AGNOSIA and INSIGHT Subclinical Stress and Disorders of Belief GRAND ROUNDS Graduate Department of Medicine, UT Medical

2. AGNOSIA and INSIGHTSubclinical Stress and Disorders of Belief GRAND ROUNDS Graduate Department of Medicine, UT Medical Center 10 June 2008 Neil Greenberg Departments of Ecology and Evolutionary Biology, Psychology, and Medicine University of Tennessee

3. OBJECTIVES Research experiences that have helped me think about cognitive dysfunction in new ways Stereotyped behavior in a model animal Ventral striatal lesions and social agnosia Subclinical stress modulating social hierarchy Reciprocity of two forms of reality testing: correspondence and coherence UT-GSM2008

4. ETHOLOGICAL BACKGROUND Precise behavioral description is crucial … and enables a close analysis of prospective causes and consequences of the behavioral pattern from the perspectives of: DEVELOPMENT (e.g., changing competence of perceptual, integrative, and action systems throughout the organism’s ontogeny and environmental experiences) ECOLOGY (e.g., specific behavioral patterns can be highly context dependent and are assessed for optimality in specific environments at specific times) UT-GSM2008

5. ETHOLOGICAL BACKGROUND EVOLUTION (e.g., specific behavioral patterns have assembled from often isolated traits which have been “recruited” to work together under the influence of alternate unifying control system) PHYSIOLOGY (e.g., diverse structures often converge to control specific behavioral patterns but are modulated by diverse stress hormones (epi, norepi, ACTH, MSH, CS, opioids, prolactin, angiotensin), each most effective at a specific concentration at a specific site) This is “DEEP” ethology to undergraduates UT-GSM2008

6. GNOSIS • Beliefs (or the lack thereof) engage specific neural structures that coordinate and represent correspondence(…of information with reality; external validity) and coherence (…of information with other preceding or collateral percepts; internal validity) • DISORDERS of BELIEF • Can reflect an uncoupling of specific neural structures leading to investments of confidence without the appropriate checks and balances UT-GSM2008

7. BASAL GANGLIA • Stereotyped behavior is an efficient expression of behavioral patterns that need to be precise. (this precision can discriminate syndromes as well as species) • But under stress these can become dysfunctional stereotypieswhich can in principle be anxiolytic.

8. BASAL GANGLIA • Animal Model • -- In the lizard, Anolis, preciselesions in ventral striatum will eliminate the species typical display that evokes social aggression without affecting any other known behavior, including courtship. • -- When aggression is allowed, social hierarchies quickly form and subordinates manifest an adaptive stress response that enables social stability. • --The stress hormone profile changes from uncontrolled to controlled coping, and • -- subordinates neglect reproductive opportunities (further reducing stress and stabilizing the male-male relationship.

9. The Anolis Model

10. Chromomotor model for the stress response • Acute, repetitive, or sustained stressors are integrated in the CNS • Autonomic neurons activate the adrenal medullary response • H-P-A axis integrates the adrenal cortical response • The Anolis body color thus reflects underlying neuroendocrine coping activities • Body color reflects autonomic tone

11. MSH and aggression • Acute stress depletes MSH • Agonistic winners manifest typical stress response: down (56% (of control values) • Agonistic losers, MSH is slightly up (127% (of control values) • Social Dominants, MSH is slightly up (128% of control values) • Social Subordinates, MSH is significantly up (217% of control values)

12. Establishment of social dominance hierarchy – Behavioral changes Color: significantly darker in subordinates Posture: comparable, subordinates slightly lower Site selection: significantly lower in subordinates Will NOT court females

13. LONG-TERM PHYSIOLOGICAL CONSEQUENCES OF LOSING • ANDROGEN REDUCED (Greenberg & Crews 1990) • CORTICOSTERONE ELEVATED (Greenberg et al. 1984) • MSH INCREASED (relative to dominants, Greenberg, Chen, and Vaughan 1986) • DOPAMINE ACTIVITY DIMINISHED, ADRENERGIC ACTIVITY ENHANCED IN THE MID AND HIND BRAIN (but back to control values by one month) (Summers & Greenberg 1995)

14. BASAL GANGLIA “a major evolutionary trend is the progressive involvement of the cortex in the processing of the thalamic sensory information relayed to the BG of tetrapods. … new insights [include] the segmental organisation of the midbrain dopaminergic cell groups, the occurrence of large numbers of dopaminergic cell bodies within the telencephalon itself, and the variability in connectivity and chemoarchitecture.” (Smeets et al. 2000)

15. VENTRAL STRIATUM and STRESS Ventral striatum monitors reliability of predictions made in prefrontal cortex … Such expectations can be cognitive as well as motor … All dissonances evoke stress in proportion to the error function… and perceived urgency of need that may be compromised UT-GSM2008

16. Connection between BASAL FOREBRAIN, and AMNESIA ?? A bleed into the anterior portion of the left basal ganglia. (nAcc & some of internal capsule, some vent caudate) Attention & executive function unimpaired, but anterograde amnesia. nucleus accumbens Goldenberg et al. 1999) UT-GSM2008

17. Effects of glucocorticoids in depression Drevets & Schulkin 2003

18. STRESS “… acute, uncontrollable stress: We become distracted and disorganized, and our working memory abilities worsen, leaving prepotent or habitual responses to control our behavior …” • Catecholamines (dopamine, norepinephrine, and epinephrine) reallocate • somatic resources for fight or flight (heart & muscles enhanced, stomach inhibited) • and cerebral resources for thought or prepotent action (subcortical structures enhanced, cerebral cortical structures inhibited via DA D1s and NE A1s) – Arnsten 1998 Perceived lack of control: impaired pfc; perceived control: enhanced performance of simple well rehersed acts UT-GSM2008

19. STRESS • . • Stimuli that affect the relative activation or relaxation of the stress response can be real or perceived. (placebo effect?) • Stressors are assessed for controllability • Perceived as controllable or uncontrollable, • Stress responses are hierarchically evoked, and can affect different neural structures at different levels of activation UT-GSM2008

20. STRESS and the EVOLUTION of BEHAVIOR The “Ritualization” of signals a model: fragments of motor patterns or autonomic reflexesbecome temporally or spatially associated as an ensemble (Morris 1956, Hinde and Tinbergen 1958) The “Central Adaptation Syndrome”(Huether 1996). Controllable stressors lead to a “go and specialize” strategy (e.g., earlier recognition and avoidance, improved fighting strategies, refined submission behavior) Uncontrollable stressors lead to a “wait and reorganize” strategy (e.g., CS reorganization of neural circuits; tuning of learning, motivation, and emotional states)

21. STRESS and the EVOLUTION of BEHAVIOR Stress-sensitive intersections of motivation, affect, and cognition are candidates for evolutionary change. Valence of affect : positive, cortical-limbic areas; negative, subcortical-limbic areas(Paradiso et al. 1999) note: male anoles with subcortical lesions act like castrates- they attend stimuli but are not motivated to respond aggressively (“social agnosia,” recalling autistic failure to recognize signals) Active versus passive copingparallel autonomic strategies correlated with activity in discrete columns of periaquaductal gray(Bandler et al. 2000)

22. COPING RESPONSES:delicately balanced alternatives ! • “Fight or flight” (the classic stress alternatives to imminent aggressive threat –not only in animals with a cerebral cortex!) • “Flee or freeze”(lizards can apparently calculate prospects for survival based on external threat , internal resources, and environmental possibilities) • “Green or brown” (the Anolis carolinensis dermal chromatophore –the “chromomotor model”)

23. SURVEY: stress-sensitive behavior • Detection, Arousal and Attention(steroids affect sensory thresholds, EPI intensifies; acute CS enhances salience) • Activity(CRF facilitates in familiar habitat, inhibits in unfamiliar habitat) • Exploration(CRF and ACTH enhances effects of novelty, CS facilitates) • Learning and memory( EPI, CRF, MSH facilitate acquisition) • Cognition( catecholamine modulation; taking prefrontal cortex “offline” (Arnsten))

24. SURVEY: stress-sensitive behavior • Feeding( CS stimulates or inhibits depending on circulating levels) • Aggression(ACTH suppresses, CS increases or decreases depending on circulating levels) • Social Dominance(CS increases submissiveness) • Reproduction( ACTH, CS, opiods, and prolactin impair HPG axis) • Dysfunctional behavior(stereotypies, neuroses, psychoses)

25. AGNOSIA Agnosia: an absence of belief: an inability to recognize objects, persons, sounds, shapes, or smells; no sensory deficit, no memory loss. • Simultanagnosia: inability to recognize more than one object or detail in their visual field at a time (common symptom of Balint's syndrome) • Prosopagnosia: (aka facial agnosia; TMWMWH) • Anosognosia: denial or unawareness of handicap (assoc w/ damage to nondominant (usually rt) cerebral hemisphere ( “disorder of belief”)

26. HYPERGNOSIA Hypergnosia: an intense belief in the validity of experience: free-floating Focused (?) “importance” of objects, persons, sounds, shapes, or smells and/or their relationships. Transcendent (a “glimpse beyond,” associated with the aura of “limbic epilepsy” (MacLean); not connected to specific percept) Integrative (connectedness, sense of harmony, resonant relationships)

27. SOCIAL AGNOSIA SOCIAL-EMOTIONAL AGNOSIA • right cerebral, or bilateral temporal and amygdala injury. An inability to correctly perceive or comprehend social-emotional nuances conveyed through voice, gesture, or facial expression (Joseph, 2000).

28. BELIEF Belief is the psychological state in which an individual is more-or-less confident in the validity of a proposition. (confidence can translate into biological fitness … if sufficiently high you might bet your life … even your immortal soul.) Validity can be more-or-less • internal (limited application; eg, individual) or • external(broad application; eg, population)

29. LEFT - RIGHT HEMISPHERE LATERALITY • When separated, EACH hemisphere is UNAWARE of the ipsilateral world • Yet neither is aware of being incomplete • Each functions as best it can with the information available

30. LEFT HEMISPHERE Coherence creates a consistent belief system – works to “save appearances” (Ramachandran 1998) Probabilistic reasoning (Osherson et al 1998) Abstract object recognition (Marsolek 1999) Activated by familiar percepts (Goldberg 2001) RIGHT HEMISPHERE Correspondence “skeptical,” tests reality and if damaged, confabulation runs rampant (Ramachandran 1998) Deductive reasoning (Osherson et al 1998) Specific object recognition (Marsolek 1999) Activated by unfamiliar percepts (Goldberg 2001)

31. DISORDERS of BELIEF? Acceptance of experience that doesn’t correspond to external reality:kinds of hallucinations, Bonnet’s Syndrome(filling in scotoma),body dismorphic disorder (?) (False positive (confident match with memories); Type I Error)) MORE CONSERVATIVE Denial of experience that corresponds to external reality: agnosias: eg, visual(left occip), associative, anasognosia(denial of dysfunction / right cerebral cortices), prosopagnosia(faces) (False negative (failure to match with memories); Type II Error))

32. Anosognosia • ANOSOGNOSIA: a term derived from the Greek: A + nosos (disease) + gnosis (knowledge) • Described by Babinski in 1914 • Ignorance or denial of the presence of disease • Most famously of paralysis in patients with non-dominant (usually right) parietal lobe damage -- patients deny their hemiparesis, & confabulate rationalizations • Right hemisphere seems unable to detect discrepancies between internal model and feedback, and left-side function works to “save appearances” or is “hallucinated.”

33. ambition • Can the perspectives that we are growing confident of help us understand gnosis with precision enough to understand their causes and remediate their dysfunctions? • Can growing insight into the implicit and explicit forms of gnosis allow us to help the system struggling to maintain stability in the face of changing competencies? UT-GSM2008

34. b. 1913 Yale 1935 Medical research during WWII “Limbic System” 1952 NIH 1957 NIMH lab chief 1971 Senior Research Scientist Emeritus 1985 d. Dec. 26, 2007 Paul D. MacLean