Imaging-Genetics of Schizophrenia

We are obtaining genetics, neuroimaging and cognitive data to understand shared and unique genetic risk mechanisms on brain structure and function in people with severe mental illness (schizophrenia and bipolar disorder). We are also using a lifespan approach to identify genetically based patterns of healthy vs. pathological aging in the brain.

We are also conducting advanced brain imaging at the beginning and end of double-blind, randomized, placebo-controlled trials. In one study we are examining the effects of antipsychotic medications on brain structure using neuroimaging using a controlled study design for the first time. Our study will answer the question of whether antipsychotic medications are neuroprotective or neurotoxic, and will influence the prescribing practices of clinicians. In our other study, we are testing whether a novel brain stimulation technique, known as repetitive transcranial magnetic stimulation can help improve working memory deficits in people with schizophrenia, and we are using neuroimaging as a predictor of treatment response.

We are also using advanced neuroimaging techniques to differentiate deficit patients from nondeficit patients, and establish biomarkers of primary negative symptoms in schizophrenia.

Finally, repetitive transcranial magnetic stimulation (rTMS) has been shown to be and effective and safe in the treatment of schizophrenia. In this proposal, as part of a larger treatment study to improve memory performance, we are conducting a type of brain imaging known as magnetic resonance imaging (MRI) and special other types of MRI reliant on movement of water in the brain, to determine whether the frontal parts of the brain important for this type of memory change with rTMS treatment. This will help us understand better what effects rTMS has on brain structure.

Supported by the Combining Brain Imaging and Genetics for Treatment Innovation in Mental Illness grant. Canada Foundation for Innovation. John R. Evans Leaders Fund. Also supported by the Assessing Effects of rTMS on Cortical Architecture when treating Working Memory in Schizophrenia grant. Brain and Behavior Research Foundation. NARSAD Independent Investigator Award. Also supported by the Dissecting the Heterogeneity of Negative Symptoms in Schizophrenia Type A Research Project Grant. Ontario Mental Health Foundation. Operating Funding. Collaborator(s): Foussias, G., Lerch, J., Remington, G., Zakzanis, K.

Biomarkers of Impaired Social Cognition in Schizophrenia

This is a multi-site Research Domain Criteria study, of which Aristotle Voineskos is team lead, and CAMH/University of Toronto is the lead site. This study investigates people with a schizophrenia spectrum disorder (SSD) present with a continuum of impairments in social function, from normal, intimate, enduring social relationships, to marked social isolation. However, the impairments in neural circuit structure and function that predict impairment in social cognitive performance and ‘real-world’ social function in the SSDs are currently not known. The proposed study will combine advanced neuroimaging techniques, detailed behavioral assessment data, and the partial least squares multivariate approach, to definitively identify dimensional brain-behavior relationships that predict social cognitive performance and social function in healthy controls and people with SSDs. This study will use a dimensional Research Domain Criteria (RDoC) approach. Individuals will be recruited who demonstrate a range of performance along an RDoC construct (social cognitive performance) using the matrix of analysis from circuits to behavior to self-reports. This study is designed to identify the critical neurocircuitry involved in the pathophysiology of lower-level and higher-level social cognitive processes and social function along a continuum of healthy controls and people with SSDs. The new knowledge gained from this study will provide essential information for RDoC based classification in the social process domain, one of the five RDoC domains. The results and new knowledge generated from this study will also provide the framework for rapid translation of behavioral neuroscience findings into treatment innovation, particularly for early intervention, given the presence of social cognitive and social function impairments at the earliest stage of illness.

Supported by the Social Processes Initiative in the Neurobiology of the Schizophrenia(s) grant. National Institute of Mental Health (NIMH). Operating Funding. 1/3 R01MH102324.

Effects of Maintenance Treatment with Olanzapine vs. Placebo on Brain Structure

The main purpose of this four-site neuroimaging study is to serve as the first-ever placebo-controlled trial to investigate the effects of antipsychotic medications on brain structure and function. Antipsychotic usage and prescriptions continue to increase in number, and FDA approvals for different populations without a primary psychotic disorder (e.g. mood disorders, the elderly, children) are increasing. Our understanding of the effects of antipsychotics on brain structure, however, is very limited, due to the absence of placebo-controlled investigations. This study should resolve the question of whether antipsychotics are neuroprotective or neurotoxic for brain structure.

Supported by the Effects of Maintenance Treatment with Olanzapine vs. Placebo on Brain Structure Research Project Grant (Parent R01). National Institutes of Mental Health (NIMH). Operating Funding. 1R01MH099167. Collaborator(s): Our site is the lead site for this four-site neuroimaging study positioned within the context of an ongoing placebo-controlled clinical trial. Collaborators from Toronto include Mulsant, B., Flint, A., Lerch, J., Chakravarty, MM., from Cornell Meyers, B., Hoptman, M., University of Massachusetts, Rothschild, A., and University of Pittsburgh, Whyte, E.

Genetic Identification of an Early Risk Pathway for Alzheimer’s Disease

Alzheimer’s Disease is a prevalent devastating neuropsychiatric disorder of late-life. Early identification is critical in order for targeted early intervention. This study aims to leverage the Alzheimer’s Disease Neuroimaging Initiative Database (ADNI) to identify interactions among specific genes within a pathway and the effects of those interactions on at-risk brain regions in people who may go on to develop Alzheimer’s disease (AD). Single gene studies are not powerful enough to provide strong prediction of brain changes prior to clinical disease onset, and it is possible that the identification of epistatic risk among genes may provide an improved prediction of brain risk for AD.

Supported by the Effects of Gene-Gene Interactions within an Early Risk Pathway for Alzheimer’s Disease on Established and Novel MRI-Based Phenotypes grant. Canadian Institutes of Health Research (CIHR). Catalyst Grant: Secondary Analysis of Neuroimaging Databases. Collaborator(s): Chakravarty, MM., Knight, J., Duchesne, S.

Subcortical Atlases

Hippocampus Atlas

The hippocampus is a neuroanatomical structure that has been widely studied in the context of learning, memory, stress, and neurodegeneration. Neuroanatomically, the hippocampus is subdivided into several subfields with intricate morphologies and complex three-dimensional relationships.

To overcome the limited availability of post-mortem specimens and expertise in state-of-the-art high-field imaging, we conducted a coupling of MR acquisition and detailed segmentation techniques that allow for the reliable identification of hippocampal anatomy (including subfields). High-resolution and -contrast T1- and T2-weighted image volumes were acquired from 5 volunteers (2 male; 3 female; age range: 29–57, avg. 37) using a clinical research-grade 3T scanner and have final super-sampled isotropic voxel dimensions of 0.3 mm.

Winterburn et al. A novel in vivo atlas of human hippocampal subfields using high-resolution 3T magnetic resonance imaging. NeuroImage 2013.

For more information and downloads, see the CoBrAlab website.

Cerebellum Atlas

We present a novel set of high-resolution in vivo atlases of the cerebellum developed by pairing MR imaging with a carefully validated manual segmentation protocol.

The cerebellum has classically been linked to motor learning and coordination. However, there is renewed interest in the role of the cerebellum in non-motor functions such as cognition and in the context of different neuropsychiatric disorders. The contribution of neuroimaging studies to advancing understanding of cerebellar structure and function has been limited, partly due to the cerebellum being understudied as a result of contrast and resolution limitations of standard structural magnetic resonance images (MRI). These limitations inhibit proper visualization of the highly compact and detailed cerebellar foliations.

Park et al. Derivation of high-resolution MRI atlases of the human cerebellum at 3 T and segmentation using multiple automatically generated templates. NeuroImage 2014.

For more information and downloads, see the CoBrAlab website.

MRI Data Management

We have developed an open-source tools for the automation of data transfer, management, and quality control, for studies involving multiple MR centers. With increase in our capacity to handle large amounts of newly collected MR data, we took on a leadership role in the MR data collection for three major multi-site clinical projects with funding support from the American Nation Institute of Health (NIH).


We are using machine learning to classify brain scans into subgroups on the basis of imaging characteristics. If successful, such an automatized process would vastly improve clinical practice. For example, high dimensional classification of brain structure might be able to identify which participants with mild cognitive impairment are suffering from early Alzheimer’s pathology.  And, in the case of schizophrenia, predictive models might be able to anticipate how certain clients are likely to respond to standard treatments on the basis of their brain structure. These methods are currently in development and we look forward to describing our findings next year.

Repetitive TMS Treatments, and Prognostic Markers

Schizophrenia poses enormous health and economic challenges for Ontario. Memory deficits are amongst the hardest problems to treat, and are the cause of poor functioning in people with schizophrenia. Therefore, finding new treatments to improve quality of life is essential. Our pilot data suggests that using repetitive transcranial magnetic stimulation (rTMS) to stimulate frontal brain regions leads to gains in working memory (WM). We will examine the efficacy of rTMS and use advanced neuroimaging to determine if rTMS results in brain structure changes important for WM performance. If successful, this would provide a new treatment option and hope for those who would otherwise suffer from this illness, improve health outcomes, and provide economic benefits for Ontarians.

Supported by the rTMS for the treatment of working memory deficits in schizophrenia and effects on brain structure grant. Ministry of Research and Innovation. Province of Ontario Early Researcher Award. Also supported by the rTMS for working memory deficits in schizophrenia grant. Canadian Institutes of Health Research (CIHR). MOP 288219. Collaborator(s): Daskalakis, Z., Blumberger, D., Brown, P., Chakravarty, MM., LePage, M., Mulsant, B., Rajji, T. Also supported by the an rTMS treatment trial of working memory deficits in schizophrenia and genetic prediction of response grant. Brain and Behavior Research Foundation. 2010 NARSAD Young Investigator Award.