Neurodegenerative Disorders

(Finger, Borrie, Montero-Odasso, Wells, Duggal, Burneo, Mirsattari, Jog, Kremenchutzky, Shoemaker, Owen, MacDonald, Menon, Bartha)

Virtually all of the studies in this group are on patients who are either too uncomfortable to hold still for long periods of time, have involuntary movements from tremor or seizures, or are unable to fully comprehend instructions to lie still. Furthermore, many of the cortical and subcortical substrates or lesions to be investigated are very small (few mm), requiring either very high resolution fMRI, MRI or DTI or very small voxels in MRS. These groups of patients dramatically benefit from the development of multi-channel RF coil arrays and real-time motion correction capabilities.

Dementia (frontotemporal, Alzheimer’s, Mild Cognitive Impairment). These research programs focus on the use of cutting-edge neuroimaging techniques to delineate early dysfunction in the dementias, to develop improved tools for early diagnosis and determine the functional mechanisms underlying patient’s symptoms (and thereby identify new treatment targets). We also characterize the response of these neural systems to novel treatments. Highly innovative paradigms for symptom-targeted cognitive tasks with fMRI (Finger) are being combined with serologic biomarkers in frontotemporal dementia patients. The use of high resolution MRI to identify the brain regions that atrophy in prodromal Alzheimer disease, the use of highly localized MRS (i.e. ≤1 cc voxels at 7T) to define the metabolic changes associated with cognitive decline and response to cholinergic treatment in Alzheimer disease, and the use of MRS and volumetric imaging to understand the neural substrates of cognitive decline associated with increased gait variability are other major thrusts in this research area.

Multiple Sclerosis (MS). MS is the most common chronic neurological disease affecting young adults, and of particular relevance because Canada’s MS prevalence rate is amongst the highest in the world. Conventional diagnostic MRI findings have not correlated well with clinical symptoms and have not demonstrated significant predictive power for disease progression, likely because conventional MRI visualizes only a few of the lesions and damage seen in histopathological studies. The Menon group has developed a high-resolution version of their multi-echo RASTAMAP sequence for measuring the intrinsic tissue magnetic parameters R2*, the microscopic magnetic fields in tissue (mB0) and the tissue magnetic susceptibility (), all of which can be linked to histopathological findings in MS (and likely many other diseases like Epilepsy and PD as described below). Funded by a large CIHR grant, Menon and Kremenchutzky are pursuing this at 3T and 7T. The 3T data shows lesions that are homogeneous on conventional MRI can be stratified using this quantitative sequence, but as it is a susceptibility-weighted sequence, motion needs to be carefully controlled. At 7T, there are strong indications of grey matter involvement in the disease from the MGH group and our own data.

Intractable Epilepsy. Drs. Burneo and Mirsattari are using highly local 1H MRS (Bartha) to measure neurologically significant metabolites such as glutamate that may be implicated in epilepsy.  They  also use DTI and novel 7T susceptibility contrasts (Menon) to the evaluate epileptic malformations of cortical development to identify areas of white matter abnormality that go beyond the defined cortical abnormality seen with structural MRI. Such images provide information about the neuronal and microstructural organization of the epileptogenic lesion and the surrounding tissue not observed with conventional MRI.   These techniques can be used in prospective cohort studies of subjects with traumatic brain injury to identify individuals at risk of developing post traumatic epilepsy, to detect it early and to improve prognosis by providing adequate treatment.

Spinal Cord Compression. In its mildest form, cervical spondylosis can cause symptoms such as stiffness, restricted range of motion as well as neck and arm pain. Surgical outcomes are unpredictable, likely depending on whether the spinal cord has undergone reversible or irreversible injury. By applying fMRI and MRS at 3T in a CIHR funded study, Duggal and Bartha have recently demonstrated cortical reorganization and recruitment of surrounding brain cortex to perform a motor task following surgery. Brain metabolite levels were altered in patients with reversible spinal cord compression as well. The future of this program involves studying the spine directly to refine the criteria used to choose surgical candidates. However studies to examine the spine with DTI and MRS are highly susceptible to motion and will require development of faster imaging and specific shim coils to improve magnetic field homogeneity within the cord (collaboration with Chronik).

Parkinson’s Disease (PD).The effect of dopamine depletion on the neurochemical pathways linking the basal ganglia, substantia nigra (SN), thalamus and cerebral cortex are not well understood. Tremor dominant (TD), akinetic rigid (AkR), and primary instability of gait (PIGD) are 3 clinical subtypes of PD. These subtypes are associated with separate patterns of change in the neurochemical pathways involved in PD. The objective of the work lead by Dr. Jog is to measure the neurometabolic profile within the SN, subthalamic nucleus (STN) and ventral anterior-ventrolateral thalamus (VA/VL) in patients with these 3 clinical subtypes and in healthy control subjects using short echo time LASER 1H MRS (Bartha). In additional to their motor symptoms, 15-20% of PD patients suffer from dementia (x6 more likely than controls), or a less severe cognitive impairment that is an important predictor of quality of life. Prof. Owen and Dr. MacDonald will build on his substantial existing body of work on the neurochemical and neuroanatomical basis of cognitive deficits in PD and their implications for frontostriatal dysfunction. Longitudinal imaging studies being developed will investigate the cognitive, anatomical and genotypic mechanisms determining the transition from PD to dementia within a large cohort of patients. Cross-sectional studies are also being geared up within sub-populations or individuals to examine the effects of medication, genotype and cognitive training. To do this, they are developing a common battery of fMRI paradigms that produce specific, performance-related activity in key cortical and sub-cortical regions (e.g. frontal-lobe, basal-gangliaand hippocampus) and obtain functional and structural connectivity measures in patients and volunteers to investigate how these regions functionally interact.

Acute Brain Injury. Improvements in intensive care have lead to an increase in the number of patients who survive severe brain injury. Some have a good prognosis, but many progress to a vegetative (VS) or minimally conscious state (MCS). Recent advances in fMRI, led by Dr. Owen and his team, have shown that fMRI can be used to assess cognitive functions in VS and MCS without the need for any overt response from the patient. Up to 20% of behaviourally vegetative patients may have some level of preserved awarenessleading other key scientists in this field to conclude that integrating the fMRI techniques pioneered by Dr. Owen and his team with existing clinical and behavioural assessments will be essential to reduce diagnostic error in these patients. These diagnostics have critically important medical, legal and ethical implications. Prof. Owen is extending his landmark studies of acute brain injury at the CFMM. As an example, a comprehensive battery of neuroimaging paradigms is being developed that will provide a standard for the assessment of cognitive deficits and residual neural function after serious brain injury. At 3T, we will develop new fMRI methods for real-time communication in the absence of any behavioural response in seriously brain-injured patients. We will also develop new techniques for acquiring and combining EEG and fMRI data in real-time, using the ‘dynamic adaptive imaging’ (DAI) technology developed by Prof. Cusack. At 7T, we will develop new methods for exploring brain damage in these clinical populations using diffusion tensor imaging (DTI) to examine the disruption of white matter fiber tracts in vivo. Somewhat surprisingly, VS and MCS patients spontaneously move quite frequently and dramatically. Therefore the ability to take quick fMRI “snapshots” of the brain activity of these patients is critical and will require the highest sensitivity for single trial fMRI paradigms.