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Untitled Document
RESEARCH
ACCOMPLISHMENTS
During the first five years, four vertically
integrated research programs were developed as a result of support: a
schizophrenia group led by Dr. Williamson, the Tanna Schulich Chair in
Neuroscience and Mental Health; a posttraumatic disorders group led by Dr. Ruth
Lanius, the Harris-Woodman Chair in Psyche and Soma; a mood and anxiety
disorders group led by Dr. Beth Osuch, the Rea Chair in Mood and Anxiety
Disorders; and an autism group led by Dr. Rob Nicolson who holds an Endowed
Chair at the Autism Centre of Excellence at the University of Western Ontario.
All programs collaborate with Medical Biophysics and imaging at both the Lawson
Health Research Institute and the Robarts Research Institute; and basic science
through the Neuroscience Program, Anatomy and Cell Biology, and Psychology
Departments at the University of Western Ontario. Highlights of collaborative
clinical and basic science research over the last year in each of these areas
are reviewed below.
Schizophrenia: Over the last two decades, molecular genetic studies have
dominated the investigation of neuropsychiatric conditions. Some promising
genetic correlates of neuropsychiatric disorders have emerged, but none explain
more than a small fraction of cases of most disorders. The Human Illnesses: Neuropsychiatric Disorders and the Nature of the Human Brain authored by the Dr.
Williamson and Dr. John Allman, an evolutionary biologist at the California
Institute of Technology, and published by Oxford University Press in January,
2011 offers a new paradigm for understanding these disorders. The thesis of the
volume is that the neuronal pathways that underlie neuropsychiatric conditions
mirror unique human capabilities. It is suggested that central to the understanding of the human brain is the
capacity for representation. Brain structures such as the frontal pole, temporal
pole, and fronto-insular cortex are highly developed in humans and may be
associated with this function. This representational network receives input from
a directed effort network including the dorsal anterior cingulate cortex,
auditory cortex, and hippocampus and an emotional encoding network including the
ventral anterior cingulate cortex, orbital frontal cortex, and amygdala. Von
Economo neurons which are particularly prominent in the human brain in the
dorsal and ventral anterior cingulate cortex and the fronto-insular cortex may
have allowed synchronization of these regions in the human brain making
representation and complex social relationships possible.
Conditions like schizophrenia might result from a failure of the
directed effort
network while bipolar disorders may arise from failure of the emotional encoding
network. Autism is likely associated with failure of the representational
network, and frontotemporal dementia may be associated with failure of several
networks including the representational and emotional encoding networks. From
this perspective, neuropsychiatric disorders are seen as selective failures of
brain networks involved in the integration of cognition, affect and perception.
Just as heart failure leads to edema and shortness of breath, failures of these
pathways lead to symptoms of psychosis, mood dysregulation and behavioural
disorder no matter whether the cause is genetic, infectious or environmental.
Although the causes of these disorders are likely to remain elusive for
sometime, a better understanding of the brain networks that underlie these
disorders could guide the search for environmental factors, genetic correlates,
and better treatments much as the description of the circulatory system led to
the development of modern medicine 400 years ago.
The model provides a framework for understanding the brain imaging findings of
the group at the University of Western Ontario, over recent years in
collaboration with Dr. Rahul Manchanda and the PEPP program, Dr. Dick Drost (now
retired), Dr. Ravi Menon and Dr. Jean Théberge. The work has been supported by a
five year grant from the Canadian Institutes of Health Research. If there is a
failure of the directed effort network in schizophrenia, then it would be
expected that there would be altered glutamatergic metabolites in key parts of
the network such as the dorsal anterior cingulate cortex. Over time, these
metabolic changes would be expected to correlate with social deficits and gray
matter losses in the directed effort network over time. Our seven year
longitudinal study of first episode schizophrenic patients to be published in
the June 2011 issue of the British Journal of Psychiatry confirms the expected
findings. Regions showing loss of glutamatergic metabolites and gray matter in the first
years of schizophrenia are associated with self-monitoring, perhaps explaining
why patients have so much difficulty identifying thoughts and actions as being
their own. Intrinsic networks associated with self-monitoring and their
relationship to losses of gray matter over time in directed effort regions are
now being examined with advanced Fit/Fusion techniques in collaboration with the
MIND Institute in Albuquerque, NM (Figure 1).
Figure 1: ICA Fit/Fusion gray matter/resting
network component separating controls from schizophrenic patients. Schizophrenic
patients show decreased connectivity in the resting network (center) associated
with decreased gray matter in directed effort networks in schizophrenic
patients. Courtesy Dr. Kristen Ford.
Dr. Williamson continues to sit on
the Advisory Board of the MIND Institute in
Albuquerque, NM and the Advisory Board of Acta Psychiatrica Scandinavica in
Aarhus, Denmark. In the last year, he has given invited lectures in Barcelona,
Spain and Aalborg, Denmark and has served on the Scientific Advisory Committee
for the first International Congress on the Default and Other Intrinsic Networks
in Health and Disease in Barcelona in June 2010. His work was highlighted in the
cover article of the March 2011 issue of Scientific American Mind.
Mood and Anxiety Disorders: The First Episode Mood and Anxiety Program (FEMAP)
is now well established and proving to be an excellent base for both clinical
and brain imaging research. Over the last year, Dr. Osuch has implemented a
novel health care delivery project for early identification and intervention for
mood and anxiety funded by a Ministry of Health Innovation Fund Award. The
project was selected for the Innovation Fund Showcase at Hart House in Toronto
in November 2010, and Dr. Osuch represented our university on a panel on ‘Mental
Health, Comprehensive Care and Core Services.’
In a project funded by the Ontario Mental Health Foundation, Dr. Osuch has been
studying neurofunctioning and cognitive interactions in major depression and
marijuana use in youth with functional and structural brain imaging. Along with
Dr. Jean Théberge and in collaboration with Dr. Vince Calhoun, The MIND
Institute, Albuquerque, NM, she was one of three runners up in the Lawson
Innovation Prize competition. Unfortunately, the project came second, but it has
received some further funding from the Lawson Health Research Institute to
complete a feasibility study. Using Fit/Fusion techniques similar to the
schizophrenia studies, it may be possible to diagnose bipolar versus unipolar
depression on the basis of a simple MR scan. This would be relevant to younger
populations where treatment of unrecognized bipolar depression with
antidepressants may lead to an exacerbation of mood cycling. Some of the
preliminary differences in these groups are shown in Figure 2. Dr. Osuch has
done a number of interviews with the CBC and other media on this work.
Figure 2: Different patterns of MRI BOLD
activation in response to attention and emotion tasks in controls, unipolar and
bipolar subjects. Courtesy of Dr. Beth Osuch and Dr. Kristen Ford in
collaboration with Dr. Vince Calhoun, The MIND Institute, Albuquerque, NM.
Dr. Derek Mitchell, trained at University College, London and recruited from the
National Institute of Health, has been collaborating with Dr. Osuch on a number
of projects on the cognitive neuroscience of affective disorders. In addition to
the paradigm development on the above studies, Dr. Mitchell has published a
paper on decision making processes in the prefrontal cortex in NeuroImage;
decision making and emotion regulation in Behavioral Brain Research; the neural
correlates of emotional awareness in Journal of Neuroscience; and deficits in
attention to emotional stimuli in bipolar youth in Journal of Abnormal
Psychology. This work has been supported by grants from Natural Sciences and
Engineering Research Council of Canada and the Social Sciences and Humanities
Research Council of Canada. In recognition of his expertise, he gave an invited
lecture to the Rotman Research Institute’s Annual Conference on the Neuroscience
of Emotion and Emotion-related Disorders in Toronto in March 2011.
Posttraumatic Stress Disorders: Dr. Ruth Lanius and Dr. Paul Frewen, who has
joined the group after completing his PhD at the University of Western Ontario,
continue to make noteworthy contributions to the understanding of posttraumatic
stress disorders. The most important of these has been the description of a new
dissociative subgroup of posttraumatic stress disorders in the lead article of
the June issue of the American Journal of Psychiatry. This is a fundamental
conceptual contribution to the field, and it is of particular note that
international leaders in the field such as Dr. J.D. Bremner were co-authors of
the paper. Dr. Lanius and Dr. Frewen have also published on social emotional processing in
these patients in Social and Cognitive Affective Neuroscience and the Journal of
Psychology. Following up on the first report of default mode anomalies in
posttraumatic stress disorder patients, Dr. Lanius has published a number of
papers on default mode connectivity and the prediction of posttraumatic stress
disorders on the basis of resting network findings in Human Brain Mapping,
Journal of Psychiatry and Neuroscience, and Acta Psychiatrica Scandinavica.
Dr. Lanius was the senior editor of an important new volume titled
The Impact of
Early Life Trauma on Health and Disease: The Hidden Epidemic published by
Cambridge University Press in 2010. The chairperson of the United Nations
Committee on the rights of the child characterized the volume as a “must read
not only for clinicians and researchers in mental health, but for all who care
for and work to protect the rights of the child.”
Much of this work has been funded by the Canadian Institutes of Health Research.
However, Dr. Lanius is one of four investigators from Harvard, New York
University, Emory University and Western who have recently been awarded $5
million over four years from the National Institute of Mental Health in United
States to study the effectiveness of a number of treatment strategies in
posttraumatic stress disorders. Dr. Lanius sits on research panels for both the
Canadian Institutes of Health Research and the National Institute of Mental
Health Research in United States. In recognition of her prominence in the field,
Dr. Lanius has given invited lectures this year in London, UK; Bethesda, MD;
Boston, MA; and Hamburg, Germany. Autism:
Dr. Nicolson, the Endowed Chair in Autism Studies, has brought together
the Autism Centre of Excellence with a substantial grant from the Government of
Ontario. Dr. Nicolson has been looking at the brain circuitry associated with
autism supported by a Canadian Institutes of Health Research grant. Findings
from this brain imaging study have implicated many brain regions associated with
unique human capabilities like ‘theory of mind’ or the ability to perceive the
intentions and feelings of others. In association with Dr. Paul Thompson at the
University of California at Los Angeles, numerous brain imaging studies in
Biological Psychiatry and other high impact journals have been published in
recent years. These publications have confirmed volumetric and magnetic
resonance spectroscopy anomalies in these patients impacting different parts of
the brain than in schizophrenia or mood and anxiety disorders.
Basic Science: Basic science investigations including genomic and proteomic
studies of antipsychotic medications led by Dr. Walter Rushlow and an animal
model of schizophrenia led by Dr. Raj Rajakumar are supported by the Ontario
Mental Health Foundation and the National Science & Engineering Research
Council. Dr. Rushlow’s novel ideas about second messenger effects of
antipsychotic medications have been published in the Neuroscience and the
Journal of Neurochemistry. Dr. Rajakumar’s animal model of schizophrenia,
published in Schizophrenia Bulletin, explores the effects of subplate lesions in
rats. While the rats were normal during early development, they subsequently
developed abnormalities in prepulse inhibition and dopaminergic
hyperresponsivity typical of patients with schizophrenia. This is a very
powerful model which is consistent with the brain imaging findings with magnetic
resonance spectroscopy. More recently, Dr. Rajakumar has been working on the
role of the prefrontal cortex in stress responsiveness and a new animal model of
autism based on the foxp2 gene with Dr. Nicolson and a number of other
investigators at Western.
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