Neurophysiological mechanisms underlying deep brain stimulation for the treatment of movement disorders

Deep brain stimulation (DBS) is an invasive neuromodulation therapy for management of the motor symptoms of several movement disorders; however, its mechanisms are complex, varied, and remain unclear. We employed a dual-microelectrode methodology for intraoperative measurement of neuronal activity and synaptic events, in order to assess the physiological response properties of different subcortical DBS target structures to electrical stimulation at different settings. A total of 50 patients with Parkinson’s disease undergoing DBS surgery of the subthalamic nucleus (STN; n=40), globus pallidus internus (GPi; n=8), or ventral intermediate nucleus (Vim; n=2); and nine patients with essential tremor undergoing DBS surgery of the Vim (n=9) participated in the studies. We found that the STN required higher frequencies for inhibition during stimulation compared to the substantia nigra par reticulata (SNr), likely due to a higher prevalence of GABAergic terminals on SNr somas; although both structures receive predominantly GABAergic inputs. In the Vim, a structure with predominantly glutamatergic synapses, higher (200Hz) frequencies were required for neuronal inhibition compared to the STN (100Hz) and SNr (50Hz). Additionally, unlike the STN and SNr, a transient period of neuronal excitation occurred prior to inhibition, reflective of the glutamatergic predominance. Thus, the effects of electrical stimulation are site specific and dependent on the weighted composition of inhibitory and excitatory inputs. We furthermore determined that an enhancement of inhibitory synaptic plasticity occurred in the SNr and GPi after continuous high frequency stimulation (HFS) at 100Hz; demonstrated by increased amplitudes of extracellular inhibitory field evoked potentials (fEPs). We found greater plasticity in the GPi compared to SNr, and that intraoperative administration of levodopa had a potent effect on SNr plasticity. Further, we determined that during stimulation at ≥30Hz, synaptic depression occurred in the SNr; demonstrated by rapid attenuation of successive fEPs. Clinically, we determined that lower levels of SNr plasticity were related to higher severity axial and global motor symptoms, and that neuronal inhibition in the Vim was necessary for tremor suppression. These findings expand upon the understanding of the physiological stimulation response properties of different brain structures in movement disorders patients, and may have implications for advancing DBS technologies.Ph.D