Meeting Program June 14, 2018

Medical Sciences Building, University of Toronto http://www.neuroscience.utoronto.ca/events/CPIN_Research_Day.htm

2018 Collaborative Program in Neuroscience (CPIN) Research Day

Career Development Workshop And

Mental Health Symposium Thursday June 14, 2018

Medical Sciences Building, University of Toronto

Program Schedule 9:30–10:00 a.m. Registration Opens (Medical Sciences Building Stone Lobby) Trainee Poster Set-up 10:00–10:10 a.m. Welcome and opening remarks (Room 3154, Medical Sciences Building)

Dr. Zhong-Ping Feng, Director, Collaborative Program In Neuroscience (CPIN); Professor, Department of Physiology, University of Toronto

Section I. Career Development Workshop (Room 3154, Medical Sciences Building) 10:10–12:00 p.m. Effective Networking and Communication (in Collaboration with the Career Centre)

Chaired by Raymond Wong (PhD student, Dr. Hong-Shuo Sun Lab, Department of Physiology) and Joseph Steinman (PhD student, Dr. John G. Sled Lab, Medical Biophysics)

10:10–10:15 a.m. Introduction of workshop

10:15–11:10 a.m. Professional Storytelling Seminar Sage Tyrtle, Professional Storytelling Coach 11:10–11:40 a.m. Networking Seminar, Career Educator, UofT Career Centre (Division of Student Life)

11:40–12:00 p.m. Student Panel on Alternative Career Paths Sonia Sugumar (Program Lead, Operations, Ontario Brain Institute; CPIN alumna) Aidin Balo (PhD student, Dr. Oliver Ernst Lab, Biochemistry, University of Toronto) Section II. Lunch and CPIN Trainee Poster Presentations (Medical Sciences Building Stone Lobby) 12:00–2:00 p.m. Lunch and Poster Presentation/Evaluation Section III. Mental Health Symposium (Room 3154, Medical Sciences Building) 2:00– 4:00 p.m. Mental Health Symposium (in collaboration with the Li Ka Shing Knowledge Institute ASR Suicide and

Depression Studies) Chaired by Dr. Sakina Rizvi, Scientist, Li Ka Shing Knowledge Institute, ASR Suicide and Depression Studies Unit, St. Michael’s Hospital; Assistant Professor of Psychiatry, University of Toronto

2:00–2:10 p.m. Opening remarks

Dr. Allan Kaplan, Vice Dean Faculty of Medicine for Education, Graduate and Academic Affairs, Professor of Psychiatry, University of Toronto

2:10–3:00 p.m. Keynote Lecture

Michael Landsberg, SickNotWeak SickNotWeak

3:00–3:20 p.m. Dr. Jeff Meyer, Scientist and Head, Neurochemical Imaging Program in Mood & Anxiety Disorders, Research Imaging Centre, Campbell Family Mental Health Research Institute, CAMH

(Neuroimaging Microglial Activation, an Important Component of Neuroinflammation, in Affective Disorders

3:20–3:40 p.m. Dr. Etienne Sibille, Professor, Department of Psychiatry, Pharmacology & Toxicoloty, UofT;

Deputy Director & Senior Scientist, Campbell Family Mental Health Research Institute, CAMH (GABA Deficits in Depression: Implications for Mood and Cognition)

3:40–4:00 p.m. Dr. Kang Lee, Professor, Applied Psychology and Human Development, OISE, UofT

(Affective Artificial Intelligence and the Future of Mental Healthcare) Section IV. Awards Ceremony, Closing Remarks, and Reception (Room 3154, Medical Sciences Building) 4:00–4:30 p.m. Jonathan Dostrovsky Award in Neuroscience

Poster presentation awards

4:30–5:30 p.m. Light Reception (MSB Stone Lobby)

Event Organizers

CPIN Research Day Organizing Committee Dr. Zhong-Ping Feng (CPIN Director) Dr. Sakina Rizvi Dr. Sofia Raitsin Jonathon Chio (Student Organizer) Tian Renton Joseph Steinman (Executive Student Organizer) Raymond Wong (Student Organizer) Career Development WorkshopAidin Balo Sonia Sugumar Sage Tyrtle Symposium Speakers Michael Landsberg (keynote) Dr. Kang Lee Dr. Jeff Meyer Dr. Etienne Sibille Trainee Presentation Judges Dr. Deryk Beal Dr. Robert Bonin Dr. Anne-Claude Bedard Dr. Trish Domi Dr. Benjamin Dunkley Dr. Zhong-Ping Feng CPIN Academic/Executive Committees; Board of Directors Applied Psychology and Human Development | Kang Lee; Earl Woodruff Biochemistry | Angus McQuibban/Oliver Ernst; Justin Nodwell Institute of Biomaterials & Biomedical Engineering | Julie Audet/Ofer Levi; Warren Chan Cell And Systems Biology | Melanie Woodin/John Peever; Les Buck Computer Science | Richard Zemel; Ravin Balakrishnan Dalla Lana School of Public Health | Geoff Anderson; Adalsteinn Brown Dentistry | Ze'ev Seltzer; Morris Manolson Laboratory Medicine and Pathobiology | Janice Robertson/Lili-Naz Hazrati; Harry Elsholtz Institute of Medical Science | Cindi Morshead/Albert Wong; Mingyao Liu Medical Biophysics | Bojana Stefanovic; Thomas Kislinger Music | Michael Thaut Pharmaceutical Sciences | Jeffrey Henderson/David R. Hampson (Honorary member); Heather Boon Pharmacology | Amy Ramsey; Ruth Ross Physiology | Jonathan Dostrovsky (Honorary member)/Doug Tweet; Graham Collingridge Physiology | Zhong-Ping Feng (CPN Director; Chair of Committees) Psychology | John S. Yeomans/Kaori Takehara-Nishiuchi; Morris Moscovitch Rehabilitation Science Institute | Karl Zabjek; Angela Colantonio

Dr. Leon French Dr. Karen Gordon Dr. Jennifer Griffin Dr. Katherine Halievski Dr. Lili-Naz Hazrati Dr. Jeffrey Henderson Dr. Kang Lee Dr. Joseph WaiHin Leung Dr. Loren Martin Dr. Peter Mastrangelo Dr. Stephen Perry Dr. Graham Pitcher Dr. Gerold Schmitt-Ulms Dr. Shannon Scratch Dr. Frances Skinner Dr. Shuzo Sugita Dr. Hong-Shuo Sun Dr. Walter Swardfager Dr. Alexander Velumian Dr. Joel Watts Dr. Paul Whissell Dr. Liang Zhang Event Program Design Jonathon Chio Joseph Steinman Raymond Wong

Trainee Volunteers Sally Abudiab Azin Amini Mahmoud Bitar Mary Boulos Dipashree Chatterjee Nancy Dong Carina Fan Ann Gong Faraz Honarvar Fiona Hobler Chantel Kowalchuk Lee Prop Nicole Richard Kairavi Shah Award Committee Dr. Zhong-Ping Feng Dr. Lili-Naz Hazrati Dr. Jeffrey Henderson Dr. Amy Ramsey Dr. Kaori Takehara-Nishiuchi Dr. Douglas Tweed Dr. Karl Zabjek

2018 Career Development Workshop

2018 Mental Health Symposium

Michael Landsberg, Sports Journalist, Mental Health Advocate Talk title: #SickNotWeak (Keynote Talk) Michael Landsberg has been a prominent face and voice on the Canadian sports scene since 1984. With his unique style, he quickly became one of this country's most polarizing personalities - perceived by some as forthright and others as arrogant. In 2009 people began to agree more on Michael after he publicly shared his, then decade long, struggle with severe depression and anxiety. Since then, he has become one of this country's loudest voices - pushing for all Canadians to see mental illness as a sickness, not a weakness. Michael frequently used his platform as producer and host of Off the Record on TSN to change people's opinion of mental illness. Michael has been an official spokesperson for Bell Let's Talk Day since that initiative was launched. In 2015 Michael launched his own initiative, a not-for-profit, called SickNotWeak. SickNotWeak is dedicated to changing the way Canadians see mental illness. www.SickNotWeak.com gives a voice to celebrities and everyday folks to share their struggles and their views on mental health issues.

Dr. Etienne Sibille Professor, Departments of Psychiatry, Pharmacology & Toxicology; Campbell Chair, Deputy Director, Campbell Family Mental Health Research Institute; Senior Scientist, Centre for Addiction and Mental Health (CAMH) Talk title: GABA Deficits in Depression: Implications for Mood and Cognition

Dr. Etienne Sibille is Deputy Director and Senior Scientist at the Campbell Family Mental Health

Institute of CAMH. He holds the Campbell Family Chair in Clinical Neuroscience at CAMH and is

a U of T Professor in the Departments of Psychiatry and Pharmacology & Toxicology. His

research focuses on the neurobiology of depression and aging in humans and animal models.

His lab demonstrated that biological pathways affected during brain aging, including inhibitory

functions, overlap with psychiatric conditions and neurological disease. In 2016, he was the

recipient of the NARSAD Distinguished Investigator Award. This award is offered by the Brain &

Behavior Research Foundation to Investigators conducting innovative research in

understanding and treating psychiatric disorders.

Sage Tyrtle, Professional Storytelling Coach Sage Tyrtle is renowned for her warm and informal storytelling workshops directed towards all audience and age groups. She tells stories all over Toronto; including True Stories Told Live, Dare, and Stories of Ours. Sage has also been invited to participated at many festivals; the SOULO Festival, the FOOL Festival and the Toronto Storytelling Festival. Her work has been featured on both NPR’s Snap Judgment and CBC’s Definitely Not The Opera.

Mary Stefanidis, Career Educator, Career Centre, Koffler Student Servives Centre, University of

Toronto

Sonia Sugumar, Program Lead, Operations, Ontario Brain Institute; CPIN alumna Aidin Balo, PhD student, Ernst Lab, Department of Biochemistry, University of Toronto

Dr. Jeffrey Meyer Scientist and Head, Neurochemical Imaging in Mood Disorders, Research Imaging Centre, Centre for Addiction and Mental Health (CAMH); Professor, Department of Psychiatry, Pharmacology & Toxicology, University of Toronto; Tier 1 Canada Research Chair, Neurochemistry of Depressive Disorder Talk title: Neuroimaging Microglial Activation, an Important Component of Neuroinflammation, in Affective Disorders

Dr. Jeffrey Meyer is a Tier 1 Canada Research Chair in the Neurochemistry of Depression. He leads the Neurochemical Imaging Program in Mood and Anxiety Disorders at the Campbell Family Mental Health Research Institute at CAMH and is a full professor at U of T’s Department of Psychiatry. Dr. Meyer has made a number of replicated discoveries including the first definitive evidence of neuroinflammation during major depressive episodes, that monoamine oxidase A level is elevated during major depressive episodes, that serotonin reuptake inhibitor medications block 80% of their target at clinical doses, and that serotonin transporter binding is increased in the brain in winter relative to summer. Much of his recent research focuses on neuroinflammation in major depressive disorder. He is an author on more than 100 peer-reviewed papers in journals including 16 papers as a lead/senior author in JAMA Psychiatry/Archives of General Psychiatry and the American Journal of Psychiatry, as well as other journals such as Lancet Psychiatry and PNAS. Dr. Meyer’s research has a strong translational component, and he has experience in a variety of techniques and technologies. .extending from a PET imaging focus including, MR spectroscopy, functional MRI, early phase clinical trials of therapeutics, natural health product development and advancement of peripheral biomarkers.

Dr. Kang Lee Professor, Applied Psychology and Human Development, Ontario Institute for Studies in Education, University of Toronto; Dr. Eric Jackman Institute of Child Study; Tier 1 Canada Research Chair, Developmental Neuroscience Talk title: Affective Artificial Intelligence and the Future of Mental Health Care Kang Lee, PhD, Professor, OISE, University of Toronto, Tier 1 Canada Research Chair in Developmental Neuroscience, and Senior Scientist at the Department of Psychology, University of California, San Diego. For over two decades, Dr. Lee has used multi-level methodologies (including neuroimaging and machine learning) to study psychological-physiological-neural correlates of human social behavior and emotion. To date, Dr. Lee has published close to 300 peer-reviewed papers and chapters in international journals, and 20 book chapters. Dr. Lee’s research has received funding from various funding agencies such as the US National Institute of Health, US National Science Foundation, Canadian Foundation for Innovation, Natural Science and Engineering Research Council of Canada, and Social Science and Humanities Research Council of Canada, and Chinese National Science Foundation. To date, the amount of funding in total exceeds 11 million dollars. His work has also been featured in various news media outlets such as New York Times, Washington Post, National Geographic, Scientific American, Fox News, and Canadian Broadcast Corporation. Dr. Lee is a co-inventor of the Transdermal Optical Imaging technology that uses a conventional digital video camera and deep machine learning to noninvasively image blood flow under the facial skin to reveal invisible psychological and physiological activities. He is a co-founder and Chief Science Officer of Nuralogix, a leading Affective Artificial Intelligence company in the world. Using Transdermal Optical Imaging, Nuralogix has developed an affective artificial intelligence engine DeepAffex that is capable of decoding not only expressed emotions (facial expressions) but also (and more importantly) internally felt, yet unexpressed emotions and even deception. Dr. Lee and his team are developing applications of DeepAffex in such fields as health, education, marketing, and risk management. Their goal is to make DeepAffex a ubiquitous affective artificial intelligence engine used in all smart devices, and to create artificial intelligence devices that are not only intellectually smart but also emotionally smart.

TRAINEE POSTER PRESENTATION ABSTRACTS

1. Salsabil Abdallah; Cell and Systems Biology Supervisor: Adriano Senatore IN-VITRO MOLECULAR AND BIOPHYSICAL PROPERTIES OF THE “PRESYNAPTIC” CAV2 CALCIUM CHANNEL HOMOLOGUE FROM TRICHOPLAX ADHAERENS, AN ANIMAL THAT LACKS SYNAPSES Abdallah S, 1,2; Smith CL, 2; Harracksingh AN, 1,2; Messak K, 2; Le P, 2; Reese TS, 3; Senatore A, 1,2 1 Cell and Systems Biology, University of Toronto; 2 Department of Biology, University of Toronto Mississauga, 3 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD USA Trichoplax adhaerens is a primitive metazoan with only six cell types that lacks a nervous system and synapses. One cell type, dubbed gland cells, line the periphery of its flat disc-shaped body and resemble neurons by expressing membrane apposed secretory vesicles and proteins required for regulated neuronal exocytosis including a presynaptic Cav2 calcium channel homologue. Remarkably, Trichoplax is a motile behaving animal that can integrate sensory information with cell activity, where it will pause its ciliary locomotion upon detecting algae under its body, then locally secrete hydrolytic enzymes to lyse and consume the algae by external digestion. In this project, we are conducting a molecular characterization of the cloned Trichoplax Cav2 channel, with a focus on its biophysical and pharmacological properties, neuromodulation through G-protein coupled receptors, and interactions with presynaptic scaffolding protein RIM, all of which are crucial for Cav2 channel function at the synapse. Subsequently, we will explore the role of TCav2 in gland cell exocytosis for the purpose of coordinating cellular activity during its feeding behavior. My work will provide insights into the evolution of the nervous system, where pre-synaptic calcium channels are essential for translating electrical signals from graded and action potentials, into regulated secretion of neurotransmitters and neuropeptides. 2. Sarah Ahmed; Institute of Medical Science Supervisor: Romina Mizrahi EXAMINING AN EVENT-RELATED BRAIN POTENTIAL INDEX OF SEMANTIC PRIMING IN CANNABIS-USING INDIVIDUALS AT CLINICAL HIGH-RISK FOR PSYCHOSIS Ahmed S, 1; Lepock JR, 1; Mizrahi R, 1, 2; Kiang, M, 1, 2 1, University of Toronto; 2, Centre for Addiction and Mental Health Purpose: Individuals at the clinical high-risk stage (CHR) experience subthreshold symptoms similar to those of schizophrenia, and are at a higher risk for developing psychosis. Additionally, regular cannabis use has been associated with the worsening of symptoms in CHRs. Abnormalities in semantic processing have been associated with psychotic and psychotic-like symptoms in schizophrenia patients, healthy individuals and regular cannabis users. To better understand the interactions between the CHR state and cannabis use, we used the N400 event-related brain potential (ERP) as a measure of semantic processing. We hypothesized that there will be a smaller difference in N400 amplitudes between related and unrelated stimuli in response to prime stimuli in cannabis-using CHRs compared to non-cannabis-using CHRs.

Methods: We recorded ERPs in 10 CHRs who had a present or present cannabis dependence disorder; 10 CHRs with no cannabis use and 11 healthy controls (HCs). Participants viewed prime words followed by targets (words related or unrelated to prime, or nonwords) at either 300- or 750-ms stimulus-onset asynchrony (SOA). Results: There were no differences between the cannabis-using CHR and non-cannabis-using CHR groups, or cannabis-using CHRs and healthy controls. However, we observed a smaller semantic priming effect in non-cannabis-using CHRs compared to HCs (Tukey HSD familywise < 0.05). Implications: The results of this small sample suggest that cannabis-using CHR patients may be less impaired on processing related versus unrelated stimuli compared to non-cannabis-using CHRs. This raises the question as to whether cannabis may serve as a protective factor in individuals at risk of developing psychosis. 3. Dhekra Al-Basha; Physiology Supervisor: Steven A. Prescott MULTIPLEXED CODING USING DIFFERENTIALLY SYNCHRONIZED SPIKES Al-Basha D, 1,2; Lankarany M, 1-3; Ratté A, 1-3; Prescott SA, 1-3 Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada Based on previous theoretical work, we had demonstrated that the rate of asynchronous spikes can encode the intensity of a slow signal while the timing of synchronous spikes simultaneously encodes abrupt changes in stimulus intensity. This suggests that a single set of neurons can represent distinct features of an external stimulus using differentially synchronized spikes. Here we tested in vivo whether this occurs in real neurons. To this end, we recorded extracellularly from single units in the primary somatosensory cortex of sedated rats. Computer-controlled mechanical stimuli were applied to the whisker pad as discrete steps of increasing force. We asked whether we could decode (1) the force during the sustained phase of the step based on the rate of asynchronous spiking and (2) the timing of the onset and offset of the step based on the timing of synchronous spikes. Using responses from 17 neurons deemed to be responsive to our mechanosensory input, we constructed a firing rate histogram (FRH) in two way. By constructing the FRH with a broad Gaussian kernel, we found that the magnitude of the firing rate tracks the intensity of the force. By constructing the FRH with a narrow Gaussian kernel, we found that abrupt changes in the force were reflected in abrupt increases in the firing rate caused by transient synchronization. Applying a synchrony threshold to the latter FRH yielded 86% sensitive and 100% specific detection of the stimulus transients. These findings demonstrate that synchrony-division multiplexing occurs in somatosensory cortex. 4. Ina Anreiter; Ecology and Evolutionary Biology Supervisor: Marla Sokolowski HISTONE METHYLATION MODULATES DIFFERENCES IN DROSOPHILA FORAGING BEHAVIOR Anreiter I, 1,2, Kramer JM 3,4, Sokolowski M B, 1,2 1. Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, ON, Canada M5S 3B2; 2. Child and Brain Development Program, Canadian Institute for Advanced Research, Toronto, ON, Canada M5G 1M1; 3. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western

University, London, ON, Canada N6A 5C1; 4. Department of Biology, Faculty of Science,Western University, London, ON, Canada N6G 2M1 Epigenetic mechanisms have important roles in modulating the expression of genes in response to external stimuli, and recent research has suggested that genotypic variation can correlate with DNA methylation and behavioral outcomes. We show that the histone methyl transferase G9a regulates behavioural differences in rover and sitter variants of the foraging (for) gene through allele specific histone methylation of for’s promoter 4 (pr4). Our results show that rovers have higher levels of pr4 H3K9me, and lower levels of pr4 expression than sitters. This expression pattern regulates rover-sitter differences in adult foraging behavior, and these differences are transgenically abolished by reducing pr4 expression in sitters. This compelling evidence shows that genetic variation can interact with an epigenetic modifier to produce differences in gene expression establishing a behavioural polymorphism in Drosophila. 5. Patrick Antonio; Rehabilitation Sciences Institute Supervisor: Stephen Perry THE INFLUENCES OF HEALTH FACTORS ON PLANTAR PRESSURE DURING STAIR GAIT Antonio P, 1,2; Perry S, 1,2 1 Rehabilitation Sciences Institute, University of Toronto; 2 Toronto Rehabilitation Institute Introduction: Diabetic peripheral neuropathy (DPN) is a dysfunction of the peripheral nerves that reduces sensation in the feet, and is prevalent in 50% of individuals with diabetes [1]. Modifiable risk factors for the incidence of neuropathy include high body mass index, elevated blood glucose levels, and hypertension [2] [3]. Diminished sensation, inadequate pressure offloading, and the cumulative effects of repetitive pressure during gait can lead to ulcer formation [4] [5]. The objective of this study was to understand how specific health factors may help indicate increased foot pressure during stair gait. Methods: Individuals with DPN (n =14) self-reported health characteristics such as age, height, weight, blood glucose (HbA1c), history of foot ulceration. Plantar sensation was assessed using touch-test monofilaments. Foot pressures and stance time (ST) were recorded during stair gait using Medilogic (Germany) pressure insoles placed inside standardized footwear. Regional pressures (expressed as a %) were calculated to determine the proportion of the total pressure on specific plantar regions. A hierarchical multiple regression analysis was conducted to predict factors such as blood glucose level and plantar sensation with the regional pressure, while controlling for BMI, age, and stance time. Results & Discussion: The hierarchical multiple regression demonstrated that ST and age significantly and uniquely predicted regional pressure by 7%, while plantar sensation and HbA1c accounted for 22% of the overall variance in regional pressure. The final model demonstrated that age (β = 0.36) and plantar sensation (β = 0.39) may best predict high foot regional pressures during stair gait. 6. Kira Antonyshyn; Institute of Medical Science Supervisor: Gregory Borschel

CORNEAL ULCERATION AND PERFORATION IS REDUCED BY CORNEAL NEUROTIZATION IN A RAT MODEL OF NEUROTROPHIC KERATOPATHY Antonyshyn K, 1,2,3; Catapano J, 3; Zhang JJ, 2,3; Borschel GH 2,3 1 Institute of Medical Science, University of Toronto; 2 Department of Neuroscience and Mental Health, The Hospital for Sick Children; 3 Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children Introduction: Neurotrophic keratopathy (NK) is a disease that develops because of absent corneal sensory innervation. The disease is characterized by corneal epithelial ulcerations and scarring that can lead to blindness. Corneal neurotization is a novel surgical procedure, developed at the Hospital for Sick Children, used to treat NK by restoring corneal innervation using nerve grafts. The present study evaluates the effect of corneal neurotization on corneal epithelial ulceration, scarring, and perforation in our previously established rat model of NK. Methods: Untreated NK rats (n=5) were compared to NK rats treated with corneal neurotization (n=10). Tarsorrhaphy, which is applied after surgeries to prevent corneal injury, was removed, exposing the denervated cornea. Standardized digital photographs were taken daily for one week under Wood’s lamp/fluorescein staining and normal light to assess corneal epithelial ulceration and scarring. The area of ulceration was calculated using ImageJ, and the data analyzed using a Fisher’s exact test or unpaired t-test. Results: On day seven, rats treated with corneal neurotization demonstrated significantly less ulceration compared to untreated rats (30.1% ± 12.7 vs. 0.0 ± 0.0, p < 0.0001). All untreated rats compared to two treated rats developed ulcerations (p = 0.007). 80% of untreated rats compared to 0% of treated rats developed corneal perforations (p = 0.0037). Corneal neurotization reduced corneal scarring. Significance: Corneal neurotization reduces ulceration and prevents perforation in rats with NK. These results suggest the procedure may improve epithelial maintenance and healing in the NK cornea. However, further investigations are necessary to elucidate underlying mechanisms. 7. Afif Aqrabawi; Cell and Systems Biology Supervisor: Junchul Kim Spatiotemporal information is differentially conveyed by hippocampal projections to the anterior olfactory nucleus during episodic-like odour memory Aqrabawi AJ, 1; Kim JC 1,2 1 Cell & Systems Biology, University of Toronto; 2 Psychology, University of Toronto The hippocampus is essential for representing spatiotemporal context and establishing its association with the sensory details of daily life to form episodic memories. The olfactory cortex in particular shares exclusive anatomical connections with the hippocampus as a result of their common evolutionary history. We selectively inhibited hippocampal projections to the anterior olfactory nucleus (AON) during behavioural tests of contextually-cued odour recall. We found that spatial odour memory and temporal odour memory are independently impaired following inhibition of distinct, topographically organized hippocampal-AON pathways. Our results not only reveal a longstanding unknown function for the AON but offer new mechanistic insights regarding the representation of odours in episodic memory.

8. Ramy Ayoub; Psychology Supervisor:Donald Mabbott METFORMIN RESULTS IN HIPPOCAMPAL REMODELING AND IMPROVED MEMORY ENCODING IN PAEDIATRIC BRAIN TUMOUR SURVIVORS TREATED WITH CRANIAL RADIATION: A PILOT RANOMIZED CONTROLLED CROSSOVER STUDY Ramy Ayoub, Freda Miller, Kiran Beera, Cynthia de Medeiros, Suzanne Laughlin, Eric Bouffet,and Donald Mabbott Ayoub R1,4, Miller F1, Kiran B1, de Medeiros C1, Laughlin S2, Bouffet E3, Mabbott D1,4 1 Neurosciences and Mental Health Program, Research Institute, The Hospital for Sick Children 2 Diagnostic Imaging, The Hospital for Sick Children 3 Paediatric Brain Tumour Program, The Hospital for Sick Children 4 University of Toronto OBJECTIVES: Although curative, cranial radiation results in hippocampal insult and memoryimpairment in children with brain tumours. Metformin stimulates hippocampal neurogenesisand improves memory performance in mice. We conducted a pilot double blind randomizedcontrolled cross-over trial to examine feasibility and test the effects of metformin versusplacebo on hippocampal volume and declarative memory in pediatric brain tumor survivorstreated with either focal or whole brain radiotherapy. METHODS: Twenty four participants (Age= 13.96 ±3.51) (M = 14, F = 7) were randomly assigned to complete consecutive 12-weekcycles of Metformin (A) and Placebo (B) in either an AB or BA sequence: 10-week washoutoccurred at crossover. Assessment at baseline and immediately following treatment for eachcondition included: (a) structural MRI to obtain overall/subfield hippocampal volume and (b)testing of memory encoding/retrieval. Linear mixed modelling was used to test the effects oftreatment condition and time on difference from baseline scores: An interaction term was usedto test for carryover. FINDINGS: Adherence was high and participants tolerated metformin. Nochange in overall hippocampal volume was observed bilaterally - but increased volume in theright subiculum and fimbria was evident for metformin vs. placebo (ps< .05). Notably,decreased right CA3 volume was evident for metformin carryover – suggesting a remodeling ofhippocampal structure. Treatment with metformin resulted in improved memory encodingimmediately and at carryover (p’s < .05). CONCLUSION: Metformin may be effective fornormalizing hippocampal structure and memory encoding in paediatric brain tumor survivorsand warrants consideration in larger trials. 9. Julianne Baarbé; Institute of Medical Science Supervisor: Robert EW Chen A CORTICAL NEURAL SIGNATURE OF MOTOR INTERRUPTION IN PATIENTS WITH PARKINSON'S DISEASE AND FREEZING OF GAIT Baarbé JK, 1,2; Brown MJ, 2,3; Saha U, 2; Lizarraga K, 1,2; Weissbach A, 1,2,4; Drummond N, 2; Rinchon C, 1,2; Kapoor P, 5; Saravanamuttu J, 1,2; Chen R, 1,2 1 Department of Medicine, University of Toronto; 2 Division of Brain, Imaging & Behaviour - Systems Neuroscience, Krembil Research Institute; 3 Department of Kinesiology, California State University; 4 Institute of Neurogenetics, University of Luebeck; 5 Department of Psychology, University of Toronto

Freezing of gait (FoG) is a major source of disability in Parkinson’s disease (PD) and is often resistant to treatment. We hypothesized that cortical oscillations involved in sensorimotor and perceptual processes [alpha (8-12 Hz), low beta (13-20 Hz) and high beta (21-35 Hz)] would increase during interruptions of motor output in Parkinson’s disease (PD) patients with freezing of gait (FoG). We recorded whole head electroencephalography in 10 PD patients (68 years old±6; disease duration: 9 years±5; levodopa equivalent dose: 880 mg±420) and 9 healthy controls (67 years old±6). Six patients had FoG confirmed by the New Freezing of Gait Questionnaire and neurologist assessment. Participants navigated through virtual reality by depressing foot pedals. Narrow doorways prompted freezing episodes. We also had participants intentionally stop. Patients with FoG experienced a total of 38 freezing episodes (mean duration 2.5 s). Freezing episodes influenced alpha power within premotor/frontal (p=0.042; Onset freezeOnset freeze; Onset freeze<During freeze). Freezing episodes affected low beta power in motor (p=0.022; Onset freeze<During freeze) and parietal clusters (p=0.039; Onset freeze<During freeze). Freezing did not induce changes to high beta power within any of the clusters, but intentional stopping increased alpha, low beta and high beta in all clusters (p<0.001). Alpha and low beta oscillations in motor areas may be important predictive signals of freezing in PD patients with FoG. Uniquely, the absence of high beta distinguishes freezing episodes from intentional stops. These findings may be useful for the development of brain stimulation or biofeedback strategies to alleviate FoG. 10. M. Amin Banihashemi; Institute of Medical Sciences Supervisor: Sandra E. Black A SYSTEMATIC REVIEW OF LITERATURE ON THE RELATIONSHIP OF APOLIPOPROTEIN E EPSILON 4 ALLELE CARRIER STATUS WITH EYE STRUCTURE MORPHOLOGY IN DEMENTIA Banihashemi MA 1,2; Black SE 1,2 1 LC Campbell Cognitive Neurology, Sunnybrook Health Sciences Center, Toronto, ON, Canada; 2 Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada Background: Identifying biomarkers for early detection of dementia is a focus of research, as therapies under active investigation appear to be more effective in the pre-dementia state. An example of a screening tool for early detection is early detectable changes in eye structures in dementia such as retinal nerve fiber layer (RNFL) and retinal ganglion cell (RGC) layer thinning. We set out to determine if the relationship of these eye structure changes with Apolipoprotein E (APOE) epsilon 4 (ε4) allele carrier status, a genetic variant widely associated with dementia, has been studied. Methods: Medline and Embase databases were searched using select keywords including: Eye; Apolipoprotein E4; Retina; Retinal vessels; Choroid; Lens, Crystalline. Observational studies comparing eye structure differences in humans and animal models between APOE-ε4 allele carrier versus non-carrier status were included in the qualitative review. Results: Out of 192 records screened, five were selected for full text review. Of the five only two animal model studies met inclusion criteria for the qualitative review. Neither study had assessed RNFL, the most widely studied eye structure in dementia. From these two studies, the following information was obtained: APOE-ε4 carrier mice demonstrated similar levels of RGC, photoreceptors, horizontal and amacrine cells, and a decrease in synaptic density and electroretinogram response compared to non-carriers. APOE-ε4

carrier Drosophila flies demonstrated significantly greater degeneration of eye photoreceptors compared to non-carriers. Conclusion: The relationship of APOE-ε4 carrier status and eye biomarkers remains unexplored in humans. 11. Andrew Barszczyk; Department of Applied Psychology Supervisor: Kang Lee VIDEO CAMERA-BASED HEART RATE VARIABILITY ANALYSIS FOR STRESS MEASUREMENT Wu S-J*, 1; Barszczyk A*, 1; Zheng P, 1; Lee K, 1 1 Applied Psychology, University of Toronto Stressful situations are a part of daily life, but prolonged stress is detrimental to psychological and cardiovascular health. Objectively measuring stress in different situations throughout the day is crucial for identifying stressful situations and thus knowing when to employ stress management techniques. The gold standard for biometric stress measurement is heart rate variability analysis using heart rate data collected through an electrocardiogram (ECG). However, the inconvenience of ECGs and their requirement for specialized equipment limits their use. Here, we present a novel technology called Transdermal Optical Imaging (TOI) for determining heart rate variability and thus measuring stress. The technology uses a conventional video camera in combination with machine learning to contactlessly extract heart blood flow information from video of the face and thus capture heart beat data. In this study, we measured stress in 136 individuals using TOI and compared it to a simultaneous stress measurement using the ECG standard. We found that the heart rate recorded with TOI technology correlates very well the heart rate recorded with ECG (r=1.00). When we analyzed the well-known heart rate variability feature SD1/SD2, the stress scores produced by TOI correlated very strongly with stress scores produced by ECG (r=0.89). Therefore, TOI technology produces valid stress scores. The implementation of this software-based technology in existing mobile devices (e.g., smartphones) could would thus constitute a novel tool for the convenient, contactless, and regular measurement of stress levels in daily life. 12. Andrew Barszczyk; Applied Psychology Supervisor: Kang Lee BASAL HEART RATE VARIABILITY CORRELATES WITH CHRONIC STRESS EFFECTS ON THE IMMUNE SYSTEMYasin, Y*, 1; Barszczyk A*, 1; Wu S-J, 1; Zheng P, 1; Lee K, 1 1 Applied Psychology, University of Toronto Chronic exposure to stress promotes activity in the sympathetic branch of the autonomic nervous system over the parasympathetic branch. Over the long term, this results in significant physiological changes in immune system function and increases the risk of health complications like cardiovascular disease. It is therefore important to determine whether people are experiencing these changes and apply stress mitigation techniques. Unfortunately, these changes are typically detected through extensive blood work panels, which are not practical on a large scale in the general population. We therefore wondered whether non-invasive measurement of basal stress level could predict chronic stress-related effects on the immune system. In this study, we measured basal stress in 907 patients during a physical examination at the doctor’s office based on heart rate variability data obtained from an electrocardiogram (ECG). We compared stress levels against immune cell counts obtained from

blood work at the same visit. We found that stress levels were positively correlated with urea levels (r=0.209), suggesting the presence of a chronic immune reaction in people with increased stress. Following from this, high stress scores were negatively correlated with cell counts of neutrophils (r=-0.076), but positively correlated with monocytes (r=0.163). These changes are consistent with chronic-stress induced immune responses. Thus, a snapshot of a person’s basal stress provides some indication of chronic stress-associated immune changes. Elevated basal stress scores might therefore help identify people that would benefit from more extensive stress monitoring. 13. Bita Behrouzi; Department of Physiology Supervisor: Douglas Tweed COSTATE-FOCUSED MODELS FOR REINFORCEMENT LEARNING Behrouzi B, 1; Liu X, 1; Tweed DB, 1, 2 1 Department of Physiology, University of Toronto; 2 Centre for Vision Research, York University Human brains and artificial neural networks both learn tasks by adjusting their synapses based on sensory feedback. For this type of learning, called reinforcement learning, there are two main classes of algorithm: model-based and model-free. Model-based methods learn a “mental model”, or internal simulation, of the agent’s body and surroundings, and use that model to learn tasks. But it is hard to learn accurate models of complex environments, and therefore recent work in artificial intelligence has favored model-free learning, even though real brains clearly possess models, i.e. we can imagine and predict the consequences of our actions. Here we present a new model-based learning mechanism called costate-focus, which uses the costate equation of optimal control to “focus” the model, training it to mimic only those features of the environment that are most relevant to its task. We show that costate-focus can learn difficult, time-optimal control problems as quickly and accurately as deep deterministic policy gradient, a recent model-free method. Costate-focus works in complex environments, both deterministic and stochastic, and it can improve by mental practice, and so acquire skills with less real-world experience than is required for model-free learning. 14. Vanessa Breton; Physiology Supervisor: Peter Carlen EXCITATORY AND INHIBITORY CURRENTS UNDERLYING CROSS FREQUENCY COUPLING FEATURES DURING SEIZURE-LIKE EVENT STATE TRANSITIONS Breton VL 1,3; Bardakjian BL 2,4; Carlen PL 1,2,3,5 1 Department of Physiology, University of Toronto; 2 Institute of Biomaterials and Biomedical Engineering, University of Toronto; 3 Krembil Research Institute, Division of Fundamental Neurobiology, Toronto Western Hospital; 4 Department of Electrical and Computer Engineering, University of Toronto; 5 University Health Network, Toronto In the neocortex, phase amplitude cross frequency coupling (CFC) is a basic feature of network communication. Different frequency bands coupled with each other can indicate the interaction of different neural populations. Evidence suggests that enhanced CFC is present before and during seizures; however, the current bases for the pathological network activity has yet to be determined.

Therefore, using an ex vivo brain slice preparation, low magnesium induced seizure-like events (SLEs) were obtained in the superficial layer of the mouse neocortex. Local field potential electrodes recorded the brain activity. From nearby pyramidal neurons, an electrode in whole cell voltage clamp configuration recorded synaptic excitatory and inhibitory currents. Using this approach, first, we observed the pattern of CFC features throughout the SLE state. Rises in the theta-HFO band signal seizure onset transition, whereas a presence of the delta-HFO band signaled seizure termination. Then, using a broad CFC feature set encompassing both theta and delta-HFO features, state distribution probabilities were computed as markers to classify the duration of SLE onset and termination transition. Next, we monitored the synaptic currents during these defined transition periods. Both the onset and termination was marked by changes in the excitatory and inhibitory currents. Crucially, the peaks in these currents had distinctive coupling to the phase of low frequency oscillations in the onset as compared to the termination states. These data are the first to demonstrate the excitatory and inhibitory current bases for CFC features during seizures. 15. Sammy Cai; Physiology Supervisor: Zhengping Jia IT'S ABOUT TIME: PKA-DEPENDENT LTP INTEGRATES THE TIMING OF STIMULI VIA LIMK1 Cai S, 1,2,3; Collingridge GL, 1,3; Jia Z 1,2 1 Department of Physiology, University of Toronto; 2 Department of Neurosciences and Mental Health, Hospital for Sick Children; 3 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital Long-term potentiation (LTP) has been studied extensively to understand the molecular mechanisms underlying learning and memory. The NMDA receptor-dependent form of LTP can be characterized into protein kinase A (PKA)-dependent and independent forms depending on the spacing between theta burst stimuli (TBS). Compressed (c)TBS does not require PKA whereas spaced (s)TBS elicits a PKA-dependent form that requires the insertion of calcium permeable AMPA receptors (CP-AMPAR) (Park et al [2016] J Neurosci.). The PKA-dependent form of LTP has implications in protein translation that may alter the molecular composition, structure, and function of synapses; however, the mechanism by which synapses integrate the timing of stimuli remains elusive. To investigate these processes, we have used electrophysiology to compare cTBS and sTBS at mouse CA1 synapses using genetic knockout (KO) or pharmacological inhibition of the PKA pathway. We found that LTP induced by sTBS was sensitive to inhibitors of PKA and protein synthesis. Mice lacking LIM kinase-1 (LIMK1), a potent regulator of actin cytoskeleton dynamics, revealed deficits in PKA-dependent LTP, and was insensitive to protein synthesis inhibitors applied throughout sTBS. Preliminary results suggest that PKA can activate LIMK1 to trigger protein synthesis-dependent pathways critical for plasticity. These findings provide insight into how spaced stimuli can be consolidated into long-term memories. 16. Fernando Caravaggio; Department of Psychiatry Supervisor: Ariel Graff-Guerrero AMOTIVATION IS ASSOCIATED WITH SMALLER VENTRAL STRIATUM VOLUMES IN OLDER PATIENTS WITH SCHIZOPHRENIA

Caravaggio F, 1,2; Fervaha G ,1; Iwata Y, 1,2; Plitman E, 1; Chung JK, 1; Nakajima S, 1; Mar W, 1; Gerretsen P, 1,2; Kim J, 1; Chakravarty MM, 3; Mulsant B, 1; Pollock B, 1; Mamo D, 1; Remington G, 1,2; Graff-Guerrero A, 1,2 1 Research Imaging Centre, Centre for Addiction & Mental Health; 2 University of Toronto, Dept. Psychiatry; 3 Cerebral Imaging Centre, McGill University Objective: Motivational deficits are prevalent in patients with schizophrenia, persist despite antipsychotic treatment, and predict

long‐term outcomes. Evidence suggests that patients with greater

amotivation have smaller ventral striatum (VS) volumes. We wished to replicate this finding in a sample of older, chronically medicated patients with schizophrenia. Using structural imaging and positron emission tomography, we examined whether amotivation uniquely predicted VS volumes beyond the effects of striatal dopamine D2/3 receptor (D2/3R) blockade by antipsychotics. Methods: Data from 41 older schizophrenia patients (mean age: 60.2 ± 6.7; 11 female) were reanalysed from previously published imaging data. We constructed multivariate linear stepwise regression models with VS volumes as the dependent variable and various sociodemographic and clinical variables as the initial predictors: age, gender, total brain volume, and antipsychotic striatal D2/3R occupancy. Amotivation was included as a subsequent step to determine any unique relationships with VS volumes beyond the contribution of the covariates. In a reduced sample (n = 36), general cognition was also included as a covariate. Results: Amotivation uniquely explained 8% and 6% of the variance in right and left VS volumes, respectively (right: β = −.38, t = −2.48, P = .01; left: β = −.31, t = −2.17, P = .03). Considering cognition, amotivation levels uniquely explained 9% of the variance in right VS volumes (β = −.43, t = −0.26, P = .03). Conclusion: We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D2/3R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit. 17. Carly Cermak; Rehabilitation Sciences Institute Supervisor: Deryk Beal COGNITIVE COMMUNICATION IMPAIRMENTS IN CHILDREN WITH TRAUMATIC BRAIN INJURY: A SCOPING REVIEW Cermak, CA 1,2,3; Scratch, SE 1,2,4; Reed, NP 1,2,5; Bradley, K 3,6; Quinn de Launay, K 1,2; Beal, DS 1,2,3 1 Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital; 2 Rehabilitation Sciences Institute, University of Toronto; 3 Department of Speech-Language Pathology, University of Toronto; 4 Department of Pediatrics, University of Toronto; 5 Department of Occupational Science and Occupational Therapy, University of Toronto; 6 St. Michael's Hospital, Toronto OBJECTIVE: This scoping review synthesizes the scholarly literature on cognitive communication impairments in traumatic brain injury (TBI) sustained during childhood to identify gaps in research, and make recommendations that will further the field of cognitive communication in pediatric TBI.

METHODS: MEDLINE, PsycINFO, CINAHL, and EMBASE were searched to identify peer reviewed studies that examined cognitive communication impairments in children that sustained a TBI between 3 months to 18 years of age. RESULTS: Twenty-eight studies met inclusion criteria with three main categories identified in relation to cognitive communication: 1) impairments according to TBI severity, 2) impairments according to age at injury, and 3) trends in recovery according to TBI severity. CONCLUSIONS: The results of this scoping review suggest that: 1) TBI severity is not the sole predictor of performance; other factors contribute to cognitive communication outcome and recovery; 2) developing skills at time of injury are most susceptible to impairment; and 3) standard, norm-referenced language assessments are not sensitive in detecting language impairments that are secondary to cognitive impairments found in TBI. Directions for future research and suggestions for clinical practice are proposed. 18. Jordan Chad; Department of Medical Biophysics Supervisor: Jean Chen SELECTIVE DEGENERATION OF CROSSING BRAIN FIBRES IN AGING Chad, JA, 1,2; Pasternak, O, 3; Salat, DH, 4; Chen, JJ, 1,2 1 Department of Medical Biophysics, University of Toronto; 2 Rotman Research Institute, Baycrest Health Sciences; 3 Brigham & Women's Hospital, Harvard Medical School; 4 Massachusetts General Hospital, Harvard Medical School The white matter of the brain is a complex structure of crossing fibres, constituting the brain’s neural connections. The structural integrity of these fibres can be assessed using diffusion tensor magnetic resonance imaging (DTI), which measures the anisotropy of water diffusion in brain tissue. However, assessment of structural integrity becomes more complicated in the presence of two distinct populations of fibres: “primary” fibres forming a principal direction (e.g., the sensorimotor fibres running from the cerebral cortex to spinal cord), and “secondary” fibres which cross approximately orthogonal to the principal direction (e.g., association fibres such as the longitudinal fasciculi). Selective degeneration of secondary crossing fibres while the primary fibres remain intact has been observed in DTI studies of Alzheimer’s disease via an increase in diffusion anisotropy (“fractional anisotropy”, FA) along the principal direction relative to healthy controls. Similar albeit more subtle selective degeneration has been suggested in healthy aging, but increased FA with age is generally not reported in cross-sectional studies of aging. In this work, we (1) use DTI tractography to confirm selective degeneration of crossing fibres in healthy aging among a cohort of 212 subjects, and (2) uncover increased FA with age in this cohort only after controlling for the diffusion of extracellular water, suggesting that extracellular water may introduce variability that obscures finer structural phenomena in DTI studies of aging. The similarities between our findings and those in the reported Alzheimer’s cohorts support the idea that the disease-related effects resemble an exaggerated form of healthy aging-related changes. 19. Cheng Chen; Institute of Medical Science Supervisor: James Kennedy THE GLUTAMATE RECEPTOR - GRM3 GENE AND ANTIPSYCHOTIC RESPONSE IN SCHIZOPHRENIA Chen CC, 1,2; Arun KT, 2; James LK, 2, 3

1 Institute of Medical Science, University of Toronto; 2 Pharmacogenetic Research Clinic, Centre for Addiction and Mental Health; 3 Department of Psychiatry, University of Toronto Schizophrenia (SCZ) is a debilitating mental disorder. Currently, antipsychotics (AP) are the best treatment for SCZ, but the clinical responses are highly variable across individuals. The glutamate system is a target for studying the pharmacogenetics of AP based on evidence from previous studies. We conducted an association study between the variants in the GRM3 gene and AP response using the CATIE dataset (n=306). We investigated 23 SNPs across the GRM3 gene. The study consists of 306 Caucasian patients that each has been treated with AP. Treatment response was evaluated using the Positive and Negative Syndrome Scale (PANSS). All SNPs within the GRM3 gene were selected from the UCSC genome browser and extracted from the CATIE dataset using PLINK. Linkage disequilibrium and Hardy-Weinberg equilibrium calculations were conducted using HaploView, and all statistical analyses were performed using IBM SPSS. Among the 23 SNPs obtained from the CATIE dataset, only rs274621 was significantly associated with AP responses (p=0.020) under the recessive model. However, the rs276421 result did not survive multiple corrections. Several studies have investigated GRM3 polymorphisms versus AP response and yielded promising results in the past. We found a trend for rs274621 to be associated with AP response. It is an upstream variant which may be located in the promoter region and may affect the transcription of GRM3. Interestingly, rs274621 was also significantly associated with bipolar disorder in a previous GWAS. Overall, our study did not support the role of GRM3 in AP response. However, further studies are required. 20. Wenliang Chen; Physiology Supervisor: Hong Shuo Sun SWELLING-INDUCED CHLORIDE CURRENT IN GLIOBLASTOMA PROLIFERATION, MIGRATION AND INVASION Wong R 1,2; Chen W 1; Zhong X 1, Rutka JT 1, Feng ZP 2, Sun HS 1,2 1 Department of Surgery; 2 Department of Physiology, University of Toronto Glioblastoma (GBM) remains the most common and aggressive malignant brain tumor originating in the central nervous system. Diagnosis is lethal with a median survival of <15 months. Aberrant swelling-induced chloride channel ICl,swell expression has been linked to GBM cellular functions (i.e. proliferation, migration and invasion). Hypothesis: Inhibition of the swelling-induced chloride channel ICl,swell suppresses GBM cellular functions. Purpose: To establish the swelling-induced chloride channel ICl,swell as a potential drug target by evaluating DCPIB, a specific antagonist for the swelling-induced chloride channel ICl,swell, on GBM cellular functions. Methods and results: We used the human GBM cell lines U251 and U87. First, with the whole-cell patch-clamp technique, we demonstrated that DCPIB enhanced the endogenous swelling-induced chloride channel ICl,swell. When assessed with MTT and colony formation assays, GBM proliferation and viability were reduced with DCPIB treatment. Moreover, GBM migration and invasion (assessed with scratch wound and Matrigel invasion assays, respectively) were significantly suppressed with DCPIB. With

Western immunoblots, we also assessed in GBM the protein levels of p-Akt/t-Akt, p-JAK2/t-JAK2, and p-STAT3/t-STAT3. We found that DCPIB inhibited the JAK/STAT as well as the PI3k/Akt signaling pathways, which could potentially be the underlying swelling-induced chloride channel ICl,swell-dependent mechanism. Conclusion: Because potentiated swelling-induced chloride channel ICl,swell activity contributes to the devastating proliferative, migratory and invasive characteristics of GBM, our study establishes the involvement of ICl,swell in GBM cellular functions. 21. Darren Cheng; Rehabilitation Sciences Institute Supervisor: Nancy Salbach RELIABILITY AND VALIDITY OF RECENTLY DEVELOPED STROKE-SPECIFIC PROTOCOLS FOR THE 10-METRE AND 6-MINUTE WALK TESTS: PRELIMINARY RESULTS Cheng DK, 1; Nelson M, 2; Brooks D, 1, 3; Salbach NM, 1, 3 1 Rehabilitation Sciences Institute, University of Toronto; 2 Lunenfeld-Tanenbaum Research Institute-Sinai Health System, Bridgepoint Collaboratory for Research and Innovation; 3 Department of Physical Therapy, University of Toronto This study aims to evaluate the test-retest reliability, measurement error, and construct validity of recently adapted stroke-specific protocols for the 10-metre walk test (10mWT) and 6-minute walk test (6MWT). Participants are ambulatory adults with stroke-related gait deficits and are recruited from inpatient and outpatient care settings. Two assessments are completed 1-2 days apart. Data on sociodemographic and stroke characteristics are collected at first assessment. The 10mWT, and the 6MWT conducted twice with a 15-m and a 30-m walkway are completed at both assessments. A sample size of 32 is desired. Complete preliminary data from 14 participants are available: 8 men and 7 women (median age 58) 1-10 months post-stroke, 1 with hemorrhagic stroke, 4 inpatients and 5 outpatients, and 1 requiring assistance to walk. Median walk test scores at time 1 and 2 were compared for test-retest reliability and minimal detectable change (MDC) was calculated. Bland-Altman plots were constructed. Spearman correlations between test scores and limb strength were examined for construct validity. Median 10mWT speed was 0.92m/s at both assessments. Median 6MWT distance on the 15m walkway was 270.2m and 296.2 at time 1 and 2, respectively. Median 6MWT distance on the 30m walkway was 328.9m and 355.4m at time 1 and 2, respectively. Individual change scores were smaller than calculated MDC values, and correlations were lower than in the current literature. Support for reliable standardized test protocols will promote their use in clinical and research settings. 22. Sun-Lim Choi; Lunenfeld-Tanenbaum Research Institute Supervisor: Graham Collindgridge ROLE OF JAK2-STAT3 IN SYNAPTIC AND HOMEOSTATIC PLASTICITY Choi SL, 1,3; Salter E, 2,3; Sanderson TM, 1; Collindgridge GL, 1,2,3 1 Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, U.K.; 2 Department of Physiology, University of Toronto, Toronto, Canada; 3 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada There are many published studies on synaptic plasticity and homeostatic synaptic plasticity. However, the extent to which

molecules or signaling pathways are shared between these distinct plasticity mechanisms remains unclear. We found that STAT3, which is necessary for input-specific long-term depression (LTD) , is differentially expressed 48 hr after bicuculline (Bic) treatment, but not after tetrodotoxin (TTX) treatment, of cultured neurons. This effect, which is associated with synaptic down-scaling, occurred in a NMDA receptor-dependent manner. The mRNA levels of all known JAKs and STAT isoforms were not altered after Bic treatment. Since STAT3 mRNA has two conserved cytoplasmic polyadenylation elements (CPE), we examined the poly A tail which was elongated after Bic treatment. These data suggest that the JAK2-STAT3 pathway may have an important role homeostatic plasticity as well as input-specific synaptic plasticity. 23. Dalya Cohen; Physiology Supervisor: Graham Collingridge THE IMPACT OF ALZHEIMER'S DISEASE ON SYNAPTIC PLASTICITY AND THE CAMP/PKA PATHWAY Cohen DR, 1,2,3; Georgiou J, 3; Jia ZP, 1,2; St. George-Hyslop P, 4; Collingridge G, 1,3 1 Dept. of Physiology, University of Toronto; 2 Neurosciences and Mental Health, Sick Kids Hospital; 3 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; 4 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto Alzheimer’s disease (AD) is a physiologically devastating form of dementia that has significant implications for those afflicted, and a high socio-economic burden. An understanding of the biological processes leading to synapse dysfunction in AD remains elusive. One promising avenue of research is to examine the dynamics of synaptic plasticity within the brain centres of learning and memory in animal models of AD. Long-term potentiation (LTP) and long-term depression (LTD) are mechanisms underlying learning and memory at the synaptic level. Deficits in synaptic plasticity, as well as disruption of the cAMP (cyclic adenosine monophosphate) pathway have been independently proposed in AD; however, it is unknown whether these are connected. The aim of this work is to examine whether synaptic defects in AD involve a neuronal signalling cascade comprising the cAMP/protein kinase A (PKA) pathway. Method: Unique modes of tetanic stimulation for induction of cAMP/PKA-dependent and -independent LTP, electrophysiological synaptic recordings in the hippocampal CA1 brain region will be used to determine whether the TgCRND8 AD model shows impairments in LTP. In addition, LTD experiments will provide the opportunity to identify the extent to which each memory formation pattern is altered in AD. Applying pharmacological agents that modulate the cAMP/PKA pathway in AD models may reveal more details about their role in synaptic plasticity. Examinations conducted on mouse models of AD may establish a physiologically representative picture of maladaptive LTP and LTD alterations. The work will establish whether targeting of synaptic plasticity and/or cAMP modulators holds promise for AD treatment. 24. Jasmyn Cunningham; Institute of Medical Science Supervisor: Colin Shapiro COGNITIVE BEHAVIOURAL THERAPY FOR INSOMNIA (CBT-I) TO TREAT DEPRESSION: A SYSTEMATIC REVIEW Cunningham JEA, 1; Shapiro CM, 2,3,4

1 Institute of Medical Science, University of Toronto; 2 Department of Psychiatry, University of Toronto; 3 Department of Ophthalmology, University of Toronto; 4 Youthdale Child & Adolescent Sleep Centre Major depressive disorder is one of the most frequently diagnosed psychiatric disorders, with a 12% lifetime prevalence of major depressive episodes in Canada. Sleep and circadian disturbances are also extremely common, with up to 90% of individuals with depression also endorsing sleep complaints. These disturbances predict worse clinical outcomes, and regulation of sleep disturbances is often necessary in order to minimize relapses in depression. Treatments for both insomnia and depression often lead to greater clinical improvement than treatments targeting depressive symptomology alone. Cognitive behavioural therapy for insomnia (CBT-I) is a multi-component approach to treating sleep disturbances which is extremely effective in reducing insomnia symptoms in sufferers of primary insomnia. CBT-I is a promising treatment for the sleep and circadian disturbances in depression, and literature suggests it may also be effective as a stand-alone treatment for symptoms of depression. A systematic review was conducted of trials investigating the use of CBT-I in treating depression. Only trials including adult patients with unipolar depression were considered. Therapy variations included in-person, telehealth, and group CBT-I. Overall, CBT-I is a promising treatment for individuals with both depression and insomnia. In-person variations of the therapy had the most supporting evidence for their efficacy, though the effects of CBT-I in treating depression may not be additive with the effects of antidepressant medications. Improvement in symptoms of insomnia may mediate the relationship between CBT-I and depressive improvement. Telehealth CBT-I has less supporting evidence for its efficacy, though a stepped care approach based on depressive severity may be worthwhile. 25. Lina Darwish; Pharmacology and Toxicology Supervisor: Walter Swardfager CIRCULATING OSTEOCALCIN AND VERBAL MEMORY PERFORMANCE IN PEOPLE WITH TYPE 2 DIABETES MELLITUS Darwish L. 1,2,3; Mitchell J. 2; Carter J. 1,2,3; Sugamori K.S. 2; Oh P.I. 3; Swardfager W. 1,2,3 1 Evaluative Clinical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON/Canada; 2 University of Toronto, Toronto, ON/Canada; 3 UHN Toronto Rehabilitation Institute, Toronto, ON/Canada Background: Osteocalcin circulates in carboxylated (cOCN) and undercarboxylated (ucOCN) forms, and ucOCN is understood to have widespread neuroendocrine effects. In type 2 diabetes mellitus (T2DM), circulating ucOCN concentrations are lower, and cognitive decline is accelerated. We aim to determine whether ucOCN is associated with verbal memory performance in people with T2DM. Methods: Fasting serum concentrations of cOC and ucOCN were assayed using isoform specific ELISAs. Verbal memory performance was assessed using the California Verbal Learning Test, 2nd Ed (CVLT-II), from which a composite Z-score was calculated from verbal learning, short-delayed free recall and long-delayed free recall. Results: In 30 people with T2DM (age 63.3±8.9, 60% women, HbA1c 7.64±0.01%, duration of diabetes 8.2±8.6 years), ucOCN (β=0.423, p=0.019), but not cOCN (β=0.052, p=0.789) or total osteocalcin (β=0.193, p=0.319), was associated with memory performance, in

models controlling for age and gender. ucOCN was associated with fasting insulin concentrations (β=0.454, p=0.021); however, fasting insulin was not significantly associated with verbal memory performance (β=0.278, p=0.181). Conclusions: The results suggest the possible relevance of a bone-derived neuroendocrine mediator to memory performance in people with T2DM." 26. Daniel Derkach; Institute of Medical Science Supervisor: Cindi Morshead EFFECTS OF METFORMIN ON NEURAL PRECURSORS IN A MODEL OF JUVENILE CRANIAL IRRADIATION Derkach D, 1; Ruddy RM, 1; Morshead CM, 1,2 1 Institute of Medical Science, University of Toronto; 2 Department of Surgery, University of Toronto Rare populations of neural stem and progenitor cells (NPCs) reside within the mammalian brain and contribute to neurogenesis throughout adulthood. NPCs are sensitive to ionizing radiation (IR), which is commonly used as an adjuvant therapy in the treatment of primary brain tumours. Despite increasing patient survival rates, cranial IR induces neuroinflammation and cognitive deficits associated with reduced neurogenesis. The type II diabetes drug, metformin, has been shown to mitigate neuroinflammation, expand the size of the neural stem cell (NSC) pool, promote neuronal differentiation, and enhance functional recovery in a model of neonatal stroke. Given the pre-planned nature of IR therapy, we hypothesized that metformin pretreatment would enhance the recovery of NSC pool size, attenuate cellular senescence, and rescue deficits to neurogenesis following cranial IR. In both male and female mice, cranial IR caused an acute loss of subependymal zone (SEZ) NSCs using the in vitro neurosphere assay, which partially recovered 8 days post-IR. Metformin administration in neonatal, but not juvenile mice, caused a transient NSC pool expansion in vitro; however, neonatal metformin pretreatment did not prevent the acute NSC pool depletion. Instead, metformin pretreatment enhanced long-term NSC pool recovery. Using in vivo immunofluorescence, we also observed an acute depletion of proliferating (Ki67+) cells and neuroblasts (DCX+) in the SEZ, which was not prevented by metformin pretreatment. However, pretreatment spared a small population of proliferative neuroblasts (Ki67+DCX+), significantly enhancing their recovery 1 month post-IR. These findings suggest that metformin has a protective effect on NSCs and rescues deficits to neurogenesis post-IR. 27. Abigail D'Souza; Pharmaceutical Sciences Supervisor: Robert P. Bonin REVERSAL OF HYPERALGESIA MEDIATED BY NON-IONOTROPIC NMDA RECEPTOR ACTIVITY FROM DORSAL HORN NEURONS IN PAIN RECONSOLIDATION D'Souza, AJ, 1; Bonin, RP, 1 1 Leslie Dan Faculty of Pharmacy, University of Toronto Pathological pain is the pain that occurs when tissue is damaged and can arise from sensitization within nociceptive pathways of the spinal cord dorsal horn. The enhancement of synaptic transmission between nociceptive afferents and dorsal horn neurons (long-term potentiation; LTP) is associated with sensitization. Pathological pain is the single most common cause of disability worldwide, affecting an estimated 7-10% of adults in the general population. Unfortunately,

current treatment options often fail to provide adequate and lasting pain relief as they do not address the underlying mechanisms of persistent pain. We have previously shown that the reactivation of sensitized pain pathways triggers a process that parallels memory reconsolidation, in which potentiated synapses undergo a simultaneous process of potentiation and depotentiation prior to restabilization, that is crucially dependent on the ionotropic and non-ionotropic (NI-NMDA) receptor activity effects. Isolating the depotentiation process can reverse synaptic potentiation and erase hyperalgesia. We hypothesize that NI-NMDA receptor activity mediates depotentiation in pain reconsolidation. We approached this hypothesis using electrophysiological recordings of dorsal root–evoked postsynaptic field potentials (fPSPs) and behavioural where mechanical withdrawal thresholds were assessed in mice at baseline and after injection of capsaicin using the SUDO testing method. Our preliminary evidence suggests that with the combination of neuronal activity and pharmacological isolation of NI-NMDA with 7-chlorokynurenate (7CK), an NMDAR glycine binding site antagonist, caused the reversal of dorsal horn LTP. These data indicate a key role for NI-NMDA in pain reconsolidation and identify this signaling pathway as a potential novel target for lasting relief. 28. Aeen Ebrahim Amini; Department of Physiology Supervisor: Graham Collingridge THE ROLE OF ENDOGENOUS CELLULAR PRION PROTEIN IN BRAIN SYNAPTIC FUNCTION Ebrahim Amini A 1, 3; Georgiou J 1; Taghibiglou C 2; Collingridge G 1,3 1) Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital; 2) Department of Pharmacology, University of Saskatchewan; 3) Department of Physiology, University of Toronto α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid receptors (AMPARs) are the major neurotransmitter receptors in the brain that are involved in glutamate-based neuronal communication. Increases and decreases in AMPAR number, distribution, and efficacy represent some of the mechanisms that neurons employ to modulate their communication strength, which is known as synaptic plasticity. Defects in synaptic plasticity may be responsible for many brain disorders including Alzheimer’s disease (AD). It has been shown that beta-amyloid oligomers bind the cellular prion protein (PrPC), a cell-surface glycoprotein with many physiological functions such as cellular differentiation, adhesion and control of cell morphology. However, the role of PrPC in synaptic plasticity and learning and memory remains obscure. We used electrophysiological techniques to explore the function of PrPC at CA1 synapses in the hippocampus, a region critical for learning and memory and preferentially affected in AD. Preliminary data suggest that C57BL/6J-Prnp knockout mice have enhanced long-term potentiation. The paired-pulse potentiation were unaffected. Ongoing investigations will confirm these initial findings and examine the role of glutamate receptors in PrPC–dependent modulation of synaptic plasticity. We conclude that PrPC may serve to limit synaptic potentiation. 29. Azin Ebrahim Amini; Institute Biomaterial and Biomedical engineering Supervisor: Peter Carlen ASTROCYTIC GAP JUNCTIONS CONTRIBUTE TO POTASSIUM REDISTRIBUTION OVER THE NEOCORTEX Ebrahim Amini, A

Biomaterial and Biomedical engineering Extracellular potassium ion concentration ([K]e) is tightly regulated throughout the brain because it has a major impact on brain functionality. Potassium concentration is disrupted in many brain diseases such as stroke and epilepsy. My project is designed base on a well-developed experimental platform to investigate the effects of extracellular potassium redistribution in physiological states. All experiments were conducted in vivo in mouse neocortex. 2 double-barreled K-sensitive electrodes coupled with local field potential(LFP) electrodes were placed 4 mm apart. 50mM KCl solution was injected focally closer to one of the K-LFP electrodes. [K]e levels and LFP were measured in two different scenarios: 1) Pharmacological intervention (Gap junction blockage) 2) Optical intervention (optogentics). Focally increased [K]e was associated with a transient depolarization which in turn spreads into neighboring tissues so called spreading depolarization. Gap junctional blockade in the peri-injection site simultaneously increased the amplitude and duration of the local [K]e response, and the local field response was greatly prolonged. While in the remote injection site, [K]e response was decreased after gap junctional blockage application. Optical stimulation decreased the [K]e both in the peri-injection and remote site. Our preliminary results are evidence of slow K redistribution (take for minutes) throughout the astrocytic syncytium which is partly mediated via astrocytic gap junctions. Potassium redistribution across a large area of the cortex is not a well-studied area because most studies have limited their focus on focal potassium dynamics. In this project we are addressing this gap using novel tools to elucidate potassium redistribution dynamics. 30. Daniel Eftekhari; Institute of Biomaterials and Biomedical Engineering Supervisors: Richard Aviv &Pascal Tyrrell A MACHINE LEARNING APPROACH TO DISTINGUISHING BETWEEN MULTIPLE SCLEROSIS AND CEREBRAL SMALL VESSEL DISEASE Eftekhari D, 1,2; Tyrrell PN, 3; Martel AN, 4; Moody AR, 2,3; Aviv R, 1,2,3 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto; 2 Sunnybrook Health Sciences Centre; 3 Department of Medical Imaging, University of Toronto; 4 Sunnybrook Research Institute Background & Purpose Multiple sclerosis (MS) and cerebral small vessel disease (SVD) may be difficult to reliably distinguish using only neuroimaging and clinical features. As early diagnosis and treatment may be associated with better long-term outcome in both diseases, and the societal and monetary cost for both diseases is potentially high, we developed an accurate and automatic diagnostic algorithm to distinguish between relapsing-remitting MS (RRMS) and SVD using neuroimaging and clinical features. Methods A mixture of t-distributions and a novel spatial heuristic algorithm were developed for the segmentation of white matter hyperintensities and T1 black holes on FLAIR and pre-contrast T1 MRI. Combined spatial probability maps of RRMS and SVD lesion masks were developed using a derivation set of patients. A novel cross entropy image distance metric was used to quantify the similarity of new cases to each disease. Bayesian learning algorithms using non-

informative priors were trained using these neuroimaging features in combination with clinical features. Model hyperparameters were tuned using Monte Carlo cross validation. Results An intraclass correlation coefficient of 0.966 between total lesion volume for the automatic segmentations and RRMS ground truth tracings was obtained. The model consisting of both neuroimaging and clinical features obtained a significant improvement on models developed using either in isolation. The model misclassified only one case out of 21 on the test set. Conclusion As the misdiagnosis rate for MS is 5-10%, and the societal and monetary cost of both diseases is high, this work has real potential for clinical impact. 31. Azin Esmaelbeigi; Medical BIiophysics Supervisor: Jean Chen QUANTITATIVE MAPPING OF CEREBROVASCULAR REACTIVITY USING RESTING STATE fMRI in Aging Esmaelbeigi A 1,2; Kayvanrad MA 1,2; Chen JJ 1,2 1 Medical Biophysics, University of Toronto With a rise in aging population, the agerelated health issues will increase, thus a better understanding of the changing relationship between health with age is crucial. To date, the most adaptable vascular marker for both healthy aging and the presence of disease of aging is found to be Cerebrovascular reactivity(CVR). CVR refers to the response of the blood flow to a vasoactive stimulus. The measurements of CVR can be gleaned from functional MRI(fMRI) responses to respiratory tasks or vascular agents with carbon-dioxide(CO2) thought to be an optimal vascular agent. However, the respiratory tasks produce some serious problems for patients and elderly. To overcome these challenges, in this work we aim to introduce a novel approach to quantify CVR based solely on resting-state fMRI. The rs-fMRI family of techniques is commonly used to capture an intrinsic brain activity. However, the rs-fMRI signal also encompasses substantial non-neural contributions, specially through intrinsic physiological processes. Therefore, we propose to exploit the vascular nature of physiological rs-fMRI as the foundation for extracting quantitative CVR. In this method, instead of inducing pressure changes in intravascular CO2, we use end-tidal pressure of CO2 (PET CO2). Considering the changes in blood oxygen level dependent fMRI signals (BOLD fMRI) as the response to the fluctuations in PETCO2, CVR is then quantified to be the percent changes in the fMRI blood oxygen level dependent (BOLD) signal due to the variation of vascular CO2. We also aim to look at the changes in CVR with aging. 32. Carina Fan; Department of Psychology/Rotman Research Institute Supervisor: Brian Levine AGE IS LINKED TO A DISSOCIATION OF FUTURE PROSPECTION FROM OTHER AUTOBIOGRAPHICAL MEMORY ABILITIES Fan CL, 1,2; Abdi H, 3; Eslami A, 4; Levine B, 1,2 1 Department of Psychology, University of Toronto; 2 Rotman Research Institute, Baycrest Health Sciences; 3 School of Behavioral and Brain Sciences, University of Texas at Dallas; 4 Centre for Heart and Lung Innovation, University of British Columbia

The Survey of Autobiographical Memory (SAM) is a validated self-report questionnaire that measures individual differences in four categories of autobiographical memory (AM)—episodic, semantic, spatial, and future prospection—but the factor structure of the SAM has not been examined in different age groups, despite the well-known finding that AM declines with age. Here, we analyze data from participants who completed the SAM online: Sample 1 comprised over 4000 subjects aged 18–85, and Sample 2 comprised over 1300 healthy older adults aged 50–93. We first examined the factor structure of the SAM in Sample 1 using PCA, and replicated previous research: Dimension 1 reflected self-reported memory across all four categories, and Dimension 2 reflected spatial memory. In Sample 2, however, we found that Dimension 2 separated future prospection—rather than spatial memory—from other memory types. To further examine this age effect, we binned participants in Sample 1 based on age. The factor map of the age bins indicated that the dimensional structure of the SAM remained relatively constant from the ages of 18 to 60, after which the future component appeared to dissociate. Existing research has linked the processes underlying episodic AM to those supporting future prospection, but our results suggest that aging may be associated with subtle shifts in memory functioning such that episodic recollection decouples from future prospection. Future work can examine whether this dissociation exists on behavioural and neural levels, and may ultimately be applied to the prevention and treatment of age-related cognitive decline. 33. Carina Patricia De Barros Freitas; Institute of Medical Science Supervisor: Evdokia Anagnostou NEURAL CORRELATES OF FAMILIARITY IN MUSIC LISTENING: A SYSTEMATIC REVIEW AND A NEUROIMAGING META-ANALYSIS Freitas C, 1,2; Manzato E, 3; Burini A, 3; Taylor MJ, 1,4,5; Lerch JP, 5,6; Anagnostou E, 1,2,5,7 1 Institute of Medical Science, University of Toronto; 2 Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto; 3 Sant’Anna School of Advanced Studies, Pisa, Italy; 4 Department of Diagnostic Imaging, Hospital for Sick Children; 5 Neuroscience & Mental Health Program, Hospital for Sick Children; 6 Department of Medical Biophysics, University of Toronto, 7 Department of Paediatrics, University of Toronto Familiarity in music has been reported as an important factor modulating emotional and hedonic responses in the brain. Neuroimaging studies have focused on identifying the brain regions involved in the processing of familiar and unfamiliar musical stimuli. However, the use of different modalities and experimental designs led to discrepant results. As such, the neural correlates underlying music familiarity remain a topic of discussion. In the present study, we conducted a systematic review from three databases (Medline, PsychoINFO and Embase) using the keywords (recognition OR familiar OR familiarity OR exposure effect) AND (music OR song) AND (brain OR brains OR neuroimaging). Of the 872 titles identified, 19 neuroimaging studies met our inclusion criteria for the systematic review. Eleven studies qualified for the meta-analysis using the activation likelihood estimation approach. Our results did not find significant peak activations consistently across included studies. Using a less conservative approach (p < 0.001, uncorrected for multiple comparisons) we found that the left superior frontal gyrus, the ventral lateral nucleus of the left thalamus, and the left medial surface of the superior frontal gyrus had the highest likelihood of being activated by familiar music. On the other

hand, the left insula and the right anterior cingulate cortex had the highest likelihood of being activated by unfamiliar music. Music familiarity had a motor pattern of activation, lateralized in the left hemisphere. This could reflect an audio-motor synchronization to the rhythm which is more engaging for familiar tunes. 34. Avideh Gharehgazlou; Institute of Medical Science Supervisor: Evdokia Anagnostou CORTICAL GYRIFICATION DIFFERENCES IN AUTISM SPECTRUM DISORDER (ASD) AND ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD) RELATIVE TO TYPICALLY DEVELOPING PEERS (TD) Gharehgazlou A, 1,2; Taylor MJ, 2,3,4,5; Lerch J, 2,4,5; Ameis SH, 7,8,9; Anagnostou E, 1,2,4,6 1 Holland Bloorview Kids Rehabilitation Hospital; 2 Institute of Medical Science, Universiy of Toronto; 3 The Hospital for Sick Children; 4 The Hospital for Sick Children Research Institute; 5 Department of Medical Imagine, University of Toronto; 6 Department of Pediatrics, University of Toronto; 7 The Hospital for Sick Children; 8 The Centre for Addiction and Mental Health; 9 Department of Psychiatry, University of Toronto ASD and ADHD are relatively common neurodevelopmental disorders (NDDs), with onset in early childhood. Magnetic Resonance Imaging (MRI) has been used extensively to study atypical brain development in both NDDs relative to TD, however, cortical folding has received less attention. We aim to examine cortical folding in individuals (6.1-15.9 years of age) with ASD and ADHD relative to TD, and the relation between cortical folding and social, attention and adaptive functioning difficulties across disorders. T1-weighted MRI, cognitive and behavioural data will be obtained from Province of Ontario Neurodevelopmental Disorders (POND) Network dataset. FreeSurfer software will be used to obtain whole-brain 3-D measures of cortical folding using local gyrification index (LGI), a surface-based measure providing vertex-wise quantification of cortical folding. General linear model analyses will be conducted on QDEC on FreeSurfer to examine LGI differences between groups. Results from 182 ASD (11.36 ± 2.5), 61 ADHD (11.05 ± 2.5) and 149 TD (11.25 ± 2.9) male participants, with IQ>70, reveal significant differences in cortical folding between each NDD relative to TD. ASD demonstrates significantly greater cortical folding compared to TD, in a left hemisphere (LH) cluster located in the temporal lobe, and clusters located in all lobes except the occipital lobe of the right hemisphere (RH). Relative to TD, ADHD demonstrates greater cortical folding in a cluster located in the frontal lobe of the LH, and greater and reduced cortical folding in RH clusters located in the parietal and frontal lobes. All results were corrected for multiple comparisons using monte-carlo simulations. 35. Farinaz Ghodrati; Laboratory Medicine and Pathobiology Supervisor: Gerold Schmitt-Ulms THE PRION PROTEIN IS EMBEDDED IN A MOLECULAR ENVIRONMENT THAT MODULATES TRANSFORMING GROWTH FACTOR Β AND INTEGRIN SIGNALING Ghodrati F 1,2; Mehrabian M 1; Williams D 1; Schmitt-Ulms G 1,2 1 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre; 2 Department of Laboratory Medicine and Pathobiology, University of Toronto

At times, it can be difficult to discern if a lack of overlap in reported interactions for a protein-of-interest reflects differences in methodology or biology. A case in point is the prion protein (PrP), best known for its central role in prion disorders. In such instances, systematic analyses of protein-protein networks across diverse paradigms can provide valuable insights. Here, we interrogated the PrP interactome in four mouse cell lines. Analyses made use of identical affinity capture and sample processing workflows. Negative controls were generated from PrP knockout lines of the respective cell models, and the relative levels of peptides were quantified with the help of isobaric labels. The study uncovered 26 proteins, which reside in proximity to PrP. All of these proteins are predicted to have access to the outer face of the plasma membrane, and approximately half of them were not reported to interact with PrP before. Strikingly, although several proteins exhibited profound co-enrichment with PrP in a given model, except for Neural Cell Adhesion Molecule 1 (NCAM1), no protein was highly enriched in all four PrP-specific interactomes. A majority of proteins that co-purified with PrP are known to play roles in epithelial-to-mesenchymal transition (EMT), either by acting as transforming growth factor β (TGF-β) signaling modulators, through facilitating the formation of NCAM1-dependent focal adhesion complexes, or by mediating integrin-mediated downstream cell signaling. 36. Talwinder Gill; Institute of Medical Science Supervisor: Isabelle Boileau EVIDENCE FOR ASTROCYTOPATHY IN PTSD: PRELIMINARY FINDINGS OF A PET STUDY WITH THE MONOAMNE OXIDASE B RADIOLIGAND [11C]SL25.1188 Gill TG 5; Richardson DR 7,8;Tong JD 1-3; McCluskey TM 1-2;Meyer JM 1-5;Warsh JW 1-5; Lanius RL 8; Rhind SR 5¬-6; Houle SH 1-3; Kish SK 1-5; Boileau IB 1-3,5 1Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 2Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada;3Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;4Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; 5Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada;6Defense Research and Development Canada, Toronto Research Centre Background: Post-traumatic stress disorder (PTSD) is a stress-related disorder which results from exposure to a traumatic or stressful event. Pre-clinical research investigating mood disorders, including depression and anxiety has consistently shown a decrease in astrocyte-related proteins. There is a lack of in vivo studies of astrocyte pathology in humans with PTSD. Our specific aim was to use positron emission tomography of the monoamine oxidase B (MAO-B) probe [11C]SL25.1188 (an index of astroglial function), to test the hypothesis that MAO-B in the brain is decreased in PTSD. Methods: MAO-B binding (VT; [11C]SL25.1188 with arterial sampling) was measured in 6 participants with PTSD and 12 healthy controls. A magnetic resonance image was acquired for delineation of regions of interest on the PET images. Results: HC and PTSD groups were matched with respect to age and sex (HC~ 31.8 years, 6F vs PTSD ~ 37.0 years, 2F). We found that PTSD was associated with wide-spread decrease (20-28%) in [11C]SL25.1188 binding across 11 cortical and subcortical regions. A RM ANOVA revealed a main group effect where MAO-B VT was significantly decreased for PTSD in all brain regions examined

(F(1,10)= 11.046; p= 0.04). [11C]SL25.1188 binding in PTSD was not associated with symptom severity. Conclusion: Our preliminary findings are in line with the preponderance of literature suggesting astrocyte dysfunction in animal models of PTSD but may also suggest an independent downregulation of MAO-B. Replication of these early findings in a larger cohort is warranted. 37. Catherin Haire; Faculty of Music Supervisor: Michael Thaut EFFICACY OF THERAPEUTIC INSTRUMENTAL MUSIC PERFORMANCE WITH SENSORY-ENHANCED MOTOR IMAGERY IN CHRONIC POST-STROKE UPPER EXTREMITY REHABILITATION: A RANDOMIZED CONTROLLED TRIAL Haire, CM, 1; Patterson, K 2,3; Tremblay, L, 4; Chen, JL 2,5,6; Thaut, MH 1,7 1 Faculty of Music, University of Toronto; 2 Department of Physical Therapy, U of T; 3 Toronto Rehabilitation Institute, University Health Network; 4 Faculty of Kinesiology & Physical Education, U of T; 5 Sunnybrook Research Institute; 6 Rehabilitation Sciences Institute, U of T; 7 Music and Health Research Collaboratory Research has shown that music engages the brain bilaterally throughout cortical and subcortical regions, accessing extended sensorimotor, cognitive, and affective networks. This research explores the hypothesis that use of these shared neural networks allows neurologic music therapy interventions targeting upper extremity motor control to promote plasticity and functional improvements in persons recovering from a cerebrovascular accident. The potential therapeutic benefits of these interventions on attentional processes and affective responding will also be examined. 38. Zachary Hall; Cell & Systems Biology Supervisor: Vince Tropepe THE IMPORTANCE OF DORSAL ROOT GANGLIA IN MEDIATING MOVEMENT-DEPENDENT FOREBRAIN NEUROGENESIS IN ZEBRAFISH LARVAE Hall ZJ, 1; Tropepe V, 1 1 Cell & Systems Biology, University of Toronto During postembryonic development, the brain exhibits substantial experience-dependent neuroplasticity, in which sensory experience guides normal brain growth. Traditionally, experience-dependent neuroplasticity is thought to occur primarily via structural and functional changes in pre-existing neurons. Whether neurogenesis also mediates the effects of experience on early brain growth is unclear. Here, we characterized the importance of motor experience on postembryonic neurogenesis in larval zebrafish. We found that swimming is critical to maintain an expanded pool of forebrain neural precursors by promoting progenitor self-renewal over the production of neurons. Physical cues associated with swimming (tail movement) increase forebrain neurogenesis and these cues appear to be conveyed, at least in part, by dorsal root ganglia (DRG) in the zebrafish body: DRG-deficient larvae exhibit attenuated neurogenic responses to changes in swimming and targeted photoactivation of DRG in immobilized larvae expands the pallial pool of proliferative cells. Our results demonstrate the importance of movement in neurogenic brain growth and provide a fundamental sensorimotor association that may couple early motor and brain development.

39. Julia Hamer; Institute of Medical Science Supervisor: Tom Schweizer SEX-SPECIFIC DIFFERENCES IN CEREBRAL BLOOD FLOW FOR ATHLETES WITH A HISTORY OF CONCUSSION Hamer JA, 1,2,5; Churchill NW, 1,2; Hutchison M, 2,3; Schweizer TA, 1,2,4,5,6 1 Neuroscience Research Program, St. Michael’s Hospital; 2 Keenan Research Centre for Biomedical Science, St. Michael’s Hospital; 3 Faculty of Kinesiology and Physical Education, University of Toronto; 4 Faculty of Medicine, Neurosurgery, Universitytute ofof Toronto, 5 Institute of Medical Science, University of Toronto; 6 The Insti Biomaterials & Biomedical Engineering (IBBME) at the University of Toronto Growing evidence suggests there are differences in concussion outcome for males and females based on initial clinical presentation, with neuroimaging studies suggesting a physiological basis for these differences. However, it is currently unknown whether there are persistent long-term sex differences in the effects of concussion on brain function, for males and females. This study evaluated sex differences in cerebral blood flow (CBF) in asymptomatic athletes with and without a history of concussion. 2D pulsed Arterial Spin Labeling (pASL) was acquired for 71 asymptomatic varsity athletes with a history of concussion (36 female), all scanned at least 9 months post-concussion, and 64 control athletes without prior concussion (30 female). All athletes (n=135) completed the Sport Concussion Assessment Tool (SCAT5), the Automated Neuropsychological Assessment Metrics (ANAM) test and the Balance Error Scoring System (BESS) test. Athlete groups did not differ significantly in age, time since last concussion, recovery time or BESS scores. Males with a history of concussion had lower thalamic and cerebellar CBF compared to females with a history of concussion. Concussed males also had lower CBF in the anterior cingulate and supplemental motor area compared to male controls. In contrast, female athlete groups showed no significant differences. This is the first large-scale study to examine sex differences in cerebral perfusion associated with concussion history and suggests subtle differences in neurovascular response, despite a lack of significant symptoms or cognitive impairments. Further investigation on biological differences in the risk for long-term concussion consequences is warranted." 40. Irene Harmsen; Institute of Medical Science Supervisor: Andres Lozano USE OF MAGNETOENCEPHALOGRAPHY TO EXAMINE CORTICAL RESPONSES TO DEEP BRAIN STIMULATION Harmsen IE, 1; Rowland NC, 2; Dominguez LG, 3; Lozano AM, 1 1 Division of Neurosurgery, University of Toronto, Toronto, ON, Canada; 2 Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA; 3 Division of Neurology, University of Toronto, Toronto, ON, Canada Background: Deep brain stimulation (DBS) is being applied to motor circuit disorders such as Parkinson’s disease and dystonia, to mood circuits to treat depression, and to cognitive circuits to treat Alzheimer’s disease. Brain regions that are activated by the focal delivery of electrical stimulation in the brain are not well understood.

This project will examine the relationship between implant location, stimulation dosage, current frequency, and brain activation. Methods: Magnetoencephalography (MEG) is a non-invasive technique for mapping brain activity by recording magnetic fields produced by electrical currents in the brain. MEG was used in DBS patients to obtain spatial and temporal measures of neuronal activity in response to various DBS settings. Brain activity was localized using source analysis techniques that superimpose functional MEG data onto patient-matched anatomical brain images obtained by magnetic resonance imaging (MRI). Results: DBS patients have been recorded from a wide spectrum of neurological and psychiatric disorders including Parkinson’s disease, essential tremor, major depression, chronic pain, and Alzheimer’s disease. The data provides evidence that MEG in DBS patients is safe, feasible and can show specific and logical activation of brain regions. Conclusions: This is an extremely novel project in a diverse set of patients involving a wide variety of disorders and brain targets. This project will provide valuable insight into the effects of DBS by comparing brain activation across various pathological states and determining the consequences of stimulating different neuronal circuits. 41. Faraz Honarvar; Institute of Medical Science Supervisor: Andrea Kassner LONGITUDINAL ASSESSMENT OF BLOOD-BRAIN BARRIER DISRUPTION IN A PHOTOTHROMBOTIC JUVENILE RODENT STROKE MODEL USING HISTOLOGY & PERMEABILITY MRI Honarvar F, 1; Domi T, 2; Stirrat E, 3; Dlamini N, 4; Kassner A, 1 1 Hospital for Sick Children, University of Toronto; 2 Hospital for Sick Children; 3 Hospital for Sick Children; 4 Hospital for Sick Children; 1 Hospital for Sick Children, University of Toronto Background: Breakdown of the blood brain barrier (BBB) is an important contributor to injury after acute ischemic stroke in adults. Animal studies of ischemic stroke observed distinct differences in BBB permeability using Evans Blue (EB) between adult and neonatal rats. However, not much is known about BBB disruption in the juvenile rat. The aim of this study was to assess the evolution of in-vivo and ex-vivo BBB permeability in a photothrombotic juvenile rat stroke model. Methods: A photothrombotic stroke model was induced in 12 rats (37±1 days old) and BBB permeability was quantitatively assessed ex-vivo by measuring EB leakage on days 0, 1, 2, and 7. Three rats were used for every time point. Dynamic contrast-enhanced (DCE) MRI was performed in a subset of rats prior to sacrifice to measure BBB permeability in-vivo and compared to ex-vivo. Results: EB leakage was expressed as mean infarct to control hemispheric ratio and was 2.72 (day 0), 2.41 (day 1), 1.99 (day 2) and 2.16 (day 7). In-vivo BBB permeability results using MRI were 2.8 (day 0), 2.00 (day 1), 1.6 (day 2), and 1.8 (day 7) ml/100/g/min. These results correlated well with EB leakage (R2= 0.861, p<0.05). Conclusion: We have characterized longitudinal BBB changes in juvenile rats using a photothrombotic ischemic stroke model. We have detected highest permeability on day 0 and confirmed persisting BBB disruption up to day 7. Future work will incorporate neuroprotective drugs stabilizing the BBB at different time points after childhood stroke.

42. Sarah House; Institute of Biomaterials and Biomedical Engineering Supervisor: Tom Chau EVALUATION OF A MOTOR IMAGERY ELECTROENCEPHALOGRAPHY BRAIN-COMPUTER INTERFACE AS A COMMUNICATION MODALITY FOR CHILDREN WITH CEREBRAL PALSY House S, 1,2; Chau T, 1,2 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto; 2 Holland Bloorview Kids Rehabilitation Hospital Cerebral palsy (CP) is the most common cause of childhood disability, limiting the ability of affected children to coordinate their movements. The majority of affected children also have speech and language impairments rendering typical communication methods difficult to use or impossible. Brain-computer interfaces (BCIs) controlled by imagination of movement of different body parts, known as motor imagery (MI), may serve as a communication solution. This study aims to create a MI-based pediatric BCI using electroencephalography (EEG) and to evaluate BCI performance when used by 20 typically developing children between the ages of 8 and 16. Classification accuracies above 70% indicate successful BCI control. To accomplish this, a MI-BCI has been created by bandpass filtering EEG signals to encompass mu and beta frequency ranges (7-30 Hz). Features in the signal are extracted using the common spatial pattern algorithm and are then classified with participant specific classification algorithms. BCI performance is tested during one offline session, where the acquired data trains the classifier, and four online sessions during which visual neurofeedback is provided while participants play a MI computer game. Participants, thus far, have achieved an online classification accuracy between 35-70% indicating that traditional MI features are not adequate to provide children with BCI control. Further post hoc analysis may uncover features that better distinguish MI patterns of activity in developing brains. The results of this study will speak, for the first time, to the potential of a MI EEG-BCI being translated as a communication method for children with CP 43. Farhana Islam; Department of Pharmacology Supervisor: Daniel Müller EFFECTS OF CYP1A2 AND CHOLINERGIC RECEPTOR MUSCARINIC 1 (CHRM1) GENE VARIANTS ON PLASMA RATION OF CLOZAPINE TO N-DESMETHYLCLOZAPHINE AND COGNITIVE PERFORMANCE IN SCHIZOPHRENIA Islam F1,2, Rajji TK1,3,4, Marshe VS1,3, Remington G1,3,4, Wong E1, Müller DJ1,2,3,4

1 Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health, Toronto ON, Canada; 2 Department of Pharmacology, University of Toronto, Toronto, ON, Canada; 3 Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 4 Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Introduction: Cognitive deficits are a core feature in individuals with schizophrenia (SCZ) that is associated with severe consequences on their quality of life and recovery process. Antipsychotic medications appear to show minimal effects on cognitive symptoms of SCZ, including clozapine (CLZ), which is generally recognized to be the most effective antipsychotic. One explanation for the mixed effects of CLZ on cognition has been proposed to involve (1) the conversion of CLZ to a metabolite (NDMC) by a metabolizing enzyme (CYP1A2)

and (2) their opposing effects on the muscarinic 1 receptor (CHRM1) that supports cognitive processes. Higher ratios of CLZ/NDMC have been associated with poorer working memory performance, indicating CLZ/NDMC ratio as a strong predictor of cognitive effects. Objectives: The present study will investigate the genetic variants of the CYP1A2 and CHRM1 genes contribution to clozapine/NDMC ratio and improvements in cognitive performance, respectively. Methods: Individuals with SCZ on CLZ monotherapy (n=105) will be assessed for performance on seven cognitive domains (MATRICS Consensus Cognitive Battery), CLZ/NDMC ratio, symptom scores (PANSS), and education level. Genetic analyses will include genome-wide coverage of genetic markers to allow for extensive coverage of the genetic variation in the two target genes. Progress: Preliminary analysis on our first cohort (n=30) revealed, that after adjusting for age, education and CLZ/NDMC ratio, rs2075748 of the CHRM1 gene was significantly associated with working memory. Implications:: This study has major clinical relevance, as the optimal CLZ/NDMC could be achieved through dietary or pharmacological interventions for the improvement of cognitive symptoms while on CLZ. 44. Grace Jacobs; Institute of Medical Science Supervisor: Aristotle Voineskos SEX-SPECIFIC OVERLAPPING STRUCTURAL AND FUNCTIONAL CIRCUIT DIFFERENCES IN YOUTH WITH PSYCHOSIS SPECTRUM SYMPTOMS Jacobs G, 1,2; Ameis S, 1,2; Jie L, 4; Viviano J, 2; DIckie E, 2; Wheeler A, 1,3; Stojanovski S, 1,3; Anticevic A, 4; Voineskos AN, 1,2 1 University of Toronto; 2 Centre for Addiction & Mental Health; 3 The Hospital for Sick Children; 4 Yale University Functional connectivity differences in the cortico-striatal-thalamic-cortical (CSTC) circuit, as well as altered subcortical region volumes have been observed in schizophrenia. In this study, magnetic resonance imaging (MRI) was used in a large child and youth sample aged 11-21 years (n=1062) to examine this circuit in children with psychosis spectrum (PS) symptoms (n=297). Structural subregions of the thalamus and striatum were identified using the segmentation tool MAGeT Brain. Functional subregions were segmented based on resting-state functional connectivity with brain networks. Average BOLD signal time series from functional subregions were correlated vertex-wide with cortical surfaces. FSL’s PALM was used to examine main effects and interactions between PS groups and sex on functional connectivity with TFCE. Age, in scanner motion, and WRAT score were included as covariates and results were corrected for using FWER. A consistent pattern was found of significantly increased volumes in girls with PS symptoms, but decreased volumes in boys with PS symptoms compared to non-PS youth in multiple thalamic nuclei (F=11, pFDR=0.034) and just below significance in the bilateral posterior putamen (F=6.8, pFDR=0.058). Overlapping with striatal structural findings, a decreased functional connectivity was found in PS youth between the right posterior putamen (corresponding to the dorsal attention network) and occipital areas (pFWE=0.005). This pattern was found to be driven by differences specifically in PS boys and not PS girls (pFWE=0.004). Our findings indicate sex-specific differences in the CSTC circuit in youth and may provide insight into diverging neural mechanisms underlying the development of psychosis and differences in clinical

features between males and females. 45. Xiang (Patrick) Ji; Institute of Medical Science Supervisor: Carol Westall THE CLINICAL FEASIBILITY OF NONINVASIVE PORTABLE OCT TECHNIQUE IN CHILDREN UNDERGOING VIGABATRIN TREATMENT Ji, X 1,2; Wright, T 3; VandenHoven, C 2; MacKeen, LD 2; Dhaliwal, S 2; Liu, H 4; Reginald, A 2; Buncic, R 2; Westall, CA 1,2. 1 Institute of Medical Science, University of Toronto; 2 Ophthalmology & Vision Sciences, Hospital For Sick Children; 3 Kensington Eye Institute, Toronto, Ontario; 4 Faculty of Medicine, University of Ottawa Purpose: The antiepileptic drug for infantile spasms, vigabatrin (VGB), is sometimes associated with visual toxicity in young children. Toxicity is in the form of retinal nerve fiber layer (RNFL) thickness attenuation. In this prospective, cross-sectional study, our purpose was to evaluate RNFL thickness using handheld optical coherence tomography (HH-OCT). Specifically, we evaluated the intra-visit reliability and clinical utility of noninvasive HH-OCT in children ≤ 3 years of age. Methods: Twenty patients taking VGB were recruited. Eight children from this group completed follow-up assessments. We performed HH-OCT in sedated children lying supine and the RNFL thickness was evaluated with segmentation software; and intra-visit reliability of the RNFL thickness was calculated using intraclass correlation coefficient (ICC) statistics. For the follow-up group, each child’s initial result was used as control for comparisons. Decline in RNFL thickness >10% was considered abnormal. Results: The HH-OCT was successfully recorded in all children. The average circumpapillary RNFL thickness (µm) in the superior, inferior, nasal, and temporal quadrants were 112.0±22.6, 105.8±23.7, 73.4±18.4, and 67.6±20.0, respectively. These results are within published normal limits for children aged 0.79-13 years. High intra-visit reliability was shown with an average ICC of 0.79 (range 0.55-0.88) across 4 retinal divisions. During follow-up, the average overall RNFL thickness reduced from 86.2µm to 79.0µm, and the temporal quadrant was only decreased by 2%. Half of the patients at follow-up demonstrated a decline >10%, and specifically, one child showed reductions within all quadrants, and 3 children had changes in 2 quadrants. Conclusions: In this cohort, RNFL assessment using HH-OCT showed intra-visit reliability. The relative sparing of temporal quadrant RNFL thickness agree with previous studies. These results add to the evidence that RNFL thickness may be a useful structural biomarker for young children taking VGB. 46. William Ju; Human Biology Program Supervisor: William Ju INCLUDING MENTAL HEALTH IN UNDERGRADUATE NEUROSCIENCE COURSE DESIGN Santos A, 1; DiVito S, 1; Bannon L,1; Barany I, 1; Shcherbina M, 1; Fischbacher A, 1; Lee CCS,1; Lee D, 1; Da Costa Gomes A, 1; Emili Garcia-Segura M, 1; Ju W, 1 1 Human Biology Program, University of Toronto Stress has been identified as one of the biggest psychosocial factors that impacts the mental health of undergraduate students. This is of particular interest because factors that impact mental health and

well-being have been shown to have profound effects in student learning and performance within a course. Here we have identified best practices in a large 3rd year undergraduate course that was designed specifically with the goals of maintaining academic rigour while reducing stress equitably using neuroscience-based approaches. Additional information on student perceptions of the changes made in this course and how our findings can be scaled to other courses is presented. 47. Kyurim Kang; Faculty of Music Supervisor: Michael Thaut INTERBRAIN ELECTROENCEPHALOGRAPHY (EEG) SIGNAL SYNCHRONIZATION AMONG NON-VERBAL CHILDREN/YOUTH WITH SEVERE DISABILITIES, THEIR PARENTS, AND MUSIC THERAPISTS Kang,K, 1; Thaut,M.H.,1; Chau T 2,3 1 Music and Health Research Collaboratory (MaHRC), Faculty of Music, University of Toronto; 2 Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto; 3 Pediatric Rehabilitation Intelligent Systems Multidisciplinary (PRISM) Lab, Holland Bloorview Kids Rehabilitation Hospital Non-verbal children with severe disabilities encounter difficulties communicating, which may lead to social isolation. Research using Electroencephalography (EEG) have investigated the idea that empathy, the essential emotion for social interaction, is coupled with brainwave synchronizations. This suggests that one way we can understand non-verbal population is the measurement of brainwave synchronizations with EEG. However, there has been no study investigating interbrain synchronization of non-verbal children. Research has shown that music and the relationship between parents and children are important aspects when non-verbal children build social relationships. Therefore, this study will explore whether music and family contact time influence interbrain synchronizations while non-verbal children are interacting with music therapists during the sessions. Non-verbal children (n=30), age range 8-18 years, their parents (n=30), and music therapists (n=3) will wear different EEG cap to measure brainwaves simultaneously during 4 music therapy and 4 storytelling sessions. To explore how family contact time influences the children’s social interaction, children will be placed in three different groups based on family contact time. The parents will watch the therapy sessions in a separate room. The strength and directionality of interpersonal brainwave synchronizations among participants will be analyzed across the type of sessions and family contact time. The results of this study will help us to understand how music supports non-verbal children to develop their social interaction. Moreover, such neural attunement can also be used for an objective assessment of children’s satisfaction with the ongoing therapy, and in turn, for tailoring the therapy to maximize children’s need. 48. Muhammad Saad Khan; Institute of Medical Science Supervisor: Romina Mizrahi IMAGING NOCICEPTIN RECEPTOR EXPRESSION IN PSYCHOSIS USING POSITRON EMISSION TOMOGRAPHY WITH THE NOVEL LIGAND [11C]NOP-1A Khan MS 1,3; Lalang N 1,4; Jacobson M 1,4; Da Silva T 1; Wilson A 1; Rusjan PM 1,3; Mizrahi R 1,2,3,4

1 Research Imaging Centre, Centre for Addiction and Mental Health; 2 Department of Psychiatry, University of Toronto; 3 Institute of Medical Science, University of Toronto; 4 Department of Pharmacology and Toxicology, University of Toronto Dysregulation of the neurotransmitters dopamine (DA) and glutamate (Glu) is observed in individuals with schizophrenia (SCZ) (dopamine and glutamate hypotheses). Additionally, deficits in cognition and aberrant responses to stress and reward are associated with SCZ symptomatology. Evidence implicates the nociceptin (NOP) receptor playing a regulatory role in each of these processes, suggesting its involvement in SCZ pathophysiology. This study aims to investigate NOP receptor expression in SCZ in vivo, thereby providing a potential biomarker of disease and a novel target for therapeutic agents. Given the findings in the preclinical literature thus far, we hypothesized that NOP receptor expression would be lower in SCZ individuals compared to healthy volunteers (HV). Participants underwent a 90-min [11C]NOP-1A PET scan. [11C]NOP-1A regional distribution volume (VT) was calculated using the Logan model with a metabolite-corrected arterial plasma input function. An MRI and standardized clinical and neuropsychological measures were also acquired. We scanned 13 SCZ individuals (3 F & 10 M, 24.38+-5.11 years) and 12 gender-matched healthy volunteers (HV) (5 F & 7 M, 20.92+-2.54). Two regions of interest important in SCZ pathophysiology were selected: the striatum and the prefrontal cortex (PFC). The mean VT was 11.46+-1.12 and 12.61+-1.40 in the striatum and PFC respectively in HV. In SCZ, the mean VT was 11.43+-1.76 and 12.54+-1.93 in the striatum and PFC respectively. This pilot study suggests no involvement of the NOP receptor system in SCZ pathophysiology. 49. Julia Kim; Institute of Medical Science Supervisor: Gerretsen & Graff-Guerrero THE EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION ON POSITIVE AND NEGATIVE SYMPTOMS IN SCHIZOPHRENIA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED SHAM-CONTROLLED STUDIES Kim J, 1,2; Graff-Guerrero A, 1,2,3,4,5; Gerretsen P, 1,2,3,4,5 1 Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, Ontario, Canada; 2 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; 3 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; 4 Geriatric Mental Health Division, CAMH, University of Toronto, Toronto, Ontario, Canada; 5 Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Toronto, Ontario, Canada Background: Transcranial direct current stimulation (tDCS) has been studied as a potential adjunctive treatment for patients with schizophrenia. Objective: The primary objective of this meta-analysis was to evaluate the effects of tDCS on positive symptoms, particularly auditory hallucinations, and negative symptoms. Methods: A literature search of randomized sham-controlled trials (RCT) was conducted using the OVID database on March 12, 2018. The standardized mean differences (SMDs) were calculated to examine changes in symptom severity between active and sham groups for the following domains: auditory hallucinations, positive symptoms (including auditory hallucinations), and negative

symptoms. Moderator analyses were performed to examine the effect of study design, and participant demographics. Results: We identified 8 eligible studies. Main-analyses showed no effect of tDCS on auditory hallucinations (6 studies, n=182), positive symptoms (7 studies, n=201), or negative symptoms (7 studies, n=201). Subgroup analyses of studies that applied 10 stimulation sessions showed a significant effect in reducing the severity of auditory hallucinations (4 studies, n=126, SMD=1.08, p=0.008) and negative symptoms (5 studies, n=145, SMD=0.52, p=0.04). Mean age was negatively associated with the effect of tDCS on auditory hallucinations and negative symptoms. Conclusion: Our findings highlight the need to optimize tDCS parameters and suggest that 10 or more stimulation sessions may be needed to improve clinical outcomes in patients with schizophrenia. 50. Yuko Koshimori; Music and Health Research Collaboratory Supervisor: Michael Thaut MOTOR SYNCHRONIZATION TO RHYTHMIC AUDITORY STIMULATION (RAS) ATTENUATES DOPAMINE RESPONSES IN THE VENTRAL STRIATUM IN YOUNG HEALTHY ADULTS Koshimori Y, 1,2; Strafella AP, 2,3,4; Valli M, 2,4; Sharma V, 1; Cho SS, 2; Houle S, 2; Thaut M, 1,2 1 Music and Health Research Collaboratory, University of Toronto; 2 Research Imaging Centre, Centre for Addition and Mental Health; 3 Morton and Gloria Shulman Movement Disorder Unit & E.J. Safra Parkinson Disease Program, Toronto Western Hospital; 4 Division of Brain, Imaging and Behaviour- Systems Neuroscience, Krembil Research Institute External auditory stimuli such as metronome clicks and rhythmic beats in music facilitate motor behaviors in healthy adults and clinical populations and modulates activities in the basal ganglia (BG). However, the exact underlying neurochemical mechanisms of dopamine (DA) are unknown. The current study is sought to investigate DA responses in BG during auditory-motor entrainment using rhythmic auditory stimulation (RAS) in young healthy adults. Eleven right-handed participants underwent two [11C]-(+)-PHNO-PET scans during which they perform a finger tapping task synchronized to RAS (RAS condition) and without RAS (No-RAS condition). Binding potential relative to the non-displaceable compartment (BPND) values in BG were compared between conditions. RAS reduced the absolute tapping period error (p = 0.077) and significantly reduced tapping variability (p = 0.034). Nine of the 11 participants showed reduced DA responses during the RAS condition in the left ventral striatum (VS) compared to the No-RAS condition (p = 0.035). In addition, the DA responses in the left VS showed a significantly positive correlation with those in the left globus pallidus during the No-RAS condition (p = 0.026), which was not observed during the RAS condition. With partial volume correction, eight of the 11 participants showed greater DA responses during the RAS condition in the right VS compared to the No-RAS condition. Our data have corroborated that RAS facilitates motor behavior and demonstrated that RAS attenuates DA responses in the left VS in young healthy adults, suggesting that finger tapping without RAS may require more motivational/attentional effort to perform the task. 51. Chantel Kowalchuk; Institute of Medical Science Supervisor: Margaret Hahn

COMPARISON OF ANTIPSYCHOTIC-INDUCED CHANGES IN INFLAMMATION AND ENERGY SENSING IN HYPOTHALAMIC NEURONS Kowalchuk C, 1,2; Kanagasundaram P, 1; Remington G, 1,2,3; Belsham D, 4,5; Hahn MK 1,2 1 Centre for Addiction and Mental Health; 2 Institute of Medical Sciences, University of Toronto; 3 Department of Psychiatry, University of Toronto; 4 Department of Physiology, University of Toronto; 5 Departments of Medicine and Obstetrics and Gynaecology, University of Toronto Antipsychotics are the gold-standard treatment for schizophrenia but cause serious metabolic side-effects. The hypothalamus is the primary brain region responsible for energy regulation, and disruptions in hypothalamic energy sensing and inflammation are implicated in insulin resistance and obesity. Thus, hypothalamic inflammation and disturbed energy sensing could be involved in antipsychotic-induced metabolic disturbances, yet direct effects of antipsychotics on the hypothalamus have yet to be examined. The rat hypothalamic cell line, rHypoE-19, was treated with olanzapine, clozapine, or aripiprazole. Western blotting was used to measure the energy sensing protein AMPK, components of the insulin signaling pathway (AKT, GSK3B), and components of the MAPK pathway (ERK1/2, JNK, p38), the latter linked to inflammation. qRT-PCR was performed to determine changes in the mRNA expression of IL-6, IL-10, and BDNF. Olanzapine and clozapine increased pERK1/2 and pJNK, while aripiprazole increased pJNK. Clozapine and aripiprazole increased pAMPK and inhibited insulin-induced pAKT. Olanzapine increased IL-6 while aripiprazole decreased IL-10. Olanzapine and aripiprazole increased BDNF expression. Clozapine did not change BDNF, IL-6, or IL-10. Upregulation of pJNK alongside olanzapine-associated increases in IL-6, and aripiprazole-associated decreases in IL-10, suggests upregulation of pro-inflammatory pathways. Aripiprazole and clozapine inhibited insulin-stimulated pAKT and increased pAMPK, suggesting impaired hypothalamic insulin action. Conversely, olanzapine and aripiprazole increased BDNF, a factor linked to the etiology of schizophrenia, suggesting BDNF upregulation as a mechanism of therapeutic action. Overall, our findings suggest highly differential effects of antipsychotics on hypothalamic neuroinflammation and energy sensing, which do not align with the known metabolic liability of these agents. 52. Saffire Krance; Department of Pharmacology and Toxicology Supervisor: Walter Swardfager COMPLEMENT PROTEINS IN ALZHEIMER’S DISEASE; A META-ANALYSIS Krance SH, 1,2; Zou Y, 1; Mao H, 1; He X, 1; Pakosh M, 3; Swardfager W, 1,2 1 Department of Pharmacology and Toxicology, University of Toronto; 2 Sunnybrook Research Institute; 3 University Health Network Purpose: Genome-wide association studies implicate complement pathway activity as a cause of Alzheimer’s disease (AD), and the hallmark AD biomarker amyloid-β has been shown to activate the complement cascade; however reports of complement proteins measured in peripheral blood and cerebrospinal fluid (CSF) have conflicted. This meta-analysis seeks to quantitatively combine data from clinical studies of complement pathway data in peripheral blood

and CSF. Methods: Literature was searched using Medline, PubMed, Embase, PsycInfo, Cochrane Controlled Trials Register, and Cochrane Database of Systematic Reviews. Original peer-reviewed studies measuring complement and complement regulator protein concentrations in AD and healthy elderly control (NC) subjects were included. Mean (± standard deviation) concentrations for AD and NC were extracted and combined in random effects models. Results: 73 studies measuring relevant CSF or peripheral blood protein concentrations have been included thus far. Preliminary results show increased CSF concentrations of complement component 1q (C1q; NAD/NNC=151/117, Z=2.46, p=0.01; I2=54%) in AD compared to NC. Concerning complement pathway regulators, clusterin concentrations were increased in both CSF (NAD/NNC=371/437, Z=4.18, p<0.0001; I2=31%) and plasma (NAD/NNC=1269/1651, Z=2.06, p=0.04; I2=97%) in AD compared to NC, and amyloid P (AP) concentrations were increased (NAD/NNC=283/109, Z=2.94, p=0.003; I2=0%) in CSF. Conclusions/Implications: CSF results support involvement of the complement pathway in AD; elevated C1q and AP levels might promote activity earlier in the complement cascade. Elevated clusterin could inhibit formation of the membrane attack complex (MAC) in the cascade’s final stages. These changes would be consistent with increased opsonization and inflammatory activity, while limiting MAC-induced cell lysis. 53. Nirsan Kunaratnam; Rehabilitation Sciences Institute Supervisor: Joyce L. Chen EFFECT OF ANODAL TRANSCRANIAL DIRECT CURRENT STIMULATION ON MOTOR LEARNING IN HEALTHY INDIVIDUALS Kunaratnam N1,2,4; Saumur T 1,2,4; Swarbrick D 1,2,4; Kiss A 2,3; Mochizuki G 1,2,4,5; Chen J 1,2,4,5 1 Rehabilitation Sciences Institute, University of Toronto; 2 Sunnybrook Research Institute; 3 Health Policy, Management and Evaluation, University of Toronto; 4 Canadian Partnership for Stroke Recovery; 5 Department of Physical Therapy, University of Toronto Introduction: Reis et al (2009) showed that transcranial direct current stimulation (tDCS) to the primary motor cortex applied concurrently with practice of a sequential visual isometric pinch force task (SVIPT), results in better skill performance, than practice alone with sham-tDCS (placebo condition). Interestingly, it appears that the sham-tDCS group who practiced the SVIPT for 5 days did not attain the same performance level as the anodal-tDCS group after 1 day of practice. However, this was not explicitly tested. Objective: To investigate how many additional days of practice are required for individuals receiving sham-tDCS to reach the same performance level as individuals who receive anodal-tDCS for 1 day. Methods: Healthy right-handed participants were randomly assigned to either the anodal-tDCS or sham-tDCS group. The sham-tDCS group practiced SVIPT for 4 consecutive days to determine if participants can reach the same improvements as the anodal-tDCS group who practiced for 1 day. In both groups, retention was measured 24- & 72-hours after the last training session. The dependent measure was total skill learning, which combines speed and accuracy. Results: N=21 (12-anodal, 23.9 years old; 9-sham, 27.2 years old) participated in the study to date. Preliminary results indicate both groups can learn the task(p<0.001). There is a trend towards anodal-tDCS enhancing skill by end of Day 1(p=0.082). No significant difference in skill demonstrated at 24 & 72-hour retention. Conclusion: Preliminary analysis provides no evidence for effects of anodal-tDCS on motor skill learning. However, this study is currently

underpowered, therefore this conclusion should be interpreted with caution. 54. Saptharishi Lalgudi Ganesan; Department of Critical Care Medicine Supervisor: Anne-Marie Guerguerian FACTORS REDUCING THE ACCURACY OF SEIZURE IDENTIFICATION USING QUANTITATIVE ELECTROENCEPHALOGRAPHY DISPLAYS IN THE INTENSIVE CARE UNIT Lalgudi Ganesan S,1; Stewart CP,2; Atenafu EG,3;Ochi A,2;Otsubo H,2;Go C,2;Hahn CD,2 1. Department of Critical Care Medicine, The Hospital for Sick Children, University of Toronto; 2. Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto; 3. Department of Biostatistics, Princess Margaret Hospital, University Health Network, University of Toronto" Introduction & Objectives: Non-convulsive seizures are common in critically ill and are detectable only by continuous electroencephalography. Quantitative electroencephalography (QEEG) trending displays are being used increasingly commonly to facilitate seizure identification during such continuous EEG monitoring. Our previous work showed that the accuracy of seizure identification using QEEG is lower in some recordings, even for EEG experts. In this study, we sought to determine which seizure, EEG recording and patient characteristics make seizure identification on QEEG more difficult. Methods: Three neurophysiologists were independently asked to mark all suspected seizures in 27 continuous EEG recordings from 22 critically ill children that were processed using two QEEG techniques: amplitude-integrated EEG (aEEG) and color density spectral array (CDSA). Seizures confirmed by a board-certified neurophysiologist on review of the raw EEG constituted the comparison standard. We analyzed the following factors for their influence on the probability of correct seizure identification: age, number of seizures per recording, seizure burden (per hour), seizure distribution and spectral characteristics of individual seizures such as power and frequency (both absolute and relative to the immediate pre-ictal background). Independent predictors of poor seizure detectability were identified using a multivariable correlation (Recording characteristics) and reduced regression modeling with autoregressive covariance (seizure characteristics). Results: Sensitivity was higher in recordings from older children (CDSA>aEEG), and those with higher seizure count and higher seizure burden, for both CDSA and aEEG (figure 1). Seizure detectability declined with decreasing seizure duration (figure 2). Using CDSA, seizure identification rates were 65% for seizure durations of >180s, 62% for 60-179s, 44% for 30-59s and 16% for less than 30s. Using aEEG, seizure identification rates were 81% for seizures lasting >180s, 67% for 60-179s, 38% for 30-59s and 13% for less than 30s. Focal seizures were more difficult to detect on CDSA/aEEG (26%/33%) compared to both hemispheric seizures (44%/53%) and generalized seizures (69%/64%). With CDSA, independent predictors of poor seizure detectability were: younger age, lower number of seizures per recording, lower ictal/pre-ictal spectral edge frequency at 50% power, lower ictal/pre-ictal spectral edge frequency at 95% power, and lower ictal/pre-ictal average total power. With aEEG, independent predictors were the same except age and ictal/pre-ictal spectral edge frequency at 95% power, which were not in the final aEEG model.

Conclusions: Independent factors reducing seizure detectability were younger age (only CDSA), lower number of seizures per recording, shorter duration, focal distribution and a lower ratio of ictal-interictal power as well as the frequency at 50% and 95% power (only CDSA). We also demonstrate that the ratios of the spectral features of ictal and interictal periods are vital determinants of seizure detectability. These insights will inform the optimal use of these displays and aid the design of newer QEEG trends that enhance the contrast between ictal and interictal periods, to achieve more accurate seizure identification. 55. Stephanie Lavigne; Music and Health Sciences Supervisor: Dr. Michael Thaut MUSIC AND EXERCISE GROUP INTERVENTION WITH OLDER ADULTS USING NEUROLOGIC MUSIC THERAPY SENSORIMOTOR TECHNIQUES FOR GAIT, BALANCE AND EXERCISE MOTIVATION Lavigne S 1; Thaut C 1; 1 Music and Health Research Collaboratory, University of Toronto The purpose of this study was to look at the effectiveness of a sensorimotor neurologic music therapy (NMT) intervention as falls prevention in older adults. Patterned sensory enhancement, rhythmic auditory stimulation and therapeutic instrumental music performance are three NMT techniques based on principles of rhythmic entrainment, priming, cueing of the movement period and stepwise limit cycle entrainment. Research objectives aimed to look at impacts of this group intervention on gait parameters, balance and exercise motivation. Twenty-three sessions were held over 6 months. Twenty-two women and two men, reported age 74.95 (n=19, SD=8.20) and group size 8.61 (SD=3.87) were recruited from the community of St. Paul’s Church in Toronto. Using a pre-post design and paired-samples t-tests, results for gait parameters (cadence, velocity, stride length) using the 10 Meter Walk Test showed improvement over three months (n=11) and six months (n=3) towards a safer walking cadence, although no statistically significant difference was found. Similarly, results for balance showed improvement over 3 months using the Timed Up and Go test although not statistically significant (n=3). Results for exercise motivation using the Behavioral Regulation in Exercise Questionnaire 3 showed improved self-determination, although not statistically significant. Results from the Exercise Motivations and Gains Inventory questionnaire using descriptive statistics showed nimbleness, revitalisation, strength and endurance and positive health as strongest concepts. These preliminary data demonstrate the possible effectiveness of NMT sensorimotor intervention as falls prevention with older adults. 56. Yena Lee; Institute of Medical Science Supervisor: Roger McIntyre AN ANTI-CYTOKINE AGENT FOR ANHEDONIA IN BIPOLAR DEPRESSION Lee Y, 1,2; Subramaniapillai M, 1; Mansur RB, 1,3; Brietzke E, 1; Pan Z, 1,2; McIntyre RS, 1-3 1 Mood Disorders Psychopharmacology Unit, Toronto Western Hospital; 2 Institute of Medical Science, University of Toronto; 3 Department of Psychiatry, University of Toronto, University Health Network

Aim: To investigate the efficacy of infliximab in treating anhedonia amongst individuals with bipolar I/II depression exhibiting baselineinflammatory activation. Methods: Adults (ages 18-65) with bipolar I/II disorder currently experiencing a major depressive episode are randomized to adjunctiveinfliximab (5 mg/kg) or saline control as part of a phase II, double-blind, 12-week clinical trial. Treatment is administered at weeks 0, 2, and6. Inclusion criteria include: baseline inflammatory activation (as determined by one of: C-reactive protein level of ≥5 mg/L; central obesityand dyslipidemia/hypertension; daily cigarette smoking; diabetes mellitus; inflammatory bowel disease); Hamilton Depression Rating scale17-item total score of ≥20 or Montgomery-Asberg Depression Scale total score ≥22; Young Mania Rating Scale total score of <12. Primaryoutcome measure is change in the Snaith-Hamilton Pleasure Scale total score (i.e. week 0 vs. 12) between placebo- and infliximab-treatedsubjects. Results: Sixty eligible adults exhibiting baseline inflammatory activation received treatment with infliximab or placebo; 48 subjects completed the study. Both treatments significantly reduced symptoms of anhedonia at endpoint; there were no significant between-groupdifferences. Conclusions: Early changes in anhedonia were observed amongst adults with bipolar I/II depression receiving infliximab when compared to placebo, but not at week 12. 57. Jenny Lepock; Institute of Medical Science Supervisor: Michael Kiang ASSOCIATION OF SEMANTIC PRIMING DEFICITS WITH PSYCHOSIS-LIKE THINKING IN PERSONS AT CLINICAL HIGH RISK FOR SCHIZOPHRENIA: AN EVENT-RELATED BRAIN POTENTIAL STUDY Lepock JR, 1; Mizrahi R, 1,2,3; Gerritsen C, 2,4; Maheandiran M, 2; Bagby RM, 1,4; Korostil M, 2,3; Kiang M, 1,2,3 1 Institute of Medical Sciences, University of Toronto; 2 Centre for Addiction and Mental Health; 3 Department of Psychiatry, University of Toronto; 4 Department of Psychology, University of Toronto Background: We sought evidence that those at clinical high-risk (CHR) for psychosis have deficits in processing relationships between meaningful stimuli, similar to abnormalities previously found to be associated with schizophrenia. We used the N400 event-related potential waveform as a neurophysiological probe of activation of concepts in semantic memory. We hypothesized that CHR patients would exhibit larger than normal N400 amplitudes in response to stimuli meaningfully related to a preceding prime stimulus reflecting deficient semantic priming. We also hypothesized that psychotic symptoms would be correlated with the N400 deficits. Methods: We recorded ERPs in 16 CHR patients and 16 control participants who viewed prime words followed at either 300- or 750-ms stimulus-onset asynchrony (SOA) by targets, which were either words related or unrelated to the prime or pronounceable nonwords. Results: Across groups and SOAs, N400 amplitudes were larger for unrelated than related targets (p=0.00). There was a significant interaction of target, electrode and group of (p=0.05), and a trend of greater semantic priming differences between the patients and controls at the 750-ms SOA (p<0.05). We found a positive correlation found between Suspiciousness/Persecutory Ideas and unrelated targets at the short SOA. Conclusions: The results suggest N400 semantic priming is deficient early in the psychotic disease process, at least at relatively long intervals. This abnormality may represent an early biomarker of the

psychotic process. More severe paranoia was found associated with smaller N400 amplitudes, suggesting that a generalized over activation of unrelated concepts may be associated with ideas of reference and suspiciousness. 58. Lilian Lin; Department of Laboratory Medicine and Pathobiology Supervisor: Janice Robertson USE OF AAV9 VIRAL MEDIATED EXPRESSION OF TDP-43 TO MODEL AMYOTROPHIC LATERAL SCLEROSIS IN MICE Lin, L, 1,2; Miletic, D, 1,2; McKeever, P 1,2; Robertson, J, 1,2 1 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto; 2 Department of Laboratory Medicine and Pathobiology, University of Toronto Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by the cytoplasmic mislocalization and aggregation of the normally nuclear TAR DNA Binding Protein-43 (TDP-43). This TDP-43 pathology is called TDP-43 proteinopathy. A splice isoform of TDP-43, called TDP-35, is abnormally expressed in ALS and forms cytoplasmic aggregates in transfected cells. Transgenic mouse models of TDP-43 or of TDP-35 have largely been unsatisfactory due to the autoregulation of TDP-43 expression, which keeps expression levels low, and as such, pathological and behavioral phenotypes have been variable. Here, we propose to circumvent these problems by using recombinant adeno-associated virus serotype 9 (rAAV9) to drive high levels of expression of EGFP-TDP-43 and EGFP-TDP-35 in mice, using the human synapsin 1 (hSyn1) promoter to give neuronal specific expression. Our results show wide-spread neuronal expression of EGFP-TDP-35 in our 8-week old rAAV9-injected mice. High levels of expression were observed in the olfactory bulb/nuclei, septal nucleus, striatum, hypothalamus, midbrain, posterior cortical areas (visual and entorhinal cortex), hippocampus (CA1 and CA2), subiculum, and amygdala. 59. Nancy Liu; Institute of Medical Science Supervisor: Cindi Morshead NICHE FACTORS DIFFERENTIALLY REGULATE NEURAL PRECURSOR CELL MIGRATION AND DIRECTEDNESS IN RESPONSE TO ELECTRIC FIELD STIMULATION Liu NX 1,2; Babona-Pilipos R 2,3; Surjeet P 2; Morshead CM 1,2,3 1 Institute of Medical Sciences; 2 Terrence Donnelly Centre for Cellular and Biomolecular Research; 3 Institute of Biomaterials and Biomedical Engineering Biological Electric Fields (EFs) play a role during development and in wound healing, with disruption of these fields causing developmental abnormalities and impaired wound healing. Neural stem and progenitor cells (NPCs) are electro-sensitive cells and respond to direct current EFs by undergoing rapid and directed migration towards the cathode (known as galvanotaxis). To understand the mechanism by which NPCs translate an electrical signal into a mechanical one, we examined channel expression and downstream signaling in the presence of an EF in vitro. We found that calcium signaling is necessary for the rapid migration of NPCs. However, the directedness of the cells towards the cathode was not affected by calcium modulation. Hence, the parameters of velocity and direction are differentially regulated by an EF. Previous work has shown a cell can change the direction of galvanotaxis based on environmental cues. We asked if the stem cell niche regulated directedness by

comparing the migration of NPCs derived from early postnatal and adult brains in the presence or absence of niche cells. Postnatal NPCs showed more tortuous migration paths (less directed) than adult NPCs. Interestingly, conditioned media (CM) from the postnatal niche was able to disrupt the directed migration of adult cells. We predict that postnatal cells will undergo directed migration in adult CM and are examining factors that underlie this change. Elucidating the fundamental biology underlying NPC galvanotaxis is relevant for understanding cell motility and the development of novel tools for neural regeneration. 60. Claire McSweeny; Institute of Medical Science Supervisor: Karen Gordon DISORDERED SPATIAL AWARENESS AND NAVIGATION IN CHILDREN WITH HEARING LOSS WHO USE BILATERAL COCHLEAR IMPLANTS TO HEAR McSweeny C 1, 2; Cushing SL 1, 2; Campos J 2,3; Papsin BC 1,2; Gordon KA 1,2 1 The Hospital for Sick Children, 2 The University of Toronto, 3 Toronto Rehabilitation Institute Our study aims to 1) identify disordered spatial perception in children presenting with both hearing loss and vestibular deficits, and 2) measure the effects on physical activity and academics. Children actively explore their world, learning their own location in space and where others are around them. This development of spatial relationships may be impaired in children with hearing loss because they have difficulties detecting locations of sounds even when using bilateral cochlear implants to hear. In addition, many may have trouble maintaining their own position in space due to concurrent deficits in the vestibular (balance) system. We hypothesize that these combined sensory deficits distort awareness of space, impair navigation through space, and have implications for learning and physical activity. Twenty children with bilateral deafness who use cochlear implants have been recruited to investigate potential deficits in spatial awareness and navigation. Spatial perception is assessed through tests of spatial memory, orientation, and navigation. Sensory deficits are confirmed by audiometric and vestibular measures. Effects on learning are measured by tests assessing language, reading and mathematics ability. Physical activity is evaluated by a questionnaire. Preliminary findings indicate that children with bilateral cochlear implants perform more poorly on measures of spatial awareness, memory, and navigation compared to published data from children with normal hearing. Effects on language, academics, and activity are being analyzed. These data suggest that the effects of hearing and vestibular impairments likely extend beyond delayed hearing and oral language development, affecting spatial perception. 61. Miranda Mellerup; Physiology Supervisor: Anne Wheeler THE TIME COURSE OF BEHAVIOURAL IMPAIRMENT IN MICE FOLLOWING MILD TRAUMATIC BRAIN INJURY Mellerup M 1,2; Gazdzinski L 2; Sled J 2,3; Wheeler AL 1,2 1 Department of Physiology, University of Toronto; 2 SickKids Research Institute, The Hospital for Sick Children; Medical Biophysics, University of Toronto

Background: Mild traumatic brain injury (mTBI), which includes concussion, causes highly variable physical, cognitive, and behavioural symptoms that are most often transient; however, 10-15% of patients experience persistent symptoms. It is not known what differentiates those who recover quickly from mTBI from those who do not. Objective: Describe the time course of behavioural impairment following mTBI in a mouse model of concussive injury. Methods: mTBI was induced in mice using a closed-skull Controlled Cortical Impact model, and behavioural assessments were conducted at an acute (3 days) and chronic (6 weeks) delay post-injury to characterize the time course of impairment. At each time-point, the open field and light/dark tests were used to assess anxiety-like behaviours, the tail suspension test was used to assess depressive-like behaviours, the Y maze was used to assess working memory, and the pre-pulse inhibition test to assess sensorimotor gating. Results: mTBI mice spent significantly more time in the centre of the arena within the first 5 minutes of the open field test compared to shams across time-points. In the tail suspension test, mTBI mice showed increased mobility compared to shams at the acute time-point. mTBI mice had significantly fewer successful novel arm transitions in the Y maze compared to shams at both time-points. There were no differences between groups in the light/dark test and in the pre-pulse inhibition test. Conclusions: These results reveal an unexpected phenotype whereby mTBI mice displayed fewer anxiety-like and depressive-like behaviours after injury, however these mice appear to have memory deficits that persist over time. 62. Homira Osman; Otolaryngology, Neurosciences & Mental Health Supervisor: Karen Gordon CHILDREN WITH COCHLEAR IMPLANTS USE VISION TO COMPENSATE FOR POOR PERCEPTION OF EMOTION IN SPEECH Osman H 1,2; Hopyan T 1,2,5; Polonenko MJ 1,2; Russo FA 4; Papsin BC 1,2,3; Gordon KA 1,2,3 1 Department of Otolaryngology, Cochlear Implant Program, The Hospital for Sick Children; 2 Program in Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children; 3 Department of Otolaryngology, Faculty of Medicine, University of Toronto; 4 Department of Psychology, Ryerson University; 5 Scientific Affairs Neuropsychology, Syneos Health We examined whether children who are deaf using cochlear implants (CIs) integrate auditory and visual cues differently from normal-hearing peers to recognize emotion in speech. Many children using CIs understand spoken language but have difficulty understanding the emotion being conveyed. These challenges reflect limited representation of sound by cochlear implants, requiring compensation from other modalities such as vision. We hypothesized that children using CIs use gender, intonation and age of speaker differently from normal to recognize emotion in speech. Participants were 23 unilateral CI users (M=11.57, SD=2.58), and 18 typically-developing children (controls) (M=11.39, SD =2.90). Children listened to the same spoken sentence presented with 4 different emotions (happy, sad, angry or fearful) by 4 different speakers. Sentences were presented in video (auditory-visual) or auditory only. Children were asked to identify the emotion of the speaker. Reaction time and accuracy were measured.

Children using CIs were less accurate than the controls with and without visual cues (p< .01) but showed greater improvement when visual information was added (p< .01). In the auditory-only condition, children with CIs were most accurate when listening to sad and angry sentences spoken by the female speakers. Reaction times were significantly longer in the CI than controls across stimuli (p< .01). Children with CIs have trouble hearing emotion across different speakers and rely on visual cues more than normal. Slower reaction times in the CI group indicate that their compensatory strategies are inefficient with implications for increased cognitive demand during challenging listening tasks. 63. Chrystalla Paleshi; Faculty of Music Supervisor: Michael Thaut IMPROVED GAIT PARAMETERS FOLLOWING GROUP NEUROLOGIC MUSIC THERAPY Paleshi C, 1, 2 1 Music and Health Research Collaboratory; 2 Faculty of Music, University of Toronto Sample data was collected in order to determine the viability of future Neurologic Music Therapy (NMT) research on gait parameters for an older population with multiple diagnoses which influence gait. A female group member who was a breast cancer survivor, diagnosed with major depressive disorder, post-traumatic stress disorder, and who had undergone bilateral total knee arthroplasty, was monitored to track progress over a period of 14 non-consecutive weeks of group NMT treatment. NMT techniques applied were Therapeutic Instrumental Music Playing (TIMP), Patterned Sensory Enhancement (PSE), and Rhythmic Auditory Stimulation (RAS). In these techniques, rhythmic, melodic, harmonic, and dynamic elements of music provided cues for movements in order to facilitate and improve gait parameters. Following the conclusion of the 14 weeks and analysis of descriptive statistics, it was determined that Neurologic Music Therapy lead to significant improvements in stride length, speed, and cadence, as well helping the client meet personal goals which were set prior to the start of the therapeutic process. This sample data is promising for the implementation of NMT in future studies with an older population with multiple diagnoses, which should aim to increase sample size and to collect additional data. 64. Zihang (Danny) Pan; Institute of Medical Science Supervisor: Roger McIntyre A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, CLINICAL TRIAL EVALUATING THE EFFICACY OF ADJUNCTIVE INFLIXIMAB FOR THE TREATMENT OF COGNITIVE SYMPTOMS OF BIPOLAR DEPRESSION Pan Z, 1,2; Mansur RB, 1,3; Subramaniapillai M, 1; Lee Y, 1,2; Carmona N, 1; Shekotikhina M, 1; McIntyre RS, 1,2,3,4 1 Mood Disorders Psychopharmacology Unit (MDPU), University Health Network; 2 Institute of Medical Science, University of Toronto; 3 Department of Psychiatry, University of Toronto; 4 Department of Pharmacology, University of Toronto Bipolar depression (BD) is a significant contributor to global functional disability. Cognitive dysfunctions are common, persistent, and neuroprogressive. Elevated levels of proinflammatory cytokines such as Tumor Necrosis Factor Alpha (TNF-α) have been implicated in the pathoetiology of cognitive dysfunction in BD. Infliximab is a TNF-α antagonist that has show preliminary efficacy in mitigating

depressive symptoms in individuals with elevated inflammation. The aim of the study is to evaluate the efficacy of infliximab in treating cognitive dysfunction in BD individuals with elevated inflammation. The study is a 12-week, randomized, double-blind, placebo-controlled phase 2 clinical trial. Infliximab was prescribed adjunctively via intravenous infusion at 5mg/kg. Saline infusion was prescribed for placebo. Depression severity was measured via the Montgomery Depression Rating Scale (MADRS). Composite cognition z-scores at 3 timepoints (week 0, week 2, and week 12) were calculated from the Digit Symbol Substitution Test (DSST) and the Rey Auditory Verbal Learning Test (RAVLT). Generalized estimating equations were used to determine significance of between- and within-group effects. A total of 60 individuals were enrolled; 31 were assigned to placebo and 29 to infliximab. Despite observing significant improvement in cognition from week 0 to week 12 for both groups, there was no significant difference between infliximab and placebo (p>.05). Negative between group results suggest a highly heterogenous sample. Improvements in cognition over time may be due to mechanisms yet uncharacterized. The relevance of inflammatory systems in the pathoetiology of mood disorders provide an impetus to investigate other inflammatory systems to mitigate cognitive dysfunction in BD. 65. Caroline Park; Institute of Medical Science Supervisor: Roger S. McIntyre USING EARLY CHANGES IN COGNITION TO PREDICT RESPONSE TO VORTIOXETINE IN MAJOR DEPRESSIVE DISORDER Caroline Park 1,2, Hannah Zuckerman 2, Dominika Fus 2, Mehala Subramaniapillai 2, Rodrigo B. Mansur 1,2,3, Roger S. McIntyre 1,2,3,4 1 Institute of Medical Science, University of Toronto, Toronto, ON, Canada 2 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada 3 Department of Psychiatry, University of Toronto, Toronto, ON, Canada. 4.Department of Pharmacology, University of Toronto, Toronto, ON, Canada BACKGROUND: Currently, antidepressant treatment selection for individuals with major depressive disorder (MDD) involves trial-and-error to determine the most effective course of treatment. This imprecise approach to medication selection contributes to treatment failure and unnecessarily exposes patients to lengthy and insufficient treatment trials. Towards minimizing the length of insufficient treatment trials, my research is focused on investigating a pragmatic predictor of antidepressant response: early improvements in cognition. OBJECTIVE: My project aims to determine whether early changes in objective and subjective cognitive measures predict response to vortioxetine in adults with MDD. METHODS: N=100 adults with DSM-5-defined MDD are being recruited for an 8-week, open-label study. Cognition is being assessed using the THINC-integrated tool. The primary outcome measure is depressive symptom severity, as measured by the Montgomery Åsberg Depression Rating Scale (MADRS). CURRENT PROGRESS: 76 MDD subjects have been enrolled (52 completed; 14 ongoing; 10 dropouts). SIGNIFICANCE: The identification of reliable early treatment predictors of antidepressant response is clinically relevant as it would reduce the amount of time patients spend taking ineffective medications. The results from my research may provide preliminary support for measuring early changes in cognition to predict antidepressant treatment outcome.

66. Nadine Parker; Institute of Medical Science Supervisor: Tomas Paus MATURATION OF THE HUMAN CEREBRAL CORTEX IS ASSOCIATED WITH REGIONAL EXPRESSION OF NR3C1 Parker N, 1,2; Paus T, 1,2 1 Institute of Medical Science, University of Toronto; 2 Rotman Research Institute, Baycrest Glucocorticoids are the main mediators of the stress response. Expression of the gene for the glucocorticoid receptor (NR3C1) varies regionally across the human cerebral cortex suggesting a mechanism for regional differences in the influence of stress on cortical maturation. Initial cross-sectional studies were based on population-based data. The purpose of this study is to devise an individual-level measure of the association between NR3C1 expression and cortical thickness. Participants aged 6-22 were from the Saguenay Youth Study (n=1029) as well as longitudinal studies IMAGEN (n=1823) and the High-Risk Cohort Study for the Development of Childhood Psychiatric Disorders (n=725). Regional expression of NR3C1 was determined using Alan Brain Atlas data. Cortical thickness was derived from the Freesurfer (version 5.3) pipeline. For each participant, cortical thickness was correlated with NR3C1 expression across 34 regions. The resulting individual-level correlation coefficient was Fisher-Z transformed and termed “NR3C1 by cortical thickness profile similarity”. In longitudinal studies, a “NR3C1 by cortical thinning profile correlation” was derived by correlating the rate of change in cortical thickness (mm/year) with NR3C1 expression. Mixed model regressions were used to determine age and sex effects on NR3C1 by thickness profile similarity. Additionally, the change in thickness profile similarity was regressed against the NR3C1 by thinning profile correlation. All participants had a negative NR3C1 by thickness profile similarity, the strength of which increased with age (beta=9.49e-04,p<0.001). Most participants (71- 78%) had greater cortical thinning in regions with high NR3C1 expression. Thinning profile correlations were negatively associated with change in thickness profile similarity (range R2=0.61,p<0.001 to R2=0.75,p<0.001). Moreover, 22-29% of individuals had greater cortical thinning in regions with low NR3C1 expression and declined in NR3C1 by thickness profile similarity with age. The similarity in cortical thickness and NR3C1 expression profiles strengthens from childhood into adulthood. This may suggest some regions are particularly vulnerable to glucocorticoids. 67. Yash Patel; Institute of Medical Science Supervisor: Tomas Paus MATURATION OF THE HUMAN CEREBRAL CORTEX DURING ADOLESCENCE: MYELIN OR DENDRITES Patel Y 1,2; Shin J 2,3; Gowland PA 4; Pausova Z 3,5; IMAGEN; Paus T 2,6,7,8 1 Institute of Medical Sciences, University of Toronto; 2 Rotman Research Institute; 3 The Hospital for Sick Children; 4 Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham; 5 Department of Physiology and Nutritional Sciences, University of Toronto; 6 Center for Developing Brain, Child Mind Institute; 7 Department of Psychiatry, University of Toronto; 8 Department of Psychology, University of Toronto Adolescence is a period of dynamic changes in the cerebral cortex that involve various cellular processes. Post mortem studies,

although limited by low sample sizes and older methodologies, have narrowed down the search to two processes: myelination and dendrites. Previous in vivo studies revealed robust age-related variations in structural properties of the human cerebral cortex during adolescence, particularly within a magnetic resonance imaging metric (MRI) which indirectly detects macromolecular/microstructural density, termed magnetization transfer ratio (MTR). Neurobiology underlying these maturational phenomena is largely unknown, however. Here we employ a virtual-histology approach to gain insights into processes associated with inter-regional variations in cortical microstructure and its maturation, as indexed by MTR. Inter-regional variations in MTR correlate with inter-regional variations in expression of genes specific to pyramidal cells (CA1) and ependymal cells; enrichment analyses indicate involvement of these genes in dendritic growth. On the other hand, inter-regional variations in the change of MTR during adolescence correlate with inter-regional profiles of oligodendrocyte-specific gene expression. Complemented by a quantitative hypothetical model of the contribution of surfaces associated with dendritic arbour (1,631m2) and myelin (48m2), these findings suggest that MTR signals are driven mainly by macromolecules associated with dendritic arbour while maturational changes in the MTR signal are associated with myelination. 68. Elana Pinchefsky; Institute of Medical Science Supervisor: Emily Tam PERIODS OF HYPERGLYCEMIA DURING NEONATAL ENCEPHALOPATHY ARE TEMPORALLY ASSOCIATED WITH WORSE EEG BACKGROUND Pinchefsky EF 1; Tam EWY 1; Kamino D 1; Chau V 1; Moore AM 2; Hahn CD 1 1 Department of Pediatrics, Division of Neurology, The Hospital for Sick Children, Toronto, ON; 2 Department of Pediatrics, Division of Neonatology, The Hospital for Sick Children, Toronto, ON OBJECTIVE: To determine whether periods of hypo- and hyperglycemia in neonates with encephalopathy are associated with immediate changes in continuous electroencephalography (cEEG) background activity. METHODS: A cohort of term newborns with encephalopathy underwent continuous interstitial glucose monitoring (placed soon after birth) and cEEG monitoring. Episodes of hypoglycemia (≤2.8mmol/L) and hyperglycemia (>8mmol/L) were identified. cEEG background activity was classified in 5-min epochs. Generalized estimating equations were used to assess the relationship of hypo- or hyperglycemia with cEEG background scores, adjusting for clinical markers of hypoxia-ischemia (Apgar scores, umbilical artery pH and base deficit). RESULTS: 30 term newborns (median GA 40.1 wk) were included (17 males). Median of 49h of concurrent cEEG and continuous glucose monitoring were available per neonate, during which 9 events of hypoglycemia were detected in 5 neonates (median duration 45 min) and 14 events of hyperglycemia in 8 neonates (median duration 212.5 min). Epochs of hypoglycemia did not correlate with significant changes in cEEG background scores (p=0.239). Epochs of hyperglycemia were associated with worse cEEG background scores, including after adjusting for clinical markers of hypoxia-ischemia (1.621; 95% CI 0.663-2.579; p=0.001). A subgroup analysis was performed examining the association of hyperglycemia with cEEG background scores including only the 8 neonates that had episodes of hyperglycemia, and demonstrated

epochs of hyperglycemia were still associated with worse cEEG background scores than epochs of normoglycemia (0.739; 95% CI 0.038-1.439; p=0.039). CONCLUSIONS: Epochs of hyperglycemia are temporally associated with worse global brain function, even after adjusting for severity of hypoxia-ischemia. 69. Sandra Poulson; Department of Psychology Supervisor: Loren Martin & Melissa Holmes CHARACTERIZING PAIN BEHAVIOR FROM NERVE INJURY IN A RODENT THAT FEELS NO SPICY HEAT Poulson, SJ, 1; Holmes, MM, 1,2,3; Martin, LJ, 1,2,3 1 Department of Psychology, University of Toronto; 2 Department of Psychology, University of Toronto Mississauga; 3 3Department of Cell & Systems Biology, University of Toronto The African naked mole-rat (Heterocephalus glaber) has been shown, by Thomas Park and colleagues (2008), to have an abnormal pain sensory system such that the fossorial rodent lacks some pain behavior present in other rodents. It is not yet known whether pain behavior in the naked mole-rat differs from other rodents after peripheral nerve injury. In this study, we used a spared nerve injury model of chronic pain along with behavioral assays for mechanical sensitivity to innocuous stimulus (allodynia), mechanical sensitivity to painful stimulus (hyperalgesia), and cold allodynia. We find that mechanical pain behavior between naked mole-rats and mice is similar following nerve injury. In contrast to mice, naked mole-rats lack responsiveness to a mild cold stimulus following nerve injury. The lack of cold-sensitization in naked mole-rats suggests that this species may have atypical receptors that process cold sensation, or this reaction to mild cold could arise from deep as opposed to superficial dorsal horn connectivity. 70. Lee Propp; Applied Psychology and Human Development Supervisor: Anne-Claude Bedard PSYCHOPATHOLOGICAL AND NEUROCOGNITIVE ENDOPHENOTYPES OF CHILDREN WITH DISRUPTIVE BEHVIOURS Propp, L, 1,2; Bedard, AC, 2; Andrade B, 1,3 1 Centre for Addiction and Mental Health; 2 Applied Psychology and Human Development, Ontario Institute for Studies in Education, University of Toronto; 3 Department of Psychiatry, University of Toronto Introduction: Childhood Disruptive Behaviour Disorders (DBD) are a robust predictor of delinquency, academic failure, social difficulties, and persistent mental health disorders in adolescence and adulthood, and one of the most frequent reasons for referral to children’s mental health services. However, evidence-based psychosocial interventions are ineffective for a subset of these children, and emerging research points to heterogeneity in symptoms and neurocognitive abilities as important limiting factors. In order to personalize intervention, and improve treatment outcomes, it is necessary to better characterize children with DBD. Methods: First, data (n=143) from children 6 – 12 years, referred referred to a clinic for children with disruptive behaviors, will be analyzed using Latent Class Analysis (LCA) to determine classes (i.e., subgroups) based on well validated parent-report measures of children’s callous-unemotional traits (CU), emotion regulation, and children’s objective neurocognitive task performance (i.e., response

inhibition, emotion recognition, and selective attention). Second, identified classes will be compared on three parent- and teacher-rated outcome variables using the 3-step solution for latent predictor variables: level of functional impairment, social functioning, and conduct problems. Results (forthcoming): As LCA is a data-driven modeling approach there were no formal hypotheses, however based on past research it is expected that classes containing elevated levels of CU traits will have the greatest levels of peer problems and functional impairment. Conclusions: This study will provide valuable information to enhance patient outcomes and clinical assessment practices by identifying subgroups of children with DBD based on dimensions of psychopathology and neurocognitive functioning. 71. Keelia Quinn de Launay; Rehabilitation Sciences Institute Supervisor: Deryk Beal THE EFFECT OF TDCS ON COGNITIVE PERFORMANCE IN YOUTH WITH CONCUSSION: A PILOT AND FEASIBILITY STUDY Quinn de Launay, K, 1,3; Cheung, S, 2; Riggs, L, 3,4; Reed, N, 1,3,5; Beal, DS, 1,2,3,6 1 Rehabilitation Sciences Institute, University of Toronto; 2 Institute of Biomaterials and Biomechanical Engineering, University of Toronto; 3 Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital; 4 Department of Pediatrics, Faculty of Medicine, University of Toronto; 5 Department of Occupational Science and Occupational Therapy, Rehabilitation Sciences Institute, University of Toronto; 6 Department of Speech-Language Pathology, Faculty of Medicine, University of Toronto Background: Pediatric concussion is a significant public health concern, with approximately 6% of youth aged 13-18 affected annually in Ontario. Despite increased recognition of the persisting challenges in working memory (WM) that can result from concussion, therapeutic interventions to treat cognitive symptoms are not well developed. Transcranial direct current stimulation (tDCS) is a brain stimulation technology that regulates cortical activity to promote adaptive plasticity for cognitive rehabilitation, including skill acquisition in WM. While it has shown to be a promising tool for brain injury recovery, the feasibility and efficacy of a tDCS intervention for a youth concussion population remains unknown. Objective: We explored the (1) potential clinical efficacy and (2) feasibility of implementing a tDCS intervention for persisting cognitive symptoms in youth post-concussion. Methods: We implemented a pilot quasi-randomized control design to investigate whether three sessions of tDCS to the left dorsolateral prefrontal cortex (LDLPFC) paired with a dual N-back WM task, (1) influenced cognitive performance, and (2) was a feasible and tolerable intervention in 12 youth post-concussion. Results: Participants (1) demonstrated significant improvements in performance on the dual WM task across three sessions, with a trend towards tDCS enhancing increases in accuracy; and, (2) participants reported receiving tDCS as tolerable, further supported by the lack of participant attrition and adverse effects. Implications: Our results confirm the potential of LDLPFC as a viable neurotarget for tDCS to support the rehabilitation of WM in youth with persisting cognitive symptoms post-concussion, and will inform future clinical trials testing this novel intervention. 72. Myles Resnick; Rehabilitation Sciences Institute Supervisor: George Mochizuki

CHARACTERIZING VELOCITY-DEPENDENT AND VELOCITY-INDEPENDENT FEATURES OF RESISTANCE TO PASSIVE STRETCH USING ROBOTIC ASSESSMENT METHODS Resnick MF 1,2; Centen A; Lowrey CR 3; Scott SH 3,4; Mochizuki G 1,2,5,6 1 Rehabilitation Sciences Institute, University of Toronto; 2 Sunnybrook Research Institute; 3 Centre for Neuroscience Studies, Queen’s University; 4 Department of Biomedical and Molecular Sciences, Queen’s University; 5 Canadian Partnership for Stroke Recovery; 6 Department of Physical Therapy, University of Toronto Background: Spasticity is defined as velocity-dependent hyperexcitability of the stretch reflex. Assessment of spasticity typically involves examining this velocity-dependence on resistance to passive movement; however, other velocity-independent features of resistance to movement may also be present. This study sought to determine whether velocity-dependent and velocity-independent components of resistance to passive movement were distinguishable in the elbow flexors in people with post-stroke spasticity. Methods: Retrospective analysis of an existing dataset in which thirty individuals with stroke (13 spastic and 17 non-spastic) and 98 healthy controls were recruited. Using the KINARM Robotic Exoskeleton, participants’ upper-limb was moved through range at two speeds (fast and slow). Catch angle, final angle, and peak velocity were the primary outcome measures. Clinical assessment of spasticity (Modified Ashworth Scale) was also performed. Results: Individuals with spasticity displayed a spastic catch, decreased range of motion, and increased tone within their affected limbs. While a catch was detected more frequently during fast stretch, range of motion and degree of tone did not differ significantly across speeds. Six participants displayed a catch at both fast and slow speeds. Kinematic outcome measures further identified a subset of non-spastic stroke participants as impaired. Conclusion: Velocity-dependent (spastic catch) and velocity-independent (reduced range, high tone) impairments are detectable in individuals post-stroke, both with and without a clinical diagnosis of spasticity. The detection of a catch at both speeds within some participants may suggest the presence of position-dependent impairments as well. 73. Leticia Ribeiro de Oliveira; Rehabilitation Sciences Institute Supervisor: Deryk Beal EXPRESSIVE AND RECEPTIVE LANGUAGE SKILLS DISCREPANCY IN CHILDREN WITH AUTISM SPECTRUM DISORDER: PRELIMINARY RESULTS Oliveira LR,1,2; Brian J,1; Anagnostou E,1; Beal DS, 1,2 1 Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital; 2 Rehabilitation Sciences Institute, University of Toronto Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder marked by impairments in social interaction and communication, and restricted interests and repetitive behaviors. Although language impairment is not a core symptom of ASD, it is an important element for our understanding of the disorder. The language profile has a great variability across the life span and individuals in the ASD population. A profile defined by lesser receptive language relative to expressive language has been investigated as one possible developmentally stable trait in ASD. Purpose: Investigate the receptive and expressive language skills in individuals diagnosed with ASD through two different two language assessments.

Method: Cross-sectional data from participants with ASD (n=249) and controls (n=152) were tested for the presence of discrepancy between expressive and receptive language skills. The association between the presence of this discrepancy and elements as diagnosis, age, sex and source of the language data were investigated. Results: Participants with ASD showed poorer language ability compared to controls (t353.142= -15.796, p < .001). Only 26% of the ASD participants presented a statistical significance difference between receptive and expressive language. A better receptive than expressive language, with higher prevalence in younger participants, were found in both groups. The performance in both language measures was moderately correlated when considering either receptive language scores (r = .394, p < .001) or expressive scores (r = .586, p < .001). Implications: A preliminary analysis of suggests that this discrepancy may be an age-specific marker on preschools with ASD, but further analysis is needed. 74. Nicole Richard, Faculty of Music Supervisor: Michael Thaut THE USE OF VOCAL INTONATION THERAPY TO IMPROVE AWARENESS AND CONTROL OF VOICE VOLUME IN INDIVIDUALS WITH AUTISM SPECTRUM DISORDER Richard, NM, 1,2. 1 Faculty of Music, University of Toronto 2 Music and Health Research Collaboratory Autism Spectrum Disorder (ASD), with a prevalence of 1 in 37 boys and 1 in 151 girls, is characterized by difficulties with social communication and the presence of repetitive behaviors or patterns of interest. Some individuals with ASD have difficulty modulating voice volume appropriately in social situations – persons may speak too loudly or too quietly and may be unaware that they are doing so. Vocal Intonation Therapy (VIT) is a Neurologic Music Therapy technique that uses vocal exercises to train, develop, and rehabilitate aspects of voice control due to neurological, physiological, psychological, or functional abnormalities of the voice apparatus. Previous research has indicated that vocal training can help neurotypical individuals modulate their voice volume in various sound environments. Other research has shown that VIT can address issues of voice volume in those with Parkinson’s disease, traumatic brain injury, and hearing impairments. Sample data from 10 weeks of VIT with one individual with ASD showed that the difference between the mean decibel (dB) level of speech before and after each VIT session decreased over the course of the 10 weeks. As well, the participant’s overall average dB level when speaking decreased from an average of 72 dB to 65 dB over the course of sessions. This indicated that over time, the participant gained awareness of how to speak at an appropriate conversational volume level. Thus, the use of VIT for increasing vocal control and awareness of voice volume in those with ASD could be a promising area for future research. 75. Nelson Rodrigues; Institute of Medical Science Supervisor: Nir Lipsman ARE COGNITIVE DEFICITS IN SEASONAL AFFECTIVE DISORDER STATE OR TRAIT MARKERS? Rodrigues NB, 1,2; Swardfager W, 3,4; Levitt A 5; Lipsman N, 2,6,7 1 Institute of Medical Science, University of Toronto; 2 Sunnybrook Research Institute, Sunnybrook Health Science Center; 3

Department of Pharmcology and Toxicology, University of Toronto; 4 Hurvitz Brain Sciences Program, Sunnybrook Research Institute; 5 Department of Psychiatry, Sunnybrook Health Sciences Centre; 6 Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto; 7 Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre Aim: Emerging evidence around Major Depressive Disorder (MDD) suggest that neurocognitive deficits may be a cardinal feature of this disease. However, it remains unclear whether patients suffering from Seasonal Affective Disorder (SAD), a subtype of MDD, experience similar deficits in attention/concentration, executive function, processing speed, and verbal fluency. SAD offers a naturalistic model, specifically seasonal changes to depressive or euthymic status, which can be examined to better understand how cognition fluctuates longitudinally. Methods: A single center, observational, mixed-design study, recruited sixteen participants diagnosed with winter SAD and twelve healthy controls who did not have seasonality symptoms. Participants underwent a cognitive battery that included the Digit Symbol Substitution Test, Trail Makers Test A and B, Digit Span forward and backward, California Verbal Learning Test-II and the FAS Verbal Fluency Test. Results: Participants SAD showed no significant differences in processing speed, concentration or working memory compared to the healthy control cohort. Interestingly however, SAD patients made significantly more errors in categorical verbal fluency (p<0.05) and significantly higher false positives in long-term verbal recognition (p<0.05). Conclusion: This study presents novel evidence that participants with SAD have impaired inhibition in verbal fluency and memory compared to healthy controls during their depressed winter state. Future Directions: This study will continue to investigate if these deficits persist throughout the summer months, which will elucidate on whether cognitive deficits are a trait or state features of depression. 76. Anton Rogachov; Institute of Medical Science Supervisor: Karen Davis REDUCED LOW FREQUENCY OSCILLATIONS IN THE DYNAMIC PAIN CONNECTOME OF CHRONIC PAIN PATIENTS Rogachov A, 1,2; Cheng J, 1,2; Hemington K, 1,2; Kim J, 1,2; Bosma R, 2; Inman R, 1,2,; Davis K, 1,2,4 1 Institute of Medical Science, University of Toronto, Canada; 2 Toronto Western Hospital/Krembil Research Institute, University Health Network, Toronto, Canada; 3 Dept. of Medicine, University of Toronto, Canada; 4 Dept. of Surgery, University of Toronto, Toronto, Canada Introduction: Neuronal oscillations have long been posited as an integral part of a stable and well-functioning nervous system, and have been linked to perceptual sensitivity across multiple sensory modalities. Using functional magnetic resonance imaging (fMRI), our previous work has shown that individuals with less pain sensitivity and greater pain coping have greater blood-oxygen-level dependent (BOLD) variability within networks of the dynamic pain connectome. Here, we tested the hypothesis that there are differences in the variation of the BOLD signal between patients with Ankylosing Spondylitis (AS; a form of arthritis that causes chronic debilitating lower back pain) and healthy individuals within regions of the

dynamic pain connectome, and how these differences relate to clinical impairments (i.e., BASDAI). Methods: 35 low-BASDAI and 29 high-BASDAI AS patients, and 35 age, sex-matched controls provided informed written consent before undergoing a 3T MRI session to acquire a T1-weighted anatomical scan, as well as a 10-minute T2*-weighted resting-state fMRI scan. Each AS patient also completed the BASDAI questionnaire. Results: A reduction in slow frequency oscillations (0.01-0.027Hz) with networks of the dynamic pain connectome was associated with greater disease severity in high-BASDAI AS patients only. Conclusion: Our work suggests regional BOLD signal variability can be used to probe pathological brain mechanisms in the chronic pain in relation to clinical symptoms. 77. Usman Saeed; Institute of Medical Science Supervisor: Mario Masellis, Sandra E. Black APOE-Ε4 ASSOCIATES WITH HIPPOCAMPAL VOLUME, LEARNING, AND MEMORY ACROSS THE SPECTRUM OF ALZHEIMER’S DISEASE AND DEMENTIA WITH LEWY BODIES Usman Saeed 1, 2, Saira S. Mirza 3, 4,Bradley J. MacIntosh 4, 5, Nathan Herrmann 1, 2, 6, Julia Keith 7, Joel Ramirez 2, 4, 8, Sean M. Nestor 2, 6, Qinggang Yu 2, Jo Knight 9, Walter Swardfager2, 4, 8, 10, Steven G. Potkin11, Ekaterina Rogaeva12, Peter St. George-Hyslop12, 13, Sandra E. Black 1, 2, 3, 4, 8, *, Mario Masellis1, 2, 3, 4, *

* Contributed equally as co-senior authors 1, Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2, LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 3, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada; 4, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 5, Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 6, Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 7, Department of Anatomical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada; 8, Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada; 9, Data Science Institute and Medical School, Lancaster University, Lancaster, UK; 10, Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada; 11, Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA; 12, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; 13, Cambridge Institute for Medical Research, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK. INTRODUCTION: The apolipoprotein E ɛ4-allele (APOE-ε4) is a susceptibility factor for Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), however, its relationship with imaging and cognitive measures across the AD/DLB spectrum remains unexplored. METHODS: We studied 298 patients (AD=250, DLB=48; 38 autopsy-confirmed; ClinicalTrials.gov ID: NCT01800214) using neuropsychological testing, volumetric MRI, and APOE genotyping to investigate the association of APOE-ε4 with hippocampal volume and learning/memory phenotypes, irrespective of the diagnosis.

RESULTS: Across the AD/DLB spectrum: (1) hippocampal volumes were smaller with increasing APOE-ε4 dosage (β=-0.20, P<0.0001), with no genotype x diagnosis interaction (P=0.9422), (2) learning performance as assessed by total recall scores of the California verbal learning test (CVLT) was directly associated with hippocampal volumes only among APOE-ε4 carriers (β=0.17, P=0.0084) but not non-carriers (β=0.14, P=0.1107), and (3) APOE-ε4 carriers performed worse on CVLT long-delay free word recall (Mann-Whitney U=6715.0, P=0.0320). The APOE-ε4 dosage was also inversely associated with hippocampal volumes within the DLB (β=-0.28, P=0.0428) and AD (β=-0.20, P=0.0006) clinical diagnostic groups, as well as when the analysis was restricted to the pathology-confirmed sub-sample (β=-0.32, P=0.0495). DISCUSSION:These findings provide evidence that APOE-ε4 is linked to hippocampal atrophy and learning/memory phenotypes across the AD/DLB spectrum, possible via shared mechanisms of neurodegeneration. In this regard, hippocampal volume in APOE-ε4 carriers may have utility as biomarkers of disease progression in therapeutic trials of AD, DLB, and AD/DLB mixed disease. 78. Usman Saeed; Institute of Medical Science Supervisor: Mario Masellis, Sandra E. Black THE INFLUENCE OF APOE-Ε4 ON HIPPOCAMPAL ATROPHY IN ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW OF STRUCTURAL MAGNETIC RESONANCE IMAGING STUDIES Usman Saeed 1, 2, Bradley J. MacIntosh 3, 4, Walter Swardfager5, 6, Nathan Herrmann 1, 2, 7, Sandra E. Black 1, 2, 3, 6, 8, Mario Masellis, 1, 2, 3, 8 1, Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2, LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 3, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 4, Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 5, Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada; 6, Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada; 7, Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 8, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada. OBJECTIVE: This systematic review synthesizes current knowledge on the association between apolipoprotein E ε4-allele (APOE-ε4) and magnetic resonance imaging-based hippocampal volumes in Alzheimer’s disease (AD). METHODS: Electronic databases of PubMed/Medline, Embase, PsycINFO, Scopus, Cochrane, and Web of Science were systematically searched for all eligible articles published up until May 31st, 2017, using PRISMA guidelines. Both volumetric and voxel-based morphometric studies in AD and those who progressed from mild cognitive impairment to AD (MCI-P) were included. Comprehensive appraisals of demographic, methodological, and analytical aspects of the studies were undertaken, research gaps were identified, and recommendations were proposed. RESULTS:A total of 34 studies (22 cross-sectional, 12 longitudinal) were identified. Longitudinal studies consistently reported greater rates of hippocampal atrophy associated with APOE-ε4 in AD and MCI-P cases. Cross-sectional associations were relatively inconsistent, which may be attributed to smaller sample sizes, and/or

study cohorts at different time-points in the disease spectrum (i.e., variability in age or disease severity among the study samples). A few studies also investigated the association of APOE-ε4 with hippocampal sub-regions, using change in volume or shape of hippocampal subfields as outcomes. DISCUSSION: Our systematic review suggests that there is a link between APOE-ε4 and greater hippocampal degeneration in AD. The literature supports the use of serial structural MRI combined with APOE genotype for measuring rate of hippocampal atrophy in AD. Future clinical trials may be optimized by over-recruiting APOE-ε4 carriers by design and using HP volume as a surrogate outcome measure. Autopsy-confirmed studies are required to further validation. 79. Eric Salter; Department of Physiology Supervisor: Graham Collingridge INVESTIGATING THE FUNCTION OF THE COMPLEMENT CASCADE IN HIPPOCAMPAL SYNAPTIC PLASTICITY Salter, EW, 1, 2; Choi, S, 2; Georgiou, J, 2; Collingridge, GL, 1, 2 1 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; 2 Department of Physiology, University of Toronto Background: Aberrant activation of the complement cascade leads to synapse loss in Alzheimer’s disease models, and is implicated in the pathogenesis of schizophrenia. Neuronal activity is able to regulate complement activation and synapse pruning by microglia, however the precise activity patterns leading to complement activation are completely unknown. Studies have demonstrated that the complement cascade activates molecular pathways which are also involved in NMDAR-dependent long-term depression (NMDAR-LTD), suggesting that the complement cascade can regulate this form of synaptic plasticity. Hypothesis: The complement cascade is involved in the induction of NMDAR-LTD in the hippocampus. Methods: Using acute brain slice electrophysiology, we measured NMDAR-LTD in area CA1 from P13-P17 mice with a genetic deletion of either Cd11b or C3. Results: There was no difference in the magnitude of NMDAR-LTD induced by low-frequency stimulation in either male or female Cd11b-/- mice compared to littermate controls; metabotropic glutamate receptor (mGluR)-LTD was similarly unaltered. However, in female C3-/- mice, there was a significant reduction in the magnitude of NMDAR-LTD. Discussion: This study provides novel insights into the function of the complement cascade in the hippocampus, which suggests that complement component C3 is critical for the induction of NMDAR-LTD independent of the complement cascade. The knowledge gained in this study will be crucial for determining the precise role of this pathway in brain disorders including Alzheimer’s disease and schizophrenia. 80. James Saravanamuttu; Institute of Medical Science Supervisor: Robert Chen MOTOR CORTICAL CIRCUIT INTERACTIONS IN PARKINSON’S DISEASE Saravanamuttu J; Radhu N; Udupa K; Gunraj C; Baarbé J; Chen R Division of Neurology, Department of Medicine, University of Toronto; Krembil Research Institute, University Health Network Using transcranial magnetic stimulation (TMS), previous work has established that motor cortical inhibitory and facilitatory circuits are abnormal in patients with Parkinson’s disease (PD). Three such circuits are short interval intracortical inhibition (SICI), short interval

intracortical facilitation (SICF) and short latency afferent inhibition (SAI). They assess GABAAergic, glutamatergic and cholinergic function, respectively. We aimed to assess how these circuits interact with each other in PD. 15 PD patients (64.8 years) were studied ON and OFF dopaminergic medications. 16 healthy participants (64.1 years) served as controls. Surface electromyography measured motor evoked potentials from the first dorsal interosseous generated by TMS of left M1 in controls and of M1 in the more affected hemisphere in PD patients. The interactions between SICI and SICF were evaluated by comparing SICF alone to SICF in the presence of SICI. The interactions between SAI and SICI were evaluated by comparing SAI alone to SAI in the presence of SICI and by comparing SICI alone to SICI in the presence of SAI. SICF was increased in PD OFF compared to controls. SICF was facilitated by SICI in controls and PD ON, but not PD OFF. SICI and SAI inhibit each other in PD ON, PD OFF and controls with no significant difference among groups. Facilitation of SICF by SICI is impaired in PD and is corrected by dopaminergic medications. Impairment of cortical facilitation could be related to decreased M1 activation reported in imaging studies. Altered interactions between cortical circuits contribute to the pathophysiology of PD. 81. Julie Sato; Psychology Supervisor: Margot Taylor ALTERATIONS IN ALPHA FUNCTIONAL CONNECTIVITY UNDERLYING WORKING MEMORY MAINTENANCE IN CHILDREN BORN VERY PRETERM Sato J, 1,2,3; Mossad SM, 1,2,3; Smith ML, 2,3,5; Taylor MJ, 1,2,3,4 1 Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Canada; 2 Department of Psychology, University of Toronto, Toronto, Canada; 3 Neuroscience & Mental Health Program, The Hospital for Sick Children Research Institute, Toronto, Canada; 4 Department of Medical Imaging, University of Toronto, Toronto, Canada; 5 Department of Psychology, Hospital for Sick Children, Toronto, Canada Children born very preterm (VPT) are at greater risk of working memory (WM) deficits due in part to their heightened susceptibility to brain injury after premature birth. We investigated the functional brain networks underlying WM maintenance in 6-year-old children born VPT compared to full-term (FT) controls. 16 VPT born children and 21 FT controls were scanned using magnetoencephalography (MEG), and completed a visual WM task. Connectivity time courses to correct and incorrect trials were examined to assess how brain networks engaged in the maintenance of visual stimuli were differentially activated during successful and unsuccessful outcomes. Behavioural measures of accuracy and reaction time did not differ between groups. Within the FT group, we observed an increase in connectivity in the alpha frequency band (8-14 Hz) during the retention interval associated with correct compared to incorrect trials. Additionally, our network analysis revealed elevated alpha synchronization during WM maintenance compared to baseline, in a distributed network of frontal, parietal, and temporal regions. Significant between-group differences were observed in the alpha-band using a priori seeds of interest, including the dorsolateral prefrontal cortex, and middle and superior temporal gyri, regions widely reported in WM processing in adults. Differences in alpha-band connectivity during WM maintenance may be attributed to attentional network alterations in VPT born children. These results have important implications for understanding the developmental trajectory of WM processing in children and the increased risk for

academic difficulties and attention problems in the VPT population, which are associated with WM impairments. 82. Raphael Schneider; Tanz Centre for Research in Neurodegenerative Diseases Supervisor: Janice Robertson EXOSOMAL MICRORNAS IN CEREBROSPINAL FLUID OF PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEMENTIA Schneider R 1,2,3; McKeever P 1,2; Tartaglia, MC 2,4; Zinman L 3; and Robertson J 1,2 1 University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Canada; 2 University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Toronto, Canada; 3 University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Canada; 4 University Health Network, Memory Clinic, Toronto, Canada Introduction: The lack of biomarkers for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results in diagnostic delays and hinders drug development. Hence, there is an urgent need for diagnostic biomarkers. MicroRNAs can regulate mRNAs in disease pathways and have remarkable potential as biomarkers. Due to vesicular protection in exosomes, microRNAs are relatively stable in body fluids. To determine whether exosomal microRNAs in cerebrospinal fluid of patients with ALS and/or FTD can serve as diagnostic biomarkers, we characterized exosomal microRNA expression in patients with ALS, FTD or both ALS and FTD. Methods: We isolated exosomes from cerebrospinal fluid using a commercially available kit. MicroRNA extraction was followed by real-time polymerase chain reaction in 384-well plates containing a total of 752 human microRNA primers. The most frequently expressed microRNAs were assessed for their potential to differentiate between patients with ALS and/or FTD and healthy controls. Results: Exosomal miR-632 was significantly decreased in both ALS and FTD compared to healthy controls. In FTD, decrease of miR-632 revealed receiver operator characteristics with an area of 0.81 [90% confidence interval of 0.68 to 0.93]. In ALS, decrease of miR-632 revealed receiver operator characteristics with an area of 0.77 [90% confidence interval of 0.58 to 0.96]. Summary/Conclusion: Decrease of exosomal miR-632 has potential as diagnostic biomarker for ALS and FTD. Validation of our results in independent patient cohorts including sporadic cases will be necessary before this test can be applied in clinical practice. 83. Nicole Schwab; Laboratory Medicine & Pathobiology Supervisor: Lili-Naz Hazrati PERSISTENT DNA DAMAGE AND EARLY ONSET SENESCENCE AFTER TRAUMATIC BRAIN INJURY Schwab, N, 1, 2; Hazrati, LN, 1, 2 1 University of Toronto Laboratory Medicine & Pathobiology, Toronto, ON, Canada; 2 The Hospital for Sick Children, Toronto, ON, Canada Mild traumatic brain injury (mTBI) occurs commonly in contact sports,and can cause brain damage with long-term symptoms, including depression, aggression,memory loss, and an increased risk of neurodegeneration later in life. Recently, there hasbeen increased attention towards concussion in sport both in research and media, howeverthe nature and pathophysiology of mTBI-induced effects remain unknown. The objective ofthis study is to identify early

pathophysiological markers of TBI. This study used a collectionof donated postmortem brains with a history of repetitive TBI in contact sports and non-TBIcontrol brains. Nanostring ncounter’s immune panel was used to quantify gene expression,and results showed that brains with a history of TBI tended to group with significantly olderbrains with no history of TBI in regards to their immune profile. Further analysis of thisexpression panel revealed that genes associated with senescence and secretory vesicles were upregulated in brains with a history of TBI. Additionally, immunohistochemistry for γ-H2AX (a marker for double stranded DNA breaks) revealed brains with a history ofrepetitive TBI accumulated a spectrum DNA damages not present in control brains. Thisdamage was widespread, and involved neurons, oligodendrocytes, and astrocytes. Morespecifically, subpial and perivascular astrocytes showed significant morphological changesincluding soma swelling and beading of processes, reminiscent of senescence-associatedsecretory phenotype (SASP). Overall, these results suggest that sustained DNA damage andacquisition of SASP may represent early upstream events in the manifestation ofpost-TBI symptoms and may lead to neurodegenerative disease later in life. 84. Vivek Sharma; Music and Health Sciences Supervisor: Claude Alain ENHANCED COGNITIVE CONTROL IN MUSCICIANS AS MEASURED BY AN AUDITORY STROOP TASK Vivek Sharma1,4, Frank Russo2. Michael Thaut1.Claude Alain1,4 1 Music & Health Sciences, University of Toronto; 2 Dept. of Psychology, University of Toronto; 3 Dept. of Psychology, Ryerson University; 4 Rotman Research Institute, Baycrest Health Sciences

The environment is constantly bombarding the human sensory systems with information conflict. The brain's ability to ameliorate information conflict and respond appropriately can be vital to survival, like when avoiding a collision with a motorist who wrongly signals. In such a case, effective and rapid responding might require inhibiting a normally habituated response, which is a situation that is referred as interference. Inhibition, interference and information conflict have been investigated using the Stroop task in past studies. It is not well understood how information conflict processing occurs during musical processing. To examine this, musicians with 2 different pitch perception abilities were compared to non-musically trained controls in 3 auditory Stroop tasks while measuring neural responses with an electroencephalogram and event-related potentials. It was hypothesized that individuals with a high level of familiarity to musical encodings for pitch, namely the musician groups, would have stronger interference for musical labels in comparison to non-musicians. Conversely, non-musicians should not show interference for musical labels, which they have not had substantial training with. Surprisingly, while musical verbal labels elicited a semantic response associated to the Stroop task and word recognition, they were able to be flexibly disassociated from incongruent pitches more rapidly in musicians. It was concluded that prolonged exposure to pitch naming may increase sensory acuity, allowing for faster suppression of irrelevant information and an enhancement of pitch classification or differentiation pathways. Musical encodings may process with more semantic and cognitive flexibility than standard English words with broader associative bonds to the stimuli.

85. Sanjana Shellikeri; Rehabilitation Sciences Institute Supervisor: Yana Yunusova NEUROIMAGING AND NEUROPATHOLOGY OF BULBAR AMYOTROPHIC LATERAL SCLEROSIS Shellikeri S, 1, 2; Myers M, 1,2; Keith J, 2; Black, SE, 1, 2; Zinman L, 1, 2; Yunusova Y, 1, 2 1 University of Toronto; 2 Sunnybrook Research Institute Background: ALS is a neurodegenerative disorder with motor and extramotor (i.e., cognitive-linguistic) involvement. Bulbar subtype has devastating motor consequences, and may also be uniquely associated with cognitive-linguistic impairments. Theories propose that (1) bulbar ALS is uniquely associated with extramotor impairments, or (2) the increased bulbar motor and cognitive-linguistic impairments are both epiphenomena of advanced disease progression. The overall goal of this work was to further our understanding of bulbar ALS and its extramotor associations by examining its neuroanatomical correlates using a multimodal approach. Methods: STUDY 1- T1 and DTI images were used to measure gray (GM) and white matter (WM) integrity in 16 ALS patients with bulbar disease and 13 healthy controls (HC) in motor and cognitive/language regions. STUDY 2- Neuropathological examination of post-mortem brain tissue was conducted on 3 bulbar-onset (bALS), 3 spinal-onset with antemortem bulbar symptoms (sALSwB), and 3 spinal-onset without (sALSnoB), in regions similar to study 1. Results: STUDY 1- Group effects indicated left WM changes in inferior frontal (IF), post. Superior temporal (pSTG), and transverse temporal (TT) gyri. Bilateral GM reduction in IF and TT was correlated with articulatory rate (SPM), but not grip strength or disease duration. STUDY 2- The extent of involvement was related to the degree of bulbar motor dysfunction. bALS presented with the most severe and widespread pathology, followed by sALSwB, and sALSnoB. Conclusions: Degree of neuroanatomic changes in cognitive-linguistic regions was related to the degree of bulbar motor dysfunction, suggesting that the propagation of disease is through structural connectomes. 86. Sanghavy Sivakumaran; Physiology Supervisor: Evelyn Lambe THE ROLE OF THE NICOTINIC α5 SUBUNIT IN KEY MIDBRAIN STRUCTURES IMPLICATED IN NICOTINE RESPONSE Sivakumaran S, 1; Sparks DW, 1; Lambe EK, 1,2,3 1 Department of Physiology, University of Toronto; 2 Department of OBGYN, University of Toronto; 3 Department of Psychiatry, University of Toronto The ventral medial habenula (vMHb) and the interpeduncular nucleus (IPN) are key midbrain structures that form the habenulopeduncular pathway, which is often implicated in processing novel nicotine exposures. Notably, expression of the α5 nicotinic receptor subunit (encoded by Chrna5 gene) within the habenulopeduncular pathway, appears to be protective against the development of nicotine dependencies. In humans, a single nucleotide polymorphism in Chrna5, which disrupts α5 protein synthesis, has been identified among individuals who readily develop chronic nicotine dependence. In situ work using mice has suggested that normally α5 is highly expressed within the IPN but only weakly expressed within the

vMHb. While the α5 subunit does not participate in the nicotinic receptor binding site, it has powerful effects on the conductance, calcium permeability and desensitization parameters of nicotinic receptors. Here, we probe the contribution of the α5 subunit to nicotine-elicited changes in neuronal excitability in the IPN and the vMHb. For these experiments, we use whole-cell patch clamp electrophysiology in brain slices from nicotine naïve α5+/+ and α5-/- mice. Initial results show that responses to nicotine are markedly attenuated in the IPN, but not the vMHb of the α5-/- mice. In both regions, α5+/+ mice show nicotine-elicited increases in neuronal excitability, as well as the emergence of depolarization block in vMHb. In future work, we aim to examine the role of the α5 subunit regarding neuron plasticity following acute nicotine exposure in vivo, as well as how such plasticity correlates to nicotine-elicited aversion behaviours. 87. Michael Solarski; Laboratory Medicine & Pathobiology Supervisor: Gerold Schmitt-Ulms SOMATOSTATIN BINDS SELECTIVELY TO THE P-TYPE FAMILY OF ATPASES IN HUMAN BRAIN Solarski M, 1,2; Williams D, 1; Wang H, 1; Wille H, 3,4; Schmitt-Ulms G, 1,2 1 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto; 2 Department of Laboratory Medicine & Pathobiology, University of Toronto; 3 Department of Biochemistry, University of Alberta; 4 Centre for Prions and Protein Folding Diseases, University of Alberta INTRODUCTION: Somatostatin (SST) is a regulatory neuropeptide and hormone produced by a wide range of tissues including the brain, pancreas, and parts of the GI tract. It was recently discovered that SST is the most selective binder to oligomeric forms of amyloid beta (oAβ), which are toxic pathological protein aggregates in Alzheimer’s disease. In addition to its high affinity for oAβ, SST also interferes with Aβ aggregation and promotes the formation of distinct Aβ assemblies with a size of 50-60 kDa. Based on these findings, and to investigate SST’s other binding partners and molecular environment, we undertook an in-depth in vitro interrogation of the SST interactome, taking advantage of advances in mass spectrometry performance characteristics. METHODS & RESULTS: Using human brain extracts as the biological source material and biotinylated-SST peptides as baits, we performed an affinity purification of SST-binding proteins followed by identification using quantitative mass spectrometry. These analyses uncovered a selective interaction between SST and the P-type superfamily of ATPases. In follow-up validation experiments, we confirmed the binding of SST to the Na+/K+-ATPase and identified that the SST receptor-binding region is critical for this interaction. CONCULSIONS & FUTURE CONSIDERATIONS: To our knowledge, this is the first in-depth analysis of SST-binders from human brain and the first report of an interaction between SST and the superfamily of P-type ATPases. While the present study does not address the functional significance of this interaction, future experiments will seek to determine the effect of SST on ATPase activity.

88. Sonja Stojanovski; Physiology Supervisor: Anne Wheeler THE EFFECT OF TRAUMATIC BRAIN INJURY ON SUPERFICIAL WHITE MATTER IN YOUTH: TOWARDS A PERSONALISED INJURY PROFILE Sonja Stojanovski 1,2, Arash Nazeri 3,4, Chris Lepage 5, Aristotle N. Voinesekos 6,7,8, Anne L. Wheeler 1,2 1. Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario; 2. Department of Physiology, University of Toronto, Toronto, Ontario; 3. Iran/Mallinckrodt Institute of Radiology, Tehran, Iran; 4. Washington University School of Medicine, St. Louis, MO, USA; 5. Toronto Rehabilitation Institute, Toronto, Ontario; 6. Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario; 7. Institute of Medical Science, University of Toronto Diffusion Tensor Imaging (DTI) studies of traumatic brain injury (TBI) have focused on alterations in microstructural features of deep white matter fibers (DWM), though post-mortem studies have demonstrated that injured axons are often observed at the gray-white matter interface where superficial white matter fibers (SWM) mediate local connectivity. The objective of this study was to examine microstructural alterations in SWM and DWM separately through groupwise comparisons of fractional anisotropy (FA) from DTI in youth with: mild TBI (n=63), healthy controls (n=63), and controls with psychopathology symptoms matched to the TBI group (n=63). All groups were matched on age, sex, and parental education. Permutation testing, revealed widespread decreases in FA in individuals with TBI compared to healthy controls in DWM and SWM as well as decreases in FA in individuals with TBI compared to their psychopathology matched controls in posterior DWM and SWM. These results demonstrate widespread differences in SWM related to mild TBI, a fiber type often overlooked in in vivo imaging in the context of TBI. 89. Dana Swarbrick; Rehabilitation Sciences Institute Supervisor: Joyce Chen HIIT THE ROAD JACK: THE EFFECTS OF EXERCISE ON PIANO LEARNING Swarbrick D, 1,3; Tremblay L, 2; Sabiston C, 2; Trehub S, 4; Alter D, 5, 6; Brooks D, 1, 7; Chen , 1,2,3,7 1 Rehabilitation Sciences Institute, University of Toronto; 2 Faculty of Kinesiology and Physical Education, University of Toronto; 3 Canadian Partnership for Stroke Recovery; 4 Department of Psychology, University of Toronto; 5 Toronto Rehabilitation Institute; 6 Faculty of Medicine, University of Toronto; 7 Department of Physical Therapy, University of Toronto Rationale: Exercising after practice improves retention of motor skills (Roig et al., 2012). Specifically, high-intensity interval training (HIIT) after practice of a motor skill leads to better task performance one day and one week later compared to low-intensity interval training (LIIT) or no exercise (Thomas et al., 2016). Neurochemicals released during HIIT are presumed to enhance neuroplastic mechanisms related to learning during early consolidation (Skriver et al., 2014). The facilitating effects of HIIT have been demonstrated for the learning of implicit motor sequence tasks. However, little is known about the impact of HIIT on the consolidation of explicit motor skills in the context of real-world learning. Piano playing is a real-world task that involves explicit learning of motor sequences. In this exploratory

study, we hypothesized that adults who perform HIIT after piano-sequence learning would exhibit better retention of the learned sequence than those who perform LIIT. Methods: We recruited healthy volunteers between the ages of 18 and 35 who were non-musicians. Participants underwent a graded maximal exercise test (GXT) to determine their cardiorespiratory fitness (VO2peak) and their maximum power output (Wmax). At least one day later, participants practiced a piano sequence before completing an interval exercise protocol (IEP). The IEP consists of 3 repetitions of alternating intervals of 2-min low-intensity and 3-min high-intensity cycling (HIIT group: 60% & 90% Wmax; LIIT group: 8% & 12% Wmax). Participants were tested on the piano sequence one hour, one day, and one week after initial practice. Statistical Analysis: Performance was quantified by pitch and rhythm accuracy, which are defined as the proportion of correct key presses and correct timing of presses, respectively. Preliminary Results: We analysed data from 16 participants (n=7 HIIT, n=9 LIIT) using a two-way mixed ANOVA with between-subjects factor of intensity (HIIT, LIIT), and within-subjects factor of retention interval (1 hr, 1 day, 7 days), and gender, fitness, and baseline performance during acquisition as covariates. No main effect of intensity was observed for pitch or rhythm accuracy (pitch: F(1,12) = 0.016, p = 0.902, eta2 = 0.001; rhythm: F(1,12) = 0.256, p = 0.623, eta2= 0.023). Conclusion: Preliminary analysis provides no evidence that HIIT enhances consolidation of piano learning. However, definitive conclusions must be reserved until data collection is complete. 90. Michelle Sweeny; Toronto Rehabilitation Institute Supervisor: George Mochizuki THE RECOVERY OF POSTURAL CONTROL FOLLOWING A CONCUSSION IN ADULTS FROM THE GENERAL POPULATION Sweeny M, 1; Singer J, 2; Inness E, 1; Comper P, 1; Bayley M, 1; Mochizuki G, 3 1 Toronto Rehabilitation Institute; 2 University of Manitoba; 3 Sunnybrook Research Institute Much of what is known about the effects of concussion on balance control comes from research involving athletes. Balance recovery occurs within the first 1-2 weeks post-concussion. However, most of this work identifies recovery using the Balance Error Scoring System (BESS), which is prone to learning effects. Alternatively, posturographic measures during quiet standing offers an objective approach to identifying balance deficits. Due to differences between athletes and adults from the general population, there is a need to determine recovery trajectories in this cohort. Sixty-two participants with concussion (CONC) were included in the analysis. Participants were assessed at Week 1, 2, 4, 8 and 12. The assessments included quiet standing conditions with; Eyes Open, Eyes Closed and Dual Task and the BESS. Recovery was determined using a Hierarchical Growth Curve Model. In an effort to determine recovery on an individual level, CONC participants were determined recovered if the value of the Week 2, 4, 8 or 12 variable was reduced by an amount greater than natural variation in control data over time, relative to their Week 1 value. Anteroposterior velocity in the Eyes Closed condition revealed significant recovery across time when using the Growth Curve Model. Using an individualistic approach, less than 50% of participants were determined recovered by Week 12. Recovery of concussion is a dynamic process. The absence of recovery across time in the quiet standing measures and BESS

score may be attributed to lack of task difficulty in the quiet standing tasks and low specificity of the BESS. 91. Abanti Tagore; Institute of Medical Science Supervisor: Romina Mizrahi CORTICAL DOPAMINE RELEASE IN RESPONSE TO A COGNITIVE CHALLENGE: PRELIMINARY RESULTS IN CLINICAL HIGH RISK FOR SCHIZOPHRENIA Tagore A, 1, 2; Rao N, 1; Schifani C, 1; Mizrahi R, 1, 2 1 Centre for Addiction and Mental Health; 2 Institute of Medical Science, University of Toronto Purpose: Investigate differences in cognitive task-induced cortical dopamine (DA) release between healthy controls (HC) and participants at clinical-high risk (CHR) state for schizophrenia (SCZ) using Positron Emission Tomography (PET) imaging with [11 C]-FLB-457 radiotracer. Methods: 14 anti-psychotic naïve CHR were recruited from the Focus on Youth Psychosis Prevention clinic at CAMH and 15 HC were recruited from the community. CHR diagnosis and symptom severity was confirmed by an active psychiatrist and Structured Interview for Prodromal Symptoms, respectively. HC had no current or past DSM-IV Axis I diagnosis and no family history of psychotic disorders. The Repeatable Battery for the Assessment of Neuropsychological Status and Wisconsin Card Sorting Task (WCST) was administered to assess cognitive abilities. All participants underwent two PET scans using a high-resolution PET-CT during which they performed 6 trials of the Control Task and the WCST. Cortical DA release was quantified as the radiotracer displacement (ΔBPND) between scans in the prefrontal cortex (PFC) and subregions. Each participant also completed an MRI scan for anatomical delineation. Analysis of covariance was used for statistical analysis. Results: No significant difference in radiotracer ΔBPND in PFC and subregions and cognitive performance between groups Conclusions/Implications: This is the first in vivo study exploring cognitive task induced cortical DA activity in prodromal SCZ. However, we report no significant differences in cortical DA release between groups. An expanded sample is required to better understand cortical DA activity in SCZ and further guide us in identifying biological risk factors and preventative treatment measures. 92. Petri Takkala; Institute of Medical Science Supervisor: Steven Prescott GABA-DEPENDENT SPIKE INITIATION IN THE CENTRAL TERMINALS OF PRIMARY AFFERENT NEURONS REQUIRES COMBINED CHANGES IN CHLORIDE REGULATION AND INTRINSIC EXCITABILITY Takkala, P 1,2; Prescott SA 1,2,3 1 Institute of Medical Science, University of Toronto; 2 Neurosciences and Mental Health, The Hospital for Sick Children; 3 Department of Physiology, University of Toronto Primary somatosensory neurons relay information from the periphery to the central nervous system via synapses formed in the spinal dorsal horn. Inhibitory interneurons in the dorsal horn in turn innervate these central terminals. Primary afferent neurons are depolarized by GABAergic input due to their high intracellular Cl-

concentration. Counterintuitively, this so-called primary afferent depolarization (PAD) normally has inhibitory effects because of the shunting and sodium channel inactivation that it causes. However, PAD can become excitatory (i.e. evoke spiking) under pathological conditions. Indeed, GABA-evoked spikes that propagate antidromically to the periphery may contribute to neurogenic inflammation observed in chronic pain conditions. Here, using GCaMP-based calcium imaging in transgenic mice, we explored what changes are required to enable GABA-evoked spike initiation in the central axon terminals of primary afferent neurons. Pharmacological manipulation of Cl- reversal potential and voltage-gated K+ conductances revealed that intracellular chloride accumulation and increased intrinsic excitability are both necessary to enable GABA-evoked spiking. The antidromic propagation of those spikes was evident from calcium signals imaged in somata. Importantly, inflammation induces both of the aforementioned biophysical changes, but reversing either change is sufficient to prevent GABA-evoked spiking. These results demonstrate that GABA-evoked spiking depends on a combination of biophysical changes, both of which are induced by inflammation, and that GABA-evoked spiking is blocked by reversing either change. The last observation, in particular, should facilitate the strategic design of therapeutic interventions. 93. Natasha Talwar; Institute of Medical Science Supervisor: Tom Schweizer FUNCTIONAL MRI OF THE CLOCK-DRAWING TEST IN MILD COGNITIVE IMPAIRTMENT Talwar N, 1; Churchill NW, 1; Hird MA, 1; Tasneem T, 1; Pshonyak I, 1; Fischer CE, 2; Graham SJ, 3; Schweizer TA, 4 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital; 2 Faculty of Medicine, Department of Psychiatry, University of Toronto; 3 Sunnybrook Health Sciences Centre; 4 Division of Neurosurgery, St. Michael’s Hospital The clock-drawing test (CDT) is a cognitive assessment tool used to screen for neurocognitive disorders including mild cognitive impairment (MCI). Individuals with MCI have shown worse performance on the CDT relative to age-matched controls, but there has been limited examination of the effect of MCI on the neural basis of CDT. This is the first study to use functional magnetic resonance imaging (fMRI), combined with a novel MRI-compatible tablet and real-time visual feedback, to reveal brain regions activated during the CDT. This study measured brain activity of 11 patients with MCI and 11 age-matched control participants during the task. Statistical activation maps were calculated using a general linear model (thresholded at an adjusted False Discovery Rate of q=0.05). Both patients with MCI and controls showed consistent activation in the bilateral occipital lobes, parietal lobes and supplementary motor area during the CDT. Patients with MCI exhibited reduced negative activation in the left temporal lobe and increased positive activation in the frontal lobes. Although individuals with MCI scored lower on the CDT, the results of a Wilcoxon test were not statistically significant (p > 0.102). This is the first study to show patterns of brain activation in MCI and control groups during completion of the CDT. The altered temporal activation among patients with MCI may reflect underlying neuropathological changes. In contrast, the observed increased frontal activity may play a compensatory role in maintaining task performance. Functional connectivity can demonstrate the effects of MCI on task performance, even when behavioural results appear unimpaired.

94. Dorothy Tan; Music Supervisor: Michael H. Thaut SENSORIMOTOR TRAINING USING NEUROLOGIC MUSIC THERAPY TECHNIQUES WITH OLDER ADULTS Tan, DM Music and Health Sciences, University of Toronto Age-related motor declines (e.g., reduced strength and endurance, impaired balance, unstable gait) are characteristic of the older adult population. Consequently, falls are highly prevalent in older adults. Research on the brain basis of music cognition and music perception demonstrates the impact of auditory rhythmic cues on sensorimotor synchronization. This principle has displayed clinical applications with a variety of conditions associated with movement disorders, which include stroke, Parkinson’s disease (PD), and traumatic brain injury (TBI), amongst others. However, a lack of research currently exists on the effects of sensorimotor synchronization and training with older adults. This prospective study analyzes the effects of two Neurologic Music Therapy (NMT) techniques called rhythmic auditory stimulation (RAS) and patterned sensory enhancement (PSE) on gait, balance, and functional mobility. Older adults (n=3) from a memory company day program participated in the study for a 5-week period, receiving 1-hour of sensorimotor training on a weekly basis. The 10m-walk test and Berg Balance Scale (BBS) were administered pre- and post-treatment, in order to measure progress. Results demonstrated improvements on both measures and in particular, displayed significant improvements (p < .05) on the BBS. Improvements were also apparent in observed kinematics, suggesting increased stability and safety during motor tasks. This study establishes potential for treatment efficacy and positive impact of RAS and PSE in sensorimotor training with older adults. 95. Joel Tan; Institute of Medical Science Supervisor: John Brumell INVESTIGATING THE ROLE OF TYPE 1 INTERFERON AND LISTERIA MONOCYTOGENES INFECTIONS IN THE BRAIN Tan JMJ, 1,2; Brumell JH 1,2 1 Institute of Medical Science, University of Toronto; 2 The Hospital for Sick Children, Toronto Listeria monocytogenes (Lm) is a food borne pathogen that is responsible for causing listeriosis in humans and animals. Lm infections can lead to severe disease with a high mortality rate (20-30%), especially in immunocompromised individuals and the elderly. The ability of Lm to invade the central nervous system (CNS) can cause patients to develop meningitis or encephalitis, which is often fatal if left untreated. Once Lm infects the brain, there is poor prognosis for the patient even with vigorous antibiotic treatments. Recent studies have shown type I interferon production increases with age, with a high abundance found in the choroid plexus of the brain, which produces cerebral spinal fluid and a potential target and transmission site for listeria-induced meningitis. To examine Lm infections in the brain, wild type (WT) and IFNAR1 KO mice were given bacteria through an intravenous injection in the lateral tail vein. To determine which regions of the brain contains Lm lesions and abscesses, sections of the entire brain were obtained and stained to visualize the size and location of infection foci in WT and IFNAR1 KO mice. Bone marrow derived macrophages were also cultivated to

examine bacterial killing and toxin-induced membrane damage. WT and IFNAR1 KO of young and old mice were infected to determine if aging increases susceptibility and fatality to Lm brain infections. Preliminary data showed that old IFNAR1 KO mice are protected against infection, indicating a promising age-associated phenotype driven by increased immune responses during Lm brain infection, and implying vast clinical implications. 96. Gaqi Tu; Psychology Supervisor: Kaori Takehara-Nishiuchi PUNISHMENT-INDUCED CHOLINERGIC TRANSIENTS IN TWO BASAL FOREBRAIN SUBPOPULATIONS HAVE OPPOSING EFFECTS ON TEMPORAL ASSOCIATIVE LEARNING Tu GQ,1; Takehara-Nishiuchi K 1,2 1 Department of Psychology, University of Toronto; 2 Department of Cell and System Biology, University of Toronto The basal forebrain (BF) cholinergic system comprises a heterogeneous set of structures close to the medial and ventral surfaces of the cerebral hemispheres and is widely known for its essentiality for cognitive function including learning and memory, attention and cue-detection. The anterior portion of the BF, consist of the medial septum and vertical limb of the diagonal band of Broca (MS/VDB), projects mainly to the hippocampus. While its posterior portion, which includes horizontal limb of the diagonal band of Broca (HDB), substantia innominata(SI) and nucleus basalis magnocellular (NBM), innervates to the neocortical regions. Conventionally, BF cholinergic neuronal function was believed to slowly modulate the activities of the cortical neurons, but recent studies revealed that cholinergic neurons in the BF respond to reward and punishment with a precision of tens of milliseconds. Here, we examine the relevance of this rapid cholinergic transient for animals’ ability to associate a stimulus with upcoming punishment, measured by trace eyeblink conditioning. We found that optogenetic inhibition of MS/VDB cholinergic neurons during punishment impaired temporal associative learning, whereas the same photoinhibition in HDB raised the asymptotic level of learning. Furthermore, in the HDB inhibition group, we detected a higher-level expression of the immediate early gene c-fos in medial prefrontal cortex (mPFC) suggesting a higher level of neuronal activations. Together, our results indicate that punishment-induced cholinergic transients to the hippocampus promote temporal associative learning while those to the neocortex may regulate the strength of neural activation and, in turn, learning. 97. Mikaeel Valli; Institute of Medical Science Supervisor: Antonio Strafella DRD2 GENOTYPE-BASED VARIANTS MODULATES D2/3 AGONIST [11C]-(+)-PHNO BINDING IN VENTRAL STRIATUM IN HEALTHY CONTROLS Valli M, 1, 2, 3; Cho SS, 1, 2; Criaud M, 1, 2; Kim J, 1, 2; Ghadery C, 1, 2; Mihaescu A, 1, 2, 3; Strafella AP, 1, 2, 3 1 Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto; 2 Division of Brain, Imaging and Behaviour – Systems Neuroscience, Krembil Research Institute, UHN, University of Toronto, Ontario; 3 Institute of Medical Science, University of Toronto Dopaminergic signaling within the striatum and prefrontal cortex are crucial for motor planning and mental functioning which are impacted

in Parkinson’s disease (PD). Neurons within these brain regions contain two dopamine D2 receptor isoforms—D2 long (D2L) and D2 short (D2S). The degree of expression for these receptor isoforms are affected by the genotype within the single nucleotide polymorphisms (SNPs), rs2283265 and rs1076560 (both are in high linkage disequilibrium; C>A), found in the DRD2 gene. PD patients with the CC genotype showed the most clinical improvement to rasagiline medication compared to A carrier patients. However, it is unclear how these SNPs affect the distribution of D2 receptors in vivo within the nigrostriatal dopaminergic system. Therefore, we aim to elucidate this with PET imaging in healthy controls using [11C]-(+)-PHNO. This is a D2/3 agonist PET tracer that binds to D2 receptors in their functionally relevant form. Healthy volunteers were genotyped for the DRD2 rs2283265 SNP and a total of 20 participated: 9 with CC genotype (mean age = 30.8 ± 3.56; 6 males), 6 with AC genotype (mean age = 24.2 ± 3.19; 3 males) and 5 with AA genotype (mean age = 25.6 ± 9.13; 3 males). All three groups underwent the PET scan. Main effect of genotype on [11C]-(+)-PHNO binding potential (BPnd) was investigated with analysis of variance. Significant main effect for the tracer was observed within the ventral striatum. Carriers of the CC and AC genotype had higher binding in this region compared to AA carriers. There were no significant main effects between genotypes for other regions of interests within the basal ganglia including the caudate, putamen and globus pallidus. Our results demonstrate that the polymorphism genotype modulate the binding of [11C]-(+)-PHNO to D2/3 receptors within the ventral striatum in healthy controls, a region rich in D2 receptors and critical for decision making and reward processing. The data implicates that the genotype affects the nigrostriatal dopaminergic system by controlling either the quantity of D2 receptors or D2 affinity or amount of endogenous dopamine in the synaptic cleft or a combination thereof within the ventral striatum. 98. Sai Vemula; Electrical and Computer Engineering, Institute of Biomaterials and Biomedical EngineeringSupervisor: Willy Wong and Kenneth Norwich EXPLORING THE MATHEMATICAL PRINCIPLES UNDERLYING SIGNAL STATISTICS IN SENSORY TRANSDUCTION Vemula S 1; Norwich KH 1,2; Wong W 3,1 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto; 2 Department of Physiology, University of Toronto; 3 Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto The study of perception involves the understanding of how information from the environment is conveyed to our senses, and how this information is processed by our sensory systems. The pathophysiology underlying sensory impairments can be viewed as deficits in information processing by our sensory organs. Developing mathematical models of sensation is critical for understanding and treating these impairments, as they can help uncover fundamental principles of the physiological systems. The entropic model of sensation, which incorporates the properties of information theory, aims to characterize sensory processing generally. The entropic model of sensation posits that perception is a result of measuring the entropy (i.e. the uncertainty) of a stimulus being presented to us. Defining the relationship between the variance and mean of a stimulus presented to our senses is integral to the model. Is there a general theory that explains the relationship between the variance and mean of sensory stimuli? Probing the mean and variance relationship involves considering the mechanism of transduction

between the physical signal and sensory epithelium. A specific prediction of this model is that there exists a functional relationship between the mean population of binding molecules and their variance. In such a model, this will lead to a Poisson-gamma distribution which gives rise to the types of mean-variance relationship found in olfaction as well as other sensory modalities. Developing a general theory of stimulus fluctuations will further strengthen our understanding of the principles which govern sensory transduction. 99. Sridevi Venkatesan; Physiology Supervisor:Evelyn Lambe THE ROLE OF THE ALPHA5 NICOTINIC RECEPTOR SUBUNIT IN CHOLINERGIC MODULATION OF THE PREFRONTAL CORTEX VENKATESAN S, 1; TURNER EE, 2,3; LAMBE EK 1,4,5 1 Dept. of Physiology, University of Toronto; 2 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA; 3 Dept. of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA; 4 Dept. of Obstetrics and Gynecology, University of Toronto; 5 Dept. of Psychiatry, University of Toronto The α5 nicotinic receptor subunit encoded by Chrna5 is an accessory subunit that is heavily expressed in L6 of the PFC and can affect receptor conductance and desensitization properties. Previous studies show that α5-/- mice are impaired during demanding attentional tasks and have reduced L6 responses to acetylcholine (ACh). However, the exact function of Chrna5 in the cellular and network response to ACh is unknown. We performed whole cell recordings of layer 6 mPFC pyramidal neurons expressing Chrna5 to measure responses to exogenous application of ACh in brain slices. BAC transgenic mice expressing Cre from the Chrna5 locus were generated and crossed with a ZsGreen reporter line (Ai6) to record from the labeled cells. Both male and female mice (postnatal day 36-40) were used. The peak inward current elicited by bath application of 1mM ACh is twofold higher in Chrna5 positive cells (-184 ± 17 pA, N=17) compared to an unlabeled population of cells (-97 ± 7 pA, mean ± SEM; N=9; p= 0.002, unpaired t test). Our results show that there is a subpopulation of cells expressing Chrna5 in layer 6 of the mPFC that have the highest responses to ACh. Future experiments will use Chrna5 transgenic mice crossed with mice expressing Channelrhodopsin 2 in cholinergic neurons, to achieve optogenetic ACh release. This will help understand the function of the Chrna5 expressing cells during endogenous ACh release in the PFC. These experiments serve to elucidate the role of the α5 subunit in the cholinergic control of attention circuitry. 100. Akshayan Vimalanathan; Institute of Medical Science Supervisor: Clement Hamani PHARMACOLOGICAL MANIPULATION OF THE ENDOCANNABINOID SYSTEM IN A PRECLINICAL MODEL OF POST-TRAUMATIC STRESS DISORDER Vimalanathan A 1,2; Diwan M, 1; Nobrega JN, 1; Hamani C 1,2,3 1 Behavioural Neurobiology Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health; 2 Institute of Medical Science, University of Toronto; 3 Division of Neurosurgery, Sunnybrook Health Sciences Centre Post-traumatic stress disorder (PTSD) is a debilitating illness associated with extinction impairment, long-term fear responses to stress-related cues, and persistent anxiety after a traumatic

experience. Using a classical fear conditioning paradigm, male Sprague-Dawley rats were segregated into weak-extinction (WE) and strong-extinction (SE) groups. WE rats present several features analogous to PTSD-like states, including impaired fear extinction and long-term anxiety. In contrast, SE rats display fast rates of extinction. This study sought to determine whether modulating the endocannabinoid (EC) system could alter extinction or anxiety-type behaviour in WE and SE rats. We hypothesized that extinction deficits in WE rats will improve with treatments that increase synaptic EC levels. The EC system has been implicated in the control of fear and anxiety, with preclinical studies suggesting that ECs facilitate fear extinction and improve anxiety. One of the main EC receptors in the brain is the type 1 cannabinoid receptor (CB1) and fatty acid amide hydrolase (FAAH) is one of the EC-degrading enzymes. Following fear conditioning, rats were subjected to a long-term recall trial and a novelty supressed feeding test. Prior to these behavioural tests, rats received acute drug injections. URB597, a FAAH inhibitor, was injected in WE rats to test whether increasing synaptic EC levels would improve extinction learning and anxiety-type behaviour. AM251, a CB1 antagonist, was injected in SE rats to test whether antagonizing ECs would impair extinction and induce anxiogenic effects. For both behavioural tests, we found no significant difference between drug and vehicle groups in WE or SE rats. 101. Ashley Waito; Rehabilitation Sciences Institute Supervisor: Catriona Steele HYOID KINEMATICS IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS (ALS): A PILOT ANALYSIS Waito AA 1,2; Peladeau-Pigeon M 2; Steele CM, 1,2; Tabor LC 3; Plowman EK 3 1 Rehabilitation Sciences Institute, University of Toronto; 2 Swallowing Rehabilitation Research Laboratory, Toronto Rehabilitation Institute - University Health Network; 3 Swallowing Systems Core, University of Florida During swallowing, several parameters of hyoid movement have been shown to vary as a function of bolus volume and consistency in healthy adults. Such modulation of hyoid kinematics has not yet been explored in patients with ALS. The purpose of this study was to (1) characterize hyoid kinematics in a sample of patients with ALS and (2) explore differences in hyoid movement related to bolus properties. Methods: Videofluoroscopy was collected from 26 adults diagnosed with ALS, aged 30-75. Blinded raters tracked hyoid position frame-by-frame, relative to an anatomical scalar, to yield measures of hyoid speed and range of movement in three directional planes. Mixed model repeated measures ANOVAs were performed to explore effects ofbolus volume (1mL/3mL/20mL) and consistency (thin/extremely thick) on hyoid kinematics, with an additional factor of ALS-onset type (bulbar/spinal). Results: A main effect of volume was observed for average superior hyoid velocity and peak speed along the anterosuperior axis. Pairwise comparisons revealed that 20mL boluses evoked faster hyoid movement compared to 1mL boluses. No statistically significant differences in maximum hyoid position were identified, and hyoid kinematics did not vary by liquid consistency. Non-significant trends were identified with respect to ALS-onset type. Conclusions: Bolus volume, but not consistency, modulates hyoid movement in patients with ALS. Compared to previous data with

healthy individuals, our results suggest differences in motor accommodation of hyoid movement in individuals with ALS. Further work is needed to explore the clinical implications of these results. 102. Xinzhu Wang; Laboratory Medicine and Pathobiology Supervisor: Gerold Schmitt-Ulms A CRISPR/CAS9-EDITED HUMAN CELL SYSTEM FOR DISSECTING THE CHRONOLOGY OF EVENTS UNDERLYING PROTEOTOXIC STRESS IN TAUOPATHIES Wang X, 1,2; Williams D, 1,; Schmitt-Ulms, G, 1, 2 1 Laboratory Medicine & Pathobiology, University of Toronto; 2 Tanz Centre for Research in Neurodegenerative Diseases Introduction: tau is central to the pathology of Alzheimer’s disease (AD) and a subset of frontotemporal dementias (FTD). In FTD, mutations in tau, e.g. P301L, can independently cause disease. Pathology is further complicated by the co-expression of tau isoforms, which have either 3 or 4 repeats (3R or 4R). While simply deleting the tau gene in humans is unrealistic, preventing soluble tau from engaging with inappropriate protein interactors might be feasible. Hypothesis: significant differences in the proteins tauWT-EGFP and tauP301L-EGFP interact with may reveal potential mechanisms of how tau may contribute to disease. Methods & Results: since finding the earliest differences between healthy and diseased cells is crucial, a CRISPR-Cas9-edited inducible tau cell model that expresses 3R/4R tau was developed in human IMR-32 cells and human neural progenitors (ReNcell VM) that can be differentiated into neurons. Quantitative LC-MS3 mass spectrometry was conducted following affinity capture of tauWT and tauP301L and their bound interactors after 12 h of induction. Samples were trypsinized and labelled with iTRAQ reagents. Protein identities were determined using the Mascot server and Sequest HT search engines operated in Proteome Discoverer. In the 12 h interactome, tauP301L preferentially bound to protein that mediate oxidative stress more than tauWT did. Since these mediators are thought to protect cells by becoming oxidized themselves, the levels of oxidized mediators and the levels cumulative oxidative stress in tauWT and tauP301L cells were assessed by and 4-hydroxynonenal modifications on proteins. Conclusions: following successful application of the inducible system, we are validating interactors for biological significance. 103. Yuen Yan Wong; Department of Cell and Systems Biology Supervisor: Adriano Senatore TRANSCRIPTOMIC PROFILING OF TRICHOPLAX ADHAERENS, A MOBILE ANIMAL THAT LACK SYNAPSES, REFLECTS A DIGESTIVE EPITHELIUM WITH CELLULAR COORDINATION AND A RICH REPERTOIRE OF NEURAL SIGNALING MACHINERY WONG, YY 1,2; LE, P 2; SENATORE, A 1,2 1 Department of Cell and Systems Biology, University of Toronto; 2 Department of Biology, University of Toronto Mississauga Trichoplax adhaerens is an early-diverging animal that can exhibit motile behavior (e.g. feeding) despite the absence of synaptically-connected neurons and muscle. Our lab has produced a high-quality T. adhaerens transcriptome in which ~85% of the assembled genes are complete protein-coding sequences, with 2,483 novel genes previously missed in the genome sequencing effort. Our main

objective is to identify genes homologous to those involved in nervous system functions. Using various in silico prediction algorithms we have identified numerous neuropeptides, GPCRs, and synaptic scaffolding proteins in T. adhaerens, though the animal lacks canonical neurons and synapses. Phylogenetic analysis of T. adhaerens homologues of the presynaptic Cav2 calcium channel nanodomain scaffolding protein Rab3-Interacting Molecule (RIM) also reveals a novel RIM type in the animal phylogeny. Our work provides insight into the metazoan origin of key molecular machineries that may serve as fundamental components contributing to the rise of the nervous system. 104. Adriana Workewych; Institute of Medical Science Supervisor: Michael D. Cusimano TRANEXAMIC ACID IN THE TREATMENT OF RESIDUAL CHRONIC SUBDURAL HEMATOMA: A SINGLE-CENTRE, RANDOMIZED CONTROLLED TRIAL (TRACE) Workewych AM 1,2; Callum J 3; Saarela O 4; Montanera W 5; Cusimano MD 1,2,6 1 Institute of Medical Science, University of Toronto; 2 Department of Neurosurgery, St. Michael's Hospital; 3 Sunnybrook Health Sciences Centre; 4 Dalla Lana School of Public Health, University of Toronto; 5 Department of Radiology, St. Michael's Hospital; 6 Department of Medicine, University of Toronto Chronic subdural hematoma (CSDH) is a frequent consequence of head trauma, particularly in older individuals. Hyperfibrinolysis may be central to CSDH enlargement by causing excessive clot degradation and liquefaction, impeding its resorption. The only current standard treatment is surgery. While generally well-received, surgery can be associated with risks of disability. Up to 31% of recurrent or residual hematomas that enlarge require repeat surgery. A non-surgical way of preventing recurrence is desirable. Tranexamic acid (TXA), a medication that prevents excessively rapid clot breakdown, is used in several other abnormal and excessive bleeding conditions. It may help prevent CSDH enlargement and potentially eliminate the need for repeat surgery. We are evaluating whether TXA is a superior treatment to conservative management for residual CSDH. We hypothesize a greater reduction in residual CSDH volume in participants treated with TXA compared to control participants. Patients undergoing surgery for CSDH will be randomized to one of two study arms: taking daily TXA therapy (1500mg/day) in the form of oral tablets, or to control. Control participants will receive no additional medication, and both groups will undergo standard clinical follow-up for at least 4-8 weeks. The primary outcome will be hematoma volume on computed tomography (CT) scans. Secondarily, neurological outcome and health-related (QOL) will be evaluated. Should TXA be shown to be more effective at reducing hematoma volume than conservative management, larger scale studies will be planned to confirm the findings, and explore TXA as a potential alternative to surgical care in patients with primary or residual CSDH. 105. Kristiana Xhima; Laboratory Medicine and Pathobiology Supervisor: Isabelle Aubert COMBINATION THERAPY USING NEUROTROPHIC FACTOR SMALL-MOLECULE MIMETICS AND BLOOD-BRAIN BARRIER OPENING INDUCED BY FOCUSED ULTRASOUND IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE Xhima K, 1,2; Saragovi HU, 4; Hynynen K, 3; Aubert I, 1,2

1 Laboratory Medicine and Pathobiology, University of Toronto; 2 Biological Sciences, Sunnybrook Research Institute; 3 Physical Sciences, Sunnybrook Research Institute; 4 Pharmacology & Therapeutics, McGill University Degeneration of basal forebrain cholinergic neurons (BFCNs) plays a key role in the pathogenesis of Alzheimer's disease (AD). BFCNs are highly dependent on nerve growth factor (NGF) for neuronal survival, growth and synaptic plasticity. However, therapeutic efficacy of NGF is limited by its inability to cross the blood-brain barrier (BBB), its short half-life and adverse effects triggered by NGF activation of p75 neurotrophin receptor in the absence of tropomyosin receptor kinase A (TrkA). In comparison to native NGF, receptor ligands designed to maximize TrkA activation may be preferable. However, like NGF, they do not cross the BBB. Here, we tested targeted delivery of a novel, high-affinity agonist of TrkA to BFCNs using MRI-guided focused ultrasound (FUS). Recent evidence also indicates that FUS alone can increase neurotrophin expression, promote neurogenesis and reduce amyloid pathology in AD animal models. Briefly, intravenously administered TrkA agonist was delivered to BFCNs using FUS in Tg and non-Tg littermates. BBB permeability was confirmed in FUS targeted areas by quantifying the influx of an MRI contrast agent at the time of sonication. Protein phosphorylation of downstream signaling effectors implicated in neuronal survival and plasticity were quantified. We observed an increase in TrkA phosphorylation, and downstream signaling, including MAPK, Akt and CREB phosphorylation after treatment. The sonicated areas showed no evidence of neuronal apoptosis or red blood cell extravasation indicating the safety of this treatment paradigm. These results demonstrate the therapeutic efficacy of the small molecule, TrkA-specific agonist combined with MRIgFUS delivery in a mouse model of AD. 106. Veronica Yuk; Psychology Supervisor: Margot Taylor ATYPICAL BRAIN CONNECTIVITY DURING A THEORY-OF-MIND TASK IN ADULTS WITH AND WITHOUT AUTISM SPECTRUM DISORDER Yuk V 1,2,3; Anagnostou E 2,4; Taylor MJ 1,2,3 1 Department of Diagnostic Imaging, The Hospital for Sick Children; 2 Neurosciences and Mental Health Program, SickKids Research Institute, The Hospital for Sick Children; 3 Department of Psychology, University of Toronto; 4 Autism Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital Individuals with autism spectrum disorder (ASD) exhibit reduced connectivity in the theory-of-mind (ToM) network, which mainly consists of the medial prefrontal cortex, temporoparietal junction, posterior superior temporal sulcus, and precuneus, and which may contribute to the social cognitive deficits that characterize ASD. However, specific differences in the temporal-spatial dynamics of this network have yet to be determined. Thus, we utilized the excellent temporal and spatial resolution of magnetoencephalography (MEG) to examine timing and frequency differences in brain connectivity between adults with and without ASD during a ToM task. We studied 39 control adults and 39 adults with ASD. While in the MEG scanner, participants performed a ToM task, which required participants to infer whether a character had a true or false belief about an object’s location. Brain connectivity in the false vs. true belief trials were compared. Whole-brain network analyses revealed that between

100-200 ms post-stimulus onset, adults with ASD showed decreased connectivity in the alpha frequency band between the precuneus and inhibitory control regions, such as the anterior cingulate cortex and right inferior frontal gyrus. Adults with ASD also simultaneously demonstrated reduced connectivity in the low gamma frequency band in a widespread network involving the bilateral temporoparietal junctions and medial prefrontal cortex. In line with the literature, our results indicate that adults with ASD show reduced brain connectivity compared to controls between areas within and outside the ToM network. Future work will correlate these connectivity findings with behavioural performance on tasks involving real world social perception abilities. 107. Ashley Zhang; Laboratory Medicine and Pathobiology Supervisor: Janice Roberston THE DYNAMICS OF TAR DNA-BINDING PROTEIN 43 IN STRESS GRANULES AND ITS ROLE IN AMYOTROPHIC LATERAL SCLEROSIS Zhang AB, 1,2; Xiao S, 1; McGoldrick P, 1; Robertson J, 1,2 1 Laboratory Medicine and Pathobiology, University of Toronto; 2 TANZ Centre for Research in Neurodegenerative Diseases, University of Toronto Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, and is pathologically typified by cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) in degenerating neurons. TDP-43 is a DNA/RNA binding protein that is recruited to stress granules. Stress granules triage translationally stalled pre-initiation complexes, promoting expression of mRNAs necessary for cell survival. TDP-43 is abnormally phosphorylated in ALS, and the role of this abnormal phosphorylation in stress granule dynamics has not been widely explored. We hypothesize that TDP-43 phosphorylation is important for stress granule dynamics and that this event is dependent on cell type and stressor. HEK293, SH-SY5Y, and HeLa cells were stressed with sodium arsenite, hydrogen peroxide, and sorbitol and allowed to recover before assessing stress granule formation and TDP-43 localization. Sodium arsenite induced stress granule formation after one hour, detected using an antibody to G3BP1. However, the dynamics of TDP-43 recruitment to stress granules were much slower, occurring only in HeLa cells after 24h recovery from sodium arsenite. Importantly, TDP-43 recruitment to stress granules correlated with phosphorylated TDP-43. Our results demonstrate that recruitment of TDP-43 to stress granules is context-specific, depending on both cell type and nature of the stressor. Further investigation into the effects of TDP-43 phosphorylation in stress granule dynamics may provide new insight into the interplay between

TDP-43 and stress granules in ALS pathogenesis. 108. Marija Zivcevska; Institute of Medical Science Supervisor: Agnes Wong BEYOND THE MONOCULAR RETINA: BINOCULAR SUMMATION WITHIN THE INTRINSIC IPRGC PATHWAYZivcevska M,1; Blakeman A,4; Lei S,3; Chen X,4; Goltz HC,1,3,4; Wong AM,1,2,3,4 1 Neurosciences and Mental Health, The Hospital for Sick Children; 2 Ophthalmology and Vision Sciences, The Hospital for Sick Children; 3 Ophthalmology and Vision Sciences, University of Toronto; 4 The Krembil Research Institute, Toronto Western Hospital Introduction: Chromatic pupillometry has propelled our understanding of the melanopsin-containing intrinsically photosensitive retinal ganglion cell (ipRGC) light detection pathway. Increasing single retinal stimulation area from hemi-field to central-field to full-field stimulation has been shown to induce increasingly larger post-illumination pupillary response (PIPR), a measure of melanopsin photoactivity. Given that binocular viewing stimulates a greater total retinal area, we hypothesize this should result in a greater response when both retinas are stimulated simultaneously. Methods. Pupillary responses were recorded with an eye tracker in 10 visually-normal participants. PIPR(10-25s Post-illumination) was induced with full-field melanopsin-active blue light (470nm) and melanopsin-silent red light (635nm) stimuli at 60 cd/m2, presented for 400 ms with a Ganzfeld screen. Individual monocular responses were measured first (closed-loop paradigm) followed by binocular responses, 3 times on separate days. To account for individual variability in pupil diameter, the pupil data was normalized to a 5s period before each stimulus. Results. PIPR responses were significantly greater for binocular than monocular viewing under blue light stimulation only (p < 0.001). No difference in PIPR was found for red light stimulation. Overall no effect of viewing eye was found on monocular trials. Conclusions. While spatial summation responses have been described within a single retina, we present the first evidence of binocular summation in the intrinsic, melanopsin-mediated ipRGC pathway. These results have implications for our understanding of the melanopsin pathway beyond the level of the retinal ganglion cells, and this information may be useful in our understanding of photophobia.

Event Sponsors