Modulation of ocular motor decisions by reward: an investigation of neural processes using converging methods

The prospect of reward or punishment is known to affect how people make decisions. However, it is not clear which neural systems are involved in this process. This is an important topic in healthcare, because impaired processing of reward information is known to affect the decision-making abilities of many people, including those with damage to the frontal lobe of their brains, Parkinson’s disease, depression/anxiety, obsessive compulsive disorder, and even normal aging. A striking example of this situation occurs among some people with Parkinson’s disease, who can develop pathological gambling behaviours as a result of taking dopaminergic drugs. An effective way to study these neural systems is to track eye movement decisions – in other words where people focus their visual attention. Typically, people are faster to make an eye movement and are more accurate in their eye positions when the movement is rewarded by monetary gain. However, these effects are degraded in certain psychiatric conditions, such as anxiety and depression. Dr. Linda Lanyon is investigating the brain circuits that mediate these reward-related decisions in healthy humans. Her findings will enable her to develop a computer model of the brain circuitry and function that is able to simulate the behaviours observed in humans. In addition to demonstrating how these systems operate in healthy humans, the computer model can also be selectively damaged in order to simulate pathological behaviours observed in patients. By using healthy subjects to create a computer model for decision-making, Linda hopes to improve the understanding of the pathology of neurologically-impaired circuits.

Functional significance of adult hippocampal neurogenesis

The hippocampus is critically important for learning and memory and is one of only two brain regions than can produce new neurons in adulthood. There is some evidence that the addition of new neurons (neurogenesis) in the hippocampus is involved in or may even be required for the normal functions of this region. The rate of neurogenesis declines with age. It is widely accepted that aging is also associated with a decrease in memory performance, especially on the types of tasks that require the hippocampus. Decreased neurogenesis has been proposed as one possible factor that may reduce the efficiency of hippocampus-mediated learning and memory. And while there is believed to be a relationship between hippocampus-dependent learning and cell proliferation and survival, it’s not known What exactly this relationship is: whether neuronal growth affects hippocampus-dependent learning, or whether hippocampus-dependent learning affects the rate of neurogenesis. Other studies also suggest there may be a critical cellular age for new neurons when their survival can be altered. However, given the many conflicting studies in the literature, it is unlikely that there is a simple relationship between level of neurogenesis and memory performance. Jonathan Epp is exploring these various factors to determine the processes by which hippocampal neurogenesis occurs in adulthood, and the importance of neurogenesis to learning and memory. Using animal models, he will clarify whether cell survival can be enhanced at all times or whether there is a critical cellular age during which survival altering factors may have an impact. Epp hopes that by developing a better understanding of these relationships in the brain, this knowledge could be applied to generating therapeutic strategies for dealing with memory loss associated with aging, dementia and brain injury

Spatial characterization of brain activation in Parkinson's Disease research

Parkinson’s disease (PD) affects 100,000 Canadians, and this number is expected to increase with the aging of the population. Primary symptoms include tremor, rigidity, slowness of movement, and posture instability. These motor disabilities are believed to be associated with the premature death of dopamine-secreting cells in the brain region Substantia Nigra pars compacta. However, the cause of this premature cell death is unknown, and symptoms often do not emerge until 80 per cent of the dopaminergic cells are lost. Detecting the onset of PD thus remains a major challenge, hindering the development of a cure. It is believed that substantial compensation occurs in the brains of PD patients, obscuring the early effects of disease. Therefore, current clinical assessments that rely on symptom severity may not provide an accurate measure of disease progression. Instead, it is predicted that abnormal brain activity changes will emerge long before substantial dopaminergic cells are lost. Thus, altered brain activity may serve as a more useful marker than symptom severity for diagnosing and treating PD. In order to disentangle compensatory mechanisms from disease effects, Bernard Ng is comparing the brain activity of PD patients at similar stages of disease progression, but with varying degrees of symptom severity. Specifically, he is using functional magnetic resonance imaging (fMRI),to study diseased-induced changes in brain activity within specific brain regions as well as changes in connectivity between brain regions. To more elaborately characterize brain activity, he is employing novel statistical spatial descriptors to examine the spatial distribution of regional activity in additional to the traditionally-employed intensity measures. By incorporating spatial information in this combined approach, better distinctions between compensatory mechanisms from disease effects would be enabled. Ng’s research aims to provide more accurate diagnosis of disease progression in PD patients, better assessment of medication effectiveness, and ultimately earlier PD detection.

The effects of Sildenafil on cardiac and lung function in heart transplant recipients during exercise

While heart transplant recipients have significantly improved tolerance for exercise post-transplant, their aerobic exercise capabilities remain 40 – 60 per cent below normal. Blood vessel dysfunction, skeletal muscle wasting, and surgical severing of the nerves to the heart have all been implicated as factors contributing to reduced aerobic capabilities in individuals following heart transplantation. Heart transplant recipients also have dramatic pressure increases in the blood vessels within their lungs during exercise. These abnormally high pressures may result in heart dysfunction and breathlessness, causing impaired exercise tolerance. The drug Sildenafil has been shown to reduce pressure in the blood vessels of the lung. Previous research has shown that Sildenafil improved heart function during exercise among heart failure patients. Ben Esch is investigating whether Sildenafil is also beneficial to heart transplant recipients during exercise. He is testing aerobic exercise capacity among 20 heart transplant recipients both with and without Sildenafil — assessing their heart function (using cardiac ultrasound) and oxygen uptake. The results from this investigation may have important implications for cardiac rehabilitation in heart transplant recipients. If Sildenafil is shown to have a positive effect on cardiac function and exercise tolerance, its use could help heart transplant recipients train at higher intensities for longer duration during their exercise rehabilitation.

Optimizing the impact of antiretroviral treatment as an HIV prevention intervention in marginalized populations

The introduction in the mid-1990s of highly active antiretroviral therapy (HAART) helped HIV become a manageable disease in industrialized settings such as Canada. Mortality and morbidity associated with HIV have been dramatically reduced with the increased use of these drug regimens and are associated with reduced transmission probability of HIV within sexual relationships. It has been proposed that HAART be integrated into HIV-prevention activities as a means of helping curb epidemic growth. Evaluating the impact of HAART is complex. For example, while the effect of reduced symptoms and increased lifespan is beneficial to the individual, modelling studies have shown that unless infectiousness of individuals is sufficiently reduced by antiretrovirals, the negative impact of an increased incubation period (leading to increased number of opportunities for transmitting infection and a larger population of transmitters) can actually increase how fast the infection spreads. Using mathemathical modelling methods, Kathleen Deering is comparing the impacts of HAART in Vancouver (where HIV-infected individuals have free access to treatment), and in southwest India (where only about 10 per cent of HIV-infected people have access). Her studies, which consider infection biology, behavioural and demographic characteristics of the population, and the spread of infection over time, will be used to compare different treatment strategies for HAART, and to project disease outcomes. Deering’s research will provide evidence for developing HIV treatment and care recommendations that will help maximize the effectiveness of HAART among marginalized groups in Canada and India.

British Columbia Burden of Injury

Injuries are a significant public health problem in BC. Every year about 1,600 British Columbians die due to injury, 42,000 are hospitalized, and an estimated 400,000 people throughout the province sustain some sort of injury. The cumulative effect of injury on a population is known as the burden of injury. Burden of injury data help policy makers and practitioners determine the effectiveness of current services in injury prevention and injury treatment, and provide direction about new interventions that would have the greatest impact. They also help provide estimates for recovery time across different injuries. However, very little is known about the burden of injury, making this an important priority for research.

Dr. Mariana Brussoni is leading a longitudinal study in BC to quantify the impacts of injury on individuals and on the health system. Drawing on her experience working in England with international experts in injury research and prevention, Brussoni is recruiting more than 1,400 injured people of all ages across urban and rural settings in BC. They will be followed for 12 months post-injury, with the research team tracking their quality of life and recovery, use of health and social services, and time away from school or work. The goal of this research is to more fully describe the various impacts of injury in British Columbia, and to identify areas where prevention and treatment interventions could make the biggest difference.

Presynaptic voltage-gated calcium channels: binding and regulation by SNARE proteins

Electrical signals are the fastest signals in our bodies. These signals are mediated by ion channels, specialized proteins that allow particular charged ions to pass through cell membranes. One class of ion channels, known as voltage-gated calcium channels, is of particular importance. They allow calcium ions to pass through the cell membrane when an appropriate electrical signal is present. In doing so, these channels play crucial roles in regulating heartbeats, in muscle contraction and in the release of hormones and neurotransmitters. The role of calcium channels in human health is significant. Mutations in the channels cause severe genetic diseases, and many drugs that are currently used to treat cardiovascular diseases, epilepsy and chronic pain target calcium channels to limit their dysfunction. Efforts to develop new drugs are hampered by the limits of what is known about the channels, particularly about their atomic structure. Dr. Filip Van Petegram is working to shed new light on the intricate workings of calcium channels that are expressed in the heart, in the brain, and in skeletal muscle. Van Petegram uses cutting edge technologies to gain a precise understanding of calcium channels. X-ray crystallography determines a protein’s atomic structure, producing high resolution structural images that serve as excellent templates for the design of new drugs, and provide valuable information about how the channels work. Electrophysiology measures the tiny electric currents that are generated when calcium ions pass through the channels. This work will contribute to novel treatment strategies for targeting calcium channels.

Social Pediatrics: A Responsive Interdisciplinary Coordinated Health [RICH] Model for Timely Accessible Services for At-Risk Families

Social pediatrics is a model of practice that places specific emphasis on the importance of the relationship between the practitioner and the child as well as focuses on family and community engagement as vital to the ways in which care is provided. Moreover, it is located in the child’s community and seeks to ensure care is accessible and responsive to the child and family’s health needs. To date, little is known about the processes needed to implement a social pediatrics model of practice within the current structure of the health system.

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Formation, stabilization, and dynamic modulation of GABAergic inhibitory synapses in the central nervous system

In the central nervous system (CNS), the chemical synapse is the major site of communication between neurons (nerve cells). There are two main types of synapses in the CNS: excitatory glutamate synapses and inhibitory gamma-aminobutyric acid (GABA) synapses. Dysfunction of GABA synapses has been identified in disorders such as autism, schizophrenia, and depression. GABA synapses are also the main targets for drugs to treat epilepsy and anxiety. The protein neuroligin is a molecule that directs a neuron to form a synapse at the place where it comes in contact with another neuron. A specific type of neuroligin, Neuroligin-2, builds GABA synapses. However, little is known about why and how Neuroligin-2 is specific for building GABA synapses. Frederick Dobie was previously funded by MSFHR for his research in protein transport in neurons. He is now studying proteins involved in synaptogenesis (the process of building a synapse). To better understand how GABA synapses are formed, he is looking at regions of Neuroligin-2 that are important for this function. He is also studying how GABA synapses can change over time, responding to the specific needs of the neuron to fit into a fully-functioning brain. He is watching the growth and maturation of synapses over a period of several days, observing in real-time the strikingly dynamic appearance, disappearance, and movement of synapses. By understanding the biology underlying GABA synapses, Dobie hopes his work will ultimately lead to the advancement of therapies for a wide range of debilitating developmental, neurological, and psychiatric disorders.

Ex vivo generation of antigen-specific human T regulatory cells with in vivo suppressive capacity

Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which insulin-secreting islet beta cells of the pancreas are destroyed by a type of white blood cell called a T cell. While most people with T1DM must receive insulin injections to maintain proper blood glucose levels, a recent option for some patients is to undergo islet transplantation, which replaces the insulin secreting cells they have lost with new donor cells. However, the immunosuppressive drugs required to prevent graft rejection are costly and have serious side effects. Researchers continue to search for new methods to achieve long term transplant survival. T regulatory (Treg) cells have great potential to protect islet grafts from rejection. Treg cells are a subset of white blood cells with the capacity to suppress immune responses. It has been shown that a key protein named FOXP3 is essential for the development and function of Treg cells. T cells expressing this protein can reduce autoimmune disease and reverse established diabetes in mice. Researchers recently developed a method for converting human T cells into Treg cells. Alicia McMurchy is generating human Treg cells and testing their ability to inhibit graft rejection in a mouse model. Her prediction is that the generated Treg cells will inhibit graft rejection and allow long-term survival of transplanted islets. If validated, this approach could indicate a promising future for clinical use of Treg cells in transplantation, potentially alleviating the need for expensive and harmful immunosuppressive drugs and improving the health and quality of life of T1DM patients and other transplant patients.