A Neuro-Cognitive
Assessment Device
Dr. John Rothman
RERC-ACT Meeting
Westminster, CO
October 25-26, 2007
References
• This presentation summarizes many
related areas in the scientific literature.
References are not provided as they
would make the presentation cluttered and
difficult to read, however an unpublished
review that subsumes this material is
available.
Concept
• From the lowest to the highest levels of the central nervous system
there exists substantial integration of the autonomic nervous system
with those systems responsible for cognitive functions.
• This integration is frequently mediated by acetylcholine, which is the
primary mediator of parasympathetic function and which is known to
mediate many cognitive functions.
• By quantitatively assessing certain autonomic reflexive responses it
is possible to quantitatively assess peripheral autonomic tone, an
indirect measure of central autonomic tone, which can be used as a
surrogate neurologic measure for cognitive function.
• I have been working on a device for this purpose.
Autonomic Tone
• Autonomic tone refers to the resting state of the
autonomic nervous system as a balance
between sympathetic and parasympathetic
influences
• Peripheral autonomic tone can be used to infer
central autonomic tone & central autonomic tone
correlates with cognitive function
• Many peripheral autonomic responses can be
used for this purpose
– The eye affords one way to visualize
peripheral autonomic tone
The Eye as a Window on Cognition
• Since Aesculapius, physicians have looked into the eye to
assess cognitive state. We “just know” that cognitive function
can be seen in the eyes.
– We reflexively look into someone’s eyes to assess the state of their cognition,
whether they are telling the truth, etc.
• The use of Belladonna as a cosmetic
• Pupil size, oscillation, saccadic eye movements can be used
to quantitate cognitive effort,
– So can cardiovascular responses and many other autonomic responses also
work.
– Very short autonomic feedback loop between Edinger-Westphal Nuclei (EWN) of
3rd Cranial nerve (ACh) that synapses on short ciliary fibers innervating the iris
sphincter & Superior Cervical Ganglion (NE) which also synapse within these
fibers.
• It is now possible to quantify these events
and analyze them statistically.
Integrated Systems
• Old Brain
– Superior Colliculus projects to:
• Cortex: Visual thalamus, pons, tegmentum, substantia nigra
– Mediates:
•
•
•
•
Vision, orienting behavior
Ocular motor events & related rotational behaviors
Heart & respiration rates, blood pressure, etc
ACh metabolism linked to retina
• Forebrain cholinergic projections
– Cognitive Projections
• Nucleus basalis, neocortex, septum, hippocampus, cingulate cortex,
amygdala, etc,
– Autonomic Projections
• Vagus, parabrachial nucleus, paraventricular nucleus
• Similarly, cortical-brainstem-thalamic cholinergic
projections effect most autonomic and cognitive
centers of the brain
Central Cholinergic Function (Nicotinic)
• Associated with increased retention, learning, memory,
avoidance acquisition, sample matching, discrimination and
maze performance in mice, rabbits, pits and monkeys.
• In humans nicotinic cholinergic systems have been shown to
increase perception, arousal and visual attention, improve
speed and accuracy of motor functions, decrease reacting
time, reverse declines in efficiency, increase the ability to
withhold inappropriate responses, and improve both short and
long term memory.
• Also associated with autonomic functions of heart rate, blood
pressure, respiration rate, tidal volume, etc.
Phasic/Tonic Pupillary Responses
• Tonic
– ~75-125 minute rhythms
• Out of phase with sleep scores, light reflexes & generalized arousal
• Correlate with circadian alertness, perceptual cycles and some EEG
rhythms
– Altered by physiologic fatigue, emotion, mood
– Indicates diminished vigilance independent of task fatigue
• Phasic
– Associated with rapidly changing thought processing
– Task produced and task linked in time
• Indicate quantitative task processing load in CNS
• Msec rise and decay time
– Diminished by task fatigue
Pupillary Size as Cognitive Marker #1
• Subjects asked to memorize long strings of numbers
– Increase in pupillary size proportionate to length of string
• When asked to repeat string backwards
– Even greater increases in pupillary size, manifest 1st during
delay period
• Less competent Ss manifest greater pupillary size
increases than do proficient Ss.
– Response due to cognitive effort and not task
• Responses are tenths of mm & considerably
less than photic responses
Pupillary Size as Cognitive Marker # 2
• Task locked pupillary dilation has 100-200 msec onset w/similar
decrement upon completion
– Dilation increases with each digit
– Dilation repeats with re-reporting
• Dilation occurs with latency if long term memory is used indicating
retrieval effect
• Slope of f(x) correlates with task complexity. Dilation is perfectly
ordered by task complexity with mental arithmetic.
• Rehearsal decreases dilation
• When numeric strings reach impossible lengths (~8-10) dilation
abates at the point when Ss give up.
Pupillary Size as Cognitive Marker # 3
• Using auditory comprehension to discriminate
the similarity of meaning between words yields
the same result
– Amplitude of dilation maximum during decision
interval
– Increasing complexity of syntax results in greater
dilation
• In the context of go/no go decision making
dilation increases linearly with uncertainty
Sensory Gating
Primacy of Cognitive over Autonomic Function
• At visual or acoustic intensities to perceive a stimulus
50% of the time (perceptual threshold) reflexive photo
flash dilation is abolished
• Ss given processing intensive tasks had significantly
reduced pupillary constriction in response to photic
stimulation. These ocular motor responses are
known to be mediated by the EWN.
• This close integration of autonomic and cognitive
functions indicates their inter-dependency.
Pupillary Dilation as Diagnostic
• Grunberger et.al. (‘96) used pupillary oscillations
to discriminate neurotic disorders (ICD9:300)
from organic brain syndrome (ICD9:290 &
291.2)
• Nozaki et. al. used anticholinergic mydriatic
agents to differentiate between Pts with
subarachnoid hemorrhage who had residual
cognitive deficiency from those who didn’t.
Beatty Insight
•
“Thus,
any response to forebrain commands modulating
activity in the cortico-reticular reticular-cortico loop will
also make its effects felt in the autonomic periphery.”
• “There is nothing incompatible in viewing the pupillary
response as a measure of the aggregate task-induced
utilization of multiple processing resources. This idea is
in some ways analogous to the use of a general
physiological measure such as oxygen uptake as an
indicator of the aggregate metabolic demands of a set of
functionally distinct organs.”
Richer, F. & Beatty, J. Contrasting effects of response uncertainty on the task-evoked
pupillary response and reaction time. Psychophysiology 24(3):258-62. 1987
Anticipation
• When stimuli are presented in a recognizable
pattern, for example when multiple stimuli are
presented in a predictably timed sequence,
pupillary dilation increases with anticipation of
each sequential stimulus. If the pattern is
interrupted, pupillary dilation is greatly increased.
• This effect is dramatically increased in dementia
• Anticipation has similar effects on autonomic
phenomena to decrease responsiveness
Emotion
• Emotion tends to be manifest in tonic
ocular rhythms and in baseline pupillary
size, but not in the phasic changes
associated with cognitive function.
• Similarly, emotion does not seem to affect
autonomic responses.
Intelligence
• A cohort study that assessed the heritability of IQ showed:
– IQ and educational level correlated with the heritability of the gene for
the cholinergic M2 receptor, a receptor associated with potentiation of
the striatum.
– a significant linear increase in IQ across 3 genotypes of the M2 receptor
and progressively higher education across these 3 genotypes.
• The measure “Inspection Time”, the minimum time an
individual requires to reach near perfect response accuracy in
a simple two-choice visual discrimination, is a measure of
early information processing associated with intelligence
presumed to be mediated by nicotinic cholinergic receptors.
In this model, ACh function is associated with processing
speed.
Alzheimer’s Disease
• ’94 Scinto found AD & Downs Pts responded aberrantly
to the mydriatic agent Tropicamide.
• ’95 Grunberger reported changes in pupillary oscillation
in response to the nootropic bifemeline which correlated
with clinical improvement in cognition.
• Over the next decade numerous, but not all, researchers
found correlates with the response to anticholinergics
administered to the eye in AD; including correlations with
ApoEε4. However, the relationship was unclear and
controversial.
Edinger-Westphal Nucleus in AD
• Well known parasympathetic structure
• Scinto & others then confirmed plaques, tangles
& cholinergic cell loss in the EWN of AD Pts
• Scinto and others showed that in autopsy of AD
Pts there was a preferential killing of ACh
neurons within the EWN consistent with the loss
of ACh neurons in other CNS structures in this
disease.
The Work of R. Rosse
• Published on the role of pupillary oscillation and
drug use, and the predictive value of
ocularmotor phenomena for drug induced
seizure. He found consistent correlations with
ocularmotor phenomena and drug mediated
changes in cognition.
• Unlike prior work with mydriatic agents, Dr.
Rosse looked at the eye in the absence of
exogenous drug administration.
Work only in the Patent Literature
• Using a device that pulsed UV light in the eye via an occlusive
helmet that he developed for drug testing, Rosse found the following
Note the
correlations
between the
single measure
of pupillary
oscillation and
standard
psychometric
tests.
• The measure of CA index is a mathematically derived
power function based upon pupillary oscillation over a
range of different frequencies created by Dr. Rosse.
Other Ocular Motor Deficiencies in AD
• The following have been reported in AD:
–
–
–
–
–
–
Prolonged saccadic latencies
Impaired anti-saccadic responses
Slower saccadic velocities
Increased small saccades, decreased long saccades
Diminished saccade amplitudes
Impaired or altered gaze fixation
• Using fMR impaired fixation correlates with diminished
activity in Brodmann’s area and diminished stereo vision
– Impaired ocular orienting response
– Diminished field of view
Cholinergic Deficits in AD
• There is an extensive literature describing functional
CNS loss associated with diminished cholinergic function
both globally and in specific structures.
• This work has resulted in the use of agents which
increase cholinergic function as first line therapy in AD
– Aracept and memantine are best known
• Similarly, Huperzine A and many other cholinergic agents
are used to mediate both enhanced and diminished
cognition in non-therapeutic regimens.
Delirium
• Impaired attention and concentration
• Most common predictor of extended post
surgical hospital stay, negative therapeutic
outcome & is very difficult to diagnose
– 2.3M cases in 1999
– Epiphenomenal to other disease.
• Many anticholinergics induce delirium
– Associated with
• changes in cortex, pons, hippocampus, basal forebrain
• muscarinic-G protein coupling
• Autonomic instability
Fatigue
• Fatigue is known to be associated with:
– Changes in pupil size
• “Fatigue waves” in pupil diameter (“Pupillary
Hippus”)
– Alterations in pupillary oscillation
– Chronic fatigue enhances vascular responses
to ACh
– Chronic fatigue associated with elevated CSF
Ab to cholinergic M1 receptor
Organophosphate Toxicity
• Well documented impairment of cognition
due to poisoning of cholinergic systems
• Simultaneous poisoning of autonomic
nervous system
Traumatic Brain Injury
• Long term cognitive impairment in TBI is associated with
diminished function in cholinergic afferent projections to
the hippocampus.
• Nicotinic receptors very sensitive to traumatic injury and
play a role in post-TBI impairment
• Animal models of TBI reveal changes in acetyltransferase
activity associated with septo-hippocampal lesions.
• Cholinergic agents seem to help many Pts.
Schizophrenia
• Cognitive impairment is a central and enduring feature of
this disease
– Diminished mental efficiency very similar to AD
• Volitional attention, selective attention, readiness to respond, no
benefit from preparation, deficient memory, diminished learning,
increased forgetting, inability to plan
– Cannot hold a thought
– Impaired prefrontal functionality
– Anticholinergic neuroleptics are drugs of choice
• Deranged autonomic function is part of the disease
– Particularly sympathetic compensation
Drug Abuse
• Rosse has shown that with cocaine:
– Pupillary oscillation can distinguish crack abuses with
paranoia from those who don’t admit to paranoia
– Pupillary changes are associated with drug induced
mania, occurring days before the mania
• Opiate, alcohol & amphetamine use are known to be
associated with changes in pupil size and
responsiveness
Non-ocular measures
• Like the eye, other ACh mediated autonomic systems
can also be used to infer central autonomic state based
upon cholinergic functionality, and thus can be used
alone, or in combination with ocular measures, to infer
cognitive deficit.
• Another such system is the cardiovascular system.
– Substantially similar information as described in the eye can be
obtained with rapid, non-invasive measures of heart rate and
blood pressure.
• Respiration rate, tidal volume & GSR
also work
How This Device Can Detect
Changes in Cognitive Function
• Loss of parasympathetic, cholinergically mediated feedback
in autonomic arcs results in deranged function. By assessing
the ability of these arcs to maintain autonomic tone central
function is revealed.
Normal
Dementia
Normal
In this example it can be seen that impairment of cholinergic
mediation of parasympathetic innervation of the pupillary sphincter
results in impaired feedback increasing the amplitude of pupillary
oscillation around a given set point necessary, especially at lower
frequencies.
Dementia
Specificity
• This methodology seeks to identify a deficit in a
common neural path which underlies cognition,
and as such is not specific. The results need to
be interpreted in the context of the overall
patient presentation. Much like the finding of
elevated blood pressure, impaired cognitive
function can result from various causes. A
specific etiology then needs to be determined.
Neuro-Cognitive Assessment Device
• Patent applications have been filed on the device and
the method
• I have collaborated with a group at Rutgers and we have
done some preliminary work.
• Non invasive
• No special conditions, can be performed in any room
• Easily integrated in most practice without specialized
training.
• Quick, ~5 minute test
Potential Benefits
• Direct neurologic assessment
– Changes can be seen before they manifest as
intellectual changes, thus can be treated
earlier
– Much quicker than pen & paper multiple
choice tests, and significantly less expensive
– Objective
– Replicable
– Quantitative
My Purpose Today
• To test my ideas by presenting to an
educated and active group of researchers
• To identify potential academic collaborators
in this area
• To identify funding sources to prove the
principle