Imaging the motor system in Parkinson's disease: identifying network deficits with isolated vs. coordinated movements of the upper and lower limbs

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Project Summary/Abstract Parkinson's disease (PD) is a debilitating movement disorder that significantly changes the lives of millions of people worldwide. The conventional viewpoint is that the disease is caused by a selective loss of dopamine- producing neurons in the substantia nigra and subsequent striatal dopamine deficiency, leading to a progressive deterioration of voluntary movements. Thus far, functional neuroimaging has been instrumental in identifying PD-related neural abnormalities following dopamine depletion, but it is important to note that most of our understanding of disease-related brain changes is based on studies of upper limb function. Despite the prolific amount of imaging research carried out to date in PD, we still do not have a clear understanding of the extent to which the brain network controlling lower limb movements is affected by the disease. Also, while brain changes associated with isolated limb control have been consistently investigated, the same is not true for simultaneous movements of limbs which are key to many of our daily behaviors including walking. We propose to address this knowledge gap by using a robust functional imaging protocol sensitive to PD changes that relies on quantifying the blood-oxygen-level dependent (BOLD) MRI response during isometric muscle contraction. We will use a force production task to investigate differences in brain activity during performance of isolated limb movements and ipsilateral coordinated movements between PD and healthy subjects. Of note, we anticipate that an interlimb coordination task will further clarify the role of the cerebellum in the pathophysiology of the disease, a largely unexplored and poorly understood area in PD. To accomplish our goals, we propose two aims. First, determine the patterns of brain activity during lower/upper limb force production and determine whether foot-related deficits in key brain regions across the two subcortical-cortical motor circuits are in a different somatotopic region than hand-related deficits. Second, we will determine differences in brain activity during simultaneous movements of non-homologous limbs between PD and healthy controls. We hypothesize the following changes in PD: extensive reduction in brain activity across the basal ganglia- and cerebello-thalamo-cortical motor circuits during isolated limb movements and in higher-order motor areas (cerebellar hemispheres, supplementary motor area, premotor cortex) during interlimb coordination, changes in somatotopic organization, motor circuit specific correlations between functional brain activity and characteristics of movements derived from wearable technology. By establishing task-specific neural activity patterns, we aim to develop a non-invasive testing platform that would: 1) allow for future assessment of disease progression and responsiveness to interventions, 2) guide future research in identifying new neural targets for therapy, 3) provide objective criteria for subtyping PD, and distinguishing it from atypical parkinsonian syndromes.