Abnormal Brain Connectivity in Mooddisordered Individuals: Promising Future Pathways

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Abnormal Brain Connectivity in Mood-disordered
Individuals Promising Future Pathways

• Mary L. Phillips, MD
• University of Pittsburgh
• Western Psychiatric Institute and Clinic
• Pittsburgh,
• Department of Psychological Medicine
• Cardiff University
• Institute of Psychiatry
• London, United Kingdom

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Bipolar Disorder

• Episodes of low mood depression - and high mood
  mania
• One of the ten most debilitating illnesses
  worldwide (Murray and Lopez, 1996). Approx. 11
  suicide rate
• Only 20 received correct diagnosis within a year
  of first consultation
• 35 did not receive correct diagnosis for 10
  years or more
• Misdiagnosis leads to incorrect treatment

Hirschfeld RM. Lewis L. Vornik LA.. Journal of
Clinical Psychiatry. 64(2)161-74, 2003 Feb.
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Misdiagnosis of bipolar disorder
Percentage of Patients
Hirschfeld RM. Lewis L. Vornik LA.. Journal of
Clinical Psychiatry. 64(2)161-74, 2003 Feb.
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The Search for Neurobiological Markers of Bipolar
Illness
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Voluntary Emotion Regulation Feedback Pathway
DLPFC
Dorsal ACG
MdPFC
Rostral ACG
Ventral Striatum
VLPFC
Thalamus
OFC Subgenual ACG
Hipp/parahipp
Amygdala
Orienting/Emotion Identification Automatic
Emotion Regulation Voluntary Emotion Regulation
Regions implicated in both
Phillips, Ladouceur, Drevets, 2008 Molecular
Psychiatry
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Automatic Emotion Regulation Feedforward Pathway
DLPFC
Dorsal ACG
MdPFC
Rostral ACG
Ventral Striatum
VLPFC
Thalamus
OFC Subgenual ACG
Hipp/parahipp
Amygdala
Orienting/Emotion Identification Automatic
Emotion Regulation Voluntary Emotion Regulation
Regions implicated in both
Phillips, Ladouceur, Drevets, 2008 Molecular
Psychiatry
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Phenotype Bipolar Disorder and Bipolar
spectrum
Endophenotypes Biological Mechanisms
Genotype
Hasler G, et al. Biol Psychiatry
200660(2)93-105.
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Neuroimaging of Emotion in Bipolar Disorder

• Goal Identifying Biological Markers of Bipolar
  Illness

Abnormalities in Neural Systems for Emotion
Regulation
Identifying Youth with genetic loading most
likely to develop bipolar disorder
Improving Diagnosis Bipolar versus Unipolar
Depression
Biological Targets for New Treatment Development
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Neural Systems for Emotion Regulation inBipolar
Disorder
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MILD HAPPY
MDD
CON
BD
L amygdala / putamen
ventromedial PFC
.04
neural response
0
- .02
CON BD MDD
CON BD MDD
Lawrence NS, et al. Biol Psychiatry
200455578-587
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Orbitomedial prefrontal Cortex
Amygdala
Uncinate Fasciculus
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Right-left asymmetry in structure of white matter
tracts between prefrontal cortex and amygdala in
bipolar disorder
L
Left more streamlined wiring
Right more noisy wiring
L
R
L
Versace et al., 2008 Arch. Gen Psychiatry
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Functional Connectivity
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Bipolar Disorder Left-Right Asymmetry of
Abnormal Functional Connectivity to Emotion
Bipolar ltControls P0.002
BipolargtControls P0.000004
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Bipolar DisorderAbnormal functional and
structural connectivity in neural systems for
emotion regulation

• Right OFC-Right amygdala connectivity
• Bad wiring fibers oriented more radially than
  normal
• Too much noise Elevated OFC -amygdala
  functional coupling to SAD
• Left OFC-Left amygdala connectivity
• More streamlined wiring fibers oriented more
  longitudinally than normal
• Not enough cross talk Decreased OFC-amygdala
  functional coupling to HAPPY
• TOGETHER
• Elevated attention to sad may predispose to
  negative ruminations and depression
• Reduced regulation of response to happy
  predisposes to switches to mania

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Potential Impairments in Neural Systems of
Emotion Regulation in Bipolar Disorder
DLPFC
Dorsal ACG
MdPFC
Ventral striatum
Rostral ACG
VLPFC
OFC Subgenual ACG
Thalamus
Hipp/parahipp
Amygdala
Left-Right Asymmetry
Phillips, Ladouceur, Drevets, 2008 Molecular
Psychiatry
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Can Neuroimaging Help Distinguish between Bipolar
and Unipolar Depression?
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MILD HAPPY
MDD
CON
BD
L amygdala / putamen
ventromedial PFC
.04
neural response
0
- .02
CON BD MDD
CON BD MDD
Lawrence NS, et al. Biol Psychiatry
200455578-587
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Bipolar Depressed show significantly reduced
right uncinate fasciculus longitudinal fiber
alignment than unipolar depressed
Plt0.001, corrected
Versace et al., in preparation
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Left OFC ? amygdala reduced positive effective
connectivity in BD depressed inverse
connectivity to happy faces in unipolar depressed
BD DEPRESSED
UNIPOLAR DEPRESSED
HEALTHY
HAPPY
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• Identifying Biological Mechanisms in Bipolar
  Disorder
• A Neural Systems Approach

Neural System abnormalities
Regional abnormalities
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Treatment ResponseBiological Mechanisms
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Decreases in abnormally elevated limbic-cortical
neural activity to sad faces post treatment
associated with greater response to
antidepressants in MDD
Keedwell et al., 2008, in press J. Psychopharm
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rTMS a Treatment for Bipolar Depression?
Transcranial magnetic stimulation (rTMS) to left
DLPFC effective for major depression - a novel
treatment (OReardon et al., 2007) Bipolar
depression?
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Markers of future development of versus
protection against bipolar disorder in healthy at
Risk Youth?
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Risk for Bipolar Disorder in Bipolar
Subthreshold Youth

• Youth who fail to meet strict criteria for BDI
  BD-subthreshold youth
• 41 convert to BDI/BDII over four years
• Only measure that predicts conversion to BDI/BDII
  is having a first/second degree relative with
  BDI/BDII but still only a 53 conversion to
  BDI/BDII
• Tremendous implications for treatment
• overdiagnosis of BDI/BDII -- inappropriate
  treatment
• misdiagnosis of BDI/BDII -- no protective
  effect of mood stabilizing medications
• Imperative that objective markers are identified
  that determine with greater sensitivity and
  specificity and as early as possible which
  BD-subthreshold youth will develop BDI/BDI

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BDI Youth vs. Healthy Youth (Amygdala)
Right
Left
Repeated measures (Hemisphere and Stimulus type
as within subjects factors group as between
Subjects). Main Effect of group, F1,144.33,
plt.056
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BD-Subthreshold Youth vs. Healthy Youth (Amygdala)
Left
Right
Repeated measures (Hemisphere and Stimulus type
as within subjects factors group as between
Subjects). Stimulus x Group interaction,
F1,88.03, plt.022
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Neuroimaging of Emotion in Bipolar Disorder

• Goal Identifying Biological Markers of Bipolar
  Illness

Abnormalities in Neural Systems for Emotion
Regulation
Identifying Youth with genetic loading most
likely to develop bipolar disorder
Improving Diagnosis Bipolar versus Unipolar
Depression
Biological Targets for New Treatment Development
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• Univeristy of Pittsburgh
• Cecile Ladouceur
• Jorge Almeida
• Amelia Versace
• Vaibhav Diwadkar
• Stefanie Hassel
• Sivia Batzeati
• Crystal Klein
• Edward Labarbara
• Greg Siegle
• David Kupfer
• Kwan-Jin Jung
• Costin Tanase and Fernando Boada
• Myrna Pollock
• Ellen Frank
• Wesley Thompson
• All Staff and Faculty at BIRC, MRRC and
  Bellefields,

Grant Support 1R01 MH076971-01 NARSAD Medical
Research Council (UK) The Wellcome Trust
(UK) James McDonnell Pew Foundation
University of Sao Paulo, Brazil Marcus
Zanetti Geraldo Bussato