Accelerator Stimulus Grants - Awarded April 2017
Using automated touchscreen tasks for cognitive assessment in a novel model Parkinson's Disease
PI: Beraldo de Paiva, Flavio Henrique
Department: Phys & Pharm
Award value: $69,937
Parkinson’s disease (PD) is the second most common age-related brain disorder after Alzheimer’s Disease (AD). It is estimated that more than 100,000 Canadians over 40 years are living with PD and this number will increase by 65% by 2031. It is now recognized that PD is more than a motor disease with cognitive decline and dementia amongst the most common non-motor symptoms (NMS) found in PD patients. In fact, cognitive alterations are reported in nearly 50% of PD patients and cognitive decline can occur even before the onset of the classical motor symptoms. The major cognitive abilities affected are executive function, visuospatial function, memory and attention. However, treatment for cognitive decline in PD is currently an unmet need. We propose to use the translational, highly sensitive and automated touchscreen tests for assessing executive function in PD models as a platform for the development of PD treatments. Our hypothesis is that, using the touchscreen technology, we are able to detect early cognitive deficits in PD models which can serve for drug testing and prediction of clinical efficacy for PD. Providing an early no-go decision, based on cognitive testing may help to focus resources on compounds that will have better chance to succeed in clinical trials.
Evaluating cognitive impairment, and imaging and blood biomarkers in a pre-clinical model of concussion
PI: Brown, Arthur
Department: Phys & Pharm
Award value: $100,000
The diagnosis, prognosis and treatment of concussion is greatly impeded by a lack of standard clinical biomarkers making evidence-based treatment protocols impossible to develop. We have recently uncovered several imaging and molecular changes that accompany concussion in athletes playing contact sports. The goal of our work is to develop a model of concussion to study and validate these biomarkers of concussion. Using state of the art imaging, molecular and behavioral analyses we will use our models to address fundamental questions about concussion:
- What are the disease processes that underlie these biomarker changes?
- Are these biomarkers changes diagnostic for concussion?
- Do these biomarkers predict outcomes? That is, do they delineate who will recover quickly from concussion and who may require longer convalescence and care?
Genetic manipulation of lactate metabolism to regulate memory and Alzheimer's disease pathogenesis
PI: Butler, Blake E
Award value: $90,265
Once considered a peripheral deficit, sensory loss is now known to dramatically alter the structure and function of the brain. In addition to significant perceptual impairment, these brain disorders have significant social and economic impacts. For example, prelingual hearing loss can significantly impair a child’s social and cognitive development, and is associated with a lifetime cost estimated to exceed $1 million per child. Moreover, age-related hearing loss has been shown to accelerate cognitive decline in the elderly; importantly, the associated impairments to memory, attention, and problem-solving appear to exceed those which might reasonably be attributed to the social isolation that often accompanies hearing loss alone. Fortunately, advanced neural prostheses exist that can bypass damaged peripheral sensory cells to provide the brain with a representation of sound. However, there remains a great degree of variability within recipient populations; despite receiving their device within the presumed sensitive period for normal recovery, some children with cochlear implants do not achieve normal language performance, and both children and adult implant recipients often have difficulty in the presence of background noise. The reason for this variability is unknown; however, cross-modal reorganization in the deaf brain is hypothesized to play a significant role. In the deaf, regions of the brain that would normally process sound contribute to enhanced function in the remaining senses. To answer this question, we plan to complete a longitudinal analysis of auditory cortical activity following hearing loss and restoration that will provide the first ever detailed examination of the initiation of a sensory representation in the brain. It is our hope that the results of this program will inform the design of neural prostheses that are optimally tuned to restore sensory representations in a patient-specific manner, thus significantly reducing the impact of cognitive disorders that arise secondary to abnormal perception both in children and in older adults.
Award value: $53,684
The human brain is an incredibly hungry organ, consuming as much as 25% of daily food derived energy. Neurons and glia are the two main cell types in the brain. Neurons are cells that process and transmit information via electrical and chemical signals; an energetically demanding process that is critical for the formation of memories. Astrocytes are star-shaped glial cells that function to provide nutrients to neurons, and to maintain the extracellular ion balance within the brain. Glucose has historically been considered the main fuel to meet the energy needs of neurons in the brain. However, aerobic glycolysis, a unique form of metabolism that involves the breakdown of glucose to lactate even in the presence of oxygen, is now known to play a key role synaptic function; specifically memory. The astrocyte-neuron lactate shuttle hypothesis (ANLSH) is a controversial theory which posits that aerobic glycolysis occurs in astrocytes, which produce lactate for subsequent export to neurons to maintain memory processes. We recently discovered an age-dependent decline in the expression of lactate dehydrogenase A (LDHA), a rate limiting enzyme of lactate production, and a concomitant decrease in lactate levels within the brains of normal mice. In agreement with the ANLSH, improved memory in aged mice correlated with maintained LDHA expression in the cortex and hippocampus. Surprisingly, elevated lactate levels where detected in the brains of aged transgenic Alzheimer’s disease mice. Our highly novel findings suggest that while lactate production is beneficial to the healthy aging brain, dysfunctional lactate metabolism may occur in the brains of Alzheimer’s disease patients and contribute to cognitive decline. To date, no study has attempted to determine the relative importance of astrocyte versus neuronal generated lactate production on memory. In light of the fact that lactate is required for memory, it is imperative to determine which CNS cell type, i.e. astrocytes or neurons, is essential for the production of this key metabolite. The outcome of our transformative research program may lead to an entirely new clinical approach to treating cognitive and neurodegenerative disorders via drugs which alter lactate metabolism.
Imaging fetal brain connectivity in high risk pregnancy: can it influence the incidence of neurodevelopmental and psychiatric problems?
PI: de Ribaupierre, Sandrine
Award value: $39,500
Many neurodevelopmental and psychiatric diseases have both environmental and genetic influences. The environmental component might start during pregnancy, and therefore risks to normal development may be reduced through timely recognition. An increasing number of papers on “fetal programming and developmental origins of health and disease (DOHAD)” have shown that high risk pregnancies are associated with autism, schizophrenia, and cerebral palsy. It has been postulated that inflammatory pathways in pregnancies complicated by auto-immune disease, excessive gestational weight gain, obesity, exposure to drugs, infection, high-fat diet or environmental pollutants underlie these alterations in susceptibility to neuropsychiatric disorders. We hypothesize that differences in fetal brain connectivity (structural and functional) can be observed with fetal fMRI as early as in the second trimester of pregnancy in fetuses who will go on to develop neurodevelopmental or psychiatric disorders in their childhood (Autism-Spectrum Disorder, Schizophrenia, Dyslexia). Similarly, we postulate that in high risk pregnancies changes in maternal markers of inflammation, metabolism and exposure to environmental pollutants are associated with abnormal fetal structural and functional connectivity scores. If we can detect differences in connectivity scores, then we could recommend interventions; and monitor the effect of the treatment on the fetal brain; thus, reducing the impact of cognitive disorders and its incidence in the pediatric population.
State-of-the-art clinical assessment of hand function in stroke and cervical spondylotic myelopathy
PI: Diedrichsen, Jorn
Department: Computer Science
Award value: $82,260
It is hard to over-state the importance of our hands in daily life. From writing on a piece of paper, to playing the guitar, our hands are the primary means through which we manipulate the environment around us. Nowhere is the importance of the hand most visible than after an injury. Whether damage is to the neural substrate that controls the hand (e.g. stroke, cervical myelopathy) or to the hand itself (e.g. nerve damage, amputation), the subsequent loss of function imposes severe limitations on a patient’s daily independence and ability to remain gainfully employed. It is not surprising that patients report that recovery of hand function is one of the most important factors associated with improved quality of life measures post-injury. Despite the importance of the hand, only rudimentary clinical assessment tools are available to evaluate hand function, either to quantify impairment after injury, or to assess improvements during rehabilitation. We strongly believe that the development of accurate, standardized clinical assessment tools for hand function is critical for accelerating progress in the restoration of hand function after injury. In this proposal, we propose to develop and validate a clinical assessment for hand function in patients with central and peripheral brain injury
Single-photon calcium imaging for interrogating the circuitry of the frontoparietal cognitive control network
PI: Everling, Stefan
Department: Phys & Pharm
Award value: $60,944
The frontoparietal cognitive control network has been implicated in a large number of neuropsychiatric disorders. While it is widely accepted that this network functions as a multiple-demand system which enables complex problem solving by supporting diverse functions such as selective attention, decision making, and task switching, it is still poorly understood how these processes are instantiated by the activities of distributed neuronal populations in health and how they fail in disease. To answer these questions, we believe it necessary to simultaneously record large ensembles of individual characterized neurons in behaving subjects.
Department: Psychology / Comm Sci & Disorders
Award value: $54,019
Compared to visual cortex, little is understood about the organization of auditory cortex in humans. Even now, the basic orientation of primary auditory cortex is not conclusively known. Homologies with other species have been helpful for understanding visual cortical organization but such parallels break down for auditory cortices, which, uniquely in humans, are adapted to process speech and music. Through this research we have a unique opportunity to explore, with unparalleled temporal and spatial resolution, the receptive-field tuning of auditory cortices to naturalistic stimuli and how tuning changes with task demands. This foundational work is critical if we are to understand mechanisms of auditory cortical abnormality in disorders such as autism, specific language impairment, auditory processing disorders and prolonged auditory deprivation (due to hearing loss).
Development of fMRI Compatible Reversible Deactivation to Examine Cerebral Networks
PI: Lomber, Steven
Department: Phys & Pharm / Psychology
Award value: $109,917
The development of functional magnetic resonance imaging (fMRI) has greatly expanded our ability to examine neural processing while subjects perform a variety of perceptual, cognitive, or motor tasks. FMRI permits the simultaneous examination of functional activity in many different brain regions and provides a better understanding of how multiple regions work in concert to produce particular behaviors. The next necessary step in the evolution of this approach is to deactivate a specific region in the brain, while a subject is being scanned, to determine the contribution of this site to the activity in sites throughout its functional network. This is accomplished by examining the activity of other network components in the absence of this region. To accomplish this goal, we propose to develop a reversible deactivation approach that is fMRI-compatible. This study will permit us, for the first time, to examine the effects of deactivation of one cortical site on large-scale neural networks. It will permit neural networks to be functionally dissected and the consequences of “reversible” lesions, strokes, or tumors to be assessed and modeled before they occur.
Award value: $36,809
Parkinson’s disease (PD), addiction, and obsessive compulsive disorder are prevalent and complex neurological and psychiatric illnesses with a) broad cognitive, mood, anxiety, and motor manifestations, and b) symptomatic but not disease-modifying therapies (DMT) or cures. Dopamine (DA) dysfunction and structural and functional abnormalities in the striatum and basal ganglia are understood to be central to these disorders, though precise processes producing most symptoms remain elusive. First, across PD, addiction, and OCD, we intend to contrast patients with and without specific symptoms and signs, regardless of their formal diagnostic labels. Second, by characterizing individual patients across a broad range of investigations—some never-before investigated in these conditions, commonalities and distinctions will be recognized, yielding biomarkers of disease. Discovering mechanisms of neurological and psychiatric symptoms will suggest new symptomatic therapies. Further, evaluation and development of DMTs depend upon availability of valid and reliable biomarkers to act as endpoints. In this way, the proposed research represents an essential step in developing effective therapies and even cures for these disabling disorders.
Award value: $109,998
Anorexia Nervosa (AN) results from a combination of genetic and environmental factors. At the onset of AN, weight loss is rewarding and the acquisition of dieting behavior is a classic example of action-outcome learning, i.e. a goal-directed behavior. Persistence and repetition of dieting behavior and the intermittent pattern of rewards associated to weight loss encourage the establishment of habitual behavior governed by stimulus-response learning. The dorsal striatum regulates complex cognitive functions, including selecting the neuronal resources required for goal-directed or habitual control of behavior. Cholinergic interneurons (CINs) modulate striatal function by a variety of mechanisms and secrete two distinct neurotransmitters, acetylcholine (ACh) and glutamate (Glu), suggesting the use of co-transmission for neuronal regulation. How regulation of co-transmission modulates cognitive outputs is poorly understood. Our overarching goal is to understand how the striatum can select between competing options to favor goal-directed behaviors or the establishment of habitual control. We will provide fundamental and transformational insights in the regulation of cognitive functions by co-transmission.