Over the last two decades, functional imaging has contributed to what might be considered a paradigm shift in our understanding of cerebellar function especially in sensory processing and cognition. However, the utility of functional imaging methods in cerebellar research has been greatly limited by the inability of to dissociate the climbing fibers'contribution to cerebellar crtex activation from that of mossy fibers. The climbing fiber system is one of the two systems that carry sensory information to the cerebellum. The climbing fibers originate exclusively from the inferior olive;a small structure in the brain-stem. With funding from the Department of Veterans Affairs, we have shown reliable activation of the inferior olive using high resolution functional magnetic resonance imaging (fMRI) at 3 Tesla, when subjects perceived the timing of visual and touch sensation (D. Xu et al., 2006;T. Liu et al., 2008). The proposed work is innovative because it capitalizes on this recent novel finding. Our ability to detect the activity of the infeior olive by fMRI methods allows us to non-invasively monitor the neural activity of the inferior olive cerebellar cortex and whole brain networks in human subjects to specifically address fundamental questions regarding the function of the inferior olive/climbing fiber system. The proposal under consideration addresses the mechanisms of timing and learning;the two major longstanding hypotheses regarding the function of the inferior olive. Our central hypothesis is that the olivo-cerebellar system contributes to both motor and non-motor processes including learning by encoding the timing of sensory input independent of voluntary cognitive control or attention. We plan to test this hypothesis and accomplish the objectives of this proposal by carrying out the following specific aims: 1. To determine the timing scale of the inferior olive response, 2. To determine the effect of attention on the inferior olive response to event timing, 3. To determine the specificity of the inferior olive activity during learning to event timing, 4. o identify the inferior olive activity pattern during learning and 5. To determine the inferior olive response to sensory input resulting from self-initiated movement. Because the inferior olive is central to theories of cerebellar function, defining the behavioral conditions in which the inferio olive is activated will have a positive impact by advancing our understanding of the functions of the cerebellum and neural mechanisms of timing, attention and learning. The proposed work is also expected to identify experimental paradigms that activate the inferior olive. Such paradigms can be used to probe the underlying mechanisms of poorly understood human disorders in which the inferior olive and the cerebellar timing mechanisms have been implicated. These include altered timing mechanisms in schizophrenia, impulsiveness in post-traumatic stress disorder as well as essential tremor;relatively common disorders in the veterans population.
Relevance of the Proposed Research to Veterans'Health. This proposal addresses the cerebellar and specifically the inferior olive and climbing fiber system mechanisms of timing and learning. Cerebellar dysfunction (predominantly stroke) is relatively common in veterans. Another disease specifically attributed to inferior olive/ climbing fiber system dysfunction is essential tremor (ET);a common disease that is 20 times more prevalent than Parkinson's disease affecting approximately 3 % of the general population. ET is a progressive disease leading to more disability at older age. Currently, about 40 percent veterans are >65 years of age (compared to about 12 % in the general population). Therefore, similar to other diseases of the elderly, disabling ET is likely to be more common in veterans than in the general population. The inferior olive and cerebellar timing mechanisms have also been implicated in multiple psychiatric and cognitive disorders including schizophrenia and impulsivity in post-traumatic stress disorder which are common in veterans.