Examining pathophysiologic mechanisms in psychiatric disorders: the role of fMRI

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Examining pathophysiologic mechanisms in
psychiatric disorders the role of fMRI

• Mary L. Phillips, MD
• University of Pittsburgh
• Western Psychiatric Institute and Clinic
• Pittsburgh, Pennsylvania
• Institute of Psychiatry
• London, United Kingdom

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Neuroimaging Why Important in Psychiatry?

• To understand the functional neural basis of
  psychiatric disorders
• To obtain neural markers / disease biomarkers and
  endophenotypes to aid diagnosis
• To identify disease enophenotypes to help
  predict treatment response

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Phenotype Bipolar Disorder and Bipolar
spectrum
Endophenotypes
Genotype
Hasler G, et al. Biol Psychiatry
200660(2)93-105.
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Phillip ML Frank E. Am J Psychiatry
2006163(7)1135-1136.
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Laboratory of Neuro Imaging, UCLA
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Morris JS et al. Nature. 383(6603)812-5,1996.
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Re-Appraisal of Negative Scenes
Blue inverse correlation with intensity of
negative emotion Orange positive correlation
relationship with intensity of negative emotion
Phan, KL et al. Biological Psychiatry.
57(3)210-9, 2005
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Hippopcampus and Parahippocampus Novelty
Detection, Context Processing, Mood Regulation
Brown MV Aggleton JP. Nat Rev Neurosci
20012(1)51-61.
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Two Neural Systems for Emotion
Amygdala
VLPFC Orbitofrontal cortex Ventral ACG
Regulation/ Reappraisal
Visual cortex
DLPFC DMPFC Dorsal ACG Hippocampus
DLPFC DMPFC Dorsal ACG
Thalamus Ventral striatum Brainstem nuclei
Identification emotional
experience
Phillips ML, et al. Biolo Psychiatry
200354504-514.
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Two Neural Systems for Emotion
Hippocampus Parahippocampal gyrus DMPFC Dorsal
ACG
Visual cortex
DLPFC VLPFC
Amygdala
Orbitofrontal cortex Ventral ACG
Thalamus Ventral striatum
Reappraisal/ Regulation
Early appraisal/ visceromotor regulation
Orienting/ Identification
Phillips ML, et al. (In preparation).
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Biomarkers of BipolarDisorder

• Nature abnormalities in function in neural
  systems underlying emotion processing
• Persistence abnormalities present during
  remission as well as depression?
• Specificity distinguish bipolar from unipolar
  depression

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Nature Bipolar Disorder
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fMRI Amygdala Reactivity Paradigm
Altshuler LL, et al., Biol Psychiatry
200558(10)763-769.
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BPgtHC Happy faces1
BPgtHC Fear faces2
BPlt HC Fear faces2
1Blumberg HP, et al. Bipolar Disord
20057(6)570-576.
2Yurgelun-Todd DA, et al. Bipolar Disord 20002(3
Pt 2)237-248.
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Bipolar Remission
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INTENSE FEAR
L amygdala / ventrolateral PFC
CON BD MDD
Lawrence NS, et al. Biol Psychiatry
200455578-587.
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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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Depressed vs. Remitted Bipolar
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Two Neural Systems for Emotion
Hippocampus Parahippocampal gyrus DMPFC Dorsal
ACG
Visual cortex
DLPFC VLPFC
Amygdala
Orbitofrontal cortex Ventral ACG
Thalamus Ventral striatum
Reappraisal/ Regulation
Early appraisal/ visceromotor regulation
Orienting/ Identification
Phillips ML, et al. (In preparation).
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Bipolar Disorder
Hippocampus Parahippocampal gyrus DMPFC Dorsal
ACG
Visual cortex
DLPFC VLPFC
Amygdala
Orbitofrontal cortex Ventral ACG
Thalamus Ventral striatum
Reappraisal/ Regulation
Early appraisal/ visceromotor regulation
Orienting/ Identification
Phillips ML, et al. (In preparation).
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Bipolar VersusUnipolar Depression
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Linear Increases to Increasing Intensity of
Happiness Healthy Individuals gtMDD
Healthy
Depressed
Surguladze S, et al. Biol Psychiatry
200557201-209.
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Linear Increases to Increasing Intensity of
Sadness MDD gt Healthy individuals
Depressed
Healthy
Surguladze S, et al. Biol Psychiatry
200557201-209.
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Two Neural Systems for Emotion
Hippocampus Parahippocampal gyrus DMPFC Dorsal
ACG
Visual cortex
DLPFC VLPFC
Amygdala
Orbitofrontal cortex Ventral ACG
Thalamus Ventral striatum
Reappraisal/ Regulation
Early appraisal/ visceromotor regulation
Orienting/ Identification
Phillips ML, et al. (In preparation).
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Unipolar Depression
Hippocampus Parahippocampal gyrus DMPFC Dorsal
ACG
Visual cortex
DLPFC VLPFC
Amygdala
Orbitofrontal cortex Ventral ACG
Thalamus Ventral striatum
Reappraisal/ Regulation
Early appraisal/ visceromotor regulation
Orienting/ Identification
Phillips ML, et al. (In preparation).
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Unipolar Depression
Hippocampus Parahippocampal gyrus DMPFC Dorsal
ACG
Visual cortex
DLPFC VLPFC
Amygdala
Orbitofrontal cortex Ventral ACG
Thalamus Ventral striatum
Reappraisal/ Regulation
Early appraisal/ visceromotor regulation
Orienting/ Identification
Phillips ML, et al. (In preparation).
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Biomarkers that predicttreatment response?
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Predictors of Antidepressant Response in MDD
Mayberg H, et al. NeuroReport 199781057-1061.
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Siegle GJ, et al. Am J Psychiatry
2006163(4)735-738.
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Decreased Limbic-Cortical Neural Activity to Sad
Faces Over Time Associated With Increased
Response to Antidepressants in MDD
Change in trend 100gt50gtneutral Sad
Happy
Keedwell P, et al. (in submission).
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BPI Depression Prefrontal Cortical Activity
Changes With Response to Repeated Total Sleep
Deprivation combined With Light Therapy for 1
Week
Benedetti F, et al. Arch Gen Psychiatry
200764179-187.
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Bipolar Disorder Endophenotypes in at Risk
Populations?
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Emotion Challenge Toward Neural Endophenotypes?
Kruger S, et al. Am J Psychiatry
2006163257-264.
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Participants BPHR No Axis I
Note Pubertal scores range from 1 to 4. There
were no significant group differences for any of
these variables.
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BPHR Brain Structure
Plt0.05, corrected
BPHRgtControls Hippocampus, Parahippocampal
gyrus
ControlsgtBPHR DLPFC
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BHR Brain Function Mild Happy Faces vs. Fixation
BPHR gt CONT
BPHR lt CONT
Anterior/rostral Cingulate t(93)3.09, p.001
Right Putamen t(93)1.95, p.03
Ladouceur et al., in prep.
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Summary

• Identifying disease biomarkers Neuroimaging can
  help distinguishdifferent psychiatric disorders
• Identifying predictors of treatment response
  Neuroimaging can help predict treatment response
• Identifying bipolar disorder endophenotypes in at
  risk populations

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• Institute of Psychiatry, London, UK
• Simon A. Surguladze Natalia Lawrence
• Maike Heining Jeffrey Gray
• Paul Keedwell Tamara Russell
• Andrew Williams Catherine Herba
• Sophia Frangou
• Natalie Kerr
• David Mataix-Cols
• Sarah Wooderson
• University of Cambridge, UK
• Dina Kronhaus
• Luke Clarke
• Barbara Sahakian
• Univeristy of Pittsburgh
• Cecile Ladouceur
• Jorge Almeida
• Amelia Versace

Grant Support Medical Research Council (UK) The
Wellcome Trust James McDonnell Pew
Foundation NARSAD