Tremor entrainment by patterned low-frequency stimulation

Abstract

High-frequency test stimulation for tremor suppression is a standard procedure for functional target localization during deep brain stimulation. This method does not work in cases where tremor vanishes intraoperatively, for example, due to general anaesthesia or due to an insertional effect. To overcome this difficulty, we developed a stimulation technique that effectively evokes tremor in a well-defined and quantifiable manner. For this, we used patterned low-frequency stimulation (PLFS), i.e. brief high-frequency pulse trains administered at pulse rates similar to neurons' preferred burst frequency. Unlike periodic single-pulse stimulation, PLFS enables one to convey effective and considerably greater integral charge densities without violation of safety requirements. In a computational investigation of an oscillatory neuronal network temporarily rendered inactive, we found that PLFS evokes synchronized activity, phase locked to the stimulus. While a stronger increase in the amount of synchrony in the neuronal population requires higher stimulus intensities, the portion of synchronously active neurons nevertheless becomes strongly phase locked to PLFS already at weak stimulus intensities. The phase entrainment effect of PLFS turned out to be robust against variations in the stimulation frequency, whereas enhancement of synchrony required precisely tuned stimulation frequencies. We applied PLFS to a patient with spinocerebellar ataxia type 2 (SCA2) with pronounced tremor that disappeared intraoperatively under general anaesthesia. In accordance with our computational results, PLFS evoked tremor, phase locked to the stimulus. In particular, weak PLFS caused low-amplitude, but strongly phase-locked tremor. PLFS test stimulations provided the only functional information about target localization. Optimal target point selection was confirmed by excellent post-operative tremor suppression.