Neurophysiological mechanisms of thalamic ventral intermediate nucleus stimulation for tremor suppression

Luka Milosevic1, 2; Suneil K Kalia3, 4, 5; Mojgan Hodaie3, 4, 5; Andres M Lozano3, 4, 5; William D Hutchison3, 5, 6; Milos R Popovic1, 2

1. Institute of Biomaterials and Biomedical Engineering, University of Toronto; 2. Rehabilitation Engineering Laboratory, Toronto Rehabilitation Institute – University Health Network; 3. Department of Surgery, University of Toronto; 4. Division of Neurosurgery, Toronto Western Hospital – University Health Network; 5. Krembil Brain Institute; 6. Department of Physiology, University of Toronto

Essential tremor (ET) is often refractory to medical therapy, and the pathophysiology and genesis of ET remain poorly understood. Ventral intermediate thalamic (Vim) deep brain stimulation (DBS) is a standard therapy for ET. The objective of this study was to investigate the frequency-dependent effects of electrical stimulation on both neuronal firing and tremor suppression.

Methods: Two closely spaced (600µm) microelectrodes were advanced into the Vim of 11 tremor patients undergoing DBS surgery. One microelectrode recorded action potential firing during stimulation trains (3s, 100µA, 150µs, nstimulations=80) at 100Hz and 200Hz from the adjacent microelectrode. A tri-axial accelerometer was used to measure postural tremor of the contralateral hand.

Results: 200Hz stimulation led to 66% inhibition of neuronal firing and suppression of tremor-related (3-7Hz) activity of the neuron, and a 52% reduction in tremor, while 100Hz only reduced firing by 13% with an associated 16% tremor reduction. Higher neuronal inhibition was associated with improved tremor reduction, which was more prominent at 200Hz (p<0.01). The degree of cell inhibition and tremor suppression were significantly correlated (p<0.01). We also found that microstimulation caused a transient high frequency discharge of the neuron which led to a tremor phase reset.

Conclusions: Effects on cell firing and tremor suppression are frequency-dependent. We hypothesize that one physiological mechanism of action that leads to this clinical benefit is neurotransmitter depletion. Another mechanism could be recurrent inhibition by way of the thalamic reticular nucleus. This study implicates the Vim as a “gate” for tremor genesis.