Emotion and Neuropathology of mood Emotional Systems Brain

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Emotion and Neuropathology of mood

• Emotional Systems
• Brain Systems and
• Depression

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Emotions
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Emotions involve

• Skeletomotor response
• Autonomic nervous system activation/ Endocrine
  activation
• Subjective state

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The brain and emotion

• Hypothalamus controls autonomic, endocrine and
  somatic responses
• Cingulate and prefrontal cortex are responsible
  for conscious emotional experience
• Amygdala helps coordinate the conscious
  experience of emotion and peripheral expressions
  of emotion
• Emotional conditioning is implicit memory

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HYPOTHALAMUS

• Coordinates the autonomic and somatic responses
  to emotional stimuli
• Animal studies demonstrates that stimulation of
  various hypothalamic regions induces emotional
  behaviors

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Limbic Lobe
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Limbic Structures
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Papez circuit
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Amygdala
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Amygdala
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Amygdala

• Bursts of EEG activity in amygdala during
  recollection for specific emotional events
  (Halgren, 1981)
• Electrical stimulation of human amygdala can
  evoke emotional experiences, especially fear or
  anxiety (Gloor et al., 1982)
• Imaging studies show that recognition of
  emotional expressions involves the amygdala
  (Morris, et al., 1996)

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Isenberg et al., 1999
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Amygdala is activated specifically when seeing
threatening words
Isenberg, et al., 1999, Proc Nat Acad Sci
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Activation of left amygdala with facial
expression discrimination (Morris, et al. 1996)
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Patient S.M. bilateral damage to the amygdala
Adolphs, 1999
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Amygdala lesions impair recognition of emotions
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Adolphs, 2003
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Amygdalas role in emotional conditioning

• Basolateral and Central nuclei play an important
  role in emotional learning, particularly fear
  learning
• LTP occurs in the amygdala during emotional
  learning

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Amygdala may also be important for pleasurable
responses

• Lesions of basolateral n. disrupt association of
  stimulus with rewarding attributes of food.
• Context conditioning, or place preference
  (stimuli such as food to sexual partners)

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Amygdala mediates both the autonomic expression
and cognitive experience of emotion

• Sends projections to hypothalamus
• Sends projections to the cingulate and prefrontal
  cortices

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Cortical Control of EmotionsHistorical look

• Phineas Gage, mid 1800s
• 1935 Fulton and Jacobsen lobotomy calmed
  chimpanzees
• Egas Moniz performed the first human prefrontal
  lobotomy (cut limbic association connections)

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Phineas Gage
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Cortical Control of EmotionsHistorical look

• Phineas Gage, mid 1800s
• 1935 Fulton and Jacobsen lobotomy calmed
  chimpanzees
• Egas Moniz performed the first human prefrontal
  lobotomy (cut limbic association connections)

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Cortex

• Multiple areas of the medial and orbital
  prefrontal cortex cingulate cortex modulate
  emotional behavior
• Extensive, reciprocal projections with the
  amygdala
• Modulate autonomic and endocrine responses

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• In patients with either amygdala or frontal lobe
  damage, there is a dissociation between autonomic
  responses to emotive stimuli and cognitive
  evaluation of those stimuli

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Mood DisorderDepression
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Depression

• Many antecedents to depression
• Genetic
• Medical
• Psychosocial
• Diversity in response to therapies
• Variable presence of neuroendocrine,
  neurochemical, neuroanatomical, circadian rhythm
  disturbances

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Hippocampal reductions in individual with
recurrent depressive episodes
Campbell, et al. 2004, J Psychiatry Neurosci, 29,
417-426
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Brain abnormalities

• Prefrontal cortex
• Basal Ganglia
• Hippocampus
• Amygdala
• Thalamus
• Cerebellum

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Hippocampus is not the only area altered in
depressive illness

• Amygdala (Sheline et al., 1998)
• Prefrontal cortex (Drevets, et al., 1997)

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AMYGDALA

• Amygdala blood flow and metabolism correlate
  positively with depression severity and
  dispositional negative affect
• Antidepressants can normalize
• Individuals who maintain high levels of activity
  during remisson are more likely to relapse
• May be associated with anxiety
• Glucocorticoids enhance NE release into the
  amygdala (Ferry et al., 1999)

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Familial MDD compared to controls
Drevets, 2001
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Overactive amygdala in familial pure depressive
disorder and bipolar disorder (during depression)
Drevets, 2001
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Amygdalar Projections

• Controls the hypothalamus, HPA axis
• Leads to behavioral changes
• Increased resting blood pressure, insomnia, and
  anxiety, and decreases in eating, grooming and
  sexual behavior

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Amygdala Dysfunction

• Hyperactivity could represent excessive or
  intrusive rumination over emotion-laden
  information, which the amygdala uniquely
  processes
• Decreased inhibition by DLPFC
• Increased NE and GCC could make neutral stimuli
  more emotionally significant
• Rumination Mechanism
• Related activity in posterior cingulate and IPC
  could be malfunctioning episodic memory retrieval

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Drevets, 2001
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Abnormal response to sad faces
Surguladze, et al. 2005
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Sustained amygdalar activity in the presence of
negative words
Siegle et al., 2002
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Amygdala volume is larger in first-episode major
depressives
Frodl et al., 2003
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Rosso et al,, 2005
20 children/adolescents with MDD vs. 24 controls
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Reductions in amygdala volume with recurrent
episodes
Sheline et al., 1998
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Cellular pathology in the amygdala
Browley, et al., 2002
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Browley, et al., 2002
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Astrocytes, as well as oligodendrocytes may be
altered
Hamidi, et al. 2004
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Hamidi, et al. 2004
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Changes in the prefrontal cortex

• Altered blood flow and glucose metabolism in
  limbic and prefrontal cortical structures (see
  Davidson, et al., 2002 for review)
• Some debate and inconsistent findings
• Increased activation in orbital cortex, medial
  thalamus, anterior cingulate
• Decreased activation in dorsomedial/dorsal
  anterolateral PFC, portions of the anterior
  cingulate cortex

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Increased activity of ventral and orbital
prefrontal cortical areas
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Orbital Ventrolateral PFC

• Increases in rCBF and Glucose metabolism found in
  both areas
• Related to emotional dysregulation and/or
  obsessive ruminations

Bremner et al., 2002
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Reductions in activity of subgenual PFC
Drevets, 2001
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Subgenual PFC

• Damasio (1997) postulates that discernment of
  punishment or reward is related to this area
• Dysregulation of emotional responses
• Difficulty using emotions to guide
  decision-making that is, cannot use
  emotionally-laden information in making decisions

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Dorsolateral Dorsomedial PFC

• In depressed, decreases in rCBF and glucose
  metabolism in both areas
• May contribute to cognitive and
  neuropsychological deficits.

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Prefrontal cortex

• Reduced activation of dorsolateral dorsomedial
  prefrontal cortex as well as subgenual region of
  anterior cingulate gyrus, particularly on the
  left side
• Sometimes decrease in these areas is accompanied
  with increase in lateral and medial prefrontal
  cortex

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Volume reductions

• May be loss of tissue in these areas of the
  prefrontal cingulate cortex (Elbis, et al., 1996
  Drevets, 1997)
• Also find abnormalities in the neurons and glial
  cells

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What does this mean?

• Loss of emotional regulation
• Perhaps the overactivity reflects attempts to
  suppress unreinforced, unpleasant thoughts and
  emotions and the underactive areas fail to lead
  to extinction of emotional responses

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Treatment with sertraline normalizes brain
activity
Drevets, 2002
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Malfunctioning Pathways

• Drevets (2001) postulates that depression
  represents a dysfunction of
• LTC Limbic-Thalamic-Cortical, or
• LCSPT Limbic-Cortical-Striatal-Pallidal-Thalamic

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Causes

• Genetic Predisposition (polygenic)
• Morbidity rate of depression is modestly higher
  in first-degree relatives
• High concordance in monozygotic twins compared to
  dizygotic twins
• Environmental factors
• Stress

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The Gene-Environment Interactionat work?

• Caspi et al. (2003) examined how stressful life
  events are related to genetic markers of
  depression
• Genetic Predisposition Functional Polymorphism
  in promoter region of Serotonin Transporter
  protein
• Short allele associated with lower
  transcriptional efficiency than Long
• Short allele associated with elevated amygdala
  activity

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The Gene-Environment Interactionat work?

• Ps with 2 Short alleles most likely to have
  experienced MDE given 1 stressful life events
• Number of life events increases risk for MDE,
  ranging from 10-33
• Those with 1 or 2 long alleles incrementally less
  likely to become depressed
• Odds of MDE increase with of stressful life
  events from 10-17
• Childhood maltreatment? 30 depressed in long
  allele group versus 70 in short!

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Future Needs in Research

• Relate specific abnormalities in particular brain
  regions to lab tasks that are sensitive to the
  function of those areas
• Measures of both functional and structural
  connectivity
• Longitudinal studies
• Postmortem studies
• On and off medication
• Relating depression subtype with neuropathology