Neural correlates of symptom provocation in pediatric obsessive-compulsive disorder (OCD)

Pediatric obsessive-compulsive disorder (OCD) is a neuropsychiatric illness that has a 1-4 percent prevalence rate in children and youth. OCD is characterized by intrusive thoughts and repetitive behaviours, and although treatments, such as cognitive behavioural therapy (CBT), are available, better treatment selection could improve response rates.

To advance our understanding of the dysfunctional brain mechanisms underlying OCD, and eventually find predictive biomarkers of treatment response, functional magnetic resonance imaging (fMRI) has been used to find the neural correlates of OCD, particularly during symptom provocation tasks (i.e. tasks that allow researchers to probe the brain areas involved in emotional processing by exposing OCD patients to OCD-related stimuli). This research has given us neural correlates of OCD, but fMRI is expensive to implement in clinics.

The goal of this proposal is to use electroencephalography (EEG) to study OCD symptom provocation because it is less costly than fMRI and easily implemented in clinics. EEG also provides an innovative way to investigate OCD, as it provides a fine-grained temporal measure of brain activity, whereas fMRI provides a fine-grained spatial measure of brain activity. Thus, EEG could provide a new set of temporal psychophysiological correlates of OCD that would be easily and inexpensively collected in clinics, and that could predict CBT outcome. In the proposed study, clinically diagnosed pediatric OCD patients (12-18 years old), siblings unaffected by OCD (12-18 years), and matched healthy controls (HCs) will complete an OCD symptom provocation task that elicits emotional responses while EEG is recorded. Event-related potentials (ERPs) will then be derived from the EEG data and will be used to characterize the OCD group in comparison to the sibling and HC group, and to use as potential predictors of CBT response.

The proposed study is novel because few EEG studies of OCD symptom provocation exist, and no emotional-related ERP studies have been conducted in children, although pediatric studies are essential to our understanding of early brain differences.

Our findings will be presented to clinicians and researchers at annual conferences and published in leading peer-reviewed journals. Lay-friendly articles will also be written and submitted to the Canadian OCD Network’s and the International OCD Foundation’s newsletters.

Exploring the mediating effect of parenting practices on the relationship between the neighbourhood environment and child physical activity

The neighbourhood environment has been found to affect the levels of physical activity among children. We are investigating the mediating effect of parenting practices on this relationship.

For example, some studies have found that children living in neighbourhoods that are more walkable or have more green space were more likely to be physically active. This may be related to parenting practices. For example, parents may restrict their children from playing outdoors if they feel that their neighbourhood is unsafe but may encourage outdoor play if they live near a park.

This study will address this gap by using survey data collected from two sample populations. First, data collected from a web-based survey of 500 parents across Canada and the USA will be used to describe the relationship between the neighbourhood environment (e.g. safety, crime, walkability) and physical activity parenting practices.

Second, one child from each of 88 living in Metro Vancouver will be provided with an accelerometer to record their physical activity patterns. Their parents will complete a questionnaire measuring their perception of the environment and the parenting practices they employ.

The goal of the project is to better understand how the environment can influence parenting practices, enabling recommendations on designing neighbourhoods to allow children to be more physically active.

Understanding the role of information in vaccine hesitant parents’ decision-making

Vaccination has been proven to be an effective tool to combat the spread of many communicable diseases. However, recent outbreaks of vaccine-preventable diseases such as measles have heightened concern regarding parents who are vaccine hesitant (i.e. who exhibit delayed acceptance or refusal of some or all vaccines).

Understanding what types of information most influence parents is key to producing effective public health messages that will improve vaccination rates.

Working in collaboration with the Canadian Immunization Research Network (CIRN), this project will examine the relationships among health information, social context, and parental decision-making around routine early childhood vaccinations.

To understand how information interventions interact with social context to influence parental decisions about routine childhood vaccinations, we will conduct:

  1. critical discourse analysis of vaccine discussions on social media
  2. a study of vaccine-hesitant new parents, following their information use and vaccination decisions over the course of a year
  3. a population survey module on health information seeking and use

This work will complement studies by CIRN and contribute to CIRN recommendations for Canadian immunization policy and practice.

Screening and development of molecules targeting presynaptic SNARE protein-protein interactions as novel pharmacological strategy in schizophrenia and other mental illnesses

Screening and development of molecules targeting presynaptic SNARE protein-protein interactions as novel pharmacological strategy in schizophrenia and other mental illnesses Schizophrenia is one of the major disabling mental disorders with a worldwide prevalence of about one percent. Although the cause  of schizophrenia remains unclear, converging data indicate that dysfunctions altering neurotransmitter levels in the synaptic cleft, the tiny space between nerve cells in which nerve impulses are conducted, might be at the core of this disorder. In presynaptic cells, neurotransmitter release is governed by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor).  Findings in the schizophrenic postmortem brain have revealed increased SNARE protein-protein interactions, which may explain the unbalanced neurotransmitter levels in schizophrenia, and reduced SNARE complexes in antipsychotic-treated patients. In accordance, genetic differences in SNARE-coding genes have been associated with schizophrenia.

Despite the growing evidence involving presynaptic dysfunction in mental illnesses, no attempts have been made to develop a pharmacological approach targeting the SNARE complex. Furthermore, the sole active agent against SNARE proteins, Botox cannot be used due to its irreversible, and lethal effects, presenting a challenge to finding SNARE-interfering compounds and pharmaceutically treating schizophrenia.

Against this background, the objective of Dr. Ramos-Miguel’s clinical research project is to find SNARE-interfering compounds, and further address their potential benefits in the pharmacological management of schizophrenia.

To meet this goal, an  agreement involving UBC, the Centre for Drug Research and Development (CDRD), and Roche-Canada, will allow Dr. Ramos-Miguel’s team to  screen the company's largest library, containing more than one million compounds. Additionally, an immunoassay-derived method has been automated for high throughput screening of compounds modifying SNARE interactions. This assay successfully screened the CDRD 26,000-compound library, and identified at least two SNARE "inhibitors". Further hits from the screening project will be subjected to a number of preclinical tests, including immunological, electrophysiological, toxicological and behavioral assays.

Identification of SNARE-interfering substances may have potential to improve pharmacological treatment of schizophrenia through a completely novel strategy.

Mechanisms of cardiovascular disease in children with mental health conditions

Prescriptions of second-generation antipsychotic  (SGA) medication for children in British Columbia increased 22-fold from 1996 to 2010. These medications treat the underlying mental health issues (e.g. psychosis, depression, attention deficit/hyperactivity disorder) but often come with side-effects, including metabolic syndrome.

Metabolic syndrome is a cluster of clinical features that includes excess weight around the middle, high blood pressure, and high blood sugar or triglyceride concentrations. Given that metabolic syndrome is a risk factor for cardiovascular disease, there are serious implications for the long-term health of these children. Development of a secondary chronic disease such as CVD, on top of an existing mental health condition, further marginalizes the life-long health of these children.

Accordingly, there is a need to develop a means by which to distinguish children at risk for developing metabolic syndrome from those who are not. The goal of this research is to identify genetic markers that will indicate which children will develop risk factors for heart disease and stroke when treated with SGAs so that appropriate prevention strategies may be implemented in these children.

Uncovering novel regulators of beta cell genesis, growth and function

To date, the only successful approach for curing type 1 diabetes is to replace the insulin-producing beta cells that have been destroyed by the disease. Pancreas- and islet-cell transplantation are promising therapeutic strategies; however, scarcity of transplantable tissue has limited their widespread use. One way to produce enough beta cells to cure type 1 diabetes is to determine how the cells develop normally within the embryo and apply this knowledge to the regeneration of beta cells in the culture dish or directly in people with diabetes.

Using human and mouse model systems, Dr. Francis Lynn’s research aims to enhance our understanding of normal regulatory pathways that govern pancreas- and insulin-producing pancreatic beta cell genesis and function. The hope is that a greater understanding will enable cell-based approaches for treating and curing diabetes. Lynn’s long-term objective is to understand how regulatory DNA-binding proteins called transcription factors drive beta cell formation and function. This research specifically focuses on one member of the Sox gene family of transcription factors named Sox4. Preliminary data suggest that Sox4 is instrumental in governing both the birth of beta cells and their replication later in life. These observations place Sox4 as a novel and previously unappreciated key regulator of beta cell biology.

Lynn hopes that a thorough characterization of the pathways through which Sox4 regulates beta cell formation and function will inform novel approaches for generation of large numbers of functional beta cells from human embryonic stem cells or induced pluripotent stem cells.

SHIP’s roles in intestinal immune homeostasis and inflammation

Dr. Laura Sly’s research program aims to improve our understanding of inflammatory bowel disease pathology and to identify and validate novel therapeutic approaches that will improve patient care. Her team has been investigating the role of SH2-containing Inositol Phosphatase (SHIP) in intestinal inflammation. SHIP is a protein that regulates enzymes involved in immune cell signaling. Sly’s research has shown that SHIP-deficient macrophages are hyper-responsive to IL-4, which drives them to an alternatively activated or M2 phenotype.

Using mice as a genetic model of M2 macrophages, Sly reported that M2 macrophages are protective against induced intestinal inflammation. Since then, her team has characterized a complimentary genetic model of M1-polarized macrophages and has identified key anti-inflammatory mediators that may be responsible for protection. Future investigations will focus on whether adoptive transfer of polarized macrophages or targeting macrophage polarization in situ can reduce intestinal inflammation in pre-clinical models of inflammatory bowel diseases.

Sly’s team has also developed a new mouse model of intestinal inflammation that shares key pathological features with Crohn’s disease. They have reported that SHIP-deficient mice develop spontaneous, discontinuous ileal inflammation accompanied by excessive collagen deposition and muscle thickening. Current research goals include targeting macrophage polarization or polarized macrophage products to reduce intestinal inflammation in pre-clinical models of inflammatory bowel disease, and identifying cell types and biochemical mechanisms that contribute to intestinal inflammation in SHIP-deficient mice. Together, these studies will identify cellular and biochemical targets and investigate new immunotherapeutic approaches that may useful in reducing intestinal inflammation in people with inflammatory bowel diseases.

Manipulating the trajectory of the human fetal, newborn & infant immune system

Millions of newborns and infants die each year from infectious diseases. Many of these deaths are preventable, and analysis of the immune development of children can help define paths for medical intervention that may save lives.

Dr. Tobias Kollmann’s research team is conducting the first global comparison of immune development in cohorts of children from different countries. This project will compare the immune development of children born in Vancouver to those born in South Africa, Mozambique, Ecuador and Belgium. Preliminary research has found striking qualitative and quantitative differences in children’s immune development that appear to be directly related to their genetic make-up as well as the particular environment to which they are exposed. Kollmann’s team is dissecting the cause-effect relationship for the role of host genetics and studying the environmental factors that direct the developmental path of the innate and adaptive immune responses. Analysis of these genetic and environmental factors will potentially reveal pathways that direct future efforts to treat and prevent infectious diseases.

Kollmann’s team is already developing a platform that will help deliver targeted vaccinations to protect newborns. Using genetically altered strains of Listeria monocytogenes, the vaccine will induce a desired immune response only in specific cells and then disappear without harming the child. Preliminary data suggest this goal is within reach, and Kollmann’s team is working in partnership with industry to design and test a Listeria-based vaccination for newborns. Through this work, safe yet effective methods will be identified to prevent millions of newborn and infant deaths due to infectious diseases.

Signalling pathways that control the development and function of T regulatory cells

Autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and psoriasis, arise from an overactive immune response against one’s own substances and tissues. If this overreaction against the body persists for an extended period of time, it results in chronic inflammation. Currently, there are no cures for autoimmune diseases; at best there are only treatments that mildly alleviate the symptoms. A patient with an autoimmune disease is typically treated with drugs to suppress the immune system, which diminishes immune responses in general. This type of treatment means that the individual becomes susceptible to infection and cancer as their immune system is effectively turned off. Dr. Scott Patterson’s research project focuses on an immune cell called a T regulatory cell (Treg). These cells have the ability to suppress immune responses and normally prevent autoimmune diseases. Since the method by which Tregs turn immune responses off is not clearly understood, Dr. Patterson’s goal is to characterize the molecular mechanisms that allow Tregs to work. In parallel, he will study how Tregs interact with other types of immune cells. Using animal models of inflammatory bowel disease and multiple sclerosis, this work will investigate the interactions Tregs have with immune cells in the body during autoimmune diseases. Gaining a greater understanding of how the actions of Tregs are controlled will be a big step in developing new therapies for autoimmune diseases and reducing the dependency on non-specific immunosuppressive drugs. Inflammatory bowel disease and diabetes each affect more than 200,000 people in Canada alone; thus, this research aims to improve the quality of life for this segment of the Canadian population.