Aristotle Voineskos MD, PhD, FRCP(C)

Head, Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health

Assistant Professor, Department of Psychiatry and Institute of Medical Science, University of Toronto

Conceptualizing the Schizophrenias As Circuit Disorders

MicroCircuit Disruption in the DLPFC in Schizophrenia

Meyer-Lindenberg, Nature, 2010 (adapted from Lewis et al, JCI, 2009)

www.neuralcircuits.uwm.edu

Hippocampal MicroCircuits

Winterburn et al, Neuroimage in press

Toward Measuring Microcircuit Structure in vivo

MacroCircuits

Analysis of gray matter morphology.

Analysis of white matter connectivity. [Images from Gray’s Anatomy]

White-matter fibers connect gray-matter structures.

From Tensors to Tracts (tractography): Measuring Long-Range Macrocircuit Structure

Mori et al.,Ann Neurol 1999

Structure->Function of the Prefrontal Interhemispheric Circuit

Voineskos, Farzan et al, Biological Psychiatry, 2010

Wheeler et al, submitted

Long-Range Regional Coupling: Cortical Thickness and Macrocircuits

Wheeler et al, submitted

Long-Range Regional Coupling: Cortical Thickness and Macrocircuits

Catani et al, Cortex, 2012

Local MacroCircuits – Superficial White Matter

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-4

0

4

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N-Back Condition

Active

Sham

1-Back 3-Back

Percent change correct response to

target

4 weeks of rTMS to bilateral DLPFC improves working memory performance: Applied knowledge of circuit disruption using a novel intervention

Barr et al, Biological Psychiatry, 2012

Kirkpatrick et al, Psych Res, 1989 and Arch Gen Psych, 2001

Schizophrenia as a Heterogeneous Disorder: Implications for Identifying Circuit Disruption for Therapeutic Development

HC = Healthy Controls, NDS = nondeficit schizophrenia, DS = deficit schizophrenia

Voineskos et al JAMA Psychiatry in press

Neuroimaging Heterogeneity Among Schizophrenia Patients and Relationship with Clinical Heterogeneity

Right fronto-parietal circuit impairment and concomitant impairment in social function

Micro-RNA (miRNA): Genetic Heterogeneity, Brain Circuit Heterogeneity, Clinical Heterogeneity, and Novel Treatment Targets

Winter et al, Nat Cell Biol 2009

MIR-137, Age-At-onset, and Brain Structure

Lett et al, Molecular Psychiatry, in press

Take home points

• Circuit disruption is present in schizophrenia at the micro, short-range macro, and long-range macro levels

• Such disruption may not be specific to schizophrenia, and can be heterogeneous among schizophrenia patients

• Circuit disruption/impairment predicts behavioral impairment

• Genetic Heterogeneity is an important consideration • Circuit disruption can be targeted for treatment

Kimel Family Translational Imaging-Genetics Laboratory Mallar Chakravarty Anne Wheeler Tris Lett Dan Felsky Arash Nazeri Jon Pipitone Julie Winterburn Aysah Amath

Geriatric Division Benoit Mulsant Bruce Pollock Tarek Rajji Dielle Miranda

Neuroscience Program Jim Kennedy Arun Tiwari Natalie Freeman Clement Zai

Kimel Family, Michael and Sonja Koerner, and Paul Garfinkel New Investigator Award

Acknowledgements/Support

HSC – Jason Lerch, Stephanie Ameis CAMH R.I.C. – Nancy Lobaugh

Schizophrenia Division Jeff Daskalakis Gary Remington George Foussias