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
-8
-4
0
4
8
12
16
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