Epilepsy

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.

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 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.

Tissues respond to low oxygen through a range of mechanisms - from genetic to behavioral. We are developing and applying a range of technologies to study oxygen levels in tissues and how these relate to disease processes. We are also using MR microscopy and quantified MRI to study white matter degeneration, vascular adaptation and molecular imaging in animal models. We have developed methods to non-invasively study angiogenesis in brain in response to chronic low-oxygen -  such as may occur in stroke, MS and high altituted medicine. Animal models include stroke, epilepsy, cancer and MS. We are translating optical technologies to the clinic in areas such as epilepsy, stroke, psychiatry and sports medicine. By using a combination of imaging and histological studies, we aim to determine how the brain adapts to hypoxia, and to apply that knowledge to treatment of conditions such as stroke and migraine.

My laboratory studies various aspects of neuronal voltage-dependent calcium channels. We are using a combination of electrophysiological (patch clamp), molecular biological (site-directed mutagenesis, chimeras, cloning of novel calcium channel genes, transfection of channels into cell lines and neurons) techniques, protein biochemistry and imaging on live cells to address our research objectives. We also have succeeded in dual patch clamp recordings from transfected mouse hippocampal neurons in culture, and we have expertise in making and dealing with KO mice. Currently, my laboratory is involved in the following major projects:

1) Regulation of presynaptic calcium channels by G proteins
2) Structure, function and physiological roles of T-type calcium channels
3) Mechanisms that regulate their membrane targeting and auxiliary subunit assembly in neurons
4) The regulation of NMDA receptors by cellular prion protein

Through a collaboration with NeuroMed Technologies. Inc. we participate in the development of novel calcium channel antagonists.

I am strongly committed to graduate and undergraduate education. I act as co-graduate director for the Department of Neuroscience and I am active on the BSc Neuroscience Education Committee.