A Brief Description of Currently Funded  Research Grants 2014 – 2015

 

Dr. Karen Milligan
Ryerson University
Toronto, ON
Co-applicants:
Dr. Marjory Phillips
Dr. Sidney Segalowitz
Dr. Louis Schmidt

Introduction: Learning Disabilities (LDs) affect approximately 6.2% of Canadian children aged 6 to 15 (PACFOLD, 2007). These neurobiological disorders affect the ability to acquire, organize, retain, understand and use infonnation in youth who have average to above average levels of intellectual ability. The processing challenges, in tum, impact on academic achievement in areas such as reading, writing. and math (LDAC, 2002). While less recognized, youth with
LDs are 15 times more likely experience significant mental health (MH) challenges, including ADHD, anxiety, and depression. This increased risk is due, in part, to common cognitive and emotion regulation processes being implicated in academic, social, and emotional pursuits. More specifically, to be able to manage and cope effectively with negative emotions, youth with LDs must ( I) be able to attend to their experience and recognize that they are faced with a challenge, (2) control their impulse to cope with the associated negative emotion by withdrawing or acting out (both forms of experiential avoidance), and (3) apply problem-solving skills that depend on both problem-specific skills and higher-order cognitive processes, such as executive functions (i.e., inhibition, cognitive flexibility, working memory, planning). These three steps act in concert to allow youth to stay present and mindfully select their course of action to assist them in achieving their goal. To date, most treatments for youth with LDs have focused on academic remediation and social skills training, with little attention to the emotion regulation needs of this population. Integra, an accredited children’s mental health centre for youth with LD+MH, has addressed this gap with their Mindfulness Martial Arts (MMA; Integra & Badali, 2002) program.
Objectives: MMA is a 20-week manualized group treatment for adolescents with LD+MH that imbeds mindfulness, cognitive therapy, and behavioural activation into an engaging martial arts treatment for adolescents. Our previous research has demonstrated that MMA is associated with significant improvements in aggression and anxiety in youth with LD+MH compared to a waidist control, and significant gains in behavioural regulation and impulse control from pre-to post-treatment. We are seeking support from the Scottish Rite Foundation to delve deeper into the cognitive and emotion regulation processes that support these positive mental health outcomes. Consistent with the objectives of the foundation, our research is biomedical in nature and will examine changes in brain-based cognitive processes (attention. working memory, impulse control, flexibility) and emotion regulation associated with MMA.
Outline of Research: 64 adolescents (aged 12-16) participating in the MMA treatment program and 64 waitlist controls will serve as participants. EEG and ECG recordings of brain and cardiac activity will be recorded during completion of 4 computer tasks (assessing attention, impulse control, flexibility, and emotion regulation) and a rest task at pre- and post-treatment, 3-and l2-month follow-up. Parents and youth will complete questionnaires regarding their behaviour and mental health. Analyses will examine if participants in the MMA program make more gains from pre- to post-treatment (and at follow-up) compared to the control group. The impact of type of LD and mental health challenge, attendance and home practice of treatment skills on treatment outcomes will also be explored.
Projected Benefits and Application of Findings: This research will support our understanding of the biological mechanisms of change associated with MMA and more broadly with mindfulness treatments for adolescents. The present study will examine changes at the behavioural and biological level and will explore participant factors (e.g., mental health and LD profile, home practice) that may moderate outcomes. This research will support Integra’s efforts to disseminate MMA nationally and will provide direction for further independent evaluation of
this treatment.

Dr. Hideto Takahashi
Institut du recherche cliniques de Montreal
Montreal, QC

Introduction: Autism spectrum disorders (ASDs) form a group of developmental disabilities characterized by impaired social interactions, communication impairment, and restricted and repetitive behaviors. These lead to lifelong difficulties in social life and mental health problems. Genetic studies have identified hundreds of candidate genes linked with ASDs. Interestingly, many of these genes are involved in the formation and function of brain structures called synapses. Synapses are adhesion sites between brain cells that permit the passing of signals and hence are fundamental for brain functions such as cognition, learning and memory. Based on the genetic evidence, dysfunction of synapses is proposed as a common pathogenesis of ASDs. However, it remains unclear how particular autism-linked genetic mutations cause synaptic pathology. Our group has identified several autism-linked genetic mutations in the synaptic proteins Cadm1 and Mupp1. These proteins form the core of an adhesion complex that is involved in synapse development and synaptic plasticity (modification of synaptic connectivity in response to experience). We propose to investigate the functional impact of the autism-linked Cadm1 and Mupp1 mutations in synaptic pathology to facilitate our understanding of a common pathogenesis of ASDs.

Objective: The objective of this study is to test our hypothesis that autism-linked genetic mutations in the Cadm1-Mupp1 synaptic adhesion complex cause aberration in synapse development as a cellular pathology of ASDs and consequently result in autistic behaviors. We further aim to define a signaling pathway that normalizes synaptic abnormalities induced by these mutations in order to develop new therapeutic strategies for ASDs.
Outline of research: We will first investigate the effects of autism-linked mutations of Cadm1 and Mupp1 on the synaptic localization of the proteins (Aim 1) and synapse development (Aim 2) in rodent brain cell cultures. We will further investigate synaptic effects of the Cadm1 and Mupp1 autism-linked mutations in live animals by using gene delivery into brain cells of live mice and by generating and analyzing genetically-modified mice possessing an autism-linked mutation of Cadm1 or Mupp1 (Aim 3). Finally, because the Cadm1-Mupp1 complex interacts with serotonin receptors, we will use pharmacological experiments to investigate the roles of serotonergic signals on the synaptic abnormalities induced by the autism-linked Cadm1 and Mupp1 mutations (Aim 4).
Projected benefits and application of findings: The functional characterization of autism-linked mutations in the Cadm1-Mupp1 complex will uncover a new molecular and cellular basis for how aberrant synaptic connections cause abnormal brain activity and behavioral disabilities in ASDs. It will thus help to improve our understanding of a common pathogenesis of ASDs. Our study could further provide several biomedical benefits to promote development of novel therapeutic strategies: 1) protocols and/or tools that reproduce ASD pathology in a dish, which would be useful for drug screening, 2) new animal models for ASDs, and 3) definition of a specific cell signaling pathway as a potential therapeutic target for ASDs.

Dr. Ryan van Lieshout
McMaster University
Hamilton, ON
Co-applicants:
Dr. Stephanie Atkinson
Dr. Michael Boyle
Dr. Alison Niccols
Dr. Louis Schmidt

Introduction: Children with intellectual impairments and their families face many challenges. Despite the fact that intellectual impairment is relatively common, its causes are not completely
understood. Research directed at understanding these causes can reduce suffering for individuals and their families and aid in the development of effective preventive strategies. The brain undergoes remarkable changes as it develops in utero. While these are aimed at preparing the fetus for life outside of the womb, exposure to adverse conditions during gestation has the potential to negatively impact brain development. Such exposures include maternal dietary deficiencies and excesses, shortages of vital nutrients, and metabolic disorders including obesity. While these problems are associated with an increased risk of intellectual problems in offspring, no studies have examined if helping the mother to consume a healthy diet and to exercise during pregnancy can improve the intellectual functioning of her children. Pregnancy is also a time when the fetal brain is especially amenable to positive environments. As a result, treatments applied during this time provide the most promise for reducing the commonness and severity of intellectual problems in children. Helping women to improve their diet during pregnancy and engage in an exercise program may be one of the best ways to optimize the pregnancy environment and children’s intellectual functioning.
Objective: The objective of this study is to determine if providing women with a structured and monitored intervention consisting of an individualized nutrition plan plus exercise training during pregnancy improves her child’s scores on intellectual testing at 12 months of age.

Outline of Research: The proposed study will assess the offspring of women already enrolled in a study aimed at optimizing maternal weight gain during pregnancy through a nutrition plus exercise intervention. At 12 months of age, the infants born to these women will be tested using the gold standard measure of intellectual functioning at this age, the Bayley Scales of Infant and Toddler Development. The mothers of half of these children will receive a tailored, high protein diet supplemented with low fat dairy products and a structured, monitored exercise regimen initiated early in pregnancy. The other half will receive care from their physician or midwife as usual. We believe that children born to women enrolled in the nutrition plus exercise group will have higher scores on intellectual testing at 12 months of age than those born to mothers in the usual care group. We also believe that the offspring of women who are overweight or obese before pregnancy and the offspring of more socioeconomically disadvantaged women will benefit more than children who are born to normal weight women or those who are less well off.
Projected Benefits and Application of Findings: Given the importance of fetal development to intellectual functioning, this study will not only help us to better understand the causes of intellectual impairment, but also has the potential to help us prevent intellectual impairment from occurring in the first place. Our intervention is based on our previous research and designed with our community partners to be as easy to follow for women as possible. Given that women have a special sensitivity to their health during pregnancy and an increased awareness of their responsibility for a future child, they are more likely to engage in treatments at this time than at any other point in their lives. As a result, we believe that this research can help to provide children with the finest start to life possible, and the best opportunity to realize their full potential.


Dr. Alana Watt
McGill University
Montreal, QC

Introduction: Autism is a developmental brain disorder characterized by abnormal social interactions and repetitive behaviour. Neurons communicate with each other using neurotransmitters, and the development of neurotransmission is critically important for brain function. GABA is the major inhibitory neurotransmitter in the adult brain, yet it acts paradoxically in the young developing brain to excite rather than inhibit neurons. Recent evidence suggests that GABA neurotransmission is improperly regulated in the autistic brain during development, particularly at the perinatal time period around birth. The cerebellum is a brain region that is involved in motor control and learning as well as likely in higher brain functions, and is one of the brain structures that is most often altered in the autistic brain. Yet surprisingly, little work has been carried out to date on cerebellar development in the autistic brain. My expertise is on GABA regulation in the developing cerebellum, which I previously showed for the first time contributes to network activity that is likely important for proper cerebellar formation. This expertise makes my lab perfectly poised to address how GABA misregulation contributes to the pathophysiology of autism.
Objectives: Building on our expertise studying GABA regulation and its effects on cerebellar activity in the perinatal cerebellum, we will explore how GABA neurotransmission is altered  developmentally using mouse models of autism. We expect that perinatal GABA regulation will be altered in the developing autistic cerebellum since this has been shown in other regions that have similar GABA actions in development. We will characterize how GABA is affected in the perinatal cerebellum and how this affects cerebellar activity in development. We then aim to pharmacologically rescue GABA neurotransmission in the cerebellum around birth, in the hopes of alleviating autistic symptoms.
Outline of Research: To determine how GABA is regulated in the developing autistic brain, we will use two distinct mouse models of autism: one genetic and one based on embryonic environmental insult. Using electrophysiology and two-photon imaging techniques that will allow us to assay synaptic and network function in mouse models of autism, we will be able to address the following Aims:
Aim1 – We will map and understand perinatal GABA regulation in the autistic mouse cerebellum.
Aim2 – We will determine how GABA-driven perinatal network activity is altered in the developing cerebellum in autistic mouse models.
Aim3 – We will alter GABA regulation pharmacologically in the autistic brain in order to rescue cerebellar function.
Projected Benefits and Application of Findings: Autistic individuals often have cerebellar lesions, suggesting that altered cerebellar development contributes to the pathology of autism. Understanding what goes awry in the developing autistic cerebellum, is likely to directly inform us about the pathology of autism. Having identified alterations in the developing autistic brain, we hope to then find ways to specifically target or reverse these changes, leading to new treatment and/or preventions for autism.