A Neuro-Cognitive Assessment Device

1. A Neuro-Cognitive Assessment Device Dr. John Rothman RERC-ACT Meeting Westminster, CO October 25-26, 2007

2. 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 References are not provided as they would make the presentation cluttered and difficult to read, however an unpublished review that subsumes this material is available.

3. 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.

4. 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

5. 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.

6. 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

7. 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.

8. 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

9. 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

10. 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.

11. 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

12. Sensory GatingPrimacy 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.

13. 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.

14. 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

15. 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

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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

23. 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.

24. 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

25. 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

26. Organophosphate Toxicity • Well documented impairment of cognition due to poisoning of cholinergic systems • Simultaneous poisoning of autonomic nervous system

27. 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.

28. 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

29. 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

30. 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

31. Normal Dementia Normal Dementia 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. 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.

32. 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.

33. 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

34. 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

35. 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