Model-based deconstruction of cortical evoked potentials generated by subthalamic nucleus deep brain stimulation

摘要

Parkinson's disease is associated with altered neural activity in the motor cortex. Chronic high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing parkinsonian motor symptoms and modulates cortical activity. However, the anatomical pathways responsible for STN DBS-mediated cortical modulation remain unclear. Cortical evoked potentials (cEP) generated by STN DBS reflect the response of cortex to subcortical stimulation, and the goal of this study was to determine the neural origin of STN DBS-generated cEP using a two-step approach. First, we recorded cEP over ipsilateral primary motor cortex during different frequencies of STN DBS in awake healthy and unilateral 6-OHDA-lesioned parkinsonian rats. Second, we used a detailed, biophysically based model of the thalamocortical network to deconstruct the neural origin of the recorded cEP. The in vivo cEP included short (Rl)-, intermediate (R2)-, and long-latency (R3) responses. Model-based cortical responses to simulated STN DBS matched remarkably well the in vivo responses. The short-latency response was generated by antidromic activation of layer 5 pyramidal neurons, whereas recurrent activation of layer 5 pyramidal neurons via excitatory axon collaterals reproduced the intermediate-latency response. The long-latency response was generated by polysynaptic activation of layer 2/3 pyramidal neurons via the cortico-thalamic-cortical pathway. Antidromic activation of the hyperdirect pathway and subsequent intracortical and cortico-thalamo-cortical synaptic interactions were sufficient to generate cortical potential evoked by STN DBS, and orthodromic activation through basal ganglia-thalamus-cortex pathways was not required. These results demonstrate the utility of cEP to determine the neural elements activated by STN DBS that might modulate cortical activity and contribute to the suppression of parkinsonian symptoms.