Medicine seminars

My research uses electrophysiological techniques to evaluate normal retinal function, dysfunction caused by blinding retinal diseases and the restoration of function using a variety of therapeutic strategies. We can use our understanding or normal retinal function and disease-related changes to construct optimal therapeutic strategies and evaluate how they ameliorate the effects of disease. Retinitis pigmentosa (RP) is a family of blinding eye diseases caused by photoreceptor degeneration. The absence of the cells that for this primary signal leads to blindness. My interest in RP involves the evaluation of therapies to restore vision: replacing degenerated photoreceptors either with: (1) new stem or other embryonic cells, manipulated to become photoreceptors or (2) prosthetics devices that replace the photoreceptor signal with an electronic signal to light. Glaucoma is caused by increased intraocular pressure and leads to ganglion cell death, which eliminates the link between the retinal output and central visual processing. We are parsing out of the effects of increased intraocular pressure and aging on ganglion cells. Congenital Stationary Night Blindness (CSNB) is a family of diseases in which signaling is eliminated between rod photoreceptors and their postsynaptic targets, rod bipolar cells. This deafferents the retinal circuit that is responsible for vision under dim lighting. My interest in CSNB involves understanding the basic interplay between excitation and inhibition in the retinal circuit and its normal development. Because of the targeted nature of this disease, we are hopeful that a gene therapy approach can be developed to restore night vision. My work utilizes rodent disease models whose mutations mimic those found in human patients. While molecular manipulation of rodents is a fairly common approach, we have recently developed a mutant NIH miniature swine model of a common form of autosomal dominant RP (Pro23His rhodopsin mutation) in collaboration with the National Swine Resource Research Center at University of Missouri. More genetically modified mini-swine models are in the pipeline to examine other retinal diseases.

Executive functions refer to a collection of mental processes such as attention, planning and problem solving, supported by a frontoparietal distributed brain network. These functions are essential for everyday life. Specifically in the context of patients with brain tumours there is a need to preserve them in order to enable good quality of life for patients. During surgeries for the removal of a brain tumour, the aim is to remove as much as possible of the tumour and at the same time prevent damage to the areas around it to preserve function and enable good quality of life for patients. In many cases, functional mapping is conducted during an awake surgery in order to identify areas critical for certain functions and avoid their surgical resection. While mapping is routinely done for functions such as movement and language, mapping executive functions is more challenging. Despite growing recognition in the importance of these functions for patient well-being in recent years, only a handful of studies addressed their intraoperative mapping. In the talk, I will present our new approach for mapping executive function areas using electrocorticography during awake brain surgery. These results will be complemented by neuroimaging data from healthy volunteers, directed at reliably localizing executive function regions in individuals using fMRI. I will also discuss more broadly challenges ofß using neuroimaging for neurosurgical applications. We aim to advance cross-modality neuroimaging of cognitive function which is pivotal to patient-tailored surgical interventions, and will ultimately lead to improved clinical outcomes.

Concussion (mild traumatic brain injury) affects approximately 50 million people annually. Headache is the most common symptom after concussion and persists in up to 50% of those affected for at least one-year. The biological underpinnings of and the efficacy and tolerability of treatments for post-traumatic headache has historically received little attention. While treatment in clinical practice is mostly directly at the underlying phenotype of the headache, persistent post-traumatic headache is considered to be less responsive to treatments used to treat migraine or tension-type headache. Over the past several years, significant pre-clinical research has begun to elucidate the mechanism(s) involved in the development of post-traumatic headache, and a concerted effort to evaluate the efficacy of selected treatments for persistent post-traumatic headache has begun. This presentation will review the epidemiology, pathophysiology, and emerging data on the prevention and treatment of post-traumatic headache.

Migraine is the third most prevalent disease worldwide and is estimated to affect upwards of 14% of the population. Our lab has used novel preclinical models to identify the delta opioid receptor (DOR) as a therapeutic target for multiple headache disorders, including migraine. We have also investigated the relationship between DOR with the pro-migraine peptide, CGRP. There is regional variation between the co-expression of DOR with CGRP or its receptor in the trigeminal complex. This work indicates that DOR agonists can moderate both CGRP release and signaling, thus regulating pro-migraine effects at two different levels. Recent work in our lab has also explored how cytoarchitectural changes in pain processing regions are critical for the maintenance of the chronic migraine state. We show that there is decreased neuronal complexity in two different models of migraine, and that restoration of tubulin dynamics, directly by HDAC6 inhibitor or indirectly by CGRP receptor antagonist, can inhibit migraine-associated symptoms. These studies provide fundamental information on how cytoskeletal dynamics are altered in chronic migraine, and form the basis for the development of HDAC6 inhibitors for headache treatment.

Dysregulation of protein synthesis both globally and locally in neurons and astrocytes is a key feature of neurodegenerative diseases. Aberrant signalling through the Unfolded Protein Response (UPR) and related Integrated Stress Response (ISR) have become major targets for neuroprotection in these disorders. In addition, other homeostatic mechanisms and stress responses, including the cold shock response, appear to regulate local translation and RNA splicing to control synapse maintenance and regeneration and can also be targeted therapeutically for neuroprotection. We have defined the role of UPR/ISR and the cold-shock response in neurodegenerative disorders and have developed translational strategies targeting them for new treatments for dementia.

The basal ganglia are a collection of brain areas that are connected by a variety of synaptic pathways and are a site of significant reward-related dopamine release. These properties suggest a possible role for the basal ganglia in action selection, guided by reinforcement learning. In this talk, I will discuss a framework for how this function might be performed. I will also present some recent experimental results and theory that call for a re-evaluation of certain aspects of this framework. Next, I will turn to the changes in basal ganglia activity observed to occur with the dopamine depletion associated with Parkinson’s disease. I will discuss some of the potential functional implications of some of these changes and, if time permits, will conclude with some new results that focus on delta oscillations under dopamine depletion.