Portable MRI for multiple sclerosis: Feasibility establishment and technical development for clinical and research applications

Magnetic resonance imaging (MRI) is an important tool for diagnosing and monitoring multiple sclerosis (MS), a disease which affects millions of people. Unfortunately, current clinical MRI scanners are expensive to purchase and operate, have long wait times, and are often inaccessible for people in remote areas or with mobility issues. Recently, the world’s first portable and easy-to-use MRI scanner was developed by a commercial company (Hyperfine), and it will be available at the UBC MRI Research Centre in early 2021. Because this portable MRI scanner has a very low magnetic field and a small size, it has few safety concerns and can be easily brought to people anywhere. This platform will vastly improve MRI accessibility for clinical use, and make large-scale MS research possible. However, the portable MRI scanner’s ability to detect MS lesions in the brain needs to be tested. My project will compare the portable MRI scans with standard clinical MRI scans in terms of image quality for MS brains, and come up with a guideline for the use of portable MRI in MS. This work will be the first application of portable MRI to MS clinical care and research, and the ultimate goal is to bring MRI technology to everyone with equal opportunity.

Determining the rhythm of post stroke activity-dependent neural repair

Stroke is the fourth leading cause of death and the main source of adult disability in Canada, costing our health system $2.7 billion annually. It is caused by the interruption of flow of blood or the rupture of blood vessels in the brain, which leads to brain cell death. Depending on the area of the brain that is affected, people experience loss of different abilities including speech, movement and memory. The effects of a stroke depend on where the brain has been injured, as well as how much damage has occurred. Recovery after stroke may be related to changes in the structure and activity of brain cells. Previous studies suggested that new regions of the brain can adopt the function of damaged regions after stroke – effectively rewiring the brain for function. However, the way that brain cells change their activity after stroke, and how these changes affect recovery, is still poorly understood. Dr. Majid Mohaherani is studying the basic mechanisms that lead to the recovery of the affected area in the brain. He is examining how brain cells that survive after stroke change their activity during the weeks and months after the initial injury, rebuilding the lost connections. This research aims to provide a better understanding of the link between previously reported structural changes that occur in the brain after stroke, and changes in the activity of individual cells and large neuronal networks. This work could lead to the development of new therapeutic tools that help the brain rewire itself, which could contribute to a reduction in disabilities in stroke patients.

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.

VITALiTY Team

Catastrophic disability is the rapid onset of disability and loss of independence in three or more basic activities of daily living. The six leading causes are stroke, congestive heart failure, pneumonia and influenza, ischemic heart disease, cancer, and hip fracture. Within the next 25 years, the number of people aged 65 years and older in British Columbia will double, resulting in a significant burden on the health care system. Novel strategies are needed to reduce both the risk of catastrophic disability, and the related increased care needs. This award funds the creation of a research team focused on developing interventions that identify and minimize risk for catastrophic disability and promote healthy aging in older adults. The team’s objectives are to determine which inflammatory markers predict catastrophic disability, relate these markers to other identified risk factors, and develop targeted, effective interventions.

Bayesian and non-bayesian aspects of probabilistic reasoning in healthy individuals and schizophrenia patients

One of the hallmarks of schizophrenia is the distortion of reality, including delusions. Delusions are fixed false beliefs that are held despite contradictory evidence. Delusional schizophrenia patients tend to overestimate the plausibility of potential beliefs that others would consider implausible. However, the mechanisms by which schizophrenia patients develop delusions and hold onto them in the face of contradictory evidence is not well understood. When individuals form beliefs, they assess the plausibility of a potential belief in the context of the evidence at hand. In doing so, they must consider two main factors: whether the potential belief can adequately account for the evidence at hand, and whether there are any other alternate potential beliefs that could account for this evidence. Once a belief has been established, most individuals tend to resist re-evaluating these beliefs when presented with contradictory evidence. This effect is stronger in delusional patients. Jennifer Whitman is working to determine the cognitive underpinnings of delusions. Her studies will compare delusional schizophrenia patients with non-delusional patients and healthy individuals, using simple guessing games to reveal the factors influencing how schizophrenic patients form their beliefs, how they remain fixated on them, and how this differs from non-delusional individuals. She will also conduct neuroimaging studies to identify the brain systems underlying these cognitive mechanisms. Whitman’s work will be useful for informing how delusion-prone individuals can be taught the logical reasoning skills they need to re-evaluate current delusions and avoid developing delusions. Understanding these brain systems may also be relevant for assessing the effectiveness of different pharmacological treatments and predicting relapse and treatment responsiveness by mapping changes in these brain systems over time.

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.

In vivo analysis of novel neuronal synapse promoting proteins

Brain cells communicate with each other at junctions called synapses. Changes in synapses underlie important cognitive processes such as learning and memory. Synapse development requires communication proteins on either side of a synaptic junction. Previous research has identified genes called leucine-rich repeat transmembrane (LRRTMs) proteins, which promote formation of mammalian synapses. These novel genes are able to promote synapse formation between neighbouring cells. LRRTMs have recently been shown to be associated with neurological disorders, including schizophrenia and late-onset Alzheimer’s disease. Mutations in functionally-related proteins have also been directly been linked to autism and mental retardation. Dr. Tabrez Siddiqui is studying how synapses are formed and modified by experience. He is working to fully characterize LRRTMs in mouse models, studying the role of LRRTMs in brain morphology and synapse development. He will also identify proteins that interact with LRRTMs across the synaptic junction. A detailed study of LRRTMs and their binding partners will lead to a greater understanding of how brain cells interact with each other, and will shed light on the molecular basis of neurological disorders.

Neural connectivity and memory in schizophrenia patients and healthy controls

Schizophrenia is a brain disease that affects one per cent of Canadians — more than 300,000 people — causing hallucinations, disordered thought and memory dysfunction. Two specific types of memory are known to be affected in schizophrenia: working memory, or the ability to temporarily store and manipulate information (e.g. remembering a phone number until you can write it down); and source memory – the ability to recall where a memory, idea or piece of information came from (e.g. remembering that it was your sister who told you that Oslo is the capital of Norway). Paul Metzak is measuring brain activity during these two types of memory in both healthy volunteers and schizophrenia patients. His goal is to see how differences in activity in various areas of the brain can lead to selective memory impairments. He is using newly-developed statistical tools to look at how networks of brain areas interact to give rise to successful remembering. These tools also enable him to determine how the different components of successful remembering are affected in the schizophrenic brain – whether memory impairment arises from a failure in storing the memory properly, or from an inability to retrieve the correct item once it has already been stored. By identifying the dysfunctional components of brain activity that give rise to memory disorders in schizophrenia, Metzak’s research provides a vital first step on the road to improving memory problems. This work could lead to the development of strategies, therapies, and techniques that can minimize the impact of memory deficiencies in the day-to-day life of patients suffering from these impairments.

The demi-globule hypothesis: a thermodynamic model for prion protein template-directed misfolding

Prions are the causative agents for many brain diseases of humans and animals. In animals, the most well-known prion-related disease is bovine spongiform encephalopathy, or mad cow disease. The human prion diseases are Creutzfeldt-Jakob disease, kuru, and fatal familial insomnia. All these diseases cause brain cell death leading to difficulty walking, dementia, muscle spasms, and seizures. They are invariably fatal, and there are currently no treatments available. The incidence of human prion diseases is roughly 1 per million people per year. Unlike most other infectious diseases that are spread by bacteria or viruses, prion diseases appear to be caused by misfolded protein molecules. Protein is made of long chains of amino acids, and how a protein folds determines its function. A misfolded prion protein can interact with a normally-folded prion protein and cause it to also misfold, setting off a chain reaction that results in widespread brain cell death. How the misfolded prion causes the normal prion to misfold remains unclear. However, a new theory called the demiglobule hypothesis proposes that the misfolded prion binds to the normal prion and causes a key part of the normal protein structure, called a beta sheet, to come apart. This ultimately results in a misfolded shape. William Guest is using a variety of theoretical and experimental techniques from physics, chemistry and biology to determine whether the demiglobule hypothesis can account for prion protein misfolding. If the results of this project support the demiglobule hypothesis, researchers will know much more about how prion conversion occurs. This knowledge could ultimately enable the development of methods to block prion conversion, thereby stopping the spread of disease.

Involvement of ErbB4 in excitatory and inhibitory synapse maturation

Synapses are the junctions across which signals are passed from one neuron to another. Generally, the type of input received through synapses can be classified into two categories: excitatory input increases the signal transmission, while inhibitory input reduces signal transmission. Problems that disrupt the coordination of excitatory and inhibitory inputs have been associated with the development of many severe psychiatric disorders, including schizophrenia. Recently, genetic analysis of families with a history of schizophrenia identified two genes potentially responsible for the onset of the disorder: Neuregulin1 (NRG1) and its protein receptor ErbB4. Daria Krivosheya’s recent research indicates that the ErbB4 protein receptor may help to stabilize existing synapses. Previous research has shown that ErbB4 interacts with PSD-95, a protein involved in regulating other proteins involved with excitatory synapses. Krivosheya believes interaction of the ErbB4 protein receptor with the PSD-95 protein may regulate the number of excitatory and inhibitory synapses formed by the nerve cell, while interaction with the NRG1 gene may stabilize synapses and promote branching out of dendrites, extensions of a nerve cell that conduct impulses from neighbouring cells. Krivosheya is investigating the role of NRG1-ErbB4 interaction at the synapse, as well as involvement of PSD-95 in mediating this interaction. Her goal is to explain the mechanism through which these molecules control excitatory and inhibitory synaptic balance. She hopes her research will ultimately help explain some of the physical or behavioral abnormalities associated with schizophrenia, and lead to the development of new therapies.