipital lobes. In schizophrenia these asymmetries tend to be
reduced (12.2.6.).
Intracranial volume (ICV) is also reduced in schizophrenia
(12.2.4.), but, in absolute terms, the volume reduction is less
than 50% of that in the brain contained within the cranium.
The difference in these two volume deficits is accounted for
by the fact that ventricular and external fluid volume is larger
than normal in schizophrenia. This implies that reduction in
brain growth in schizophrenia occurs partly before, and partly
after cranial size is finalized (at age about 10 years), and
probably occurs progressively from infancy to adulthood
(12.2.5.).
From study of cases of schizophrenia with childhood or
adolescent onset (12.2.5.), it is likely that, during adolescence,
the fluid spaces expand more and brain parenchyma may even
reduce, in schizophrenia compared to age-matched controls.
This suggests that the volume expansion which normally
occurs in childhood and adolescence is reduced as a precursor
to emergence of schizophrenia. This probably reflects a
combination of normal reduction in GM due to synaptic and
axonal pruning, combined with less-than-normal expansion of
white matter (WhM). Since expansion of WhM in childhood
and adolescence is normally largely due to myelination, a
plausible hypothesis for schizophrenia is that myelination
occurs more slowly and less completely than normal.
In each of the individual lobes, volume reduction is found
in schizophrenia, as expected from the reduction in WBV
Conclusions: The Concept of Schizophrenia
(12.2.7.). There is a tendency in the frontal lobe and a
suggestion of one in the temporal lobe, for reduction to be
greater on right than left side, and in parieto-occipital lobes
(on the basis of rather few studies) reduction appears to be
greater on left than right. Possibly across all lobes, normal
asymmetry is reduced or reversed in schizophrenia, although,
in the data sets available, the interaction between diagnosis
and asymmetry does not reach statistical significance.
It has been difficult to estimate the relative contribution of
grey matter (GM ) vs white matter (WhM) reduction to the
overall reduction of brain tissue in schizophrenia. There are
substantial methodological problems, related to signal
thresholding in MRI studies, which make accurate estimation
of the volume of each tissue type difficult (12.2.8.). Many
MRI studies have reported GM volume deficits. It has been
less clear whether there are also deficits in WhM volume, but
this may reflect a type II error, since coefficients of variation
for WhM volume estimates are generally larger than for GM,
so that statistical significance is harder to achieve in a single
study. Meta-analyses over many studies confirm the GM
volume deficit (of ~3% across both hemispheres)(12.2.8.2.).
This is associated with reduction of cortical thickness
(12.2.8.6.) rather than area. Meta-analyses also find a deficit
of similar proportion for WhM (12.2.8.2.). Other approaches
(reduction of the “radius of gyration” [12.2.8.2.]; reduction of
the “gyrification index” [12.2.8.3]; reduction of the crosssection area of the corpus callosum [12.2.8.4.]; voxel-based
morphometry [12.2.8.5.]) support the view that the volume of
WhM as well as that of GM is reduced in schizophrenia. In
individual lobes there is also reduction of both tissue types
(12.2.8.7.). In frontal lobe, GM and WhM are reduced to
similar extents (~5%). In the temporal lobe GM appears to be
reduced more than WhM (4.6% vs 2.2%), while, from the
limited data available on the parieto-occipital lobes, GM
reduction (2.8%) is less than that of WhM (5.4%). This could
signify that WhM deficit in the frontal lobe is due to reduction
of mean axon calibre in both incoming and outgoing fibers,
while that in the temporal lobe is mainly due to reduction in
outgoing fibers and that in parieto-occipital lobes is due to
reduction in incoming fibers (see 12.3.2.). The stage of
development when these volume deficits arise is not well
documented, especially for GM. However there is some
evidence that progressive expansion of WhM occurs to lessthan-normal extent in schizophrenia, in early adulthood, and
perhaps earlier (12.2.8.9.).
Study of volume deficits in localized regions of cortical
GM (12.2.8.9.) has shown that volume reduction in
schizophrenia is not uniform across the neocortex, the
percentage deficit being largest in the frontal lobe (especially
its inferior parts) and the left superior temporal region. Other
structures of the medial temporal lobe (amygdala,
parahippocampal gyrus, and perhaps the hippocampus) also
show large percentage reductions. However, the volume
reduction in these structures does not account for the whole
deficit in WBV. Primary sensory areas and the primary motor
area, and most other cortical region show lesser volume
reductions, although data is limited for many such regions.
There is also a volume reduction in subcortical structures
(thalamus and probably the caudate nucleus)(12.2.9.). The
evidence on regional volume reduction does not support a
strictly localizationist view of cerebral abnormality in
schizophrenia. A regional approach to defining WhM volume
reduction is not possible, since this tissue has no clear
regional boundaries in MRI.
Correlation between different volume measures (12.2.11.)
reveals two significant features of the volume changes in
schizophrenia. First, the decrease in WBV is correlated
negatively with increase in ventricular spaces. Increase of
ventricular volume may thus be developmentally related to
reduction of brain parenchyma. Second, a correlation between
volumes of frontal and temporal lobes, found in normal
subjects, is lacking in schizophrenia. It has been suggested
that there is relative fronto-temporal dissociation in
schizophrenia, perhaps due to lack of mutual or common
trophic influences.
2.13.2.
Microscopic studies of post-mortem brain tissue.
From the “central hypothesis”, that in schizophrenia there
is a relative absence of rapidly-conducting cortico-cortical
axons, predictions can be made for cytology of both WhM
and GM (12.3.). For WhM one would expect a reduction in
the proportion of large caliber or myelinated axons, and an
increase in axonal packing density, compared to normal
WhM, differences which would explain the overall volume
deficits for WhM. Evidence on these predictions (12.3.1.) is
scanty and inconsistent, partly because unmyelinated axons
can only be identified using electron microscopy in well fixed
tissue, and this is not possible for human tissues. The best
stereological study, that of Marner and Pakkenberg (2003)
produces data implying higher than normal axonal packing
density in schizophrenia. Total axonal length in the
hemispheres in schizophrenia was 6% below normal, a nonsignificant difference. From this, and the volume reduction for
WhM, it might be concluded that mean axonal caliber is
reduced. However, since unmyelinated axons are not
considered, and since coefficients of variation for all estimates
are large, it is not possible to use the data in this study for
precise theoretical reasoning. Nevertheless, evidence of a
different sort - showing reduced numbers of oligodendrocytes,
which are involved in producing myelin sheaths - gives
support to the idea that myelination is reduced in
schizophrenia (12.3.3.).
Predictions about GM are less direct. However, since it is
generally true that the size of neuronal somata and their
dendritic trees are proportional to the amount of axoplasm the
neuron has to support, one would expect reductions in these
measures, in parallel with a reduction in large caliber or
myelinated axons. There is substantial evidence that neuronal
soma size is reduced in schizophrenia in many (but not all)
cortical areas (12.3.2.). These reductions occur most
prominently in areas where overall GM volume reduction is
most marked, and are of a magnitude which could explain
such volume reductions.
There have also been several reports that the number of
dendritic spines on cortical pyramidal cells is reduced in
schizophrenia (12.3.2.). It is less clear that this represents a
stable feature of cytology, since in normal animals many
transient influences can modify the number of such spines.
There have also been suggestions that numbers of inhibitory
interneurons in the cortex are reduced in schizophrenia
48
Conclusions: The Concept of Schizophrenia
(12.3.2.), but not all studies show this, and some related
results can be explained as a dynamic consequence of other
functional abnormalities rather than a fundamental cytological
difference from normal.
2.13.3.
Characteristics of brain tissue revealed from
signals used in brain scanning.
Attenuation by biological tissues of the X-rays used in
computerized tomography is determined by atomic
composition of the tissues (12.5.1.1.). In brain tissue,
attenuation is greater in GM than myelinated WhM, with
unmyelinated WhM giving intermediate degrees of
attenuation. Quantitative comparisons of attenuation by brain
tissue between sides and groups is made difficult by several
artifacts, especially “beam hardening” by the skull.
Nevertheless, there is consistent evidence that attenuation in
WhM is greater than normal in schizophrenia (12.5.1.2.), and
some studies find this to be correlated with enlargement of
ventricles or reduction of volume of brain parenchyma
(12.5.1.3.). These results would be expected if myelinated
WhM was partially replaced by unmyelinated WhM, with
resulting reduction of tissue volume.
The signals used for MR imaging distinguish between
tissues on the basis of their water content, and thus can
separate WhM from GM, due to the lower water content of
the former (12.5.2.1.). Unmyelinated WhM has a higher water
content than myelinated WhM, and therefore is more like
GM. Most studies which have compared WhM between
normal subjects and those with schizophrenia find the latter to
have signal characteristics to be expected of reduced
myelination (12.5.2.3.), although the regions in which group
differences are seen vary greatly between studies.
An elaboration of conventional MRI - magnetization
transfer imaging (MTI) - makes use of the fact that myelinassociated water has special properties in MR, so that
estimates can be made of the abundance of myelin-associated
water, and therefore of myelin (12.5.3.). When this method is
used to compare normal subjects and those with
schizophrenia, the latter give evidence of reduced myelination
in WhM, although again, there is wide variation between
studies in the regions where group differences are found.
Another method using MRI technology is diffusion tensor
imaging (DTI) (12.5.4.). This method measures rates of
diffusion of water, in a directionally-selective manner. In pure
water, diffusion is the same in all directions, and in GM the
same is true, because there is no preferred direction for
cellular processes (although overall rates of diffusion are less
than in water). In WhM, diffusion has directional biases (that
is, it is “anisotropic”), as a result of the tendency to coherent
bundling of axons running in parallel. In DTI, the degree of
anisotropy is assessed in each voxel (~1 mm3). In
schizophrenia, anisotropy in WhM has been found to be less
than in normal subjects, although the group differences are
found in different regions in different studies (12.5.4.2.). The
explanation of this finding has been debated. It is suggested
here (12.5.4.1.) that WhM in which mean axonal caliber is
small will produce WhM which is more “finely woven” than
if the axons are of larger caliber. As a result, it will be more
likely that axons running is a variety of directions will be
49
integrated within each voxel, so that, overall, observed
anisotropy will be less than in the normal case.
2.13.4.
“Best quantitative estimate” of the extent of WhM
changes in schizophrenia.
In Sect. 11.3.4.5., dealing with paired-stimulus
potentiation of the N100 potential, it was possible to make a
tentative reconstruction of the axonal conduction time
histograms needed to produce the observed results in normal
subjects and in those with schizophrenia. This led to the
estimate that in normal subjects the relevant pathway had 70%
of axons with conduction velocity above 1 m/sec, the
remainder below 1 m/sec. In schizophrenia, the respective
figures were about 50% and 50%. We can then make
assumptions which permit us to estimate the extent of volume
loss in hemispheric WhM (12.6.). We assume that the division
between conduction velocities above and below 1 m/sec
corresponds roughly to that between myelinated and
unmyelinated axons; that the latter have a cross-section area
approximately one fifth that of the former; and that axons
comprise about 33% of the total volume of WhM (the rest
being made up of glial cells, blood vessels, extracellular space
etc). As a result the fractional reduction in WhM volume in
schizophrenia would be about 7%. This figure is somewhat
larger than observed empirically. The discrepancy may be
accounted for if one assumes that part of the WhM volume is
made up of large caliber axons (e.g. those descending to
spinal cord and brain stem, and ascending from the thalamus),
which are unaffected in schizophrenia. If these made up a
significant volume fraction of WhM, the volume reduction in
schizophrenia would be less than 7%, as found empirically.
2.13.5.
Processes contributing to changes of volume of
brain tissue in schizophrenia.
In Sect. 12.2.5., the developmental origin to the volume
changes in schizophrenia are discussed. It is suggested that the
normal process of GM volume reduction occurs normally, but
expansion of WhM, due to myelination is less than normal.
Thus the expansion of WhM does not keep pace with GM
volume reduction. This process is considered to be in
operation throughout adolescence, and to a lesser extent in
early adult years, and therefore in some cases even after onset
of the manifest illness. However, additional processes are
required to give a full account of the differences in volume of
brain tissue between normal subjects and those with
schizophrenia (12.7.). Reductions of brain volume (or
alternatively, increases in fluid space volume) occur after
onset of illness (12.7.2.). The most parsimonious explanation
of most of this evidence is that tissue, perhaps in specific
brain regions, may have increased blood flow, associated with
increases in neural activity during active psychosis, and this
produces a slight, but detectable volume increase. After
treatment and remission of symptoms, blood flow decreases,
and so does tissue volume (12.7.1., 12.7.3.). In the past, such
volume changes have been attributed, by this author and
others to a “lesion” (i.e. cell loss) occurring in relation to
active psychosis. However, this suggestion is not necessary:
The two processes just mentioned, acting together can account
for evidence available on early stages of the manifest illness,
and there is no cytological evidence for cell loss. In later
Conclusions: The Concept of Schizophrenia
stages of the illness, reduction of tissue volume may occur to
a greater-than-normal extent in schizophrenia (12.7.4.). This is
unlikely to be the cause of the disorder, but may be a
secondary consequence of the persistent disturbance in brain
dynamics the disorder produces.
2.13.6.
Correlations between morphological abnormality
and symptom groups.
Many studies explore possible correlations between brain
morphology and symptoms groups in schizophrenia (12.8.).
Non-significant findings are common and may have many
explanations other than lack of causal relation between the
variables. Focusing on significant correlations, it is an almost
universal finding that negative symptoms are associated with
expansion of ventricles or reduction of volume of brain tissue.
This is to be expected from theory, if negative symptoms are
the clinical expression of the stable underlying traits of
schizophrenia, since these morphological abnormalities are
also stable aspects of the brain. Positive symptoms have more
complex correlations with morphological variables.
Hallucinations, particularly auditory hallucinations which
persist in stabilized patients, are consistently associated with
reduction of brain tissue volume, especially in the left superior
temporal gyrus. Correlations in a similar direction are also
usually found for thought disorder or Schneiderian symptoms,
although more diverse in the morphological measures
involved. Volume reduction in STG is probably due in part to
reduced neuronal size, a likely indicator of reduced axonal
calibre or myelination in the axonal projections of these
neurons. Given this, the correlation with auditory
hallucinations supports the explanation of this symptom given
in Sect. 7.3.4. (summary in 2.7.2.). Correlations between brain
morphology and the symptom of delusions are more diverse,
some reports indicating positive correlation, others negative
correlation with reductions in tissue volume (or expansion of
ventricles). The diversity of results may be an indication that
two causal relations are implicated: On the one hand, the
tendency to experience delusions, like the tendency to
episodes of active psychosis, is an enduring trait, likely to be
associated with the cytological changes discussed above,
associated with volume reductions in GM and WhM. On the
other hand, during the actual episodes of active psychosis,
there may be detectable expansion of brain tissue, probably
due to increased blood flow.
2.13.7.
Genetic vs environmental determinants of brain
morphology in schizophrenia.
In normal subjects, twin studies have shown that some
aspects of brain morphology, such as WBV, and the form of
the deeper sulci, are under a high degree of genetic control
(12.9.1.2.). Other aspects, such as ventricular size, or form of
the superficial sulci are under lesser genetic control. Given
these findings as a background, one can ask to what extent the
deviations in morphology in schizophrenia are part of the
genetic diathesis for the disorder, or have some other origin.
Amongst the latter, there are significant non-genetic effects on
morphology which predispose to the disorder, but are not seen
in unaffected MZ co-twins (12.9.1.3.). Whether these
differences arise from non-shared environmental influences or
from essentially random processes during development is
unresolved. Genetic effects, unconfounded by either of these
would be seen in comparisons of unaffected MZ vs DZ cotwins of discordant pairs (12.9.1.4.). Only one study has used
this design, and has found volume deficits in GM, related to
the genetic predisposition for schizophrenia, in regions similar
to but not identical with those for non-genetic effects. Another
design which has shown unambiguous genetic effects
involves comparison of unaffected obligate carriers of
schizophrenia with non-carrier, non-affected relatives.
Few studies examine the influence of pre- and peri-natal
factors on brain morphology (12.9.2.), and it is not clear that
the effects described distinguish schizophrenia births from
births of unaffected subjects. However, recent studies have
succeeded in defining interactions between such factors and
genetic load (12.9.3.): Both fetal hypoxia and the genetic
loading for schizophrenia were needed to produce brain
morphological changes. A third influence - being born
premature or small for their gestational age - increased the
effect. Each of these, acting alone was not sufficient to
produce morphological change.
Human and animals studies have shown that the
progenitors of oligodendrocytes, responsible for cerebral
myelination, originate in the mid-trimester, well before
myelination starts, and at this stage are vulnerable to fetal
hypoxia (12.3.3.). Other studies in sheep (12.9.4.) show that
placental insufficiency or prolonged hypoxemia can be
followed by development of a cortex which is thinner than
normal, with increased neuronal density, and, in reduced
caliber and myelination of axons (at least in cranial nerves).
Such evidence provides hints of the way in which pre-natal
environmental problems may combine with genetic liability to
produce the brain abnormalities predisposing to
schizophrenia. It may be that the same developmental
trajectory starting in the mid-trimester can be set in motion by
either environmental or genetic influences, and especially a
combination of the two. There is no research investigating
whether psychosocial adversity predisposing to schizophrenic
psychoses has an influence on brain morphology.
2.13.8.
Brain morphology in disorders related to
schizophrenia.
There is little evidence from brain morphology that the
different disorders in the “schizophrenia spectrum” are
categorically separate (12.10.). For schizoaffective disorder,
the various forms of affective disorder, and personality
disorders related to schizophrenia, various volumetric
measures of the brain display changes from normal similar in
kind, but usually less in degree compared to those found in
schizophrenia. However, in the affective disorders, there is
some evidence that depression with psychotic features shows
greater morphological abnormality than that without such
features. The only hint of categorical separation between
affective disorder and schizophrenia is a small amount of
evidence that GM volumes in some cortical areas are larger
than normal in bipolar disorder, findings against the general
trend to volume reduction.
2.13.9.
Miscellaneous correlations of brain morphology.
The degree of abnormality of brain morphology is related
to various aspects of severity of schizophrenic disorder,
50
Conclusions: The Concept of Schizophrenia
including measures of premorbid adjustment, longer-term
outcome, and responsiveness to antipsychotic drugs. The
reduced responsiveness to medication in those with more
pronounced morphological abnormality probably reflects
slower response rather than categorical non-response.
Cognitive impairment, assessed by a wide variety of measures
is generally correlated with greater morphological
abnormality, but the complexity of this literature prevents its
being used for testing the “central hypothesis” of this book in
a precise way. Correlations with psychophysiological
measures have also been documented, but again contribute
little to theory development
51
Conclusions: The Concept of Schizophrenia
.
Chapter 13.
The concept of schizophrenia: neurodynamic consequences of delayed and incomplete
maturation of cerebral white matter.
13.1.
“Psychosis” vs
nearly-separate theories.
“schizophrenia”:
two
A crucial premise for this book is that the theory needed to
explain “psychotic” manifestations of schizophrenia is almost
completely separate from that needed for schizophrenia as a
whole. Psychosis does occur in schizophrenia, but is not
specific to schizophrenia. Moreover, most features of
psychosis are in principle parts of a transient state.
Admittedly, this statement needs to be qualified in three
ways: (i) Some psychotic symptoms, notably delusional
beliefs, may persist long after the active phase of psychosis
has abated. (ii) Schneiderian symptoms and auditory
hallucinations are often not completely controlled by
medication. (iii) In some patients, active psychotic states may
persist because they are medication-resistant. Despite these
qualifications, psychoses associated with schizophrenia are
usually episodic in the days of modern drug treatment.
Therefore psychotic symptoms should not be of predominant
importance in defining schizophrenia, which is an on-going
disorder when psychosis is under control.
Schizophrenia includes many enduring non-psychotic trait
abnormalities. These do not sharply differentiate normal
subjects from those with schizophrenia. They are present
before, during and after psychotic episodes, and are present
also in relatives of schizophrenia probands most of whom
never have psychotic episodes. Although they tend to be
inherited, this inheritance is not of the single factor variety,
but, as with schizophrenia itself, fits better a multi-factor type
of inheritance. Nevertheless, some of them show stronger
heritability than the diagnosis itself, presumably because
environmental factors contribute significantly to the cause of
the diagnosis, but less to individual traits. These traits may be
more important for definition of schizophrenia than are the
features of psychosis. This formulation is supported by the
fact that, in chronic schizophrenia, the traits defined by
experimental methods correlate with negative symptoms,
thought disorder (or both), but rarely with positive symptoms.
Thus, even when positive symptoms are present outside the
times of active psychosis, they appear to have a basis different
from that of negative symptoms and thought disorder. This is
consistent with the idea that some positive symptoms endure
as a memory or “cognitive habit”, first established during
earlier periods of active psychosis, and are not true traits.
13.2.
Explanation as the criterion
scientifically-valid concept of disease.
for
a
In Sect. 1.8., the guideline was suggested that “the
criterion for a scientifically-valid definition is that it will
support a comprehensive and rigorous explanatory argument”.
According to this principle, the concept of “dopaminemediated psychosis” in schizophrenia is strongly validated:
By extension to humans of psychobiological principles, wellestablished for the action of dopamine in animals, most of the
important features of schizophrenic psychoses can be
explained.
With regard to trait aspects of schizophrenia, many
measures show group differences from normal control groups.
However, none of them distinguishes schizophrenia from
either normal controls or a number of other disorders well
enough to support a valid definition of a concept of mental
disorder, if the argument is to be based just on statistics and
correlations. However, if we bear in mind the above guideline
(i.e., that definition depends on prior explanatory arguments),
the theoretical arguments presented in this book give
coherence to a concept of schizophrenia, although this
concept is in several ways not congruent with those embodied
in several widely-used diagnostic systems. The basic premise
of these theoretical arguments is that there is a relative
absence of rapidly-conducting cortico-cortical axons. This
premise is used to explain much evidence in the areas of
psychology, psychophysiology, clinical electrophysiology,
and brain morphology examined with both classical
neuropathological methods, and with modern methods of
brain scanning. Brain volume, and the volumes of both GM
and WhM in the hemispheres are reduced. However, there is
no evidence of a degenerative process, and very little for a
reduction in number of cortical neurons. Some studies of
brain development during adolescence in schizophrenia are
compatible with the idea that the normal process of
myelination of cortico-cortical axons occurring between birth
and adulthood is delayed and incomplete. The reduced
expansion of WhM volume combined with normal loss of
GM volume during adolescence accounts for the expansion of
fluid spaces and deficit in volume of brain parenchyma in
schizophrenia. Evidence from molecular genetics converges
with these lines of evidence, pointing to abnormalities in
myelination in schizophrenia. In normal subjects myelination
of cortico-cortical axons is still continuing in early adulthood,
and, in schizophrenia, the deficit in brain volume is still
increasing at this stage. This can account for volume loss after
the onset of psychotic illness, without postulating a psychosisrelated loss of tissue.
Normal female subjects have brain volumes 12-15% less
than in male subjects, a difference accounted for by lower
numbers of neurons in females, and there may be different
patterns of asymmetry in the two genders. In schizophrenia,
the same gender differences are present. Schizophrenia in
female subjects has a later age of onset than in males, and is
generally more benign, but this difference probably does not
have a basis in brain morphology. Probably it depends on the
protective effect of estrogens in females, acting to limit
psychotic decompensation.
52
Conclusions: The Concept of Schizophrenia
13.3.
The
schizophrenia,
laterality.
“central
hypothesis”
for
and that for normal cerebral
The central hypothesis for schizophrenia - a relative
absence of rapidly conducting cortico-cortical axons - is
closely related to a previous hypothesis for normal cerebral
asymmetry - that the left hemisphere has an abundance of
slowly conducting axons, the right a predominance of more
rapidly conducting ones. As a result the slogan “two left
hemispheres” captures many of the trait abnormalities in
schizophrenia, implying either a selective loss of right
hemisphere functions, or an exaggeration of left hemisphere
ones. However, the difference between normal and
schizophrenia (in either hemisphere) is considerably larger
than that between right and left hemisphere in normal
subjects. This can be seen not only for morphological
comparisons, but also in studies of visual and auditory
perception, where, although the right hemisphere is most
affected in schizophrenia, both hemispheres are impaired to
some degree. Impairment of the left hemisphere in auditory
threshold or vigilance tests is somewhat labile, depending on
such things as time of day, long testing sessions, or a
tendency to hallucinations. One possibility is that the more
easily excitable right hemisphere normally “boosts” left
hemisphere performance, but this boosting is prone to failure
in schizophrenia.
There are some facts which do not fit the “two left
hemispheres” formulation. People with schizophrenia may
have impairment in recognition of consonant speech sounds, a
left hemisphere-preferred function in normal subjects. In
dichotic listening studies, in accordance with the “two left
hemisphere” slogan, there is loss of asymmetry in
schizophrenia when the test is purely perceptual in nature.
However, when the test includes a short-term memory
component, asymmetry (left hemisphere superiority) is
increased. Likewise in one study of visuo-manual control the
right hand (left hemisphere) was found to be more impaired
than the left hand (right hemisphere). Amongst
electrophysiological findings, several measures reveal greater
abnormality on the left than the right side: Thus the excess of
power in the EEG beta frequency range is more prominent on
the left than the right side. The reduction of amplitude of the
P300 potential is more prominent on the left than the right
side, especially for posterior temporal derivations. In
morphological terms, volume reduction in the superior
temporal gyrus is more pronounced on the left than the right
side, a finding which correlates consistently with the
predisposition to verbal auditory hallucinations. To account
for some of these findings, a hypothesis, supplementary to the
main theory, is proposed. This assumes that in the normal left
hemisphere, projections from Broca’s to Wernicke’s areas are
unusually fast-conducting, this morphological specialization
mediating some of the normal left hemisphere’s facility with
language. In schizophrenia, in accord with the “central
hypothesis”, but not the simplifying slogan “two left
hemispheres”, there is a relative loss of rapidly-conducting
axons in this pathway, one of the consequences of which is a
predisposition to auditory verbal hallucinations. At present,
not all of the unexpected findings which contradict the
53
principle of “two left hemispheres” have been related to
occurrence of this sort of hallucination. Further correlational
studies are needed.
There are suggestions that in active psychosis in
schizophrenia, the pattern of abnormal asymmetry is different
from that during stable remission. However, no consistent
picture emerges. In some tests (e.g. tactile discrimination),
during active psychosis the left hemisphere is more impaired
than in remission, while in others the left hemisphere is less
impaired (e.g. in some auditory and visual tests) and the left
hemisphere advantage increases.
13.4.
The “deepest question”: the relation
between enduring traits and psychotic episodes in
schizophrenia.
The deepest question about schizophrenia is on the
relation between the two bodies of theory, namely that for
dopamine-mediated psychosis, and that for the enduring trait
abnormalities. This question can be translated into
neurodynamic terms: How can sustained over-activity of
midbrain dopamine neurons arise when the hemispheres are
connected by cortico-cortical connections with slower-thannormal conduction, allowing greater-than-normal temporal
divergence of signals? From analysis of the neurodynamic
basis of one area of psychological dysfunction (difficulty in
shift of attention), supplemented by more direct
electrographic evidence, it is possible to give an answer to
this question: In schizophrenia, assuming a relative
abundance of slowly-conducting axons, the hemispheres have
greater “inertia” than normal - that is, they require more
vigorous activation before transcortical signal propagation
occurs reliably; but, once they reach this state, they have more
“momentum” than normal, so the hemispheres are prone to
prolonged periods of reverberatory activity. This state, likely
to be related in real life to psychological traumata, in turn
leads to sustained over-activity of the midbrain dopamine
neurons, and therefore to onset of active psychosis.
13.5.
Variability of schizophrenia: Fundamental
heterogeneity or varied expression of a single
process?
The manifestations of schizophrenia are very varied. A
hitherto unresolved controversy is whether this variability
signifies one disorder with many manifestations, or many
fundamentally different disorders, arbitrarily gathered
together because of some surface similarity. The theory
presented here is more compatible with the first than the
second of these alternatives, since all the trait abnormalities,
as well as the vulnerability to psychosis can be accounted for
in terms of the same premise about properties of corticocortical axons. Moreover, the idea that the varied expression
of schizophrenia reflects the action of a variety of separate
genetic factors (genetic heterogeneity) does not fit data on
inheritance as well as the polygene model. However, there are
a number of relatively rare conditions, whose genetics is
simpler than that of schizophrenia in which there is also a
predisposition to psychosis and abnormality of cerebral white
matter similar to that proposed for schizophrenia. These
uncommon and discrete disorders may appear similar to the
Conclusions: The Concept of Schizophrenia
broad run of schizophrenic disorders, which, in their varied
form, make up most of the people who have this diagnosis.
The idea that there is an underlying unity to schizophrenia
which encompasses most cases need not imply that all trait
abnormalities are found together in each patient with
schizophrenia. It is not known how different trait measures
associate or dissociate across patients. There is room for
much further work here. Such work may give improved
validation to subtype differentiation, in terms of explanatory
arguments. Specifically, a combination of morphological and
functional studies may be able to show how different trait
manifestations of schizophrenia arise when there is loss of
rapidly-conducting axons in different parts of cerebral white
matter. A more detailed factorization of symptoms than has
hitherto been established may then arise.
13.6.
The broad concept of schizophrenia
defined by traits vs schizophrenia defined in terms of
psychotic symptoms.
The present concept of schizophrenia differs from ones
previously adopted in several ways: (i) The heart of the
concept is the collection of trait abnormalities. Indeed, in
genetic terms, some traits (pursuit eye movement
abnormalities; impairment in tests of sustained attention) are
inherited more strongly than the schizophrenia diagnosis itself
(which has additional, non-genetic causal contributions). The
psychotic manifestations of the disorder are then conceived as
severe complications of the underlying diathesis. While
psychosis may cause long-lasting damage to the psychosocial
fabric of a young person’s life, and in practice may be the
area of disorder requiring most urgent attention, psychosis is
not the core of the disorder. (ii) The diathesis for
schizophrenia occurs far more widely than schizophrenia as
defined by the occurrence of psychotic symptoms. Many
people with a variety of the trait abnormalities may escape the
psychotic manifestations, due, perhaps to a benign early
environmental factors which does not predispose to the
transition to psychosis. (iii) In terms of currently used
diagnoses, the broadened concept of schizophrenia developed
here overlaps with several other current diagnoses. This is
evident both in studies of inheritance of one disorder in
relatives with another disorder, and also in the degree of
functional or morphological abnormality seen in
schizophrenia compared to other related disorders. A
particular example of the relationship of schizophrenia to
other disorders is the dichotomy (originating with Kraepelin)
between schizophrenia (a.k.a. dementia praecox) and bipolar
disorder (a.k.a. manic-depressive illness). This dichotomy is
central for psychiatry, and merits more detailed discussion.
13.6.1.
Are schizophrenia and manic-depressive illness
separate and distinct disorders?
In genetic terms, schizophrenia and manic-depressive
illness, as diagnosed, are mainly, but not completely separate.
The pattern of cross-prevalence for disorders in the broad
schizophrenia spectrum is not well accounted for on the
assumption that these disorders represent different degrees of
a single disease process. Further differentiation between these
two comes from the fact the schizophrenia has earlier onset
and is more severe in males than females, but the opposite is
true for bipolar disorder (see Sect. 3.5.1.). There appears to be
more than one disease process involved in this broad
spectrum, but the different processes do not correspond
exactly to diagnostic labels. In terms of diagnostic stability, a
patient may receive one diagnosis at one time, another in a
later episode. Diagnostic stability across time is less than the
reliability between raters at a single point in time. Change of
diagnosis is therefore is not due solely to imperfect inter-rater
reliability. Any symptom of schizophrenia may also occur in
manic-depressive disorder, although there are quantitative
group differences in incidence of specific symptoms in
different diagnostic groups. Evidence on putative contributory
environmental causes (for instance obstetric complications)
sometimes appear to shift diagnosis from affective to
schizophrenic disorder, again bringing into question their
genetic distinctness.
Functional traits associated with schizophrenia might give
hints of qualitative differences from manic-depressive illness.
One diagnostic group might show impairment in a particular
test, while another group shows test performance above
normal. If more than one test is considered, there may be
some tests in which group A is significantly more impaired
than group B, and other tests in which group B is the more
impaired than group A. Such patterns of results would suggest
the existence of separate disease processes in the two groups.
Little of the evidence reviewed in this book shows either of
these patterns. Usually patients with schizophrenia show
impairment, while those with affective disorder show milder
or no impairment. Quraishi and Frangou (2002) tabulate many
studies where comparisons were made between the two
diagnoses, with respect to general intelligence, attention,
memory and learning, and executive function. Regardless of
whether the affective subjects were ill or stabilized at the time
of testing, there were no clear dissociations of trait
abnormalities, suggestive of separate diatheses for
schizophrenia and affective disorder, though generally the
former were more impaired than the latter.
A few studies of traits give hints of dissociations. In
Chapter 6, it was mentioned that, in factor analyses of
symptoms, patient groups with bipolar disorder do not give a
clear Disorganization factor. High performance at age 20y in
an arithmetic reasoning task is characteristic of subjects who
later develop bipolar disorder, and differentiates them from
those who develop schizophrenia, although both groups share
impairment in visuo-spatial reasoning tasks (Tiihonen et al,
2005). Park and Holzman (1992) found, in a memory-guided
oculomotor delayed response task, that patients with
schizophrenia were less accurate than normal subjects, while
medicated bipolar patients were more accurate. However, the
bipolar subjects also had slower reaction times than controls,
so they may have differed from controls merely in how they
traded off speed against accuracy. Lohr and Caligiuri (1995b)
measured hand force stability, and found that schizophrenia
patients were impaired with both hands, but had greater rightthan left-hand instability, while bipolar patients had greater
left-hand instability. Normal controls were symmetrical in
this task. V.A.Curtis et al (2001) found that functional
activation of frontal lobes in a verbal fluency task was above
normal in stabilized bipolar patients, but below normal in
54
Conclusions: The Concept of Schizophrenia
schizophrenia. Greater focus on results of this sort might help
to clarify underlying differences between these two
diagnoses.
Different medications (e.g. lithium vs antipsychotic drugs)
are effective in different illnesses, but the effectiveness does
not correlate exactly with diagnosis: Lithium can be effective
in schizophrenia (Alexander et al, 1979; Hirschowitz et al,
1980), and antipsychotic drugs can be effective in manic
depressive disorder when lithium has failed (Garver et al,
1988).
The conclusion again appears to be that there is more than
one disease process within the broad schizophrenia spectrum,
but they cannot be distinguished categorically on the basis of
symptoms. What the disease processes may be other than
those analyzed here is beyond the scope of this book. The
dimension emphasized here - the repertoire of conduction
times in cortico-cortical axons - allows many variants other
than the “central hypothesis” for schizophrenia, which could
form the basis for a theoretically-based definitions of a
number of psychiatric conditions. For instance, evidence of
greater-than-normal GM volumes in some cortical regions in
bipolar disorder (Sect. 12.10.2.), could indicate that in these
regions neurons are larger than normal, and give rise to
abnormally rapidly-conducting axons. Another starting point
would be to examine how lithium acts.
Schizophrenia defined in terms of any of its associated
traits is in complete continuity with the range of normal
personality variants. Those most strongly linked to
schizophrenia, in terms of traits held in common, are
“schizotypy” as defined psychometrically, and schizotypal
personality disorder as defined with clinical instruments.
(There is little to chose between these two in strength of
association to schizophrenia itself.) None of the trait
abnormalities, nor schizophrenia itself, show a tendency to be
inherited in a categorical fashion. However, by long usage we
have become accustomed to thinking of schizophrenia as a
sharply-defined category. Psychotic states can claim to be
categorically separate from normality, but this does not apply
at all to the concept of schizophrenia as a whole, as it emerges
in the present theory. The view that schizophrenia is a
sharply-defined category also has its cultural roots in the
unfortunate tendency in most human societies to identify one
or other group of marginalized people as “aliens”. For these
reasons a new name is required for this disorder, in whatever
way it is eventually conceived in coming years. This is
currently a matter of discussion by the committee developing
the forthcoming DSMV document (Kingdon et al, 2007), and
one of the proposals is a “general psychosis syndrome”. The
present author does not have the experience to propose a new
name. However, while perhaps of some pragmatic value, this
proposal misses the point that the enduring traits are a surer
guide to the cause of what is now called “schizophrenia” than
are psychotic episode. It is suggested that a new name should
incorporate the concept of “delayed or incomplete maturation
of cerebral white matter”.
13.7.
Traits aspects of schizophrenia and normal
functional development.
Many of the traits of schizophrenia are similar to features
55
found in normal pre-adult development. Amongst
psychological measures, this is the case for the abnormalities
in smooth pursuit eye movement, sustained attention (as
assessed with the CPT), span of apprehension, antisaccade
errors, and (tentatively) the reaction time cross-over effect.
Amongst electrophysiological measures it is the case for
interhemispheric transfer time, P50 suppression, and
amplitude of the mismatch negativity and P300 potentials.
This is all in accordance with theory, since children and
adolescents have relatively incomplete myelination of
cerebral white matter, just as, according to the theory
presented here, is the case for adult schizophrenia. It may then
be asked why normal children and adolescents show active
phases of psychosis very rarely10. Turned around, this
question becomes: Why is the age of onset of schizophrenic
disorder delayed to late adolescence or early adulthood? This
may be because, as Weinberger (1987) has noted, dopamine
levels in the brain reach their peak at about the time when
schizophrenia makes itself manifest. However, there may be
another contributing effect: The theory relating the trait
abnormalities (and their supposed basis in axonal properties)
to psychosis (and its basis in over-activity of dopamine
mechanisms) was based on the fact that in schizophrenia, the
activated cortex is capable of prolonged reverberatory
activity. In other terms this amounts to a tendency to
activation of long chains of neuronal firing (mediating “long
chains of thought”). Such chains are likely to be progressively
acquired (learned) during development by Hebbian
strengthening of synapses at each of the links in the chain. In
real-life terms, this process continues throughout the years
from early childhood to adulthood. Thus, given the
schizophrenia diathesis, the ability to produce the
reverberatory activity leading to psychotic destabilization
may also be conditional on a certain degree of “cognitive
maturity”, associated, at least in people with the
schizophrenia diathesis, with the capacity to sustain long
chains of thought.
13.8.
Correlations between traits assessed in the
laboratory and symptoms assessed clinically.
The analysis of functional trait abnormalities in
schizophrenia included a review of the correlations of each
measure with the three main symptom groups (psychomotor
poverty [negative symptoms], disorganization [thought
disorder], and reality distortion [positive symptoms]). As
10 Childhood schizophrenia is a controversial concept,
partly because it cannot be assumed that the underlying disease
process is expressed phenomenologically in the same way in
children as in adults. However cases are known where
psychotic symptoms occur in children between ages of 5 and
10 years, which progress to the recognizable adult form of
schizophrenia (Annell, 1963; Eggers et al, 1989; Werry et al,
1991). These are responsive to antipsychotic drugs, although
clozapine and other atypical drugs are more effective
(Remschmidt, 1993; Frazier et al, 1994; Kumra et al, 1996;
Turetz et al, 1997). They have increased incidence of
schizophrenia-spectrum disorders in FDR (Kallman and Roth,
1956; Bender, 1975). Such cases are quite rare, ~50-fold less
common than adult-onset schizophrenia (Burd and Kerbeshian,
1987; Thomsen, 1996)
Conclusions: The Concept of Schizophrenia
mentioned above positive symptoms rarely show significant
association with trait measures. However, on the basis of
correlations with symptoms, it is possible to separate two
classes of trait abnormality. The first, including lengthened
critical stimulus duration, and impaired visual backward
masking, impairment in smooth pursuit, vigilance tests, visuospatial WM and olfactory identification, correlate with
negative symptoms but not with thought disorder or
Disorganization factor scores. The second, including
excessive semantic priming, impairment in pre-pulse
inhibition of startle. Measures of persistence of set in
attention-shifting paradigms are associated with thought
disorder/disorganization. The so-called glutamate hypothesis
of schizophrenia has drawn attention to the fact that NMDA
antagonists such as ketamine can produce effects in normal
subjects similar to negative symptoms. Ketamine can also
mimic in normal subjects some of the trait abnormalities
surveyed in Chapter 7-11. It is of interest to note that the trait
abnormalities to which this applies (i.e. smooth pursuit eye
and hand movements, sustained attention, rote learning,
mismatch negativity) are ones which correlate mainly with
negative symptoms, whereas for other traits (such as those in
semantic priming, prepulse inhibition, WCST or P300
potentials) there are no reports of NMDA antagonists
producing the same effect in normal subjects. The theory
explaining the similarity between schizophrenia traits and the
effects of NMDA antagonists would also involve just the
traits similar to negative symptoms, not those produced in
states of higher cerebral activation.
13.9.
Psychosocial influences contributing to
occurrence of schizophrenia.
Most of this book is devoted to exploring the brain
dynamics underlying the state and trait aspects of
schizophrenia. However, in Chapter 4, evidence was reviewed
showing that psychosocial factors in the environment could
have a major impact on the incidence of diagnosed
schizophrenia, notably in certain immigrant groups: The
evidence on this is clear, but it is less obvious how
psychosocial adversity during pre-adult years can interact
with the supposed biological factor - a relative absence of
rapidly-conducting axons - in determining the appearance of
definite illness. There are three possibilities to consider: (i)
Psychosocial adversity might affect gene expression, which in
turn determines cellular development during childhood and
adolescence. (ii) Such adversity might influence plastic
processes in synapses, mediating cell assembly development.
Without changing the actual morphological substrate in the
brain, this could still affect the repertoire of cognitive abilities
seen in the adult, and predispose a person to schizophrenia,
including its underlying traits. (iii) Prolonged psychosocial
adversity during upbringing, might have an influence at the
level of “whole person” psychology, which interacts with the
substrate of brain morphology to produce manifest illness.
Specifically, when a person grows up in an environment
dominated by all-prevailing disadvantage and discrimination,
he or she may develop a personal style of “all-out striving” to
succeed, which may nevertheless fail. Such an attitude to life
may have the consequence that the activated “up-state” of the
cortex may be generated more commonly than in more
relaxed young people who do not grow up having to deal with
such adversity. This could precipitate the transition to
psychosis in vulnerable people who would otherwise escape
psychotic aspects of the schizophrenia diathesis.
The studies of immigration in relation to schizophrenia
show increased incidence of schizophrenic psychosis, but
there is no evidence that it increases the incidence of the
underlying traits (a topic which has never been explored).
Thus, from evidence available at present, one does not need to
postulate a psychosocial environmental effect which alters the
morphological substrate during development (the first
alternative). The second alternative carries the implication
that psychosocial adversity would, by processes of synaptic
plasticity, lead (without actual morphological change) to
unusual functional predominance of slowly-conducting
components of the repertoire of axons, with relative neglect of
the rapidly-conducting ones. This is not inconceivable: A
social environment dominated by negative reinforcement and
punishment may produce a general suppression of
spontaneous voluntary acts, and an encouragement of mental
“rumination” when action is suppressed. These may
correspond to plastic synaptic changes which suppress the
influence of the rapidly-conducting axons and strengthen that
of slowly-conducting components of the axonal repertoire.
However, if this environmental influence on the cortical
network could “mould” the potentialities of the morphological
substrate, it is expected that it would enhance both trait and
state aspects of schizophrenia beyond that specified
genetically. Schizophrenic illness in which psychosocial
adversity was an important contributory cause would then be
predicted to have a lower genetic loading than that arising
without this influence. This appears not to be the case: In
studies of Afro-Caribbean immigrants in Britain, the best
studied example of the contributory psychosocial cause of
schizophrenia, relatives of the immigrant probands living in
the Caribbean islands from which the immigrant families
came have an incidence of schizophrenia which is elevated
above the baseline rate by an amount similar to that in control
FDR in the UK-born white population. By exclusion
therefore, of the three possibilities listed in the previous
paragraph, the third, where environmental pressures shapes
people’s attitude to life, leading to a predisposition to
psychosis rather than to the underlying traits, appears most
likely. This conclusion can plausibly apply not only to the
impact of immigrant status, but also to that of urban birth and
upbringing. In support of this, some trait abnormalities are
inherited more strongly than the diagnosis itself (which
derives mainly from psychotic manifestations). The latter but
not the former may combine both genetic and psychosocial
determinants.
13.10.
Schizophrenia and the “self”.
Bleuler’s term “schizophrenia” means, literally, “a
fragmentation of the mind or the ‘self’”. This “whole person”
aspect of the psychology of schizophrenia can be considered
in relation to both trait and state aspects of the disorder. The
symptoms which are most conspicuously captured by this
definition, which appear to be traits, but exacerbated in
psychotic states, are those emphasized by Kurt Schneider
56
Conclusions: The Concept of Schizophrenia
(otherwise known as “passivity symptoms”): A person may
have the experience that his thoughts, actions or words are
“not his own”, but the product of some other agency. This
sounds like a contradiction in terms, since thoughts and
voluntary actions or emitted speech, are by definition, “of the
person”. The description of these symptoms make sense only
if one realizes that the very processes which work together to
produce a unified person are compromised in schizophrenia.
Other traits also imply a “weakened sense of self”, though
less dramatically so. For instance, the slowing of reactions in
motor control tasks mediated moment-by-moment by sensory
guidance can be extended as a personality trait so that a
person cannot “pull himself together” to give a quick and
accurate response in a testing moment. Such an impairment
may be particularly limiting in social interactions, involving
defense against social threats, or in initiating friendships.
Amongst the strictly psychotic symptoms, delusional beliefs
undermine a person’s “sense of self” in a different way: For a
person to have to accept that firmly held beliefs are (or were)
the symptom of a mental illness, shakes his or her confidence
in any of his beliefs, and undermines his capacity to believe
anything. Overall we see a pattern evident in study of many of
the traits covered in Chapter 7-10: Definite trait impairments
are present in well stabilized patients, but they become more
severe when studied in actively psychotic ones.
There is however another side to “sense of self” in
schizophrenia: In some respects the trait aspects of “sense of
self” are advantageous, rather than detrimental. Thus, in some
circumstances, the ability to follow through “long trains of
thought” may confer an advantage, compared with a person
who can give a quick spontaneous response in a testing
moment. Whereas the latter may have great confidence in
their ability to react immediately in challenging and rapidlychanging situations, the former may have superior confidence
in their ability to think through and plan strategies of response
in advance of their actual use. In these two faces of the “sense
of self”, one sees, writ large, the same characteristics evident
in many of the more specific traits. Indeed “the self”, in the
sense of being able to respond quickly in an emergency
situation, can be regarded as a very complex Gestalt, bringing
together, in a moment of time, all the habits, idiosyncrasies,
implicit learning and explicit memories of a person’s life.
13.11.
Schizophrenia:
condition.
a
uniquely
human
One of the enduring puzzles about schizophrenia is that it
appears to be quite unique to humans. No schizophrenia-like
disorder is known in any animal species. Of course it is
difficult to know how such a disorder would be expressed in
animals. Nevertheless, we do have plausible animal models of
dopamine-mediated psychosis, but not of schizophrenia itself.
In a general way, this conundrum might be answered by
pointing out that schizophrenia does not correspond to any of
the broad classes of disease found in all animal species
(infective, degenerative, autoimmune etc), but rather to a
distinctively human class - neurodynamic disorders - as
discussed in Chapter 1. However, a more detailed answer is
needed.
In this context, T.J.Crow (Crow, 1997, 2000; Berlim et al,
57
2003), has suggested that the origin of schizophrenia is
closely related to the evolutionary origin of language. Indeed,
he sees the vulnerability to schizophrenia and the origin of
language as critical events in the origin of the human species.
These ideas are based on several subsidiary propositions: that
the symptoms of schizophrenia are fundamentally related to
language dysfunction; that human language is related to the
development of cerebral asymmetry; that cerebral asymmetry
is unique to humans; that human language capacity is based
on mutation at a single gene, variants of which lead to
schizophrenia; and that there must be some heterozygote
advantage to compensate for the reproductive disadvantage
associated with schizophrenia.
This thesis has one important point in common with the
theory in the present book: Schizophrenia is seen as a disorder
of cerebral asymmetry. Apart from this, each of the subsidiary
propositions is questionable. It is a biased view of
schizophrenia to link it so specifically to language problems.
This is possibly related to one interpretation of the concept of
schizophrenia arising from the British psychopathological
system - the Present State Examination. However, from
survey of all the traits associated with the diagnosis of
schizophrenia, it is clear that the abnormalities cover many
areas other than language functions. Human language
functions derive from specializations in addition to cerebral
asymmetry: Such asymmetry influences many psychological
functions, not just language. Cerebral asymmetry is not
unique to humans: Lateral specialization bearing some
similarity to that in humans has been documented in rodents
(Ehret, 1987; Bianki, 1988; Fitch et al, 1993; O’Connor et al,
1993; Güven et al, 2003), sheep (Peirce et al, 2000) and
monkeys (Hamilton and Vermeire, 1988; Vermeire et al,
1998), and, if properly examined, may be quite widespread
amongst mammalian species. In Chapter 4, it was argued that
the genetics of schizophrenia could not be based on genes of
such major influence that there was strong selection pressure
to eliminate such genes. This being so, the concept of
compensatory heterozygote advantage is irrelevant to
schizophrenia. There is no paradox in the survival of
schizophrenia despite fertility disadvantage, if one accepts
that the inheritance is multifactorial, with phenotype
dependent epistatically on genotype. More generally,
although Crow refers to biological evidence (gross
morphology; genetic factors), there is no attempt at “crosslevel” explanations of symptoms in terms neurobiology.
Notably the account of Schneiderian nuclear symptoms fails
to link neurodynamic parameters with the psychological
symptoms. Furthermore, Crow tends to equate schizophrenia
with psychosis; but it is clear from the evidence surveyed in
the present book that the abnormalities in schizophrenia cover
areas of function with little relation to psychosis.
In terms of the present theory, the idea that there is no
equivalent of schizophrenia in animals (even allowing for the
difficulty in knowing how it would be expressed in animals)
may be related to the much larger brain size of humans
compared to any animal species (except cetaceans and
elephants). As a result, the disparity between the spread of
conduction times in a population of axons and the neuronal
integration time is comparably much greater in humans. This
disparity underlies much of the theoretical reasoning in the
Conclusions: The Concept of Schizophrenia
present theory.
13.12
Neuropathology vs psychopathology.
Pathology is the science of disease processes. In what
sense is schizophrenia a disease? In what sense is there a
pathology in this condition? Since the time of Virchow,
cellular pathology has had a central place in the science of
disease processes, although more recently, chemical and
molecular pathology have become important, and, in
psychiatry, psychopathology is a major focus. In almost every
example of cellular pathology, the cells seen in the
microscope are in themselves pathological: They are not
normally present, are necessary for the disease to appear, and
often are sufficient to make a diagnosis. However, these
characteristics do not apply to the cellular changes postulated
here for schizophrenia: There is nothing abnormal about fine
calibre or unmyelinated cortico-cortical axons, or small
cortical pyramidal cells. At the level of gross morphology,
slight reductions in volume of the hemispheres or of grey or
white matter within them are also not in themselves abnormal,
or necessary or sufficient for schizophrenic illness to occur.
They may prove to be necessary for the broadened concept of
schizophrenia defined here in terms of traits. However that
broad concept of schizophrenia is not necessarily a pathology
or a disease. The real pathology arises partly as a result of
changes in neurodynamics made possible by the altered
repertoire of axonal conduction times, with causal
contributions from psychosocial adverse experiences. The
pathology is then primarily psychopathology rather than
neuropathology.
13.13.
Implications for treatment, and prevention
of disability.
What are the implications of the theory presented here for
treatment of schizophrenic disorders, and for prevention (at
least) of the disability they produce, if not of the disorders
themselves? Clearly the most damaging aspect of
schizophrenia is active psychosis. In itself, the mental turmoil
of florid psychosis may do severe damage to the social fabric
of a person’s life, occurring, as it often does, at an age when
higher education, establishment of work and employment
patterns, and development of close relationships are normally
all taking place. Episodes of psychosis, especially if repeated,
undermine development in all these areas. Even assuming that
further psychotic episodes can be prevented, it may take years
to rebuild and to recover the lost ground, after such assaults
on expected development of adult roles; and sometimes such
development is forever forestalled, or adult roles are never
regained. Quite apart from the damage at the psychosocial
level, it is also possible that florid psychotic episodes are
“neurotoxic”, in the sense of causing neuronal loss. This
possibility is discussed in Chapter 12. In the author’s view the
neurotoxic effect of psychosis is not proven. Regardless of
this, it is clear that psychosis is very damaging. An important
focus therefore is not only to treat psychotic episodes when
they occur, but also to prevent them occurring in the first
place.
This is easier said than done. Effective strategies for
prevention require that persons who are highly likely to
develop psychotic disorders, whether the diagnosis is
schizophrenia or some other condition, can be identified, with
a minimum of false negative and (especially) false positive
identification. In principle this might be possible by screening
for trait abnormalities. However, for mass screening, this
would require development of methods of assessment much
simpler and less expensive than most of the methods used in a
research laboratory. This may become possible. However,
there are further complications. Traits merge imperceptibly
into the normal range of personality variations, and the
transition from definite trait abnormalities to manifest
psychosis appears to be highly conditional upon stressors in
the psychosocial environment. It is therefore probably beyond
what is practical to identify the very individuals who will
become psychotic in advance of their doing so. Thus true
“pre-emptive” early intervention is probably too ambitious a
goal.
Nevertheless, preventive strategies can be realized in other
ways. Many young people who eventually suffer psychotic
breakdowns, are, in the early prodromal stages, well aware
that they are becoming unwell, and engage in help-seeking
behavior. This “window of opportunity” is probably the time
when early intervention measures can be instituted in a
manner which is administratively and financially practical,
and ethically acceptable. If left until later, when florid active
psychosis is present, coercive treatment may be needed, and
for this and other reasons, lasting damage may be done, not
only to the social fabric of the person’s life, but also to the
possibility of a good therapeutic relationship being
established with mental health services. However, to make
full use of this “window of opportunity” is a complex
pragmatic matter, only partly dependent on scientific issues
about the underlying disorders. As in many areas of
preventive medicine, ideas that sound good in principle, need
to be developed in a cautious manner, since their deployment
involves complex financial, political and ethical
considerations, differing from one society to another.
A pre-requisite for such an approach to prevention of
psychosis, or forestalling its adverse impact by treatment as
early as possible, is public education. It is important that
young people (and others) who might become ill have the
knowledge to recognize those aspects of their own mental
processes which might be a sign of developing psychotic
illness. It is also important that the population as a whole has
an accurate and non-stigmatizing view of mental illness, so
that the prevailing social environment of people with
developing problems does not deter them from seeking
psychiatric help. Also these young people should have a
reasonably accurate view of what modern mental health
services can offer, and know that if they present themselves to
the services their problems will be dealt with effectively and
safely. If public education can achieve these goals, the
outlook for psychosis prevention may be favorable.
The trait abnormalities discussed in the present work are
often inherently less disruptive to everyday life than the
episodes of psychosis, and by themselves need not inevitably
prevent a person from leading an independent and fulfilled
life. However, since, at the present stage of development of
mental health care, assessment of trait impairments is often
compounded by the effects of present or past psychotic
58
Conclusions: The Concept of Schizophrenia
episodes, it is difficult to say how disabling and severe these
impairments can be, when considered in isolation. The
Schneiderian symptoms, often regarded as the most severe
psychopathology, emerge, in the present work, as partly traits
and partly aspects of the psychotic state. Even if prevention of
active (dopamine-mediated) psychosis was completely
effective, it is likely that many patients would still experience
such symptoms, resistant to drug treatment, because they are
only partly dopamine-mediated.
The full benefits of early intervention will emerge from
future developments in research and service delivery. The
degree of disability the enduring traits produce is partly a
function of the prevailing psychological stressors in the
family, the employment environment, and other aspects of
day-to-day life. Of course one could ask that societies in
general become less stressful, but this is perhaps not a very
feasible public health goal. More realistically, there are a
number of situations in which awareness of the trait
abnormalities, and the limits they impose on social
functioning, can play a part in helping young people with
their choice of employment or careers. For instance, people
with a problem in continual switching of attention would be
ill-advised to seek employment in front-line situations where
they deal, face-to-face, with very widely varying demands of
the general public, and have to make continual quick
decisions. A better working environment would be one where
the person’s facility for forward planning, imagination and
creativity can be fully utilized.
Just how far all this can go in alleviating distress and
disablement due to schizophrenia is uncertain. Since these
strategies depend on public education and effective antistigma campaigns, which are in the present time only just
beginning to have significant impact, we cannot say how far
early detection and prevention strategies can become effective
in future years. However, indications that schizophrenic
illness is generally less disabling in developing countries than
in the developed world11 gives one hope that substantial
improvement in the lives of persons with this disorder can be
achieved.
Some of the more ambitious biologically-based
researchers might ask whether it is possible to intervene
directly to change the morphological substrate proposed here
as the basis of schizophrenia, or to mitigate its effects. To
change the morphological substrate, that is the repertoire of
axons with their particular range of calibers, types and
conduction velocities, seems to imply that the developmental
processes by which the adult repertoire is acquired could be
modified. However, such a repertoire appears to be one of the
core structural substrates of human personality. Making the
big assumption that it is possible to interfere with such
processes implies that permanent changes to personality
would be produced. This seems to the present author to be at
least very expensive, and probably in the realm of science
fiction. To attempt such a drastic change seems hit-and-miss.
It is not warranted, given that the psychological traits
underlying schizophrenia are often not severely
incapacitating, and in some measures reflect better-thannormal abilities. However, given that several of the abnormal
11
but see Patel et al (2006).
59
traits can be mimicked by NMDA antagonists, it is
conceivable that pharmacological agents might be developed
which could act in the opposite direction to mitigate these
traits, as well as associated negative symptoms. An example
of this is to use glycine or related amino acids in treatment of
negative symptoms. This is based on the fact that the NMDA
receptor has a glycine-modulatory site. Several clinical trials
have shown glycine or related agents to be effective against
negative symptoms (Coyle et al, 2002; Coyle and Tsai, 2004;
review by Javitt, 2006). Nevertheless, it should be borne in
mind that glutamate antagonists cannot totally reproduce the
effects of a relative absence of rapidly-conducting corticocortical axons. For instance, in the literature on smoothpursuit eye movements, ketamine reproduces in normal
subjects the reduced closed-loop gain, but not the prolonged
latency in initiating eye movement responses.
Much progress has already been achieved in the years in
which this author has been studying the disorder; further
improvement is to be expected. However, it is also clear that
this progress can be attributed only in part to improved
scientific understanding of the fundamental basis of the
disorder. Changes in overall societal attitudes, including legal
changes outlawing discrimination, and more optimistic views
of what are considered realistic goals for human fulfilment
have played a major part in progress so far.
Nevertheless, the most important practical implication of
the theory presented here may be that it offers a way of
understanding schizophrenia. The great fear with which this
illness is associated in the public mind arises not mainly from
any objective reason, but because, subjectively, it is so
difficult to understand. Indeed “incomprehensibility” has even
been suggested as one of its defining features. Certainly some
of its manifestations undermine fundamental assumptions
most of us make about what a person is or can be. Only time
will tell whether and to what extent the theory presented here
is correct. It is virtually certain that future research will lead
to substantial modifications of it. Nevertheless the author
hopes that its central features will survive critical tests. If so,
the theory may, over time, help to dispel the fear - borne of
incomprehension - surrounding the subject of schizophrenia.
Bitter polemics still continue about biological vs
psychosocial causation of schizophrenia, and this hinders the
development of effective modern services. The theory
presented here, is mainly about brain mechanisms,
understandably so since its author is a brain scientist.
However, it should be clear that the author also accepts that
psychosocial factors are important contributory causes. It is
much easier to present simplistic formulations of
schizophrenia leaning heavily to one or other side of this great
divide, than to develop an even-handed perspective which
shows in detail how the two sorts of contributory cause
interact. If the main tenets of the theory presented here
become accepted by those on both sides of this age-old
divide, it may help to defuse the more strident and
acrimonious manifestations of this debate, and allow mental
health services to develop with more unity of purpose than
has often been the case in the past.
Conclusions: The Concept of Schizophrenia
60