Neural Systems and Behaviour

I am a psychiatrist with a focus on advancing understanding of the early natural history of mood disorders in youth.  This research aims to understand the nature of inherited vulnerability, describe the natural history and associated biological markers and identify early targets for effective treatment and prevention of recurrence, morbidity and mortality.  I am the principal investigator of a study of offspring of bipolar parents funded by CIHR yielding novel findings characterizing the early clinical stages in the development of bipolar disorder and investigating associated biological, psychological and social influences.  With funding from the CAIP Professorship, I am developing an integrated clinical research program for patients with primary recurrent mood disorders, their adult relatives and children at the FMC.  This translational research platform seeks to advance understanding of mood disorders within individuals over development and across generations. The cornerstone of successful translation research is based on careful clinical characterization.

My research goal is to build a framework that links cognitive integrity and neural dynamics to provide a coherent understanding of how cognition emerges from operations in the intact and impaired brain.  The following two areas of interest give the flavor of this approach.

Network Reorganization Following Brain Damage
Focal brain damage can be best understood in the context of neural networks; behavioral deficits following damage can reflect either the abnormal operation of a damaged network or the formation of a completely different network with a new behavioral repertoire. Ideally, to predict functional outcome after brain damage, one should take into account network reorganization. My recent work focuses on how hippocampal damage affects neural networks supporting episodic memory and other cognitive functions.  I have identified compensatory network changes in task-related signal that support good memory and verbal performance in patients with medial temporal lobe epilepsy (mTLE) and patients with amnestic mild congitive impariment.

Brain Signal Variability in the Context of Brain Damage
Computational research suggests that brain signal variability is an important parameter reflecting the functional integrity of neural systems. Thus, we can think of variability as a metric of what the system is capable of doing (whereas task-related signal indicates what the system is doing at any given moment of observation). I have shown that variability tracks both tissue health and functional capacity in patients with mTLE.  In my current work, I am trying to use signal varibility to to identify individual differences in the capacity to benefit from treatment in psychiatric or neurologic disorders.

Endocannabinoids are the brains endogenous version of THC, the psychoactive constituent of cannabis (similar to how endorphins are the body’s endogenous version of morphine). Over the past few years I have been interested in the role of the endocannabinoid system in the regulation of stress and emotional behavior. Research from us, and others, has demonstrated that endocannabinoid signaling largely acts to decrease stress responses. Deficits in endocannabinoid signaling in rodents can increase neuroendocrine and behavioral responses to stress, and in humans, disruption of endocannabinoid signaling can produce symptoms of depression and anxiety. Interestingly, we have demonstrated that stress can mobilize endocannabinoid signaling, and that this increase in endocannabinoid signaling is required for both the normal recovery from acute stress as well as the larger adaptive processes that occur following repeated exposure to stress. More so, we have found that under conditions of chronic stress, endocannabinoid signaling “breaks down”, and that the loss of this buffer system may be one of the mechanisms by which chronic stress increases the risk of affective illnesses, such as depression and anxiety disorders. This hypothesis has been supported by translational clinical studies we have performed demonstrating that circulating levels of endocannabinoids are reduced individuals afflicted with major depression.

The primary focus of research in my laboratory is to understand the role of the endocannabinoid system in the effects of stress and glucocorticoids. Within this focus, my research is particularly interested in determining the role of the endocannabinoid system in the effects of stress on a) neuroendocrine function; b) emotional behaviour; c) energy balance and metabolism; d) neuroinflammation and neurodegeneration. This is achieved through a systems level approach incorporating a range of neuroscientific techniques ranging from cellular/biochemical to behavioural.

The major goal of our laboratory is to elucidate the molecular and cellular mechanisms underlying the clinical anticonvulsant effects of the ketogenic diet (KD), an effective non-pharmacological treatment for medically refractory epilepsy. We are also attempting to validate the neuroprotective (and potentially) disease-modifying effects of the KD. Recent published studies have focused on the antioxidant properties of ketone bodies – which are produced during KD treatment – and fatty acids (particularly, polyunsaturated fatty acids). The laboratory utilizes cellular in vitro electrophysiological techniques (i.e., single-channel and whole-cell patch-clamp, and IR-DIC slice recordings), combined with molecular genetic approaches, behavioral assessments (e.g., continuous video-EEG monitoring, high-density multi-electrode recordings of brain slices), and cellular fluorescence imaging. The principal animal model of epilepsy studied in our laboratory is the epileptic Kcna1-null mouse, which develops spontaneous recurrent seizures early in post-natal development.

I am interested in mental disorders in a broad context – both etiological and applications to legal questions; applied psychopharmacology; clinical and forensic neuropsychology particularly memory and executive functioning; concussions – consultant to the NHL and Canadian Pro Rodeo association

I have three main research areas:

1) Health outcomes research in neurosciences, particularly the evaluation of medical and surgical interventions, assessment of clinically important change, quality of life, economic analyses and meta-analyses. I have addressed both methodological and clinical aspects of these research areas

2) Health services research, particularly using linked administrative databases and health surveys, as well as determining the appropriateness and necessity of clinical interventions

3) Establishing a successful Clinical Research Unit within the Hotchkiss Brain Institute. This unit supports study design, data management, and data analysis for clinical research in the neurosciences.