Cognitive Neuroscience
Luba Benuskova
1. What is Cognitive Neuroscience
First, we describe what is neuroscience. Neuroscience (neural science) investigates how
healthy and faulty animal and human neural systems work, how the neural system has evolved
in evolution, how it develops during an individual’s life, how individual nerve cells (neurons)
function, from the genetic level up to the level of their mutual communication, how different
parts of a neural system work and how they are interconnected, how different parts of a neural
system form hierarchically organized neural networks, how they cooperate and lead to
behavior of animals and humans. Cognitive neuroscience is such a part of neuroscience that
investigates what is happening in the human (animal) brain during cognitive processes such as
perception, learning, memory storage and recall, thinking, language processing, and so on.
Cognitive neuroscience is trying to find out relationships between different neural levels (from
the genetic level up to the level of neural networks) in order to discover causal rules to explain
cognition, that is the human and animal knowing of the world. Neuroscience and cognitive
neuroscience are natural sciences. Thus, they lean upon an experimental research. New
concepts and theories are being experimentally tested, verified or falsified.
What is the place of cognitive neuroscience within cognitive sciences? According to
the contemporary authority, the MIT Encyclopedia of the Cognitive Sciences (MITECS),
cognitive sciences are comprised of six main fields (in alphabetical order) (WILSON, R.A. –
KEIL, F.C 1999):
1.
2.
3.
4.
5.
6.
Computational intelligence
Culture, Cognition and Evolution
Linguistics and Language
Neuroscience
Philosophy
Psychology
According to the MITECS, since their beginnings in the seventies of the twentieth century,
cognitive sciences have been offering multidisciplinary ways towards understanding of human
mind and cognition. Thus, neuroscience is one of the ways towards understanding of human
mind.
A short history tour
A history of cognitive neuroscience is related to the history of neuroscience. The first Nobel prize for
pioneering discoveries related to the brain microscopic organization was given to the Spanish scientist
Santiago Ramón y Cajal (1852-1934) and Italian Camillo Golgi (1843-1926). These scientists are
considered to be the founders of neuroscience. German physicist Herman Ludwig Ferdinand von
Helmholtz (1821-1894) is the founder of psychophysics, that is a quantitative experimental and
theoretical research of relations between mental and neural functions. Up to these days, the division of
cerebral cortex based on its microstructure made by a neuroanatomist Korbinian Brodmann (18681918), is being used. Frenchman Paul Broca (1824-1880) and Russian Alexander Romanovich Luriya
(1902-1977) pioneered research on brain localization of cognitive functions based upon cognitive
deficits caused by brain lesions.
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2. Neuron and the Brain
2.1 About the brain
It is estimated that there are10111012 of nerve cells (neurons) in the human brain (KANDEL
et al. 1991). Three quarters of neurons form a 46 mm thick cerebral cortex that constitutes a
heavily wrinkled brain surface. Cerebral cortex is thought to be a seat of cognitive functions.
The cortex cooperates with evolutionary older subcortical nuclei that are located in the middle
of the brain, in and around the so-called brain stem (Fig. 2.1). Subcortical structures and
nuclei are comprised for instance of thalamus, basal ganglia, limbic system, hypothalamus and
dozens of other groups of neurons with more or less specific functions. For example, the input
from all sensory organs comes to the cortex through thalamus. Emotions and memory
functions depend upon an intact limbic system. When one of its crucial parts, hippocampus, is
lesioned, humans (and animals) loose their ability to store new events and form new
memories. Fig. 2.1 shows a schematic functional division of the human cerebral cortex. The
same division applies for the other, in this case, the right hemisphere. When a particular
cortical area has been damaged, a particular cognitive deficit follows. All the brain parts,
either cortical or subcortical, are directly or indirectly heavily interconnected. Thus, we cannot
speak of totally isolated neuroanatomic modules.
Fig. 2.1. Gross anatomical and functional
division of the human cerebral cortex. One third
of the cortex is devoted to processing of visual
information: the primary visual cortex and
higher-order visual areas. Association cortices
take about one half of the whole cortical surface.
In the parietal-temporal-occipital association
cortex, sensory and language informations are
being associated. Memory and emotional
informations are associated in the limbic
association cortex (internal and bottom portion of
hemispheres). The prefrontal association cortex
takes care of all associations, evaluation,
planning ahead and attention. A dashed curve
marks the position of evolutionary older
subcortical nuclei in the middle of the brain.
Each of the depicted areas has far more
subdivisions. (According to KANDEL et al.
1991.)
At the border between the frontal and parietal lobes, there is a somatic sensory cortex, which
processes touch and other tactile signals (temperature, pain, etc.) from the body surface and
interior. In the front of it, there is a primary motor cortex, which issues signals for voluntary
muscle movements including speech. These signals are preceded by the preparation and
anticipation of movements that takes place in the premotor cortex. The plan of actions and
their consequences, inclusion and exclusion of motor actions into and from the overall goal of
an organism, are performed within the prefrontal association cortex. Subcortical basal ganglia
and cerebellum also participate in preparation and tuning of motor outputs, in the sense of
particular movements. For instance, cerebellum executes rutine automatized movements like
walking, biking, driving, etc. Language processing takes place within the temporal cortex,
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parietal-temporal-occipital association cortex, and frontal cortex. We want to point out that
there are far more anatomical and functional subdivisions within each of the mentioned areas.
Invaluable detailed information comes from the study of patients with mental deficits caused
by injuries of particular brain areas. Currently, noninvasive imaging techniques like fMRI,
PET, EEG, and others (see next section), provide a rich source of information about the
dynamics and organization of work within the healthy and faulty brain.
Functions, or better, dominances of the right and left hemispheres in different
cognitive functions are different (KANDEL et al. 1991). It was shown by Roger Sperry and
Michael Gazzaniga in the studies of the so-called “split-brain” patients to whom connections
between the two hemispheres were cut because of the therapeutic reasons. The dominant
hemisphere (usually the left one) is specialized for language, logical reasoning, awarenes of
cognitive processes and awareness of the results of cognitive processes. Although the nondominant hemisphere (usually the right one) is able to carry out cognitive tasks, it is not aware
of them nor their results. It is specialized for emotional and holistic processing, intra- and
extrapersonal representation of space. Its intactness is crucial for the awareness of the body
integrity (DAMASIO 1994). We will return to the dominances of hemispeheres more
thoroughly later.
2.2 Methods of brain investigation
At present, a number of techniques is available to investigate how and where in the brain
particular cognitive (and other kinds) of processes occur. In this section, we provide an
overview of them.
Brain damaged subjects. Deficits in cognitive processing are observed in people who
have suffered some kind of brain damage. The damaged areas indicate where these processes
normally occur. Problems: Observation is made after the event and therefore lacks the proper
experimental control. Specific deficits in processing are rarely found without the occurrence
of other deficits.
Lesion studies. Comparison is made between cognitive performance before and after
the removal or lesion of part of the brain. Problems: Lesions may damage other systems
which happen to be next to or pass through the target part.
Stimulation. Electrical, magnetic or chemical stimulation of some neural circuit or part
of it, and observing the consequences. Problems: Intensity of an artificial stimulation does
not have to be the same as the level of spontaneous activity in the target circuit. Difficulties in
determining which structures have been actually affected by the stimulation.
Single- and multi unit recordings. Microelectrode recordings from individual neurons
or from an array of neighboring neurons indicate specicific neural networks dedicated to
processing of particular stimuli (e.g. bars of a certain orientation, movement in a particular
direction, particular objects like faces, and so on). Problems: It is an invasive method, i.e
requires invasion into the brain and into the cells. Without a post-mortem histology, it is
almost impossible to tell where exactly the recordings were actually made from.
Histology and staining. These are classical anatomical methods, by means of which
Cajal made his discoveries. Anatomists still use to dissect dead brains, stain their cells, and
trace them under the microscope. Thus they can study the microscopic structure of the brain in
terms of cell types and neural connectivity between cells.
Computer Tomography (CT). X-rays reflect the relative density of the tissue through
which they pass. If a narrow X-ray beam is passed through the same point at many different
angles, it is possible to construct a cross-sectional visual image of the brain. A 3D X-ray
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technique is called the CAT (Computerized axial tomography). CT is noninvasive and shows
only the anatomical structure of the brain, not its function.
Positron Emission Tomography (PET). This noninvasive method involves an on-site
use of a machine called cyclotron to “label“ specific drugs or analogues of natural body
compounds (such as glucose or oxygen), with small amounts of radioactivity. The labeled
compound (a radiotracer) is then injected into the bloodstream which carries it into the brain.
Radiotracers break down, giving off sub-atomic particles (positrons). By surrounding the
subject’s head with a detector array, it is possible to build up images of the brain showing
different levels of radioactivity, and therefore, cortical activity. Thus, depending on whether
we used glucose (oxygen) or some drug, PET can provide images of ongoing cortical or
biochemical activity, respectively. Problems: Expense, lack of temporal (40 seconds) and
spatial (4 mm – 1 cm) resolution.
Single-Photon Emission Computed Tomography (SPECT). Similar to PET, this
noninvasive procedure also uses radiotracers and a scanner to record different levels of
radioactivity over the brain. Special SPECT tracers have long decay time, thus no on-site
cyclotron is needed, which makes this method much less expensive than PET. However, the
temporal and spatial resolution of brain activity is even smaller than in PET.
Magnetic Resonance Imaging (MRI). A large (and loud) cylindrical magnet creates a
magnetic field around the subject’s head. Detectors measure local magnetic fields caused by
alignment of atoms in the brain with the externally applied magnetic field. The degree of
alignment depends upon the structural properties of the scanned tissue. It provides a precise
anatomical image of both surface and deep brain structures, and thus can be combined with
PET. MRI images provide greater detail than CT images. Problems: Expense, cannot be used
in patients with metallic devices, patient must hold still for 40–90 min.
Functional MRI (fMRI). This noninvasive technique measures the ratio of oxygenated
to deoxygenated haemoglobin which have different magnetic properties. Active brain areas
have higher levels of oxygenated haemoglobin than less active areas. An fMRI can produce
images of brain activity as fast as every 12 seconds, with very precise sptatial resolution of
about 12 mm. Thus, fMRI provides both an anatomical and functional view of the brain.
Electroencephalogram (EEG). The oldest noninvasive method to measure electrical
activity of the brain. In recent years, EEG has undergone technological advances that have
increased its ability to read brain activity from the entire head simultaneously (from up to 128
sites). The greatest advantage of EEG is that it can record changes in the brain activity almost
instantaneously. On the other hand, the spatial resolution is poor, and thus should be
combined with MRI. Related method, called magnetoencephalography (MEG), measures
millisecond-long changes in magnetic fields created by the brain's electrical currents.
There is a serious interpretation problem with all the methods that measure cortical activity
(PET, fMRI, EEG). How does an experimenter decide which cortical activity is specifically
related to the psychological process in question? It is done by the so-called subtraction
method. The experimenter calculates the difference image between that of the process and that
of a control situation (which one that should be?). The difference images from individual
subjects are averaged to produce a group mean difference image.
It is also problematic to align individual or average functional images with anatomical
structures, when comparing the coordinates of an activation to a standard atlas which by no
means has been proven to reflect the borders of particular areas for all people. In fact, the
converse is true; most Brodmann areas differ between individuals (likely representing the
result of prenatal development, and later an activity-based competition between neuronal cell
populations for survival in the early infant brain).
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Nevertheless, comparing images taken during some cognitive processing to those taken before
or after it, scientists are gaining many new insights about the brain. Studies show, for
example, that the brain areas used in a new task are often different than those used in the same
task after it is learned. A good example is the following language processing task (see Fig.
2.2).
Fig. 2.2. In the uppermost PET image, an individual
was hearing a text, in order to learn a new task. The
PET machine shows the degree of activity in several
tones of color. Yellow and red regions indicate a
higher cell activity. Blue and black regions show
decreased activity or none at all. The highest brain
activities are shown in an area called temporal lobe,
responsible for the hearing perception, and in another
area called prefrontal cortex, responsible for
understanding language. In the lowermost image, the
same individual has now learned the language task and
is spelling out. You can easily see in the color map
that two different regions of the brain were activated
in each condition. Now the activity is concentrated in
the area of the cortex which is responsible for the
motor control of voice, the so-called area of Broca.
(Images have been made by Dr. Marcus Raichle, at the
Washington University School of Medicine, St Louis,
USA.)
2.3 Processing of signals by neurons
A neuron (Fig. 2.3) receives and sends out electric and chemical signals. The place of signal
transmission is a synapse. In the synapse, the signal can be nonlinearly strengthened or
weakened. The strength of synaptic transmission is also called a synaptic weight. One neuron
receives and sends out signals through 103 to 105 synapses. Dendrites and soma constitute the
input surface.
dendritic tree
synapse
soma
axon
spine
basal dendrites
Fig. 2.3. Schematic illustration of a neuron and its parts. There is a synapse at every dendritic spine,
while we drew only three of them. Synapses are also formed on the dendritic shafts and on the soma.
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Dendritic tree consists of thousands of dendrites which are covered by tiny extensions called
spines. Most of synapses is formed on dendrites, particularly on spines. Spines are very
important devices in relation to learning and memory. Electrical signals transmitted by
synapses can have a positive or negative electric sign. In the former case, we speak about
excitatory synapses, and in the latter case about inhibitory synapses. When the sum of positive
and negative contributions (signals) weighted by synaptic weights gets bigger than a particular
value, called the excitatory threshold, a neuron fires, that is, emits an output signal called a
spike. A spike is also called an action potential or a nerve impulse. Usually, as a result of
synaptic stimulation and summation of positive and negative signals, a neuron fires a whole
series (train) of spikes (Fig. 2.4). Mean frequencies of these spike trains range from 1 to102
Hz. The output frequency is proportional to the overall sum of positive and negative synaptic
contributions. Spikes are produced at the initial segment of an axon (the only neuronal output
extension). Then they propagate very quickly along the axon towards other neurons within a
network. At its distant end, an axon makes thousands of branches, each of which is ended by a
synaptic terminal (bouton).
Spike train

EPSPIPSP  
EPSP
IPSP
Na+
K+
Ion channels
in the neuron
membrane
axónu
Fig. 2.4. Electric synaptic potentials and ion channels. EPSP = excitatory postsynaptic potential,
IPSP = inhibitory postsynaptic potential,  = excitatory threshold for an output spike
generation.
2.5 Process of synaptic transmission
A synapse consists of a presynaptic terminal (bouton), synaptic cleft and postsynaptic
membrane (Fig. 2.5). In the presynaptic terminal, there are dozens of vesicles filled with
molecules of neurotransmitter (NT) ready to be released. When a presynaptic spike arrives
into a terminal, calcium ions rush in and cause the fusion of vesicles with the presynaptic
membrane. This process is also called exocytosis. Molecules of NT are released into the
synaptic cleft (Fig. 2.5b), and diffuse towards the receptors within a postsynaptic membrane.
Molecules of NT form a transient bond with the molecules of receptors. This causes opening
of ion channels associated with postsynaptic receptors. In the excitatory synapse, receptors are
associated with sodium (Na+) ion channels, and a positive excitatory postsynaptic potential
(EPSP) is generated. In the inhibitory synapse, receptors are associated with chlorine (Cl) ion
channels, and a negative inhibitory postsynaptic potential is generated. Eventually, NT
releases its bond with receptors and diffuses back to the presynaptic membrane and out of the
synaptic cleft. Special molecular transporters within a presynaptic membrane take molecules
of NT back inside the terminal, where they are recycled into new vesicles.
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This process is called a reuptake of NT. The whole synaptic transmission lasts for about 1
milisecond. Such a synapse is called a chemical synapse, because the transmission of an
electric signal is performed in a chemical way.
(b)
(a)
presynaptic
termina l
(c)
Ca2+
106 m
Ca2+
vesicles
NT
Na+
Ca2+
Na+
cleft
R
N
postsynaptic membrane
Fig. 2.5. Scheme of synaptic transmission. (a) and (c) A chemical synapse is ready to transmit a
signal. (b) Transmission of electric signal in a chemical synapse. NT = neurotransmitter, R = AMPAreceptor-gated ion channel for sodium, N = NMDA-receptor-gated ion channel for sodium and
calcium.
The postsynaptic potential (PSP), either excitatory or inhibitory, has some amplitude
and duration. The amplitude and duration of PSP depend upon the number of activated
receptor-ion channels and upon the time for how long they stay open. This may last for
miliseconds, tens of miliseconds or hundreds of miliseconds. The duration of channel opening
depends upon the number of released NT molecules and upon the type of receptors that are
associated with ion channels. The amplitude of PSP also depends upon the electric input
resistance for ions, which in turn depends upon the size and shape of a postsynaptic spine and
dendrites, and upon the distance of synapse from soma. For instance, a short and stubby
dendritic spine has a much smaller electric resistance than a long and thin spine. All these preand postsynaptic factors determine the weight (strength, efficacy) of a particular synapse.
Within a postsynaptic membrane, there are also such kinds of receptors that are not
associated with an ion channel, but instead with an enzyme. When the overall amount of
released NT reaches some critical concentration, these receptor-enzyme complexes activate
particular cytoplasmatic enzymes, the so-called second messengers. Second messengers
trigger chains of various biochemical reactions which may lead to a change in synaptic weight,
or even to transient changes in gene expression. Under the gene expression, we understand a
process of initiation, reading and replication of genetic information leading to alteration of
biomolecular synthesis of receptors, neurotransmitters and enzymes. Thus, second messengers
may act locally within a synapse itself, or they may activate further (third, and so on)
messengers that carry the message to the genome of a neuron, thus causing a change in its
biochemical machinery related to signal processing. Therefore, it is now widely accepted that
the activity of a neuron itself, influences its processing of information, and even its life itself,
whether it survives or not.
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Computational modeling in neuroscience and cognitive science
(a) Multilayer perceptron
(b) Realistic models of neural networks
Output neurons
Recurrent connections
(optional)
Hidden neurons
Inputs
Feedforward connections
Outputs
Input values
Computational modeling in neuroscience (computational neuroscience) provides mathematical and
computational means for creation of models of small or large brain parts. Relations between elements
of the brain (like neurotranmitters, receptors, synapses, neurons, connections within and between
brain areas) are expressed by means of mathematical relations and formulas. Then, a computer
program that simulates a model dynamical system is written. Theoreticians work on the internal
design of a model dynamical system (Fig.b) until its observable behavior does match the observable
behavior of a real neural network. Then they can make suggestions about hypothetical neural
mechanisms that they had to incorporate into their model in order to make it work. These suggestions
can be experimentally tested, and thus may serve as a guidance for experimenters. Alternatively,
computational models can serve to add credit to the theories about neural mechanisms that were
already formulated by neuroscientists verbally. The final word is always with experimental data. It is
important to realize that models are decoupled both from a modeled neural system as well as from
psychology and behavior. The role of interpretation is profound. It is always based upon the
framework of the used theory.
Currently, models perfectly consistent with experiments exist in these areas of neuroscience :
Individual neurons and small networks
 neurotransmitters, receptors and synaptic transmission
 processing of signals within individual neurons (using theories derived from the cable theory)
 processing of information in relatively small neural systems of worm-like invertebrates
Cortical plasticity
 detailed biophysical models of LTD and LTP, spike-timing dependent plasticity
 developmental plasticity in the primary visual cortex (various formulations of the Hebb rule)
 adult plasticity in the primary somatosensory cortex
Behaviourally relevant dynamics of large ensambles of neurons
 visual system (still the vast majority of processing has not been accounted for)
Cognitive connectionist modeling
In the cognitive modeling, there is not a strong emphasis upon biological plausibility of model neural
networks. The so-called perceptron-like or connectionist artificial neural networks (Fig.a) are being
used. It has been mathematically proven that these networks can approximate any shape of function.
Major success with these simplified abstractions has been achieved in the area of modelling
language processing, i.e. learning to read aloud (NetTalk), learning of verb past tense,
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sentence parsing, etc.
2.6
Synaptic transmission and psychoactive drugs
It is estimated that there are about 50 different neurotransmitters acting in the human brain.
Let us name for example acetylcholin (ACh), serotonin (5-HT, 5-hydroxytryptophan),
dopamine (DA), noradrenaline (norepinephrin), opioids, endorphins, enkephalins, and so on.
A vast majority of these different NTs is being produced in evolutionary older subcortical
nuclei. It can be said, that almost every subcortical nucleus has its own NT or NTs (they may
synthetize more than just one NT). These different subcortical groups of neurons and their
axons which are sent and spread all over the brain including the cortex, constitute different
neurotransmitter systems. On the other hand, cortical excitatory neurons release only one type
of NT – glutamate. Cortical inhibitory neurons also realease only one type of NT – GABA (amino-butyric acid). Thus, upon every neuron within a cortex, many NTs act, depending upon
which nuclei contact it. Action of different NTs causes influx of different ions and activations
of different second messengers. Thus, the information-processing properties of neurons are
subject to complex short- and long-term influences.
Later, we will be more precise, but for now we state only that different
neurotransmitter systems and thus different subcortical and cortical brain parts are related to
different mental processes or functions. Extraordinary low or high activity of NT systems
leads to disorders of mental functions (KANDEL et al. 1991, KAPLAN - SADOCK 1999).
Thus, NTs themselves are endogenous psychoactive drugs. Since levels of NT production in
every nucleus are pre-programmed genetically, a gene error or gene mutation can lead to a
permanently altered production of a particular NT. Neuronal genetic program itself is subject
to such influences as hormones, stress, aging, and as we now know, also to activity of neurons
themselves. The so-called psychoactive substances, that is drugs and medicines used to treat
mental disorders, act in synapses upon different types of receptors. They are psychoactive
because their chemical structure resembles that of endogenous neurotransmitters. Thus, they
can chemically bind to their receptors. Neurons react as if there was present a natural NT.
2.7
Biochemistry of mental disorders
As we have mentioned in part 2.6., brain neurotransmitters themselves act as psychoactive
drugs. Thus their action, or lack of their action, affects our subjective mental experience.
Biochemical and neuroscientific research finds systematic and reproducible changes in the
brain that are typical for particular mental disorders (KANDEL et al. 1991, KAPLAN SADOCK 1999). We will illustrate the character of these cerebral alterations on the two
mental disorders, namely depression and schizophrenia.
There are hundreds of studies which demonstrate that both depression and
schizophrenia have the so-called polygenetic type of heredity (KAPLAN - SADOCK 1999).
Individuals carrying a specific genetic predisposition (i.e. complex tiny genetic mutations)
may or may not develop a disorder. It is said that these individuals are vulnerable against a
given disease. They are vulnerable in a sense that various life stress events may trigger or
switch on the disease process. If an endogenous genetic predisposition is too strong, the
process of disease may start spontaneously, that is without a triggering external event.
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Almost everyone of us was ever sad, suffering, anhedonic, irritable, tense, and so on.
T h i s happens. However, when depression lasts for the period of months or even years,
almost every day, regardless whether any major stress event had happened before (like death
of a close one, divorce, serious illness, delivery, accident, job loss, etc.), this is not going to be
all right and it will not go away by itself. The long-term loss of motivation, internal energy,
and pleasure from achievements at work and in life, must necessarily lead to deterioration of
the ways how a person treats himself/herself, and how a person deals with family and work.
Statistically, women are 3-4 times more prone to develop depression than men. Other factors,
like education, family and social status statistically do not play a role. In psychiatry, it is
widely accepted that the lack of serotonin and/or noradrenaline in the brain, are responsible
for the core depressive symptoms (KAPLAN - SADOCK 1999).
4 2 3 1
Fig.
2.6.
Schematic
illustration of diffuse
projections that originate
in the
noradrenergic
(NA), serotonergic (5HT) and dopaminergic
(DA) nuclei in the brain
stem, and spread all over
the
cerebral
cortex
(projections into other
brain parts are not
illustrated). (According to
KANDEL et al. 1991.)
Neurons that produce noradrenaline are located in the brain stem in the nucleus called
locus ceruleus (Fig. 2.6). They send their axons all over the cerebral cortex, limbic system,
basal ganglia, thalamus and hypothalamus. These diffuse projections serve to initiate and
maintain mental vigility, and have a reinforcing effect upon learning. (We learn all the time
not only for school.) In mammals, stimulation of noradrenaline pathways leading to the frontal
cortex, caused an enhanced effort to reach a goal of some actions (for example to get a
reward). On the other hand, lasting stress response to some stress event leads to the lowering
of noradrenaline levels in the frontal cortex. This is accompanied with anergia (lack of energy)
and anhedonia (loss of pleasure)
Neurons that produce serotonin are located in the brain stem in the nucleus raphe.
They send their axons all over the cerebral cortex, limbic system, basal ganglia, thalamus and
hypothalamus. Target neurons posses different types of serotonin receptors, thus somewhere
the serotonin acts as an excitatory NT and elsewhere as an inhibitory NT. Serotonin regulates
sleep, apetite, libido. It also suppresses aggressive behavior – it can be said that it is a
neurotransmitter of “mental comfort“.
There is not only one type of depression. Depressions can have various severities of
symptoms and various courses – some may be chronic, some may irregularly or regularly
return, with different periods, some may alternate with mania, and so on. In all of them, there
is suppossed to be a reduction in the levels of serotonin and/or noradrenalin, however the
causes of this reduction may be different. There may be an alteration at the level of DNA,
RNA, transport, recycling, degradation, etc. The biochemical alteration may occur not at the
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level of neurotransmitters, but instead at the level of their receptors. At present, it is not
possible to reveal the true cause of any of depressions.
Antidepressants are medicines that reduce the reuptake of serotonin and/or
noradrenalin back into synaptic terminals, thus increasing their availability within synaptic
clefts. This may help the brain neurotransmitter systems to regain their original healthy
balance. Treatment may last for years since original causes may last for years. There are
different types of antidepressants, and none of them produces dependence. If it is not
indicated, they do not sedate, on the contrary, they restore a normal subjective mental feelings.
However, they do not repair the original metabolic causes, they only correct their outcomes.
A lot of what has been said about depression and its treatment applies also for another
mental disorder – schizophrenia. Schizophrenic symptoms can be very bizarre and vary a lot
from person to person. Statistically, 1% of population suffers schizophrenia regardless of the
rase, gender, education, family and social status, etc. There are several sybtypes of
schizophrenia with typical symptoms, different severity of symptoms and different courses of
the disease. The most characteristic symptoms are delusions, hallucinations, and various
thinking and perceptual disorders. Schizophrenic withdrawal from reality can manifest itself
in many peculariar ways. Disorder is accompanied by serious deterioration from previous
level of functioning in such areas as work, social relations, and self-care. Schizophrenia has
also a polygenetic type of heredity (KAPLAN - SADOCK 1999). Neuropathological research
on the brains of schizophernics has shown that there are specific alterations on some types of
neurons within the frontal and temporal cortices. They seem to be less mature, with altered
and retarded signs of differentiation. Major altered NT systems are the dopaminergic (DA),
glutamatergic (Glu) and serotonergic (5-HT).
There are four relatively separated dopaminergic systems in the brain. The first one
acts in hypothalamus and affects the neurohormonal secretion. The second one, acting in basal
ganglia, plays a crucial role in planning and executing muscular, particularly involuntary,
movements. The third DA systems, the so-called mesolimbic system, originates in ventral
tegmentum in the brain stem and innervates the limbic system and the limbic association
cortex. It regulates expression of emotions, feelings of satisfaction, reward and pleasure. The
fourth DA system, the so-called mesocortical system, has its neurons also in the ventral
tegmentum. These neurons send their axons to the frontal and prefrontal cortices (Fig. 2.6).
Release of DA in these cortices regulates motivation, concentration and goal-directed planned
begavior, which requires a complex organization of thoughts.
Based on experimental data, it is assumed that a disbalance of DA levels in the brain
includes its lack in the frontal and prefrontal cortices, and its excess in the limbic and
subcortical areas. Reduction of DA levels in the frontal cortex results in the so-called
hypofrontality, that is unusually reduced levels of activity in the frontal cortex, revelaed by
means of brain imaging techniques. Reduced frontal activity is hypothetized to result in such
cognitive deficits as a specific “cognitive emptiness“, an absence of cognitive motivation and
contents. On the other hand, increased levels of DA in the emotional and subcortical centres
may lead to an impaired filtration and discrimination of stimuli, thus in turn leading to
delusions at the thinking level and hallucinations at the perceptual level. For instance, a longterm abuse of amphetamines, e.g. drugs which increase levels of DA in the brain, results in
development of paranoid delusions.
The second major system altered in schizophrenia is a glutamatergic system.
Glutamate is being released from axonal terminals of cortical excitatory neurons that make
synapses with other cortical neurons and with subcortical neurons in the brain stem nuclei to
which they relay their feedback influence. Neurochemical research has revealed a decrease in
the number of glutamate receptors and glutamate itself in the frontal cortices of
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schizophrenics. Importance of the role played in schizophrenia by the reduced action of
glutamate is related to the fact that it is a neurotransmitter of learning. Long-term changes of
synaptic weights occur in glutamate synapses. Thus, reduced levels of glutamate in the frontal
cortex may lead to altered synaptic plasticity during learning (adaptation). The drug PCP
(phencyclidin, „angel dust”), that blocks postsynaptic glutamate receptors and increases levels
of dopamine and serotonin, causes similar psychic experiences like in schizophrenia, e.g.
hallucinations, disorders of thinking and cognition, emptiness.
Antipsychotic medicines (neuroleptics) used in psychiatry to alleviate schizophrenic
symptoms, block postsynaptic receptors for DA. Differences between effects of different
antipsychotics depend on which subtypes of DA receptors they affect. Recently, it has been
found that antipsychotics that reduce not only the DA synaptic transmission but also a
serotonergic synaptic transmission, have more desirable effects upon schizophrenic
symptoms. It is not surprising since it has been known for a long time, that LSD (lysergic acid
dyethylamid) enhances serotonergic transmission and produces gross perceptual and thinking
alterations. Treatment of schizophrenia is usually a life-long process. Since medicines still do
not cure the original biochemical defect, they can only help the shattered NT systems to regain
more or less stable balance.
Biochemistry of drugs
Drugs are chemical substances that chemically resemble the structure of natural brain
neurotransmitters and thus can act upon neurons through their synaptic receptors. They engage into
activity various combinantions of brain areas, thus causing more or less profound alterations in
subjective experience.
Benzodiazepins.These substances have anxiolytic and/or sedative effects. They enhance the
inhibitory GABAergic synaptic transmission through modulating an activity of GABA receptors.
Their long-term abuse produces dependence and unpleasant withdrawal symptoms.
Cannabis. The brain NT equivalent is anandamid. Anandamid and cannabis affect several NT
systems, like DA, GABA, 5-HT, NA, ACh, opioidergic, histaminergic, and perhaps also others.
Mechanisms of action are complex and not fully understood. Dependence has not been proven,
although a long-term abuse may lead to paranoid states.
Cocain. Increases synaptic levels of DA, 5-HT and NA. Neurons compensate for unusually high
synaptic levels of these NTs in such a way that they synthetize less and less synaptic receptors. When
such an altered brain lacks the drug, normal levels of NTs do not provide for a normal synaptic
transmission, and the result is severe depression and pain.
Opioids. The structures of the brain stem produce several endogenous opioids, like endorphins,
enkephalins, dynorphins, and other. They are related to euphoria, elevated mood and act against pain.
They are naturally released due to a physical exercise. Artificial opiods are for instance opium,
morphine, and heroin. Again, neurons compensate for unusually high synaptic levels of these NTs in
such a way that they synthetize less and less opioid synaptic receptors. When such an altered brain
lacks the drug, normal levels of NTs do not provide for a normal synaptic transmission, which results
in severely painful withdrawal.
Alcohol. It does not resemble any natural NT. There are several mutually complementary
theories about its action. According to one of them, alcohol dilutes neuronal membranes, thus causing
increase in influx of various substances in and out. In such a way it also causes marked dehydratation
of cells. Other researchers find that alcohol acts upon inibitory GABA receptors. Another theory
points out the ability of alcohol metabolite, called acetaldehyde, to react with DA and 5-HT to create
alcaloids similar to opioids. It has been shown that an acute alcohol intake blocks NMDA receptors,
that are present mainly in the cerebral cortex and are related to learning and memory. Thus,
mechanisms of action are complex and not fully understood. A long-term abuse causes dependence.
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