Characterization of the cortical electrophysiological effects of motor thalamic DBS and assessment of a pharmacological model for essential tremor

Abstract

Deep brain stimulation (DBS) of the cerebellar-receiving area of motor thalamus has proven to be a highly effective neurosurgical treatment for Essential tremor (ET). Previous clinical studies, however, have also indicated that the overall efficacy and efficiency of the therapy can vary from patient to patient and that the physiological rationale for this outcome variability is not well understood. Functional imaging studies have shown that the pathological state of ET and thalamic DBS treatment each exert a distributed effect on the motor control network including the primary motor cortex (M1). What this effect is on the neuronal level in M1 is not known. Through a series of electrophysiological experiments in a large preclinical animal model, we investigated first how neuronal spike rates and patterns in M1 change during thalamic DBS and second how such changes might explain the clinical observations that (1) higher frequency pulse trains for thalamic DBS are more effective in suppressing tremor and (2) electrode contacts at the ventral pole of motor thalamus are more efficient at reducing tremor. Higher frequency thalamic DBS resulted in a mild increase in the population averaged neuronal spike rate in M1, a significant decrease in population-averaged spike pattern entropy, and a strong increase in the proportion of neurons with phase-locked spike activity. In contrast, high-frequency DBS through electrodes at the ventral pole of motor thalamus at low current amplitudes (in comparison to electrodes within motor thalamus proper) was found to predominantly affect phase-locked spike activity but not spike rate and spike-pattern entropy. Together, these data suggest that M1 phase-locked spike activity may be a useful biomarker for future studies seeking to develop and assess new approaches for optimizing DBS therapy for action and postural tremors. Toward this goal, we also characterized and assessed the suitability of the alkaloid harmaline in generating a robust and consistent tremor in a large preclinical animal for future translational efforts developing technology to help individuals living with ET.