Is Closed Loop, Time Locked Primary Motor Cortex Stimulation an Ideal Target for Improving Movements in Neurological Disorders?
The basal ganglia play a critical role in motor control as evidenced by movement impairments in neurological disorders, including bradykinesia in Parkinson's disease (PD) Using a two virus labeling system in genetically modified mice, approximately 60% to 70% of monosynaptic glutamatergic input onto direct and indirect pathway medium spiny neurons (dMSN, iMSN) in dorsal striatum was found to originate from cortical areas, with dense primary motor cortex (M1) projections to iMSN. A recent study examined experience dependent plasticity associated with goaldirected, rewarded reaching movements in mice combined with closed loop, time locked optical stimulation of dorsal striatal iMSN or dMSN. Stimulation occurred within 15 ms after movement initiation and lasted for 450 ms using 10 ms pulses at 16.7 Hz during the slowest or fastest third of movements. Overall, dMSN stimulation increased, whereas iMSN stimulation decreased movement velocity during the fastest movements. In contrast, during the slowest movements, iMSN stimulation increased whereas dMSN stimulation decreased movement velocity. Administration of D1 and D2 receptor antagonists abolished the effects of iMSN or dMSN stimulation on movement velocity. Importantly, stimulation of both fast and slow movements on every trial or random stimulation had no effects. This elegant study used optogenetic techniques to selectively stimulate the direct or the indirect pathway in the context of specific types of movements and has important implications for motor control. A prominent model of the basal ganglia is that the direct pathway promotes intended movements whereas the indirect pathway inhibits competing actions. However, the current results suggest that this model is too simplistic because both indirect and direct pathways can undergo activity dependent plasticity and, more important, both pathways can bidirectionally modulate movement kinematics. Furthermore, these results suggest that closed loop, timelocked stimulation of iMSN may improve bradykinesia with prominent slow movements. Stimulations should occur in the presence of dopaminergic medications attributed to the dopamine dependency and target only slower movements and iMSN. Electrical stimulation of dorsal striatum where iMSN and dMSN are intermingled would not be ideal, and optogenetic stimulation in humans will not be feasible in the foreseeable future. However, the STN in the indirect pathway or targeting M1 corticostriatal pathways upstream may be viable options. Selective M1 stimulation during slow movements should activate iMSN, leading to activity dependent plasticity and higher movement velocity. This type of closedloop M1 stimulation, time locked to onset of slow movement, may be able to overcome previous negative results of openloop, continuous epidural M1 stimulation in PD.
Movement disorders official journal of the Movement Disorder Society