BrainsCAN Fellows

Research Information:
Multiple sclerosis (MS) leads to devastating impairments in cognitive functions due to loss of myelin and associated disruption of nerve conduction. Presently, existing treatments for MS are ineffective in treating the accompanying cognitive dysfunctions. Thus, effective treatment of this debilitating demyelinating disease represents an urgent unmet need. Recent findings indicate that remyelination can be stimulated by artificially-driven neuronal activity. Particularly promising is optogenetic stimulation (OS); a precise way to manipulate neurons with light by genetic introduction of light-sensitive proteins. Given that cognitive impairments are a major issue in MS, it would be of considerable interest if this strategy could be successfully applied to enhance cognition. Hippocampal glutamatergic neurons (HGNs) are excitatory neurons essential for learning, memory and attention. The disruptions in their numbers and density have been implicated in the pathogenesis of MS.My focus is to target HGNs via OS with the aim of improving cognition and promoting remyelination in MS. Our findings may be used to guide procedures using extant techniques such as MRI-informed deep brain stimulation of regions which could potentially accomplish the same cognitive rescue in a less target specific stimulation approach.

Research Information:
The recent legalization of cannabis for both medicinal and recreational purposes has altered the perception of risks, resulting in a sustained increase of cannabis use mainly among adolescents. This trend is concerning given that sustained consumption of marijuana during such vulnerable neurodevelopmental window has been associated with a wide range of long-lasting cognitive impairments and enhanced risks for neuropsychiatric diseases, such as schizophrenia, anxiety and mood disorders. In addition, emerging evidence has pointed out critical sex-related differences in neuropathological outcomes induced by marijuana consumption. In this study, the impairments in cognitive and affective processing will be investigated in a translational rodent model of adolescent cannabis exposure. Using a multi-level approach, cognitive performances, anxiety and psychiatric-like manifestations will be evaluated, concomitant with a detailed examination of molecular biomarkers and neural activity in selected brain regions relevant for cognition and neuropsychiatric disorders. The findings obtained by the proposed research will enhance our knowledge on the neurobiological mechanisms underlying the side effects of cannabis exposure on the adolescent brains in both genders and will aid in developing novel potential pharmacotherapeutic strategies to reverse the cannabis-related pathology. 

Research Information:
Hearing loss is one of the most prevalent chronic health conditions, affecting more than 1.2 billion people worldwide. It is well-recognized that excessive exposure to loud noise, resulting from environmental (e.g., city noise), recreational (e.g., loud music) and occupational (e.g., industry workers) insults, is a leading cause of permanent hearing loss. Beyond the devastating effects of hearing impairment itself, there is clear evidence that loud noise exposure also leads to pathology in brain regions both within and beyond the auditory pathway. For example, noise exposure can cause aberrant auditory perceptions such as tinnitus (i.e., “ringing in the ears”), as well as cognitive impairments in learning and memory tasks that do not depend on the auditory system. While the neural mechanisms contributing to noise-induced tinnitus and cognitive impairment remain elusive, accumulating evidence suggests that neuroinflammation plays an important role in mediating the brain plasticity thought to underlie these disorders. Using a combination of cell-specific in vivo neuroimaging and auditory/cognitive behavioural testing, my research aims to reveal how noise-induced neuroinflammation leads to aberrant neural activity in areas of the brain that control auditory perception, learning, memory and other higher-order cognitive functions. Ultimately, this work will address our crucial need to better understand the adverse effects of noise exposure on brain health.

Research Information:
Sensory loss has significant perceptual, social, and economic impacts. Deaf children often experience challenges in receiving appropriate learning accommodations. Among these difficulties, mathematics learning is an important issue, as school-entry numerical skills are a more important predictor of subsequent academic achievement than early reading and socio-emotional skills. That hearing impairment might exacerbate mathematics difficulties (which are present at a rate comparable to reading difficulty in normally developed children) also warrants considerable concern. However, little is known about how deafness impacts brain processes beyond the domain of low-level perception. Thus, my research seeks to investigate how sensory impairment affects higher-level cognitive functions associated with mathematics, in order to gather evidence potentially informing remediation strategies in this population. My work aims: 1) to determine whether behavioral differences exist between hearing and deaf individuals on mathematical tasks that engage different components of working memory, 2) to characterize differences in the neural correlates of these tasks between groups, and 3) to compare developmental trajectories of behavioral and neural measures between groups by examining both children and adults.

Research Information:
The sustained and excessive consumption of calorie-dense foods is the leading cause of preventable chronic disease and premature death worldwide. Limiting the consumption of these foods is therefore essential to maintain optimal health. However, in the modern food-rich environment, maintaining a healthy diet has become a difficult endeavor. The environment is saturated with unhealthy ultra-processed calorie-dense foods (those high in saturated fats and sugar), and these foods are often cheaper than their healthier counterparts. This is coupled with omnipresent cues, in the form of media advertisements, to consume these foods. While some individuals find it really difficult to control calorie-dense food consumption in this environment, others are more adept. My research seeks to understand why some individuals are more prone to overconsumption than others. Specifically, my body of research seeks to understand the neural circuits underlying vulnerability to over consumption, with the particular focus on how the prefrontal cortex regulates reward circuits in the brain to modulate consumptive behaviours across developmental contexts. By delineating these neurobiological processes, we will be able to identify the subtle cognitive and neural markers that increase the propensity to overeat. This would enable researchers and clinicians to identify those individuals that may be more likely to respond to a given intervention and provide the foundational work necessary to develop novel evidence-based interventions.

 

Publications: 
Trends in Cognitive Sciences: Review suggests a reciprocal relationship between obesity and self-control
The Lancet: Adolescents prone to poor dietary choices, leading to changes in the brain 

Research Information:
Biological systems such as the human brain learn from and adapt to the environment and optimize behavioral outcomes through strategically selecting from a wide range of options. Experimental and computational neuroscience studies have investigated the biological processes underlying adaptation, learning and reward-driven behavior, and have highlighted the role of neuromodulators. Despite the success of artificial neural networks in many fields of application, the competition and cooperation of multiple neuromodulators and their role in function flexibility and learning beyond the reward-based learning scheme remains largely unexplored in the context of brain-inspired deep learning. In this study, we will integrate neuroscience findings on how neuromodulation affects attention and learning into a mechanistic model devised based on existing deep learning models to understand whether neuromodulation would further improve the performance of deep learning models. We will (1) investigate how multi-level neuromodulation could be employed by deep learning models to enable learning and action selection based on environmental inputs, feedback signals and the state of the neural network, and (2) understand the level of biological plausibility and complexity required to improve performance in behavioral tasks.

Research Information:
Parkinson’s disease (PD) and Lewy body dementia (LBD) are neurodegenerative disorders characterized by accumulation of misfolded α-synuclein aggregates in the central nervous system. With improvements in the management of motor symptoms in recent decades, non-motor features of these synucleinopathies are now a major cause of morbidity, especially cognitive deficits. The molecular and cellular mechanisms underlying PD and LBD-associated cognitive decline remain to be fully revealed. Chaperones and co-chaperones assist protein folding, stability and degradation. Epichaperomes are maladaptive protein networks reflecting abnormal connectivity of chaperones with their interactomes. Multiple chaperones, including Hsp90, Hsp70 and their co-chaperone STIP1, interact with α-synuclein, supporting the notion that abnormal chaperone activity may contribute to the pathogenesis of synucleinopathies. Chaperones also influence the stability and the activation of several proteins related to signal transduction and immunity. For instance, the chaperone Hsp90 prevents the degradation of the NLRP3 inflammasome, a group of cytosolic multiprotein complexes mainly expressed in macrophages/microglia that recognize several stimuli, triggering innate inflammatory processes. Herein, by using transgenic mice expressing the mutant A53T human α-synuclein in neurons as a model of synucleinopathies and high-throughput touchscreen tests we aim to investigate whether epichaperome and NLRP3 inflammasome act synergistically to accelerate PD and LBD-associated cognitive decline.

Research Information:
Intrauterine growth restriction (IUGR) is a serious condition where the placenta stops growing late in pregnancy, limiting oxygen to the fetal brain. In the early stages of IUGR, blood flow is still being directed to the frontal lobes. Later, however, blood is directed to midbrain areas important for keeping the fetus alive. This redistribution referred to as ‘brain sparing’. Brain sparing can result in severe brain injury, with adverse consequences for cognitive function, including language. For these fetuses, early delivery can prevent death; however premature birth also comes at a cost. The neonatal ICU is a stressful environment, and preterm babies are at risk of both short- and long-term health issues. Objective measures to guide decisions regarding delivery time to maximize developmental outcomes are crucial to neonatal care in this population. My research aims to evaluate whether brain sparing is associated with decreased functional and structural connectivity in the language network in utero, and if connectivity measures are associated with language outcomes at 12- and 24-months. By using MRI-based methods to monitor fetuses at risk for IUGR, and following the developmental trajectory of the newborns, I aim to improve newborn brain health and cognitive outcomes, specifically later language development.

Research Information:
Understanding the role of the cerebellum in human cognition asks for the functional mapping of its territories upon performance of a wide array of behavioral tasks. To this end, functional Magnetic Resonance Imaging (fMRI) has been used to measure brain activation related to specific behaviors as means to extensively characterize functional responses in the cerebellar circuitry. The overlap of the neural substrates across tasks can elucidate us about the contribution of the cerebellum to brain processes directly linked to elementary mental functions. Herein, we will adopt this cognitive-atlasing approach to investigate the interplay of the cortico-cerebellar circuits in the domain of music cognition. We will generate a large-scale task-fMRI dataset comprising both the Multi-Domain Task Battery—which covers a broad range of cognitive modules—and a new set of musical tasks dedicated to specifically assessing different music abilities. This resource will allow us to determine the common basis and relationship between music and general cognition as well as obtain a systematic picture of the involvement of cerebellar regions in these neurocognitive mechanisms. Moreover, the dataset will be made publicly available in dedicated neuroimaging repositories, in order to become the groundwork for the development of cognitive brain-atlasing infrastructures targeting the human cerebellum.

Research Information:
Speech is arguably the most important form of human communication. Since the goal of speech production is the transfer of information, speech production must be carefully regulated to ensure the desired information is conveyed. During speech production sensory feedback, such as auditory feedback, plays an important role in maintaining the fluidity of speech, as it allows speech motor movements to be monitored and production errors to be detected and corrected. A major focus of my research program is investigating how the role of sensory feedback in the control of speech changes throughout development in individuals with and without autism spectrum disorder. I am also interested in how the ability to extract and utilize the information contained in sensory feedback influences the development of higher-order cognitive processes such as speech communication, emotion regulation, and social competence.

Research Information:
To form a coherent perception of the world around us, we are constantly processing and integrating sensory information from multiple modalities. In fact, when auditory and visual stimuli occur within ~100 ms of each other, individuals tend to perceive the stimuli as a single event, even though they occurred at separately. Although this integration of closely-timed audiovisual stimuli can offer certain behavioral advantages, an overly broad window of temporal integration can be problematic (e.g., in autism and schizophrenia), as information from truly separate events may not be perceived correctly. While recent studies in humans have suggested that the binding of audiovisual stimuli is regulated by neural oscillations, the brain circuits and cellular mechanisms that regulate the putative oscillatory activity subserving audiovisual perceptual binding remains unknown. Using our translational behavioural task in combination with optogenetics and in vivo electrophysiology, my research aims to uncover the mechanisms by which inhibitory neurotransmission finely controls audiovisual perception. Ultimately, these studies will significantly advance our understanding of the neuronal circuitry underlying audiovisual temporal perception, and will be the first to establish the role of interneurons in regulating the synchronized neural activity that is thought to contribute to the precise binding of audiovisual stimuli.