Motor Cortex Involvement in Deep Brain Stimulation Therapeutic Action and Motor Learning Impairment in Parkinsonism.

摘要

The primary motor cortex (MI) controls movement directly, but is an under-investigated brain region in the pathogenesis and treatment of Parkinsonian motor disability, when compared with the basal ganglia circuitry. In this study, the roles of MI in underlying the therapeutic action of surgical deep brain stimulation and motor learning impairment were investigated.;Deep brain stimulation of the subthalamic nucleus (STN-DBS) is now a recognized therapeutic option for Parkinson's disease (PD). Although this surgical strategy provides behavioral benefits remarkably, its exact mechanism is still a matter of controversy. In principle, STN-DBS can directly activate a wide range of neuronal elements within the STN and surrounding areas. As the corticofugal neurons (CxFn) in the layer V motor cortex provide a major input to the STN, we hypothesized that the stimulation evoked antidromic cortical activation is involved in the therapeutic mechanism of STN-DBS. In the first series of experiments, we performed simultaneous recordings of multi-unit neuronal activities and local field potentials (LFPs) in MI in freely moving hemi-parkinsonian rats. By identifying stimulation evoked antidromic spike, which occurred at a fixed, short latency, CxFn located in the layer V MI were identified. Increasing stimulation frequency also increased failure rate of activation, resulting in a peak frequency of stochastic antidromic spikes at 125Hz STN-DBS, which was correlated with the optimal therapeutic efficacy observed in behavioral tests. Meanwhile, this antidromic effect was accompanied by the rectification of pathological neuronal activities including increased spontaneous firing rate, reduced burst discharge and synchrony among the CxFn. Field potential analysis revealed that STN-DBS alleviated the dominance of pathological beta band oscillation and spike-field coherence in the MI. More importantly, it was found that the firing probability of CxFn could only be modified following the occurrence of antidromic spikes, suggesting that direct interference of stochastic antidromic spikes with pathological neuronal activities underlies the beneficial effect of STN-DBS.;The MI is not simply a static motor control structure. It also contains a dynamic substrate that participates in motor learning or stores motor memory. In PD patients, loss of cortical plasticity and impaired motor learning is a common feature. As the intrinsic horizontal neuronal connections in MI are a strong candidate of cellular correlate for activity-dependent plasticity, in the second series of experiments, we developed in vivo long-term potentiation (LTP) technique in the MI to investigate the dynamics of cortical plasticity during motor skill learning and the role of the innervation by mesocortical dopamine input. Local depletion of dopamine in the primary motor cortex resulted in reduced performance in the forelimb reaching for food learning task. Although the performance of the PD rats in the initial learning phase was comparable to that of the sham-operated group, as training continued, these animals exhibited deficit in consolidating the motor skill. These deficits closely paralleled the impairment in training-enhanced synaptic connections in layer V neurons, and the in vivo LTP of evoked field excitatory postsynaptic potentials induced by intermittent high frequency stimulation. In addition, progressive recruitment of task-specific neurons was suppressed. Our study therefore revealed that dopamine depletion confined to the MI could lead to impairment in cortical synaptic plasticity which may preferentially affect the consolidation, but not the acquisition, of motor skills. These findings shed light on the cellular mechanisms of motor skill learning and could explain the decreased ability of PD patients in learning new motor skills.