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Finding and Fixing Broken Brain Circuits in Depression Conor Liston, MD, PhD Brain and Mind Research Institute and Department of Psychiatry Weill Cornell Medicine

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Page 1: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Finding and Fixing Broken Brain Circuits

in Depression

Conor Liston, MD, PhD

Brain and Mind Research Instituteand Department of Psychiatry

Weill Cornell Medicine

Page 2: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Social and Economic Burdens of Mental Illness

St. Elizabeth’s Hospital, Washington, DCSt. Elizabeth’s Hospital, Washington, DC% of Total Burden of

Disease (Years Lost)

Annual Economic

Costs of Depression

$70.7B

$28B

$ 102B

$9.7B

Total Annual Costs

in US:

$210 billion

Sources: World Health Organization; CDC;

Jiang & Hessler, 2012; Greenberg et al., 2010

Page 3: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

256 unique manifestations of depression

St. Elizabeth’s Hospital, Washington, DCChoose 5 or more of 9 symptoms:

1. Depressed or irritable mood2. Decreased interest in activities3. Weight loss (or weight gain)4. Insomnia (or hypersomnia)5. Psychomotor agitation (or retardation)6. Fatigue or loss of energy7. Rumination on guilt / worthlessness8. Impaired concentration9. Suicidal thoughts

Page 4: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Defining Subtypes of Depression

St. Elizabeth’s Hospital, Washington, DC

MelancholicDepression

AtypicalDepression

SeasonalDepression

CatatonicDepression

DEPRESSION

NeurophysiologicalCorrelates

NeurophysiologicalCorrelates

NeurophysiologicalCorrelates

NeurophysiologicalCorrelates

Page 5: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Defining Subtypes of Depression: An Alternative Approach

Neurophysiological Subtype 1

DEPRESSION

ClinicalCorrelates

Neurophysiological Subtype 2

Neurophysiological Subtype 3

ClinicalCorrelates

ClinicalCorrelates

Page 6: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Defining Subtypes of Depression: An Alternative Approach

Page 7: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Finding Broken Brain Circuits in Depression

Whole-brain “connectivity” map

Correlated fluctuations in “connected”brain regions

Page 8: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Finding Broken Brain Circuits in Depression

Cornell: Andrew Drysdale, Marc

Dubin, B.J. Casey, Faith Gunning,

George Alexopoulos, Henning Voss

Stanford: Amit Etkin, Alan Schatzberg

Emory: Helen Mayberg

Toronto: Jonathan Downar

Harvard: Mike Fox, Alvaro Pasqual-

Leone

Consultation and Advice: Jonathan

Power (NIMH), Damien Fair (OHSU),

Logan Grosenick (Stanford)

1000 Functional Connectomes Project

Dataset 1: 711 subjects (333 unipolar depressed patients from 5 sites) => training/optimization

Dataset 2: 477 subjects (215 unipolar depressed patients from 4 sites) => replication

Page 9: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Finding Broken Brain Circuits in Depression

Drysdale et al., Nature Medicine, 2017

Page 10: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Finding Broken Brain Circuits in Depression

Drysdale et al., Nature Medicine, 2017

Page 11: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Broken Circuits Underlying Four Depression Subtypes

Drysdale et al., Nature Medicine, 2017

Page 12: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Broken Circuits Underlying Four Depression Subtypes

Drysdale et al., Nature Medicine, 2017

Page 13: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Broken Circuits Underlying Four Depression Subtypes

Subtype 1 Subtype 2 Subtype 3 Subtype 4

Page 14: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Depression Subtypes Predict Differing Symptoms

Page 15: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Developing Biomarkers for Diagnosing Depression Subtypes

Page 16: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Developing Biomarkers for Diagnosing Depression Subtypes

Page 17: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

“Depression Subtypes” Cross Diagnostic Boundaries

Page 18: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

“Depression Subtypes” Cross Diagnostic Boundaries

MDD:

AnxietyAnhedonia

Page 19: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Fixing Dysfunctional Brain Circuits in Depression

Repetitive Transcranial Magnetic Stimulationof the left dorsolateral prefrontal cortex

(3000 pulses per session delivered at 10 Hz, 25 sessions)

Liston et al., Biol Psych, 2014With Marc Dubin, Ashley Chen, Amit Etkin

Page 20: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Fixing Dysfunctional Brain Circuits in Depression

Page 21: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Toward Precision Medicine For Depression

With Jonathan Downar, Marc Dubin, Faith Gunning

Page 22: Finding and Fixing Broken Brain Circuits in Depression...256 unique manifestations of depression Choose 5 or more of 9 symptoms: St. Elizabeth’s Hospital, Washington, DC 1. Depressed

Thank you!Cornell Lab Members:

Andrew Drysdale

Rob Fetcho

Baila Hall

Ben Huang

Thu Huynh

Yue Meng

Rachel Moda

Mitchell Murdock

Puja Parekh

David Rosenthal

Joseph Stujenske

Tim Spellman

Jonathan Witztum

Naomi Xia

Cornell Collaborators:

Marc Dubin

Faith Gunning

George Alexopoulos

Jonathan Power

Francis Lee

Other Financial Support:

Other Collaborators:

Toronto:

Jonathan Downar

Yale:

B.J. Casey

Harvard:

Mike Fox

Alvaro Pasqual-Leone

Emory:

Helen Mayberg

Stanford:

Amit Etkin

Alan Schatzberg

Karl Deisseroth

Logan Grosenick

Emily Ferenczi

Gary Glover


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