Neurons-to-Networks

(Everling, Corneil, Lomber, Goodale, Culham, Vilis, Grahn, Shoemaker, Gribble, Menon, Cusack)

There is an accomplished group of investigators probing the fine-grained structure and organization of cortical substrates for sensorimotor control, multisensory integration for action, and the networks for the autonomic control of cardiovascular responses. These studies need millimeter resolution MRI and fMRI in humans at 3T and sub-millimeter resolution in humans and the small brains of infants, NHPs and cats at 7T. Therefore SNR is pushed to the limit. In addition, a variety of electrophysiological and physiological recording and stimulating techniques as well as pharmacological and cooling inactivation techniques will be simultaneously used with these MRI studies. This kind of neuroscience research has fundamentally important and far-reaching consequences for interpreting human fMRI work because single-unit recording is the ‘gold standard’ of neurophysiology, but opportunities for invasive work in humans are extremely limited. These studies will establish methodologies and model systems that are important for the understanding of patient groups.

A NHP model for schizophrenia. Patients with schizophrenia exhibit cognitive problems such as reduced attention span, difficulties in memorizing things, poor judgment skills, and difficulties in planning and prioritizing in everyday life. Measures of a number of these cognitive deficits can be obtained with simple eye movement tasks such as saccades and antisaccades, and NHPs provide an opportunity to develop animal models of cognitive function and dysfunction that more accurately reflect what happens in humans. For example, Prof. Everling uses ketamine in a reversible model of schizophrenia in NHPs using saccadic eye movements and resting-state fMRI as powerful tools to directly compare the behavioural and neural effects of N-methyl-D-aspartate receptor  (NMDAR) antagonism in non-human primates with cognitive impairments and alterations in cortical network organization in schizophrenic patients. This allows us for the first time, to test the hypothesis that NMDAR antagonists alter functional cortical network connectivity in primates similar to the changes found in patients with schizophrenia by Williamson and Théberge.

Plasticity and cochlear implants. The use of cochlear implants in congenitally deaf cats in Prof. Lomber’s lab has given us the unique ability to examine adaptive plasticity following the initiation of a sensory input, instead of only following the loss of a sensory input. By understanding how the cerebral cortex can adapt to process signals generated by a cochlear prosthetic, it will be possible to alter the use of cochlear prosthetics to better serve the needs of the cerebrum. This optimization could potentially be done with fMRI or EEG in humans, as well as using MRI compatible implants.

Effects of TMS on neural activity. In a research setting, transcranial magnetic stimulation, (TMS) can perturb neural activity within an area, enabling causal insights into the area’s contribution to a given task, and the time window during which the contribution is vital. Clinically, TMS provides a way to systematically alter neural activity for therapeutic benefit. Despite the growing use and therapeutic potential of TMS, a precise understanding of its effects on interconnected brain areas, and how such effects ultimately influence behaviour, is still largely lacking. Tools being developed in the CFMM allow Prof. Corneil to develop, validate, and study NHP models for the effects of TMS on brain and behavior using simultaneous fMRI, implanted recording electrodes and TMS (developed with Chronik, a magnetic stimulation expert). Optimization of TMS in brain networks can be measured with fMRI and could be done in humans at 3T. A similar methodology using direct current stimulation at 7T is also feasible and is being explored.

Neural substrates of voluntary movements. The Culham lab is one of the few labs worldwide studying the human neural substrates of voluntary movements using real actions upon real objects in MRI systems. Her aim is to understand the neural signals involved in programming important everyday actions such as reaching, grasping and tool use.  The results can be used to understand a variety of neuropathologies and also to inform the development of neural prosthetics. The Culham lab has developed a device to present real objects to subjects in the magnet, but the research needs RF coil arrays designed for an unconventional head-tilted configuration that enables direct viewing of the hands’ workspace and less vulnerability to movement-related artifacts (which include not just head movement but limb movements that alter the magnetic fields at the head) that are perhaps the biggest limitation in designing realistic experiments.

Musical rhythm and the motor system. The Grahn lab is investigating how music and rhythm may affect motor responses and may ameliorate movement problems in gait disorders such as Parkinson’s, studies for which she recently received a rare GrammyTM Foundation scientific award (www.grammy.org). The program examines how specific musical parameters (such as rhythm, event rate, energy levels) modulate activity in motor brain areas. By assessing patient-specific motor area responses, these parameters may be individually tailored for maximum therapeutic effect. High-resolution MRI and fMRI of the small brain structures (e.g., the basal ganglia) that are affected in gait disorders are crucial to this research. In addition, this work will measure the neural responses that underlie real-time changes in movement kinematics (e.g., foot-tapping or hand movements) when particular musical parameters are adjusted, requiring reduced motion sensitivity in fMRI.

Vision for action, vision for perception. The Goodale lab is best known for pioneering work showing that neural processes that give rise to visual perception differ from those that control actions. The next step requires assessment of the fine-grained retinotopic organization of visual cortex. For example after pituitary tumor removal, most patients recover their visual functions but have compromised visual control of reaching, grasping, and other skilled actions. To determine whether the magnocellular fibers that eventually project to visuomotor brain areas might be damaged requires high-resolution fMRI. Moreover, it is important that the data be reliable at the single-subject level so that the pattern of activity in visual brain areas can be related directly to behavioural measures of recovery in individual patients. Goodale’s groundbreaking research is shedding new light on neuroplasticity and sensory substitution (in the anatomic location of the visual cortex) in blind “echolocators” who navigate by using the echos of clicking sounds they make.

Autonomic control of cardiovascular responses. The Shoemaker lab studies the cortical circuitry associated with the autonomic nervous system with particular emphasis on the cortical pathways involved in coordinating the cardiovascular response to physical stressors such as muscle contraction or blood pressure changes. Using fMRI methods, they have identified the cortical regions involved in this control in healthy and young humans and are extending this work to understand how age and disease damage the brain and alter cardiovascular control. Experiments to date use heavily trained controls in MRI compatible positive/negative pressure chambers. These are very motion susceptible experiments that would benefit from faster imaging and motion correction in order to be applied in patients.   Movement disorders such as Parkinson’s disease, or mood disorders also produce comorbid alterations in autonomic outflow. New MRI developments will allow the study of deep brain stimulation on cardiovascular control and autonomic neural systems in humans, a new area of interest to the group. Most neuroscientists treat the autonomic nervous system outcomes as “nuisance” variables in fMRI studies.  However, Shoemaker’s team has established the cortical network that actually underpins the “confounds” of heart rate and blood pressure. Understanding these effects is critical in diseases such as Alzheimer’s and stroke and even in the interpretation of resting state fMRI data. This research program serves as a major platform for understanding cardiovascular and neurovascular interactions in many of our patient populations.