The neural correlates of cognition in depression

Recent data suggest that 1.5 million Canadians, or 12 per cent of the population, will experience an episode of major depression at some point in their lives. For many, depression often becomes a chronic illness, with recurrent episodes. Cognitive neuroscience researchers are currently examining networks in the brain that are involved in depression, in the hope of developing better treatments and therapies for this devastating disease. MSFHR previously funded Fern Jaspers-Fayer for her Master’s research on the electrical brain activity changes associated with Seasonal Affective Disorder (SAD). For her PhD work, Jaspers-Fayer is continuing her studies in this area. She has studied the timing and location of electrical brain signals from electroencephalograms (EEGs) that were recorded from people with symptoms of depression while they completed a number of cognitive tests. She found that although everyone pays more attention to negative events than positive ones, people with low mood will go on to ruminate about these events. This contemplation, which may become persistent and brooding, then affects how they behave. Using new techniques to localize these effects in the brain, Jaspers-Fayer is now disentangling both when and where in the brain the process of rumination begins and what conditions increase the likelihood and the duration of rumination. Jaspers-Fayer’s work will ultimately lend knowledge to our understanding of the underlying cognitive mechanisms involved in emotion, helping to pinpoint the timing and activation of brain areas involved in depression. Her research in rumination could potentially inform new approaches and therapies for treating depression.

Integrating gene expression data, interaction network information and evolutionary analysis to investigate mammalian innate immunity at the systems level

The immune response is the set of defenses our bodies mount to counter harmful microbes. The innate immune response is our first line of defense, providing protection until the adaptive immune response is activated. Unfortunately, the innate immune response can also be a double-edged sword. It can spin out of control and cause an overwhelming immune response called sepsis, which is responsible for 200,000 deaths every year in the US. The innate immune response is initiated and regulated by complex signalling pathways of genes in our cells. These pathways identify which type of microbe is invading (bacteria or viruses, for example) and mounts appropriate responses. Dr. David Lynn is investigating the genes involved in the innate immune response, how they are turned on and off in particular infections, and what goes wrong in cases of sepsis. This work generates vast quantities of data, requiring computer-based approaches (bioinformatics) to understand and handle such large datasets. Lynn’s work integrates gene expression data with information about how genes and proteins are interconnected in our cells in signalling networks or pathways – providing new information about gene interconnections influence their regulation. He is also investigating the same networks and pathways in other species such as mouse and cow, determining the differences and similarities in their innate immune response. Lynn’s work will help identify potential therapeutic or drug targets that could help safely boost the immune response. It will also highlight cases where important immunological differences make animal models unsuitable for research on human immunity.

Improved characterization of orthologs to facilitate cross-species analysis of innate immune system gene responses

The innate immune system is the body’s first line of defense to protect us from disease-causing microbes in our environment. However, the innate immune system can also generate other unintended and serious effects such as prolonged – and sometimes fatal – inflammation. The study of human systems such as the innate immune system is assisted by examining similar systems in other organisms, known as model organisms. Researchers link equivalent genes in the model organism to human genes, so that knowledge can be transferred from the model organism to humans. However, identifying equivalent genes between species can be a difficult task. The Brinkman laboratory at Simon Fraser University has developed a software program called Ortholuge that can detect pairs of genes that are likely to be “orthologs” – genes in different species that are similar to each other because they originated from a common ancestor. Orthologs are of significant interest when inferring function in humans based on different species, or when linking equivalent genes between species for large scale comparative analyses. Matthew Whiteside is working to improve the accuracy and speed of Ortholuge, adding functionality to the program that will resolve some of the more complex gene relationships. He will then use the software to perform a large-scale study of the innate immune system in humans, mice and animals important in agriculture, such as cattle. Whiteside’s work will be the first large-scale cross-species comparative analysis of the innate immune system. He hopes that this study will provide fundamental new insights regarding the evolution of innate immune system. This analysis may also highlight important innate immunity genes that are conserved between the species, with potential for identifying new therapeutic targets for immune diseases.

Spatial epidemiology of trauma: understanding and preventing injury through geographic analysis

Over the course of the last two decades, the notion that health and well-being is tied to societal and environmental circumstances that may overlap and intersect with important elements of individual experiences has been widely utilized as a means of characterizing the inequitable distribution of a wide range of health outcomes, including injuries. Importantly, the population health perspective model is transforming how we understand the complex interaction between the environment and injuries, and tailoring prevention and policy responses to address the inequitable distribution of their occurrence. Yet, there are currently no frameworks in place for how we quantify the interconnectivity between social, environmental, and geographical determinants of injury and building evidence that highlights the underlying relationship between all three factors with injuries. Addressing the ecological and geographical questions regarding this complex interaction entails integrating the current injury prevention models with the tools and analysis functions of geographic information systems (GIS). GIS are widely recognized as essential tools in public health promotion and surveillance as they allow for the integration of multiple data sources and the visual and spatial analysis of health data in relation to locations, distances, or proximities. GIS can increase our understanding of current population access to emergency medical services, the extent that injuries ‘cluster’ in certain areas and among certain population groups, as well as help researchers better understand and locate the links between people and their environments that may either reduce or increase injury risk. Nathaniel is currently applying GIS in a number of research areas in order to determine where important systems elements might be augmented to improve population access to critical care, for identifying incidence patterns that might have gone under noticed had they not been examined using GIS, as well as how this technology might be used to help researchers more accurately target prevention efforts to reach communities in-need. This research will help structure ongoing injury prevention efforts in British Columbia as well as provide future researchers with a number of frameworks for using GIS to improve our understanding of the societal, environmental, and geographic factors associated with injury.

Production of high-quality proteins in plants for screening and treatment of human lysosomal storage diseases

Lysosomes are structures that digest materials within the cell. Lysosomal storage diseases are devastating diseases caused by deficiencies of specific enzymes within the lysosomes. Mucopolysaccharidosis I (MPS I) is a progressive lysosomal storage disease that affects most organ systems. In severely affected humans, this genetic disease leads to early death because of profound disturbances to the heart, brain and other organ systems. One way to correct lysosomal enzyme deficiency is through using purified enzymes for enzyme replacement therapies (ERT). However, the current methods used to commercially produce the enzymes for ERT are prohibitively costly. Because of this, sustained financial support for ERT among affected Canadians is uncertain. Dr. Allison Kermode is exploring whether using plants as hosts to produce these human enzymes will offer a more economical way to provide ERT treatments for MPS I, as well as for Gaucher disease, another lysosomal storage disease. She will test whether plant-made human enzymes are effective as ERTs. She will also establish a plant-based system for assessing potential small molecule treatments for these diseases. Finally, in collaborative work, Kermode will test plant-made lysosomal enzymes in assays for newborn screening of lysosomal storage diseases. Some of the research will be expanded to other therapeutic proteins relevant to Type I diabetes, providing a general platform for plant production of therapeutic proteins.

Redefining community resilience: community perspectives on the intersection of gender, mental health and adaptive capacity in the context of the Mountain Pine Beetle disaster

Much of British Columbia’s forests have been infested with the mountain pine beetle (MPB), an epidemic that is predicted to result in the loss of more than 80 per cent of the province’s pine forests by 2013. The MPB is also expected to result in the widespread loss of jobs, shifts in traditional resource cultures of affected communities, and an increased risk of forest fires and other natural disasters (e.g. slides, flooding). Gender is recognized as one of the most critical determinants of disaster-related vulnerability. Women and children are disproportionately affected by disasters, reporting higher rates of stress-related health problems (e.g., post-traumatic stress, anxiety, depression), an increased risk of sexual and domestic violence, greater economic marginalization, and substantial increases in their work. They are also less likely to be involved in community-based planning and decision-making processes. Dr. Robin Cox is analyzing individual and collective stressors associated with MPB in four forestry-dependent communities: Barriere/Louis Creek, Clearwater, Quesnel and Wells. She is piloting a community-based research strategy intended to engage affected residents in each community in a series of workshops and focus group interviews. The focus of these events is to identify and elaborate community-based definitions and strategies of resilience that reflect the specific cultural, social, and political contexts of participants. The proposed study will contribute to the development of knowledge around community resilience that integrates a gender perspective, and will lead to the development of policies and procedures that are relevant and responsive to different communities affected by MPB.

The reliability and validity of the External Hostile Attributions Scale (EHAS) in a sample of civil psychiatric patients and criminal offenders

Violence, victimization, and suicide-related behaviours have many negative consequences on society and are viewed as critical public health issues. It is estimated that 2,000,000 violent crimes are committed each year in Canada, and that costs to victims, such as health services, approximate $47 billion annually (Statistics Canada, 2003). In addition to the important costs to the healthcare system, these violent outcomes greatly affect individuals’ quality of life as well as mental and physical health. Melissa Hendry’s research aims to reduce the risk of these negative behaviours by investigating risk factors for such behaviours; specifically, she is interested in hostile attributions, which is the attribution of malevolent intent to others, which she will study in a sample of civil psychiatric patients and criminal offenders. This research will assess participants’ level of hostile attributions using a new measure of hostile attributions, as well as other variables such as psychiatric symptoms, substance use, and criminal attitudes, to see how these relate to one another. Another purpose of her project is to look at the association between hostile attributions and behaviours such as violence, victimization, self-harm, and suicidal ideation and attempts. Exploring this research area to a greater degree could have far-reaching consequences in terms of decreasing the incidence of violence-related adverse outcomes in civil psychiatric patients and criminal offenders, thereby enhancing overall population health and reducing health care system costs. The results of Melissa’s research are expected to raise implications for reducing the risk of harmful behaviours in these individuals in terms of implementing new treatment and intervention programs.

Early mother-infant interaction and infant mental health

The quality of the mother-infant relationship early in infancy forms a foundation for infants’ subsequent social and emotional development. In particular, mothers’ sensitive responses to behavioural and emotional cues help their infants develop a sense of self and help them regulate their emotions. Attachment — or the bond between infants and their caregivers — is a developmental achievement in the first year of life that is essential for healthy physical and psychological growth. Studies have shown that insecurely-attached infants are at risk for a range of negative developmental outcomes. Nancy Mcquaid was funded by MSFHR for her early PhD work into the relationship between attachment and infant mental health. She is continuing this longitudinal investigation among a community sample of mothers and their infants. Mcquaid’s research is now evaluating whether maternal responsiveness and infant social expectations observed at four months are related to subsequent infant mental health at 12 and 30 months of age. She is also assessing the impact of mother and infant temperament to healthy developmental outcomes. Mcquaid’s research will contribute to our understanding of healthy infant development and will help develop means of intervention for infants who are at risk for developmental emotional and interactive disturbances, such as infants of mothers with postpartum depression and low birth weight infants.

Structural dynamics of hERG potassium channel gating studied using voltage clamp fluorimetry

Ion channels are cardiac membrane proteins that control the flow of ions like sodium and potassium in and out of heart cells, regulating both cardiac electrical impulses and the contractions associated with the heart beating. Voltage-gated potassium channels, such as the human ether-a-go-go related gene (hERG). are a class of ion channels that open and close – an action known as gating – in response to changes in the electrical potential across the cell’s plasma membrane. In the heart, hERG channels play a crucial role in regulating heart rate and rhythm. Reduced hERG channel function has been associated with loss of the normal heart rhythm and sudden cardiac death. The unique role played by hERG channels in the heart is a result of their unusual gating properties. However, there is limited knowledge about the molecular mechanisms of these gating processes and how they are modulated.

Dr. Tom Claydon is using a new fluorescence technique that he established as a post doctoral fellow that provides a real-time analysis of the protein motions that cause hERG channels to open and close. With a small fluorescent probe attached directly to the channel protein, Claydon’s team can directly study movements that occur within the channel as it opens and closes and measure the electrical current passing through the channel during this activity. Only a handful of researchers worldwide are currently using fluorescence experiments to study ion channel gating. These experiments will provide a comprehensive and unparalleled view of hERG channel function and how it is modulated in health and disease. An understanding of these processes will lay the foundation for new therapies for cardiovascular disease.

BPD as a disorder of intersubjectivity: identity disturbances in borderline personality disorder

Borderline Personality Disorder (BPD) is a psychiatric condition marked by instability in interpersonal relationships, behaviour, mood and self-image. BPD is associated with high rates of suicide, self-harm, substance abuse and hospitalization, and comes at a significant cost to both individuals and society. One symptom of BPD is an inability to maintain a stable sense of identity, which is associated with distress and health risk behaviours. However, the specific types of identity problems, the factors that contribute to identity problems, and the effects of identity disturbance in BPD are unclear. In recent decades, it has been proposed that personal identity is related to life narratives, where a cohesive life story helps a person to maintain a stable sense of identity. Nathalie Lovasz is clarifying the specific identity problems experienced by persons with BPD. Using measures of identity disturbance, she is comparing people with and without BPD. She is also examining potential contributors to identity disturbance in BPD, focusing in particular on whether narrative coherence mediates or accounts for identity disturbance, and the relationship between identity disturbances and emotional states. This research could help clinicians zero in on the specific types of identity problems faced by people with BPD. This research could also lead to improved diagnosis, identifying components of the symptom that are most unique and important to BPD.