Brain Star Awards - Recipients for 2010

Simon Chen

Biosketch

I have been involved with neuroscience research for the last 5 years. In 2005, while an undergraduate at the University of British Columbia, I joined Dr. Kurt Haas' lab at the Brain Research Centre as a Volunteer Research Assistant. During the next three years, I contributed to a number of research projects. I participated in developing a novel experimental model system to investigate the effects of common early-life seizures on brain circuit formation. In our paper published in Experimental Neurology, we demonstrate the potential use of this new model system for conducting direct in vivo time-lapse imaging of neuronal growth, synapse formation, and network activity during the course of seizures in the intact and awake developing brain. This model has provided new insights on how seizures alter neuronal network structural and functional development potentially contributing to persistent neurological deficits, and we are currently preparing a manuscript describing these results to a high-impact journal. Furthermore, I also independently developed new techniques to rapidly image neuronal growth within the intact and awake tadpole brain. This undergraduate research experience has been critical to my development of advanced skills in developing novel experimental methods and strategies, as well as fostering my strong interests in the field of developmental neuroscience.

For my Ph.D work, I decided to continue my research in Dr. Kurt Haas' lab with the focus of investigating how patterned neuronal activity and synapse formation direct development of complex functional brain neuronal networks. Within 3 years, I made significant progress on a study of the roles of the cell adhesion molecules, Neurexin and Neuroligin in directing brain neuron dendritic arbor growth. My first author publication on this work has just been published in Neuron in September 2010.
In addition to designing and conducting cutting-edge research, my training has included active mentorship of other graduate and undergraduate students, and presenting my results in meetings. I instruct all students on the imaging and morphometric analysis techniques I have developed, and have directly mentored and supervised 5 undergraduate research interns in the Haas Lab. I have attended national and international conferences, including two small and prestigious meetings; the Synapse: from Molecules to Circuits & Behaviour meeting at Cold Spring Harbour Laboratory in NY, and the Cell Biology of the Neuron Gordon Research Conference in NH. I also gave an oral-presentation at the annual Society for Neuroscience meeting in Chicago last year. These meeting have provided invaluable opportunities for me to directly discuss my research with top experts in the field. This interactive and successful training experience has strengthened my resolve to pursue a career as an academic research scientist in Developmental Neuroscience.

Article

Neurexin-Neuroligin Cell Adhesion Complexes Contribute to Synaptotropic Dendritogenesis via Growth Stabilization Mechanisms In Vivo

Significance of Paper

My paper makes significant advances both in methods for the study of brain neuronal development and in understanding the roles of cell adhesion molecules in directing brain neuron structural growth. My research has particular significance to understanding the pathophysiological origins of Autism Spectrum Disorders (ASDs). ASDs incorporate a range of disorders with shared social and cognitive dysfunction, and due to the early age at which behavioral problems emerge strongly support common origins in brain development. A recent breakthrough in understanding the origins of ASD comes from the identification of gene mutations in a small number of patients with familial ASD. Mutations were found in the cell adhesion molecules, Neurexin and Neuroligin, and other proteins with which they closely interact. While important research has investigated the roles of these proteins in synapse formation and function, little was known of their roles in the larger context of brain neuron structural growth, which is linked to synaptic function. Since brain neuron dendritic arbor structure dictates the computational complexity and function of brain neural circuits, correct structural growth is essential for proper brain function, and abnormal structural growth may lead to lasting dysfunction underlying neurological disorders.

Here, in the research presented in my Neuron paper I demonstrate our novel cutting-edge technologies to quantify brain neuron dendritic arbor growth within the intact and awake developing brain to determine the roles of these ASD-associated proteins in these processes. In this work, I performed direct real-time imaging to monitor the dynamic growth of individual brain neurons with normal or altered Neurexin and Neuroligin function. Furthermore, I employed techniques to directly image synapses in these individual brain neurons to correlate dynamic dendrite growth with synaptic formation. Our results offer a comprehensive analysis of how an ASD-associated protein affects brain neuronal structural growth within the intact and awake developing brain. We chose to submit our work to Neuron because it is one of the most influential and respected journals in the field of Neuroscience. The highly critical selection and review process provided by Neuron ensures that this work meets the highest standards of innovative and technical excellence, while providing results of critical importance and general interest to the entire Neuroscience community.


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Yi-Mei Yang, Ph.D.

Biosketch

Dr. Yi-Mei Yang-Postdoctoral Fellow
I began my research career as a Ph.D. student in cardiovascular pharmacology studying cellular and molecular mechanisms underlying myocardial ischemia/reperfusion injury at Tongji Medical School, HuaZhong University of Science and Technology in China. As my research proceeded in this area, I gradually developed strong interests in ischemia research of the brain and decided to make a career move into neuroscience. I am currently pursuing postdoctoral training under the supervision of Dr. Lu-Yang Wang in Program in Neuroscience and Mental Health, the Hospital for Sick Children and Department of Physiology, University of Toronto. My interest resides in the relationship between synaptic structure and functions, which is of central importance for understanding how the nervous system works and further developing clinical therapies for neurological disorders.

My work focused on presynaptic and postsynaptic adaptations of developing central synapses using the calyx of Held-MNTB synapse in the auditory brainstem as a model. Its rapid functional maturation with clearly defined "critical period of development" and large dimension of the nerve terminal have made this synapse an ideal system for investigating neurotransmission and developmental plasticity. Employing cutting-edge biophysical approaches as well as pharmacological and immunochemical techniques, we have delineated an intricate counteraction between developmental action potential shortening and upregulation of downstream coupling efficacy for Ca2+ dependent transmitter release, which serves as an imperative presynaptic strategy to enhance synaptic strength and temporal precision of neurotransmission (Yang & Wang, J. Neurosci. 2006; Wang, Fedchyshyn & Yang, Mol. Brain 2009). We have further demonstrated that filamentous protein, Septin5, is the critical molecular substrate underlying the developmental transformation of spatial coupling between presynaptic Ca2+ channels and synaptic vesicles from "microdomain" to "nanodomain" modalities (Yang, Fedchyshyn et al., Neuron 2010). In parallel to such presynaptic remodeling, we have identified a novel form of postsynaptic plasticity, namely persistent down-regulation of NMDARs (Joshi, Yang et al., J. Neurosci. 2007), and molecular correlates of subunit switch from GluR1-dominant to GluR4-dominant phenotypes in native AMPARs, which underlies acceleration in postsynaptic responses at maturity (Yang et al., in preparation and SFN abstract 2008). These lines of work have provided important insights into molecular mechanisms underpinning development of high-fidelity neurotransmission and significantly advanced the understanding of developmental plasticity at central synapses.

In addition to my scientific training, I have been an active member of Canadian Association of Neuroscience and Society for Neuroscience, and regularly present my work at the annual meetings as well as in Toronto's neuroscience community. I am involved in teaching undergraduate and graduate students both in the classroom and in the laboratory. My long-term goal is to institute a creative, independent and productive research lab, where we will unravel mechanisms of synaptic transmission and plasticity as well as neurological diseases, and meanwhile provide the next generation of graduate students and postdoctoral fellows with the opportunities and training to pursue intellectually and technically challenging questions in neuroscience.

Dr. Michael J Fedchyshyn-Graduate Student (Degree conferred)
My interest in neuroscience began in a 2nd year undergraduate physiology course where I was introduced to the mechanisms of the neural signal transduction cascade. However, my passion fell within the 'physical' (rather than the 'biological') aspects of how signal transduction occurs and information is coded in these processes. I transferred into the Biophysics Program at University of Toronto and was fortunate enough to meet Prof. Lu-Yang Wang at the Hospital for Sick Children, who introduced me to the calyx of Held synapse in the auditory brainstem, one of the few systems in the central neural system where questions of a biophysical nature can be probed directly with simultaneous recordings from presynaptic and postsynaptic elements.

After completing a 4th year research project with Prof. Wang, investigating presynaptic short-term plasticity, I elected to continue my graduate studies towards Ph.D. in physiology at University of Toronto. I began learning the complex electrophysiological techniques that would be required to directly assay the presynaptic mechanisms of neurotransmitter release and how they are modulated during development. Together we developed the unique capability to perform simultaneous pre- and postsynaptic recordings from the Calyx of Held-MNTB synapse across a wide range of developmental stages. The most groundbreaking result of this work was the discovery that both the physical orientation and subtype of voltage-gated calcium channels (VGCCs) that trigger synaptic vesicle (SV) release changed during development – beginning in a cooperative but loosely-coupled array of mixed N- and P/Q-type VGCCs (microdomain) and shifting to a tightly-coupled arrangement of only P/Q-type VGCCs (nanodomain) (Fedchyshyn & Wang, J. Neurosci. 2005).

Our subsequent work demonstrated that this shift in coupling modality is mediated by a filamentous protein Septin 5 (Yang, Fedchyshyn et al., Neuron 2010). Developmental downregulation of Septin 5 near release sites reduces the physical barrier for fusion and consequently potentiates quantal output, accelerates the kinetics of SV release, and changes the patterns of short-term plasticity during high-frequency activities. All of these alterations could be accounted for by simple computational models of SV activation and release (Fedchyshyn & Wang, J. Physiol. 2007; Wang, Fedchyshyn & Yang, Mol. Brain 2009; Yang, Fedchyshyn et al., Neuron 2010). My studies have resolved the long-standing debate about the coupling modality between VGCCs and SVs in the field and led to a paradigm shift in the current thinking of mechanisms underlying transmitter release and developmental plasticity at central synapses.

Article

Septins Regulate Developmental Switching from Microdomain to Nanodomain Coupling of Ca2+ Influx
to Neurotransmitter Release at a Central Synapse

Significance of Paper

Septins, a conserved family of GTP/GDP-binding proteins encoded by 14 genes in mammals, are filamentous proteins implicated in a wide range of neurological diseases such as Parkinson's, schizophrenia, Down's syndrome, and Alzheimer's disease. Although septins are abundantly expressed in postmitotic neurons, their functions remain largely unknown. Using multidisciplinary approaches, we have discovered the surprising effect of septins at a developing central synapse where they regulate the spatiotemporal coupling of synaptic vesicles (SVs) to incoming calcium transients via voltage-gated Ca2+ channels (VGCCs), ultimately determining the accuracy and efficiency of transmitter release at a mammalian central synapse. The new insightful understanding of physiological roles of septins in our study has provided a direct link of these filamentous proteins to their neuropathology, and may help develop innovative strategies for diagnosis and treatment at the early stage of these neurological disorders.

Our work strongly aligns with the mandate and vision of CIHR-INMHA in two significant ways. (1) Auditory system is one of the most important sensory systems for the brain to interface with the environment; our work demonstrating that septins play a critical role in gating maturation process of neurotransmission in the binaural sound localization pathway is significant for understanding fundamental mechanisms of hearing in the developing brain. (2) Our work represents the first evidence implicating the role of septins in synaptic functions and plasticity in the brain, paving the way for further unlocking long-standing mysteries of these filamentous proteins in the healthy brain and neurological disorders.


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Tabrez J Siddiqui

Biosketch

I completed my M.Sc. (2003) and Ph.D (2006) at the Max Planck Institute for Biophysical Chemistry, Goettingen, Germany. During my Ph.D., under the supervision of Professor Reinhard Jahn, I probed the structural and regulatory basis for the activity of synaptobrevin 2/VAMP 2, the protein responsible for regulated exocytosis in brain cells. [1]. During my Ph.D. training, I employed extensive biochemical and biophysical techniques, including fluorescence spectroscopy and computer simulations to decipher reaction pathways.

I joined the laboratory of Professor Ann Marie Craig at the Brain Research Centre, University of British Columbia because of her excellent work in synapse formation and development. I have been working with synapse organizing molecules, particularly the Leucine rich repeat transmembrane neuronal (LRRTM) proteins [2] since I joined her laboratory. The LRRTMs alone are sufficient to trigger formation of neurotransmitter release sites in nerve cells. LRRTM1 was recently shown to be associated with handedness and schizophrenia whereas LRRTM3 was suggested to be a candidate gene for late-onset Alzheimer's disease. My aim is to understand how the LRRTMs contribute to synaptogenesis and synapse maintenance, and their overall role in brain development and nervous system function in vivo. To fully characterize the role of the LRRTMs in vivo, I recently generated mice lacking specific LRRTM genes.

I have also identified the trans-synaptic binding partners for the LRRTMs [3], which have considerably aided in our understanding of the functions of LRRTMs. Furthermore, these trans-synaptic binding partners, called neurexins, are themselves linked to psychiatric disorders. Further work on the LRRTMs and neurexins will lead to greater understanding of the molecular mechanisms of synapse formation.

Article

Siddiqui TJ, Pancaroglu R, Kang Y, Rooyakkers A, Craig AM. LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development. J Neurosci 2010; 30: 7495-506.

Significance of Paper

The Leucine-rich repeat transmembrane (LRRTMs) proteins were identified in our laboratory to promote the formation of mammalian synapses. These genes have recently been shown to be associated with neurological disorders as varied as autism, schizophrenia, handedness and late-onset Alzheimer's disease [1-4]. Mutations in functionally related proteins, the neuroligins, have directly been linked to autism and mental retardation [5].

To understand the in vivo mechanism of action of the LRRTMs, I identified neurexins as the binding partners of the LRRTMs[6]. Neurexins are themselves linked to psychiatric disorders [5]. Protein-truncating variants in neurexins are linked to schizophrenia and to autism in multiple patient families, and animal models mimicking these genetic variants phenocopy some associated behaviors. Furthermore, my study showed how the cross-interactions of the LRRTMs, Neuroligins and Neurexins are orchestrated at the molecular level and how they may co-operate in glutamate synapse development. Thus my study is in line with INMHA's vision of uncovering the molecular basis of numerous mental illnesses.


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Tracie O. Afifi, PhD

Biosketch

My interest in neuroscience became solidified as a career aspiration after I watched a close family member deteriorate from Alzheimer's disease. The disease slowly took the person I knew in a way that devastated our family. It became a passion of mine to learn more about the brain and neuroscience in general in order to research and understand these prevalent pathologies. Luckily, I was at a turning point in my educational career that allowed me to pursue a Master's degree in neuroscience. I completed all of my neuroscience training at the University of Calgary. I obtained my Mater's in Neuroscience studying the pattern generation of movement in the spinal cord. I carried on to complete my PhD in Neuroscience examining peripheral nerve injury in the Zochodne lab. In particular I looked at increasing nerve growth after injury. Currently I am a post-doc in the Zochodne lab, continuing to examine molecules to enhance regeneration after nerve injury. In the future, I have a keen interest to continue researching pathologies of the nervous system.

Article

PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. Journal of Neuroscience Jul; 30(27) 9306-15.

Significance of Paper

My paper is of broader relevance because the molecule (PTEN) I studied is ubiquitously expressed in the body. This means that my findings could extend from the peripheral nerve to the central nervous system including the brain and spinal cord. Spinal cord injuries and brain pathologies could benefit from similar regeneration enhancements shown in my research. It was for this reason that we chose to publish the paper in the Journal of Neuroscience, in hopes that it would reach the general neuroscience community. Not only is it important to notify the science community about the peripheral nerve, but there is a significant amount to learn and extrapolate from and apply to other areas of the nervous system.


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Eric Trudel

Biosketch

Ever since high school, I had interests in biological science. Later on, I started doing a B.Sc. degree in medical biology at "Université du Québec à Trois-Rivières" where I had the opportunity to learn about the systems of human physiology and was introduced to scientific research. The neuroscience aspect of the course outline was the one that intrigued me the most and lead me to do an internship in the neurobiology of memory in Dr Guy Massicotte's Lab. The fascination I developed during this work lead me to choose to pursue graduate studies in neuroscience. I then started an M.Sc. degree in Dr Charles W. Bourque's lab at the Centre for Neuroscience at McGill University. The interests of the lab rests on the balance of water and minerals maintained by the brain through close monitoring of the blood osmolality (organum vasculosum of the lamina terminalis; OVLT) and secretion of two hormones from the supraoptic nucleus (SON) that promote water reabsorption (vasopressin) and salt excretion (oxytocin). To better study this system, I developed an angled slice that retained all of these structures (OVLT and SON), as well as other structures (suprachiasmatic nucleus; SCN) and their synaptic connections. These structures cannot be found in a single coronal or horizontal slice. This angle slice offered the advantage of allowing visual guidance and the performance of patch-clamp recordings to allow a better study of synaptic interactions (Journal of Neuroscience Methods, 2003, 128, p67-77). Preliminary results using this slice to investigate the circadian control on osmosensory gain revealed to be promising and I chose to pursue a PhD degree on this subject using this angle slice preparation. The results of this research showed that the decrease in activity of the SCN enhanced the secretion of vasopressin in late sleep (Nature Neuroscience, 2010, Apr 13(4), p 467-474). I have since obtained my Ph.D. degree and have continued a post-doctoral degree to finalize the project, do several other small projects and investigate more on the osmoreceptors of the OVLT. I now want to find another post-doctoral position in a similar field and contribute to improve knowledge in the neuroscience field.

Article

Central clock excites vasopressin neurons by waking osmosensory afferents during late sleep


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Bechara Saab

Biosketch

I was first exposed to research at Procter & Gamble in Rome Italy in 2000 during an internship offered to me while on exchange at Glasgow University. I invented a novel tablet disintegration mechanism. I then finished my B.Sc. at UBC while synthesizing site-specific inhibitors of transcription. I completed my PhD with John Roder at the SLRI. Among several projects and much time teaching hands-on science to youths, I discovered elevating NCS-1 in the adult murine dentate gyrus enhanced learning and memory and elucidated the first-ever a molecular link between learning and curiosity. The research was published in Neuron, was reported on in the National Post and Fox Business, and has immediate practical applications.

Article

DG NCS-1 Underlies Exploration and Spatial Memory. Saab - Roder. Neuron 63, 643-56

Significance of Paper

Although there is an obvious, intuitive relationship between intelligence and curiosity, the paper illustrates the first-ever molecular link. It suggests strengthening one will strengthen the other since the molecules and circuits involved overlap. This is the broadest, most practical significance. Neuroscientists of mental health and addiction will find large significant in a novel in vivo mechanism of D2R regulation. Faculty 1000 selected the paper as "one of the most influential in biology" because the findings "directly link NCS-1 regulation of dopamine-D2 receptor activity with the processes of learning and memory." The journal, Neuron, was selected because it is the top of neuroscience, reaching the widest audience possible.


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Jing Wang

Biosketch

After getting my undergraduate Medical Degree in China, I decided to shift my academic interest into basic science, especially in the field of neuroscience. Following graduation I was employed as a research assistant and lecturer in Dept. of Physiology in Xi'an Medical University in China for one year. During that year, I started participating in the neurophysiological research to understand pain mechanism. This led me to get an opportunity to go abroad for MSc. training in Dr. James L. Henry's lab in Dept. of Physiology at McGill University. My Master's work focused on studying of antinociceptive mechanism of delta opioid receptor in the spinal cord. Both behavioral and in vivo electrophysiological study indicated that delta-opioid receptor agonists selectively inhibit relatively prolonged acting pro-nociceptive transmitters-induced excitation without any influence on fast acting transmitter-induced excitation. The results implied that delta-opioid receptor agonists might have potential treatment on chronic pain without interfering with other sensations. My Master thesis work has been poster-presented in 30th Society for Neuroscience in 2000. In order to get another aspect of research experiences in the molecular cell biology, I went to University of Ottawa to pursue my Ph.D study in Dept. of Biochemistry. Using Xenopus oocyte maturation as a model system, my Ph.D. work contained characterization of G protein coupled receptor (GpCR)-protein kinase A (PKA) pathways for maintenance of frog oocyte prophase arrest and development of a novel approach for measuring endogenous PKA activity in live cells. The Ph.D thesis work has been published in 3 peer-reviewed papers and one book chapter (J. Biol. Chem., 278:15809-14, 2003; j. Cell Sci.,117:5107-5116, 2004; Cell Cycle, 5: 213-217, 2006; Methods Mol. Biol., 322:425-433, 2006). After eight-year graduate training with a broad and multidisciplinary basis, I joined Dr. Freda Miller's lab as a post-doctoral fellow in Hospital for Sick Children in 2006. Since then I have been working on defining signaling pathways from environmental cues to epigenetic modifications that promote neural precursor differentiation into oligodendrocytes, astrocytes and neurons. My recent published paper in Developmental Cell has indicated that aPKC-CBP pathway is essential for embryonic neural precursor differentiation into oligodendrocytes, astrocytes and neurons. My ultimate goal is to have my own independent academic research laboratory to study signaling pathway involved in the neural development and, in particular, in the area of neural stem cells.

Article

CBP Histone Acetyltransferase Activity Regulates Embryonic Neural Differentiation in the Normal and Rubinstein-Taybi Syndrome Brain

Significance of Paper

My research paper for the first time demonstrates that CBP haploinsufficiency in the genetic disorder called Rubinstein-Taybi syndrome, which occurs 1 in 300 patients institutionalized for mental retardation, perturbs neural cell genesis during brain development, thereby explaining the resultant cognitive deficits and neuroanatomical abnormalities in the RTS patients. My Innovative research provides new biological knowledge underlying the mental disorder and sheds a light for designing early intervening treatments for the genetic mental disorders. In addition, my research paper also identified a novel pathway to promote three neural cell genesis including neurons, astrocytes and oligodendrocytes in the brain. Manipulation of the novel pathway with small molecules may have potentials to treat some neurodegenerative disorders, neural injury and Multiple Sclerosis by enhancing the three neural cell genesis in the brain. This discovery certainly will improve treatments and enhance the quality of life of Canadians suffering from mental illnesses.


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Kim Christie

Biosketch

My interest in neuroscience became solidified as a career aspiration after I watched a close family member deteriorate from Alzheimer's disease. The disease slowly took the person I knew in a way that devastated our family. It became a passion of mine to learn more about the brain and neuroscience in general in order to research and understand these prevalent pathologies. Luckily, I was at a turning point in my educational career that allowed me to pursue a Master's degree in neuroscience. I completed all of my neuroscience training at the University of Calgary. I obtained my Mater's in Neuroscience studying the pattern generation of movement in the spinal cord. I carried on to complete my PhD in Neuroscience examining peripheral nerve injury in the Zochodne lab. In particular I looked at increasing nerve growth after injury. Currently I am a post-doc in the Zochodne lab, continuing to examine molecules to enhance regeneration after nerve injury. In the future, I have a keen interest to continue researching pathologies of the nervous system.

Article

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Significance of Paper

My paper is of broader relevance because the molecule (PTEN) I studied is ubiquitously expressed in the body. This means that my findings could extend from the peripheral nerve to the central nervous system including the brain and spinal cord. Spinal cord injuries and brain pathologies could benefit from similar regeneration enhancements shown in my research. It was for this reason that we chose to publish the paper in the Journal of Neuroscience, in hopes that it would reach the general neuroscience community. Not only is it important to notify the science community about the peripheral nerve, but there is a significant amount to learn and extrapolate from and apply to other areas of the nervous system.


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Aristotle Voineskos

Title: Voineskos AN, Lobaugh NJ, Bouix S, Rajji T, Miranda D, Kennedy JL, Mulsant BH, Pollock BG, Shenton ME. Diffusion Tensor Tractography Findings in Schizophrenia Across the Adult Lifespan. Brain. 2010. May;133(Pt 5):1494-504

Biosketch:

I began my PhD studies in the fourth year of my residency training in psychiatry, and I decided to focus on combining brain imaging and genetics in schizophrenia and aging, using the novel MRI technique of diffusion tensor imaging that can measure white matter connections in the brain. I am now completing my fellowship training at CAMH, and have just completed my PhD. During my final year of residency I trained at Harvard with the leading DTI expert in schizophrenia, Dr. Martha Shenton. Simultaneously, I chose to use an "across the lifespan" approach and thus received mentorship and worked closely with internationally renowned geriatric psychiatrists in Toronto, Dr. Bruce Pollock, and Dr. Benoit Mulsant. We recruited a dataset of schizophrenia patients and healthy controls across the adult lifespan with genetics, brain imaging, and cognitive measures. We have now published major findings from this dataset that include the attached manuscript in the journal, 'Brain'. A major theme in my current, and future research projects is to understand the genetic determinants of impaired brain connectivity in schizophrenia patients, and, in parallel, to use these approaches to refine the interface between healthy and pathological aging. As we have recently shown in other work, the combination of brain imaging and genetics can provide early identification of genetically-mediated disease risk patterns in the brain in vivo. In addition, as we have also shown, such a combination of techniques can also support or refute our current diagnostic classification paradigms. My clinical and research interests are tightly aligned as I see patients with schizophrenia at all stages of the adult lifespan, and my research focus is in schizophrenia and aging using transational imaging-genetics approaches.

Significance of paper:

Schizophrenia has long been thought of as a 'disconnectivity' syndrome (i.e. the brain regions don't communicate properly with each other), but few studies have examined the structures that comprise these major connections that would allow brain regions to communicate effectively between each other. We used a state of the art technique known as diffusion tensor tractography (a special MRI technique) to examine these connections (known as white matter tracts). Our study was unique in that it was the first to examine these major connections in schizophrenia patients across the adult lifespan (i.e. including individuals from 20-80 years old). We found that the structures connecting the frontal and temporal brain regions were disrupted in schizophrenia compared to healthy controls, supporting the theory of schizophrenia as a disconnectivity syndrome. We also found that these white matter tracts are dramatically affected by age, both in healthy individuals and in schizophrenia. Interestingly, we found that elderly patients with schizophrenia (in their 60s and 70s) were not different than healthy controls, suggesting a resilience in these elderly patients, who in fact have lived longer than expected (the average lifespan of a schizophrenia patient is 15-20 years less than in the general population). We think that genes may influence these white matter tracts both in terms of healthy aging and schizophrenia, and our next step is to look at the relationship between genes and white matter in the brain using imaging-genetics approaches. Overall our research approach of examining 'brain connectivity' is of interest in several neurological and psychiatric disorders, as the tools are now available to examine white matter tracts in vivo. We chose the journal 'Brain' because it is a leading journal of neurology that also has an interest in severe mental illness and neuroimaging. Brain is widely read by neurologists, psychiatrists, and neuroscientists, and over the past one hundred years or so, has been an important journal that lies at the interface of these fields.


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Vaneeta Verma

Title: Dopamine D1-D2 receptor Heteromer-mediated calcium release is desensitized by D1 receptor occupancy with or without signal activation: dual functional regulation by G protein-coupled receptor kinase 2. Verma, V; Hasbi, A; O'Dowd, BF; George, SR. Journal of Biological Chemistry, 285(45) 35092-103, Nov.5th 2010

Biosketch:

I started my research training at the University of Prince Edward Island where I received two NSERC undergraduate research awards. I then received a NSERC post graduate scholarship and attained my Masters degree in Neuropharmacology from McMaster University. I am currently enrolled in the Pharmacology PhD program at the University of Toronto. I have research training in several molecular techniques at the in vitro level as well as with rat animal models. I am currently investigating the regulation of the dopamine D1-D2 receptor heteromeric complex and its involvement in dopamine related disorders.

Significance of paper:

Receptor desensitization is an important process that occurs to regulate and turn off signaling. For dopamine (DA) receptors, this process maybe relevant to the outcome of hyper-dopaminergic states, such as schizophrenia, as well as to the development of therapeutic tolerance in the treatment of DA related diseases. The results from the current paper demonstrate a distinct form of regulation for the D1-D2 receptor heterooligomer different from that of D1 and D2 receptor homo-oligomeric units, therefore enhancing our understanding of the available repertoire of mechanisms regulating DA receptor signaling.


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Michael Vesia

Title: Specificity of Human Parietal Saccade and Reach Regions during Transcranial Magnetic Stimulation

Biosketch:

Drs. Lauren Sergio and Doug Crawford, Canada Research Chair in Visuomotor Neuroscience. My research focuses on how the brain uses sensory information to guide action and is aimed at understanding the effects of disease, injury, and developmental disorders to aid in the development of evidence-based, patient-specific intervention strategies. My master"s thesis examined the time course for kinetic versus kinematic planning of goal-directed human motor behaviour using a psychophysical approach. Here we found that the motor system may initially use a coarse approximation of movement-related limb dynamics, allowing for the refinement of the motor plan as the movement unfolds. My doctoral research focused on the neural mechanisms of the parietal cortex and its role in visuomotor processing. In a series of experiments, we examined the brain-behaviour relations of healthy individuals during goal-directed eye and arm movements to visual targets while applying a non-invasive method of induction of a focal current in the brain called transcranial magnetic stimulation (TMS). This research was well recognized by both national and international organizations (i.e., Canadian Association for Neuroscience Young Neuroscientist Award, Society for Neuroscience and Vision Sciences Society Travel Awards), funded by several Ontario Graduate Scholarships, and published in several peer-reviewed journals such as Experimental Brain Research, Journal of Neurophysiology, and Journal of Neuroscience.

In addition to my dissertation work, I had the opportunity to expand my understanding of the neural mechanisms underlying visual perception and the visual control of action through several research projects. Specifically, these projects examined: 1) reversing prism adaptation in disorders of parietal cortex and its potential for rehabilitative treatment for neglect and optic ataxia and 2) the neural mechanisms of trans-saccadic memory. The former experience allowed me to establish future collaborations with individuals from many related fields and gain invaluable experience with patient populations, while the latter allowed me to integrate my expertise in TMS with novel psychophysical methodologies. This work was published as a book chapter in Cortical Mechanisms of Vision and several high-impact journals, respectively - i.e., Journal of Neuroscience and Cerebral Cortex.

Collectively, these experiences have provided me with extensive training and expertise in a number of research approaches and techniques such as TMS (I formally was trained on noninvasive brain stimulation for health care and research at Harvard Medical School by a distinguished, leading expert in stimulation techniques, Dr. Alvaro Pascual-Leone), EMG, psychophysical testing, neuropsychological studies, eye-tracking systems, stereotaxic neuronavigation systems, and 3-D motion-tracking systems.

My ongoing research includes established collaborative projects with two international leaders in sensory motor control (Drs. Yves Rossetti and Laure Pisella at INSERM in Bron, France). This work will examine the role of parietal cortex in reach movements to auditory targets in optic ataxic patients – a disorder associated with parietal lobe lesions. This collaboration recently was awarded the prestigious, international Human Frontier Science Program Short-Term Fellowship.

I chose to carry out a post-doctoral fellowship in sensorimotor integration with Dr. Richard Staines, Canada Research Chair in Sensorimotor Control, at University of Waterloo to expand my research outlook and utilize novel experimental approaches to investigate specific relationships of interactions in the control and representation of sensory information at a cortical level and the influence this has on the neural control of movement. Furthermore, through Dr. Staines" established collaborations with colleagues at the Centre for Stroke Recovery at Sunnybrook Health Science Centre (Drs. Sandra Black and William McIlroy), I also will have opportunities to be involved in research of patients with sensorimotor disorders such as apraxia, sensory extinction, hemiparesis, and problems with sensorimotor integration. Moreover, I will have the opportunity to add to my armamentarium of neuroscience tools by developing expertise in multiple experimental techniques, including functional magnetic resonance imaging (fMRI), human electroencephalographic (EEG), and other behavioural measures of motor performance. The overall goal of this research is to understand how the sensorimotor system plans and executes goal directed actions as well as provide anatomical explanations for the behavioural deficits found in parietal lobe patients.

Significance of paper:

This innovative research is aligned with the vision of INMHA and provides new knowledge of the biological processes underlying neurological disorders. In particular, this work increases our knowledge of the functioning and disorders of the brain, with specific emphasis on how different regions within the parietal cortex transform sensory information into goal-directed, motor actions. Knowledge of fundamental motor control mechanisms is critical to aid in the development of evidence-based, patient-specific intervention strategies that focus on the prevention of injury from motor dysfunction and post-stroke sensorimotor recovery. This research examines how the CNS controls and interprets sensory information for sensorimotor behaviour and its importance in contributing to sensory and motor deficits following brain injury. The goal of this work is to translate this new knowledge into a better quality of life for all Canadians through improved health care services. Insight from this research will assist in the development of evidence-based interventions following stroke. The end benefit will be improved health-care for Canadians with neurological disorders.


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Marion Van Horn

Title: Local Neural Processing and the Generation of Dynamic Motor Commands within the Saccadic Premotor Network

Biosketch:

I studied Physiology and Psychology during my undergraduate degree at McGill University and subsequently did a PhD in Systems Neurophysiology in the department of Physiology under the guidance of Dr. Kathleen Cullen. My thesis explored how the brain controls 3-dimensional eye movements, focusing primarily on how the neural activity of individual neurons shapes the dynamic movement of each eye when we change our focus from near to far. During my PhD studies I gained a thorough understanding of the techniques used in Systems Neuroscience, including experimental non-human primate surgery, extracellular single unit and field recordings from neurons in vivo, computer programming, and the analysis of data using system identification techniques. To better understand neurological disorders I fully appreciate how important it is to study neural development at both a system and cellular level. Accordingly, I have recently started my post doctorate studies with Dr .Edward Ruthazer in the department of Neurology and Neurosurgery at the Montreal Neurological Institute. I will combine electrophysiology and single-cell two photon imaging, as well as pharmacological and molecular manipulations, to better understand how the brain develops under normal and perturbed conditions, in the Xenopus tadpole. The long term goal of my research is to better understand the causes of particular eye movement and visual disorders.

Significance of paper:

A central goal of the INMHA is to understand how the brain generates precise neural signals to guide behaviour. Recordings of high-frequency electrical events in the brain (i.e., spikes) have become a standard tool for examining how individual neurons are involved in guiding behavior. Recently, there has been increased interest in investigating the information that is carried by low-frequency electrical activity (i.e., local field potentials (LFPs)). While spiking activity represents the action potentials (i.e., output signal) produced by a neuron, LFPs are generally thought to reflect the summed activity of synaptic potentials occurring around the tip of the recording electrode. Accordingly, LFPs are considered to reflect the input to a given brain area, whereas spiking activity represents the output that is sent to other parts of the brain. Concurrent recordings of LFPs and spikes could theoretically provide an effective means for evaluating the local computations that take place to produce accurate commands. This paper improves our understanding of the local computations that take place in order to produce an accurate behavioural command. In particular it clearly demonstrates how simultaneous recordings of local field potentials and spiking responses provides as effective means for evaluating the local computations that take place within the brain. This method is expected to be a highly effective way for evaluating local processing within many brain areas and will enhance our knowledge of how the brain generates accurate neural signals.


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Jeffrey Dason

Title: Dason JS, Smith AJ, Marin L, & Charlton MP (2010). Vesicular Sterols Are Essential for Synaptic Vesicle Cycling. Journal of Neuroscience, 30(47):15856-15865.

Biosketch:

My initial interest in Neuroscience stems from my undergraduate training at the University of Toronto Scarborough, where I did a double major in Neuroscience and Biological Sciences (Honours Bachelor of Science). Subsequently, I did a Master of Science in Biology at York University under the supervision of Dr. Brian Colman. Next, I did a PhD in Dr. Harold Atwood"s lab at the University of Toronto, where I studied the role of a calcium-binding protein called Frequenin in synaptic transmission and nerve terminal growth. This project was done in collaboration with Dr. Alberto Ferrús and Dr. Jesús Romero-Pozuelo at the Instituto Cajal in Madrid, Spain. My training involved a multidisciplinary approach, which allowed me to learn several techniques such as electrophysiology, calcium imaging, genetics, and molecular biology. I created two Frequenin null mutants and characterized the physiological and morphological consequences of the absence and overexpression of Frequenin. Currently, I"m working as a post-doctoral fellow in Dr. Milton Charlton"s lab at the University of Toronto, where I"m studying the role of lipids in synaptic vesicle endocytosis. My recent work demonstrates that vesicular sterols are required for synaptic vesicle endocytosis and that little intermixing occurs between vesicular and plasma membrane sterols during endocytosis.

Significance of paper:

This paper is the first to examine the role of cholesterol in the function of synaptic vesicles. Cholesterol is involved in several diseases of the nervous system such as Niemann-Pick disease, Alzheimer"s disease, and Huntington"s disease. Thus, the role of cholesterol in synaptic function has important implications for several diseases. Cholesterol helps to stabilize membrane fluidity and many membrane proteins interact with cholesterol and are functionally clustered in cholesterol rich "rafts". However, despite its importance, the role of cholesterol in synaptic vesicle cycling is not well understood.


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Renée El-Gabalawy

Title: Comorbidity and associated severity of borderline personality disorder and physical health conditions

Biosketch:

I am currently a first year PhD student in the Clinical Psychology program at the University of Manitoba. I previously completed my MA (2010) and Honours Undergraduate BSc (2008) at the University of Manitoba. In 2010, I was awarded the prestigious CIHR Vanier Canada Graduate Scholarship to fund my doctoral research. Throughout my studies in psychology, my primary goal has been to develop an understanding of how to improve the health and well-being of individuals, communities, and society as a whole. Through my academic program, I have had a significant amount of both practical experience and research training. My practical experience has included direct experience treating, assessing and diagnosing clients who suffer from a variety of mental health issues. In terms of research, I have developed methodological skills particularly quantitative methods and I am able to apply complex analyses to novel research questions. In my own research, I have experience with both primary data collection and secondary data analysis. My PhD co-supervisors, Dr. Jitender Sareen and Dr. Corey Mackenzie, are prolific researchers who work with a multidisciplinary team that allows them to stay on the leading edge of research. They have provided me with significant mentorship thus far and I am confident that they will continue to help me establish myself as a successful academic. In their labs I have been involved in several research projects and unique research endeavours. For example, I have published three articles (on two of which I am the first author) and submitted two others, I am the first author on a book chapter, I have ad hoc reviewed for eight journals, presented my research at several conferences and mentored more junior students. Notably, for the purpose of this application, my Psychosomatic Medicine paper investigating the relationship between borderline personality disorder and physical health conditions was featured in Journal Watch. In addition to my research platform, I also volunteer for several mental health community initiatives. My future research program aims to build on the relationship between mental disorders and physical health conditions using clinical, community, and population-based datasets. My PhD program will continue to train me in statistics and methodology as well as assessment and psychotherapy. I currently have several research projects underway and plan to publish my findings in high impact journals and hope to make national and international contributions in the field of mental health.

Significance of paper:

In this paper, I investigated the relationship between borderline personality disorder and several physical health conditions. Additionally, I examined quality of life and suicide outcomes of comorbid relationships. I was primarily responsible for the development of the research idea, data analysis, interpretation of results, and manuscript writing. In line with the mandate of INMHA, this innovative investigation was the first to examine these comorbid relationships in a large, nationally representative sample of over 34,000 adults. Personality disorders, notably borderline personality disorder, are associated with severe dysfunction and several maladaptive behaviors. In addition, this population is at high risk for suicidal behaviors. Results of this study indicated that the presence of several physical health conditions are associated with borderline personality disorder, even after controlling for sociodemographic variables and commonly occurring mental disorders. In addition, the comorbidity of several physical health conditions and borderline personality disorder was associated with an increased likelihood of poor quality of life and suicide attempts in comparison to those suffering from this mental disorder alone. In line with the Gender and Sex-Based Analysis, I performed an interaction analysis with the sex variable. Results indicated that there were no stratum specific associations for this variable among the findings. As INMHA asserts, I concur that it is crucial to integrate research across health domains. This research stresses the importance of the integration of medical and psychiatric research to understand the unique co-dependent relationships and resulting outcomes of these co-occurring conditions. Understanding these mind-body relationships will increase the quality of life for thousands of suffering individuals.


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Noufissa Kabli

Title: Agonists at the delta-Opioid Receptor Modify the Binding of mu-Agonists to the mu-delta Opioid Receptor Hetero-oligomer. Kabli, N., Martin, N., Fan, T., Nguyen, T., Hasbi, A., Balboni, G., O'Dowd, B.F., and S.R. George. British Journal of Pharmacology 2010 (161): 1122-1136

Biosketch:

I completed my undergraduate training in Life Sciences at Queen"s University (1999-2003) where I undertook undergraduate thesis research in Physiology. My project aimed at using proteomic approaches to investigate biomarkers for cardiac disease. My passion for Neuroscience research was sparked by a senior-level Neuropharmacology course that exposed me to recent advances and research methods in the field.

In 2003, I embarked on the MSc program under the supervision of Dr. Cahill in the Department of Pharmacology and Toxicology where I used molecular and behavioural approaches to investigate the function of delta opioid receptors in neuropathic pain. My findings challenged the dogma that neuropathic pain is inherently resistant to opioid treatment, and validated the development of effective, non-invasive, peripherally-selective delta agonists as a novel therapeutic approach for treating neuropathic pain conditions. I presented my work at local and internationational meetings where I won awards for Best Poster Presentation. I was awarded the Eli Lilly Young Neuroscientist Award by the Canadian Association of Neuroscience (2005). My findings were published in Pain (Kabli et al. 2006) and replicated by other groups. The unique opportunity of being the first student to graduate from a newly-established laboratory allowed me to experience the joys and challenges of setting up a new laboratory and research program. I learned the skills of self reliance and resourcefulness and gained the ability to design simple experiments that address complex questions.

During the later stages of my MSc program, I became intrigued by the increasing reports of G protein coupled receptor hetero-oligomerization, especially those pertaining to opioid receptors. In 2005, I enrolled in the PhD program under the supervision of Dr. George in the Department of Pharmacology and Toxicology and Collaborative Program in Neuroscience at the University of Toronto in order to study the functional implications of mu- and delta-opioid receptor hetero-oligomerization. During the tenure of my PhD, I have added to my repertoire of laboratory techniques and gained important insight into the field of GPCR research. My research provides novel insight into the ligand binding pocket of the mu-delta hetero-oligomer and suggests that this receptor complex may be a better therapeutic target for treating conditions requiring prolonged exposure to morphine. It also prompts an evaluation of the contribution of the mu-delta heteromer to the analgesic and anxiolytic effects of delta opioid agonists. This work has been published in the British Journal of Pharmcology (Attached; Kabli et al. 2010) and is a precursor to other reports characterizing mu-delta hetero-oligomer function. I was the recipient of a three-year Ontario Mental Health Foundation Studentship as well as OGS (Declined), NSERC (Declined), and several University of Toronto Fellowships. I received the Eli Lilly Young Neuroscientist Award at the Canadian Association of Neuroscience meeting (2008), awards for Best Poster Presentation, and travel awards by my department and the Program in Neuroscience to present my work at international meetings.

I enjoy mentoring and teaching. Throughout my graduate studies, I have been a teaching assistant in senior Pharmacology courses supervised undergraduate thesis research and summer students. I strive to expose students to the joys of research and rigorous scientific inquiry.

Significance of paper:

By investigating the pharmacology and molecular regulation of the mu-delta opioid receptor hetero-oligomer under basal conditions and following chronic morphine treatment, this study advances our understanding of the opioidergic system which is intricately involved in modulating several neurological functions including analgesia, mood states and adaptations to prolonged exposure to drugs of abuse. Our findings suggest that the mu-delta opioid receptor hetero-oligomer may be a suitable therapeutic target for treating neurological disorders requiring prolonged exposure to morphine. This research is tightly aligned with the mandate of the INMHA as it seeks to advance our understanding of the mechanisms underlying pain, mood disorders, and drug addiction –diseases of the nervous system which affect millions of Canadians- and the novel therapeutic approaches to treat them.


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Ping Situ

Title: Interaction of corneal nociceptive stimulation and lacrimal secretion. Situ & Simpson IOVS v51:5640-5 2010

Biosketch:

I have had previous training in medicine (ophthalmologist) in China. After completing my masters degree in Vision Science from University of Waterloo, I started to work as clinical scientist at the Centre for Contact Lens Research (CCLR), University of Waterloo; I currently am a Senior Research Scientist in the CCLR. I have had opportunities to do research related to ocular discomfort which is often reported by normal people, post refractive and cataract surgery patients and in contact lens wearers, even when no clinical signs of ocular surface damage are present. My curiosity is driven primarily by trying to understand the neural mechanisms contributing to these sensations in humans.

This clinical research experience and difficulty in addressing some issues clinically motivated me to pursue a PhD focused on sensory processing of the ocular surface.

I defended my thesis in April 2010, and I plan to continue investigating neural mechanisms contributing to ocular sensory processing and the exteroceptive and interoceptive properties of the ocular surface sensory nervous system.

Significance of paper:

The cornea possesses the richest sensory innervation in the body. Sensory signals arising from the cornea (thus the ocular surface) play an important part in the lacrimal functional unit comprising the ocular surface (cornea, conjunctiva and meibomian glands), the lacrimal glands, and the sensory afferent and autonomic efferent nerves that connect them. The overall function of the functional unit is to protect the integrity of the tear film and the ocular surface and maintain the quality of the principle optical component of the eye. Acting though the central nervous system, the components of the functional unit are linked into a homeostatic loop by specific sensory input and efferent output pathways. This paper investigated the interaction between sensory stimulation and the efferent output as determined by tear secretion, in an attempt to understand the neural mechanisms contributing to sensory processing of the ocular surface and the linkage of psychophysics and neurophysiology. A stated mission of the Institute centres on understanding sensory and motor systems and my work, for the first time, quantitatively attacked a specific question about neural sensory control and the efferent outputs of this lacrimal functional system in humans. This is not only aligned with the specific Institute objective but is also in line with a more general mission of work that will impact the health of Canadians since ocular discomfort and dry eye symptoms are very common in Canada and understanding the processes of the lacrimal functional unit is an important first step in treating and eliminating the problem of dry eye.


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Muhammad Qasim Khan

Title: Prion disease susceptibility is affected by beta-structure folding propensity and local side-chain interactions in PrP

Biosketch:

I joined the laboratory of Dr. Chakrabartty in September of 2005, enrolled as a Masters student with the department of Biochemistry at the University of Toronto. Now a Ph. D candidate, I have greatly benefited from Dr. Chakrabartty's laboratory, which uses the latest technology in the field of biochemistry to study the characteristics of protein folding and misfolding, the latter playing a crucial role in diseases such as Alzheimer"s disease, amyotrophic lateral sclerosis (ALS), and mammalian prion diseases. Furthermore, the collaborations with protein structural laboratories, such as NMR and Xray crystallography, and other cell culture laboratories, have served to widen my research knowledge in protein biochemistry.

Our collaborations extend beyond the campus of the University of Toronto. We have started a collaboration with Dr. Aru Balachandran, a government scientist with the Canadian Food and Inspection Agency (CFIA). The facilities and personnel at the CFIA will enable us to work with animals, infectious scrapie material and diagnostic equipment in order to assess the efficacy of a potential vaccine to prion diseases. Ironically, the CFIA provided me with my first taste of laboratory research (not literally), as I performed high-school co-op terms in the department of Mycology and Nematology, and was subsequently hired during the summers of my undergraduate years.

Significance of paper:

As stated in Remi Quirion's assessment of the INMHA (Trends in Neuroscience, 2002, 35:268-270) 'The vision of the INMHA is to lead the way in providing new knowledge of the biological and socio–cultural processes underlying neurological, mental and addictive disorders.' Our paper provided new insights into the biology of prion diseases, a neurological and mental disorder that is caused by the misfolding of normally-expressed prion protein into disease-associated forms. The new knowledge that our paper provided was that a common toxic oligomer can be formed by the prion protein from different mammalian species including hamsters, mice, rabbits, horses and dogs. Furthermore, the occurrence of prion diseases in these animals relates to the propensity of the prion protein from these animals to form toxic oligomers, a novel finding that emphasizes the importance of polymorphisms within the prion protein and how they affect misfolding. Our paper also fulfills one of the long-term, major initiatives of the INMHA - 'First episodes in neurological and mental illness, and in addiction.' It does so by indicating that the accumulation of toxic oligomers may represent the first stages in the development of not only prion diseases, but also other protein-misfolding diseases such as Alzheimer"s disease and Parkinson's disease.


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Joel Ramirez

Title: Lesion Explorer: A comprehensive segmentation and parcellation package to obtainregional volumetrics for subcortical hyperintensities and intracranial tissue

Biosketch:

Joel Ramirez was first introduced to the neurosciences as an undergraduate psychology student at Glendon College, where his undergraduate thesis on visual-spatial attention, under Dr. Josee Rivest, led him to his Master's Work at York University. Through the Kinesiology and Health Science Department, under Dr. Barry Fowler, his Master's work specializing in cognitive electrophysiology led to a first-author publication in the journal 'Biological Psychology'. During his Master's work, he also worked on various projects as a junior research assistant with the Defense and Civil Institute of Environmental Medicine (DCIEM) and the Canada Space Agency (CSA). Joel is currently completing a Ph.D. through the Institute of Medical Sciences at the University of Toronto under Dr. Sandra Black. His current work at the Sunnybrook Health Sciences Centre's LC Campbell Cognitive Neurology Research Unit and the Heart & Stroke Foundation's Centre for Stroke Recovery, is focused on structural neuroimaging of the aging brain examining Alzheimer's Disease, dementia, and cerebrovascular disease. He was also the recipient of the Biomedical Doctoral Training Award by the Alzheimer Society of Canada in 2008.

Significance of paper:

In addition to changes in the brain's tissue volumes, the Lesion Explorer methodology provides researchers and clinicians with an individualized comprehensive volumetric profile where various lesions in the brain can be localized, quantified, and characterized, in order to better our understanding of these so-called 'silent strokes' within the brain. The Lesion Explorer software package is currently being applied in research projects in Chicago, Taiwan, Sherbrooke, Hong Kong, Buffalo, and UC San Francisco and is proving to be a useful tool in brain-behavior studies with cognition and memory. Lesion Explorer is currently being applied in the Sunnybrook Dementia and Aging study, examining signs of cerebrovascular disease and Alzheimer's Disease in a CIHR-funded longitudinal study at the LC Campbell Cognitive Neurology research unit. As subcortical vasculopathy in the brain is becoming of particular interest to clinically-driven neuroscience, along with the increasing availability of neuroimaging through MRIs, this publication is targeted to the clinical research neuroscience community studying dementia and aging through neuroimaging. The paper was submitted to NeuroImage, by Elsevier, as one of the highest rated journals in the radiology, nuclear medicine & medical imaging fields, to reach the largest audience in the medical imaging community.