2017 Accelerator - Round 2

Development of a novel pharmaceutical to prevent noise-induced hearing loss
PI: Allman, Brian

Department: Schulich School of Medicine & Dentistry - Anatomy & Cell Biology

Award value: $69,000

Hearing loss is the fastest growing chronic health condition facing Canadians. In addition to aging, excessive exposure to loud noise is a leading cause of hearing loss worldwide. Given the prevalence and insidious consequences of noise-induced hearing loss, there is a crucial need to develop novel compounds that can be administered prophylactically or in the hours/days post-noise exposure to limit the permanent damage. Unfortunately, despite decades of research, there is no widely-accepted pharmacotherapy against noise trauma, largely because the field has been unable to effectively thwart the oxidative stress that ultimately kills the sensory cells in the inner ear (cochlea). Therefore, the long-term goal of our newly-formed team is to develop a safe and effective pharmaceutical for preventing noise-induced hearing loss. Normally found in the cochlear cells, the endogenous antioxidant, catalase, plays a crucial role in protecting against oxidative stress. Thus, to limit the damage caused by noise-induced oxidative stress, we seek to determine the most efficacious way to deliver a customized version of catalase to the vulnerable sensory hair cells in the cochlea. To that end, we will use rat models to conduct the foundational studies necessary to establish the world’s first catalase-based pharmaceutical.

Magneto-Vestibular stimulation (MVS): effects on behaviour and resting state networks
PI: Corneil, Brian

Department: Schulich School of Medicine & Dentistry - Physiology & Pharmacology

Award Value: $63,895 

Magnetic resonance imaging (MRI) has revolutionized cognitive neuroscience, offering unparalleled insights into human brain function in health and disease. Recent results however show that the MRI environment can stimulate the balance sensors within the inner ear. Such magneto-vestibular stimulation (MVS) arises because of biophysical interactions between the fluids within our inner ear, these balance sensors, and the static field within an MRI machine. Due to MVS, subjects placed within an MRI in the dark exhibit nystagmus, or periodic patterns of eye movements similar to what is produced when one is dizzy. And just as happens when one is dizzy, the brain learns to adapt to MVS, with nystagmus decreasing (but never fully disappearing) while the subject is in the magnet, and then re-appearing and reversing when the subject leaves the magnet. The broad goals of this grant are to 1) explore the effects of MVS on eye movement behaviour, and 2) investigate the influence of MVS on functional networks in the brain. Such data will constitute baseline data for future comparisons to patients suffering from a variety of conditions, many of which impair the brain’s ability to learn and adapt.

Neurocognitive, Genetic and Environmental Risk Factors of Learning Disorders in Children
PI: Joanisse, Marc

Department: Social Science - Psychology

Award Value: $97,209

The project brings together labs examining risk factors associated with learning disabilities such as reading disability/dyslexia (RD), language learning disorders (LLD), and math disability/dyscalculia (MD). Our research has previously uncovered a range of behavioural and neural factors that differentiate impaired children from their typically developing peers. Intriguingly, however, our recent finding suggests high levels of comorbidity among learning disorders, and learning difficulties among children with general cognitive difficulties like Autism and ADHD, or internalizing/externalizing disorders. Our data suggest there is a wealth of untapped knowledge in examining common risk factors for learning disabilities. The present BrainsCAN Stimulus grant takes a novel team approach in which we deploy our collective expertise to identify the behavioural, neural, environmental and genetic factor that explain learning disorders in school-age children, and why these disorders tend to co-occur.

System-wide electrophysiological assessment of hearing
PI: Johnsrude, Ingrid

Department: Social Science - Psychology, Health Science - Communication Science & Disorders

Award Value: $57,259

Hearing loss affects about one of two Canadians aged 60 and older, and puts them at risk for a reduced quality of life and poor health outcomes (e.g., depression, cognitive decline). Current standard hearing assessment still relies on pure-tone audiometry, although it is a poor predictor of real-world hearing abilities. The audiogram measures sensitivity to quiet (at- threshold) sounds, but it fails to capture many of the suprathreshold impairments reported by older people, including perceiving sounds at moderate intensities to be unpleasantly loud, finding sounds to be abnormally distracting, and, most importantly, experiencing difficulty understanding speech in the presence of background sound. Recent work suggests that much of the effect of age on hearing deficits with suprathreshold sounds may be the result of accumulated noise that damages the auditory nerve (AN), with long-term consequences for cortical function. The current work proposes to develop and evaluate an electrophysiological recording setup capable of assessing neural function at all levels of the auditory neural pathway, including hair cells, auditory nerve fibers, brainstem, and cortex. We will test the relation of neural responses across those levels of the auditory pathway in younger and older people.

Diffusion MRI modelling of the cortex informed by macro- and myelo-architecture
PI: Khan, Ali

Department: Schulich School of Medicine & Dentistry - Medical Biophysics

Award Value: $75,900

The overall goal of this transformative program is to develop a novel imaging & analysis technique for quantifying cortical architecture, providing a means to characterize and quantify structural features that have been thus far “invisible” to MRI. The novel approach we are taking will fuse complementary measurements of structure, using high-resolution cortical surface reconstruction with joint modelling of diffusion MRI, to specifically model the radial and tangential architecture of neuronal bodies in the cortex, providing a new set of multi-modal quantitative indices. This technique could have wide-ranging applications, not only in understanding of subject-specific cytoarchitectonic mapping for neuroscientific questions, but in improving our ability to detect subtle cortical abnormalities in brain disorders such as epilepsy, autism, and schizophrenia. The critical, foundational milestone that must be achieved first is the development and validation of this technique, using simulations, phantom experiments and human post-mortem tissue imaging.

The role of the basolateral amygdala in gaze avoidance behaviour
PI: Martinez-Trujillo, Julio

Department: Schulich School of Medicine & Dentistry - Physiology & Pharmacology

Award Value: $85,910

In the current project, we test the general hypothesis that dysregulation in the activation of gaze contact neurons in the amygdala produces gaze avoidance phenotypes that are observed in mental diseases such as Autism Spectrum Disorders and Schizophrenia. We will use a combination of behavioural measurements, electrophysiology and optogenetics to reverse engineer brain circuits involed in gaze avoidance and provide causal evidence in favor of this hypothesis. We will probe specific compotents of brain circuits involved in gaze orienting, face recognition, social interactions and autonomic response that lead to control of emotions during social behaviour. Using this approach will help to pinpoint specific deficits in circuit components function observed in disease such as Schizophrenia and Autism Spectrum Disorder. Finally, our circuit approach will potentially lead to innovative interventions to treat core symptoms of mental disease using technologies such as deep brain stimulation and local drug delivery.

The impact of maternal immune activation on fetal brain development
PI: Renaud, Stephen

Department:Schulich School of Medicine & Dentistry - Anatomy & Cell Biology

Award Value: $68,300

Disruptions during early brain development are leading causes of severe neurological disorders. For example, viral or bacterial infections during early pregnancy can impact fetal brain development, and increase the child’s risk of developing serious neurological disorders later in life, including autism spectrum disorder (ASD) and schizophrenia. How maternal infection causes fetal brain maldevelopment is not well understood; however, in many cases, the pathogen is not transmitted to the fetus, suggesting that maternal immune activation (MIA) in response to the pathogen is responsible for the increased risk of neurological disorders in affected offspring. The goal of this pilot study is to dissect the contribution of two immune cell lineages to MIA-induced neurodevelopmental disorders: uterine natural killer (NK) cells, the main immune cells in the uterus, and fetal microglial cells, the main immune cells in the developing fetal brain. We hypothesize that uterine NK cells and fetal microglia respond to MIA or MIA-induced cytokines, and that activation of at least one of them disrupts normal prenatal brain development leading to postnatal cognitive deficiencies consistent with ASD/schizophrenia. Identifying which immune cells contribute to MIA-induced fetal brain maldevelopment is a crucial first step for developing targeted interventions that mitigate neurodevelopmental disorders in offspring.