Mechanisms and characterization of upper and lower limb motor pathway activation in people with parkinson's disease

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder defined by the characteristic patterns of alpha-synuclein buildup and neuronal degeneration of dopaminergic cells in the substantia nigra pars compacta. Degeneration is accompanied by the emergence of cardinal motor symptoms of bradykinesia, akinesia, resting tremor, muscle rigidity, postural instability, and gait dysfunction. Many of the primary motor symptoms (bradykinesia, rigidity, tremor) can be improved with therapies (dopamine replacement therapy and deep brain stimulation (DBS)) but other motor signs (posture, balance, gait) are often resistant to treatment. Currently, the mechanisms and characteristics driving impaired neural control of the upper and lower limbs in PD and their responses to DBS are unknown but likely reflect differences in corticospinal, basal ganglia, and corticoreticular contributions to muscle control. In this dissertation, three projects assessed upper and lower extremity motor control in people with PD. Project 1 characterized responses of upper and lower extremities to corticospinal activation, demonstrating that there are larger magnitudes of responses in upper compared to lower extremities and in distal compared to proximal muscles in people with PD. Project 2 used transcranial magnetic stimulation to examine the excitability of intracortical, corticospinal and corticoreticular pathways projecting to the ankle muscles during isometric contractions in people with PD and age matched controls. These experiments demonstrated that the excitability of corticoreticular projections of plantar flexors during isometric plantar, but not dorsiflexion, were increased in PD. Lastly, in Project 3, we examined the mechanisms by which DBS reduces upper limb rigidity using patient-specific pathway activation models of the basal ganglia in people with PD and pallidal DBS. This project showed that activation of efferent fibers projecting from the globus pallidus internus were associated with decreased rigidity. The results of this dissertation provide a greater understanding of the impacts of disease and DBS on upper and lower extremity function which can directly enhance our knowledge of and improve the quality of life for those with PD.