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AGNOSIA and INSIGHT
Subclinical 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
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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

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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 organisms 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)

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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

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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

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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 stereotypies which can in
principle be anxiolytic.
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BASAL GANGLIA

• Animal Model
• -- In the lizard, Anolis, precise lesions 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.

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The Anolis Model
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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

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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)

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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

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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)

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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)
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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
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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)
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Effects of glucocorticoids in depression
Drevets Schulkin 2003
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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
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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

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STRESS and the EVOLUTION of BEHAVIOR

• The Ritualization of signals a model
• fragments of motor patterns or autonomic
  reflexes become 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)

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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 coping parallel autonomic
  strategies correlated with activity in discrete
  columns of periaquaductal gray (Bandler et al.
  2000)

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COPING RESPONSESdelicately 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)

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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))

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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)

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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)

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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)

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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).

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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)

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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

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LEFT HEMISPHERE Coherence creates a consistent
belief system works to save appearances (Ramac
handran 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)
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DISORDERS of BELIEF?

• Acceptance of experience that doesnt correspond
  to external reality kinds of hallucinations,
  Bonnets 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))

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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.

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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?

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Paul D. MacLean

• 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

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OVERVIEW

• BASAL GANGLIA
• Stereotyped behavior is an efficient expression
  of behavioral patterns that need to be precise
  these can become dysfunctional stereotypies under
  stress
• Social Agnosia in lower animals is a way of
  reducing stress

• STRESS
• Stressors are real or perceived
• Stress responses are hierarchically evoked and
  can affect different neural structures at
  different levels

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Hypothetical Causes of Anosognosia

• Freudian denial avoidance of confrontation with
  dysfunction, preserve self image.
• Phantom function as with phantom limbs, signals
  from motor cortex go to parietal monitoring area
  AND to muscles (that no longer exist). In the
  absence of feedback (confirming dysfunction)
  parietal area prevails
• Right hemisphere impairment would mute
  emotionality, flatten affect, and lead to
  apparent indifference