Selective Attenuation of Afferent Synaptic Transmission as a Mechanism of Thalamic Deep Brain Stimulation-Induced Tremor Arrest

Abstract

Deep brain stimulation (DBS) of the ventrolateral thalamus stops several forms of tremor. Microelectrode recordings in the humanthalamus have revealed tremor cells that fire synchronous with electromyographic tremor. The efficacy of DBS likely depends on its ability to modify the activity of these tremor cells either synaptically by stopping afferent tremor signals or by directly altering the intrinsic membrane currents of the neurons. To test these possibilities, whole-cell patch-clamp recordings of ventral thalamic neurons were obtained from rat brain slices. DBS was simulated (sDBS) using extracellular constant current pulse trains (125 Hz, 60 -80 s, 0.25-5 mA, 1-30 s) applied through a bipolar electrode. Using a paired-pulse protocol, we first established that thalamocortical relay neurons receive converging input from multiple independent afferent fibers. Second, although sDBS induced homosynaptic depression of EPSPs along its own pathway, it did not alter the response from a second independent pathway. Third, in contrast to the subthalamic nucleus, sDBS in the thalamus failed to inhibit the rebound potential and the persistent Na ϩ current but did activate the I h current. Finally, in eight patients undergoing thalamic DBS surgery for essential tremor, microstimulation was most effective in alleviating tremor when applied in close proximity to recorded tremor cells. However, stimulation could still suppress tremor at distances incapable of directly spreading to recorded tremor cells. These complementary data indicate that DBS may induce a "functional deafferentation" of afferent axons to thalamic tremor cells, thereby preventing tremor signal propagation in humans.

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

“…Several possibilities have been proposed, including depolarization block due to an increase in potassium current 28 or an inactivation of sodium channels, 29,30 presynaptic depression of excitatory afferents, 31 and stimulation-induced activation of inhibitory afferents. 32,33 Support for the depolarization block hypothesis comes primarily from in vitro experiments.…”

“…Hyperpolarization-activated cation (HCN) and low-threshold calcium (T-type) channel currents, for example, may be activated during HFS resulting in an excitatory time-locked rebound. 31,33 The contribution of network and reentrant loops 35 also warrants further investigation with in vivo experiments that incorporate local infusion of specific antagonists during HFS.…”

Mechanisms of Deep Brain Stimulation in Movement Disorders as Revealed by Changes in Stimulus Frequency

“…21 A similar decrease in STN neuron firing rates was observed during STN high-frequency stimulation (HFS) of Parkinsonian monkeys. 22 Such somatic inhibition may occur by either activation of the axons of inhibitory afferents, 23 presynaptic depression at excitatory afferent axon terminals, 24 and/or depolarization-induced blockade of somatic ion channels. 25 On the other hand, there is abundant evidence that suggests that the efferent axons of the stimulated nucleus are activated by high frequency DBS.…”

“…59 High-frequency (Ͼ70 Hz) STN DBS reduced pallidal beta oscillations (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) in PD subjects in a manner similar to the administration of dopamine precursors, whereas 25 Hz DBS increased the power of pallidal beta oscillations. 60 In addition, high-frequency STN DBS at 130 Hz or 185 Hz attenuated STN beta oscillations in subjects with PD during the period just after DBS was turned off.…”

High frequency stimulation of the ventrolateral and mediodorsal thalamic nuclei: differential effects on impulsive action

“…Thalamic DBS is most effective when performed in the ventrolateral (VL) nucleus, which contains "tremor cells", and is nowadays predominantly used for essential tremor (Anderson et al, 2006;Kobayashi et al, 2003). DeLong, 1990).…”