When they are functioning well, intimate relationships contribute to better health and increased longevity. A cornerstone of well-functioning relationships is the ability to forgive a partner for relationship transgressions, such as telling lies, flirting with another person, or saying hurtful things. Repairing a relationship following the hurtful actions of one partner has consequences, not only for relationship quality, but also for physical health. One way that the act of forgiveness may be associated with health relates to cortisol production. Cortisol is a hormone released by the adrenal gland during times of stress. Chronic elevations of cortisol have negative effects on cardiovascular, immune, and brain systems and potentially increase the risk for diabetes, hypertension, immune system deficiency, and other illnesses. Being unforgiving has been shown to produce cortisol in a similar pattern to that which is experienced during other stress responses. Kim Watt is examining whether cortisol production is a mechanism for the link between forgiveness and general physical health. She is conducting her study with 200 newlywed couples, recording their physical health and measuring their cortisol levels at baseline and following a set of emotionally stressful marital discussions. Results from this study will contribute to a clearer understanding of the risk pathways by which negative relationship processes may lead to poor physical health. This may suggest that a focus on strengthening close relationships by improving couples’ skills when discussing relationship issues is a way of ultimately reducing health problems.
Research Pillar: Clinical
Cognitive contributions to checking compulsions
Obsessive-compulsive disorder (OCD) is an anxiety disorder that afflicts three percent of all Canadians. The disorder is characterized by intrusive and unwanted thoughts, images or impulses that cause anxiety, and that are temporarily relieved by the execution of specific compulsions. Obsessions and compulsions can occupy a large proportion of individuals’ time and energy and can interfere with daily routines, functioning at work, social activities and relationships with others. Checking compulsions are among the most common manifestations of OCD. Individuals with checking compulsions have intrusive concerns that they have failed to perform some task (such as locking the door or turning off the stove) and feel compelled to repeatedly check to ensure that the task was indeed completed. Preliminary evidence suggests that impaired prospective memory may play an important role in checking compulsions. Prospective memory is the ability to remember plans and intentions at a later moment. Everyday life and clinical observations show that checkers’ compulsions are related to this future-oriented aspect of memory and that the types of activities that tend to trigger checking compulsions are prospective memory tasks. Dr. Carrie Cuttler was previously supported by MSFHR with two research training awards. Her current work continues her exploration of whether individuals with checking compulsions have a cognitive deficit related to prospective memory. She hypothesizes that checking compulsions may develop to compensate for an impairment in prospective memory. In other words, individuals who frequently forget to perform tasks may develop a strategy of repeatedly checking to ensure that important tasks are not forgotten. Cuttler’s research focuses on improving our understanding of the mechanisms underlying OCD. The results will improve the quality of OCD patients’ lives by setting the stage for more effective treatments for reducing the frequency of checking compulsions.
Antiangiogenesis-induced changes in the tumour microenvironment: a window for therapeutic exploitation in pancreatic cancer
Pancreatic cancer is the deadliest form of cancer, with an average life expectancy of three to six months after diagnosis. Surgical removal of the tumour is the only curative treatment, but the majority of patients have inoperable tumours. A promising treatment strategy for many cancers types is to kill blood vessels in tumours. When blood vessels are disrupted, the tumour becomes starved of nutrients and oxygen. Some success in has already been seen with two different types of drug treatment: drugs that act specifically on blood vessels, and standard anti-cancer drugs delivered at low but continuous doses. While these treatments are promising in the context of pancreatic cancer therapy, their specific effects on pancreatic tumours are unknown. Dr. Jennifer Flexman is studying the effects of both types of drug on tumour growth and blood vessels. Using a variety of imaging techniques and biological methods, she will investigate how the tumour microenvironment (e.g. blood flow, oxygen levels) is changed by antiangiogenic drug therapies. Experimental results could lead to a rational basis for selecting treatments that takes advantage of physiological changes in the tumour. Dr. Flexman hopes her research will ultimately lead to the development of novel and more effective treatments for a deadly and largely untreatable disease, with the end goal of improving the quality of life and prognosis for patients
Peripheral neurophysiological basis of sensorimotor deficits in individuals with essential tremor
Essential tremor (ET) is a neurological disorder characterized by shaking of the hands (and sometimes other parts of the body) that occurs with voluntary movement. Often mistaken for Parkinson’s disease, it is the most common tremor disorder. Approximately 75 per cent of people living with ET experience some limitation in their activities, and these limitations typically get worse with increasing age. Therapies for essential tremor focus on tremor reducing medications, but effective treatments remain limited. Consequently, new insights into disease mechanisms are needed to guide the development of more effective therapies. The origins of essential tremor are believed to involve abnormal rhythmic activity in the brain, which then travels down to the peripheral nervous system. However, the specific neural pathways that the tremor travels, as well as how ET influences the recruitment of muscles for movement, remains unclear. Also unknown is the impact of tremor on sensory receptors found within skeletal muscles, which provide the sense of position and movement of the limbs. Dr. Martin Héroux is conducting studies on British Columbians with ET to determine how their muscles and sensory receptors are affected by abnormal rhythmic activities of essential tremor. He hopes these studies will increase our knowledge of the neural mechanisms involved in the generation of essential tremor and provide a better understanding of the motor-sensory deficits associated with tremor disorders. Ultimately, this knowledge could contribute to the development of more effective anti-tremor therapies.
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.
Examining the interplay between adherence and antiretroviral treatment on disease outcomes over time in HIV/AIDS-infected patients
HIV therapy has evolved tremendously due to the development of new drugs, new technologies to measure viral response and drug resistance, and an improved understanding of how the virus progresses in the body. Modern highly active antiretroviral therapies (HAART) suppress the amount of virus circulating in the blood to nearly undetectable levels for long periods, enabling the immune system to rebound, reducing HIV drug resistance and preventing this otherwise fatal disease from progressing. Clinicians have identified that many people on HAART therapies do not fully adhere to the prescribed therapy, and that their level of adherence typically changes over time. This lack of adherence is known to increase the risk of illness and death, but the specifics remain unclear. More information is needed to determine how adherence dynamically affects disease progression and outcomes, so those at higher risk of treatment failure can be identified in advance and helped with their treatment. Dr. Viviane Lima is exploring the relationship between regimen-specific adherence for key HAART therapies and the disease outcomes for patients. She will determine the levels of adherence required at each stage to reduce or prevent a number of disease outcomes: viral rebound, immune cell loss, HIV drug resistance, the emergence of AIDS-related conditions, and death. She hypothesizes that for each disease outcome, there is a distinct, clinically-significant interaction between adherence and type of HAART therapy. Long-term management of HIV/AIDS requires a long-term commitment from patients to adhere to therapy, a high level of expertise among practitioners to deal with complex and rapidly evolving treatments, and the development of clinically meaningful tools to enhance adherence over time and across varied treatments. Lima’s study will provide an evidence base to identify best treatment practices.
Genetics of healthy cardiovascular aging
Statistics Canada projects that there will be more than 1.6 million seniors over 85 by the year 2041. Only a minority who reach this age maintain a good quality of life and are free of major age-related diseases such as cardiovascular disease (CVD), cancer, lung disease, diabetes, and Alzheimer’s disease. Advancing age is the biggest risk factor for cardiovascular disease. However, a minority of people older than 85 — called “”super seniors”” — seem resistant to the most common age-related diseases, including CVD. These people may represent a group that either lacks genetic susceptibility factors that contribute to disease in the majority of people or may possess genetic resistance factors that enhance their ability to resist disease and prolong lifespan. Dr. Maziar Rahmani seeks to answer whether people whose hearts remain healthy well into their 80s and 90s have “good genes.” He is studying more than one thousand residents in the Metro Vancouver area, using cutting-edge technologies to scan the entire genome of each study participant. He will look across more than a million potential variances to find genetic commonalities among super seniors in Vancouver, and compare these findings to other studies using European and other North American populations. Identifying and understanding genetic factors that influence resistance or susceptibility to heart problems could open the way for personalized, optimized disease prevention and treatment strategies.
Statistical models for clinical genomics of cancer
Ovarian cancer is the most fatal gynecological cancer in North American women and the fifth most common cause of cancer death. Breast cancer is the most common cancer in women worldwide. Recent approaches to improving clinical outcomes for these two diseases have focused on defining distinct subtypes within ovarian and breast tumours that differ in their clinical outcomes and responses to therapy. Preliminary evidence suggests that subtypes can be detected from biopsies by performing state-of-the-art molecular tests to determine specific molecules (called markers) that distinguish the subtypes. It is also expected that an even smaller subset of markers could be used as indicators for determining prognosis and for directing therapy tailored to the subtype. A number of BC research programs are currently working collaboratively to identify and characterize the subtypes of ovarian and breast cancers, using more than 2,000 breast cancer and 400 ovarian cancer tumours for which clinical outcomes are known. This work generates massive amounts of molecular data (more than 100,000 data points per tumour). Previously supported by MSFHR funding for his PhD training, Dr. Sohrab Shah focuses his post doctoral work on developing bioinformatics (the application of computer science tools and research to biology) and statistical modeling approaches that can help pinpoint potential markers among the reams of data. Shah’s research is key to developing tools that help uncover the molecular characteristics of the subtypes of breast and ovarian cancers, and provide state-of-the-art classifiers for improved outcomes for patients with these devastating diseases.
Modulating mood with transcranial direct current stimulation: basic research and clinical applications for treating depression
Approximately 8 per cent of all Canadian adults will experience at least one major episode of depression during their lifetimes, and up to 6.5 per cent of Canadian children currently meet the criteria for clinical depression. Efforts to understand the neural mechanisms underlying depression and to develop new treatment methods for the mood disorder have the potential to facilitate improvements in quality of life for people throughout Canada and around the world. Neuroimaging studies show that negative mood and depression are associated with increased activity in the right prefrontal cortex and decreased neural activity in the left prefrontal cortex. Dr. Bradley Vines is examining how changes in neural activity in the prefrontal cortex influence mood. He is also exploring the therapeutic potential of transcranial direct current stimulation (TDCS) as a treatment for clinical depression. TDCS is a safe, painless, and non-invasive brain stimulation technique that modulates neural activity in targeted brain areas. It has been shown to significantly influence behavioural and cognitive performance. The technique involves running a low-level direct current between two electrodes placed on a person’s scalp. The neurons underneath the positively-charged anode fire more rapidly, whereas the neurons underneath the negatively-charged cathode become less active. Using tDCS, it would be possible to simultaneously increase neural activity in the left prefrontal cortex and decrease activity in the right prefrontal cortex – potentially correcting the neural imbalance that is characteristic of depression. Vines’ research promises to advance our understanding of how the prefrontal cortex contributes to emotional states and mood disorders, and to determine the viability of using tDCS as a therapy for depression.
SNARE protein properties in schizophrenia
Schizophrenia is a severe psychiatric illness affecting one percent of the general population. Symptoms typically manifest in early adulthood and often have a devastating effect on an individual’s quality of life and functioning in society. The diverse and debilitating symptoms associated with schizophrenia include hallucinations, delusions, dampened emotion and poverty of speech. It has been hypothesized that faulty neuronal function may contribute to these symptoms. Communication between neurons is achieved by neurotransmission at synapses. Because soluble NSF-attachment receptor (SNARE) proteins mediate this process, they are important in neuronal communication and normal brain function. Altered levels of SNARE proteins have been found in patients with schizophrenia. Vilte Barakauskas was funded by MSFHR for her initial PhD work in this area. Based on her previous findings, she hypothesizes that among people with schizophrenia, SNARE proteins function abnormally at the synapse, contributing to the disorder. She is now working to further characterize SNARE proteins in brain tissue, comparing control subjects to those with schizophrenia in order to identify which protein properties are different in the disorder, and how these differences contribute to altered neuronal communication and brain function. Comparison of protein properties between control subjects and those with schizophrenia may suggest a specific molecular mechanism contributing to altered neurotransmission. This new knowledge could lead to novel treatment targets for this devastating psychiatric disorder.