Title: Abnormal Brain Connectivity in Mooddisordered Individuals: Promising Future Pathways
1Abnormal 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
2Bipolar 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.
3Misdiagnosis of bipolar disorder
Percentage of Patients
Hirschfeld RM. Lewis L. Vornik LA.. Journal of
Clinical Psychiatry. 64(2)161-74, 2003 Feb.
4The Search for Neurobiological Markers of Bipolar
Illness
5(No Transcript)
6Voluntary 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
7Automatic 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
8Phenotype Bipolar Disorder and Bipolar
spectrum
Endophenotypes Biological Mechanisms
Genotype
Hasler G, et al. Biol Psychiatry
200660(2)93-105.
9Neuroimaging 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
10Neural Systems for Emotion Regulation inBipolar
Disorder
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12MILD 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
13Orbitomedial prefrontal Cortex
Amygdala
Uncinate Fasciculus
14Right-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
15Functional Connectivity
16Bipolar Disorder Left-Right Asymmetry of
Abnormal Functional Connectivity to Emotion
Bipolar ltControls P0.002
BipolargtControls P0.000004
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18Bipolar 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
19Potential 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
20Can Neuroimaging Help Distinguish between Bipolar
and Unipolar Depression?
21MILD 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
22Bipolar Depressed show significantly reduced
right uncinate fasciculus longitudinal fiber
alignment than unipolar depressed
Plt0.001, corrected
Versace et al., in preparation
23Left OFC ? amygdala reduced positive effective
connectivity in BD depressed inverse
connectivity to happy faces in unipolar depressed
BD DEPRESSED
UNIPOLAR DEPRESSED
HEALTHY
HAPPY
24- Identifying Biological Mechanisms in Bipolar
Disorder - A Neural Systems Approach
Neural System abnormalities
Regional abnormalities
25Treatment ResponseBiological Mechanisms
26Decreases 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
27rTMS 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?
28Markers of future development of versus
protection against bipolar disorder in healthy at
Risk Youth?
29Risk 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
30BDI 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
31BD-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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33Neuroimaging 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
34-
- 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