Tremor reduction and modeled neural activity during cycling thalamic deep brain stimulation

Abstract

Objective The effectiveness of deep brain stimulation (DBS) depends on both the frequency and the temporal pattern of stimulation. We quantified responses to cycling DBS with constant frequency to determine if there was a critical on and/or off time for alleviating tremor. Methods We measured postural tremor in 10 subjects with thalamic DBS and quantified neuronal entropy in a network model of Vim thalamic DBS. We tested 12 combinations of cycling on/off times that maintained the same average frequenc7y of 125 Hz, four constant frequency settings, and baseline. Results Tremor and neural firing pattern entropy decreased as the percent on time increased from 50% to 100%. Cycling with stimulation on for at least 60% of the time was as effective as regular stimulation. All cycling settings reduced the firing pattern entropy of model neurons from the no stimulation condition by regularizing pathological firing patterns, either through synaptically-mediated inhibition or axon excitation. Conclusions These results indicate that pauses present in cycling stimulation decreased its effectiveness in suppressing tremor, and that changes in the amount of tremor suppression were strongly correlated with changes in the firing pattern entropy of model neurons. Significance Cycling stimulation may reduce power consumption during clinical DBS, and thereby increase the battery life of the implanted pulse generator.

Short pauses in thalamic deep brain stimulation promote tremor and neuronal bursting

“…All stimulation patterns reduced tremor relative to the stimulation off condition (p<0.0001, Tukey’s HSD). Constant frequency stimulation without pauses provided the greatest reduction of tremor relative to the off condition (p<0.0001, Tukey’s HSD), as in previous reports on DBS with pauses [Birdno et al, 2012; Kuncel et al, 2012]. Stimulation with all pause patterns was less effective than stimulation without pauses, but 15 ms pause patterns did not produce statistically different tremor reduction than continuous DBS (p = 0.077, Tukey’s HSD).…”

“…For example, longer pauses in stimulation trains (≥50 ms) result in decreased postural tremor control in response to irregular Vim thalamic DBS [Birdno et al, 2012; Kuncel et al, 2012]. We performed clinical experiments to determine whether short pauses during high frequency thalamic DBS (≤50 ms) modulate the severity of essential tremor.…”

“…Average spike train entropy was calculated to quantify the irregularity of the model neuron firing patterns as this measure correlates well with the efficacy of DBS in treating the symptoms of movement disorders in humans [Dorval et al, 2010; Kuncel et al, 2012] and non-human primates [Dorval et al, 2008]. We calculated the first order estimate of entropy ( H ) for log-transformed interspike intervals (ISIs) of all model TC neurons as:…”

“…The effects of DBS are strongly dependent on stimulation frequency; high frequency (> 100 Hz) DBS alleviates postural tremor [Kuncel et al, 2006; Sydow et al, 2003], whereas low frequency DBS is clinically ineffective and may exacerbate tremor [Cagnan et al, 2013; Pedrosa et al, 2013]. Therapeutic efficacy is also sensitive to the temporal pattern of stimulation [Birdno et al, 2007, 2008; Brocker et al, 2013; Dorval et al, 2010; Montgomery et al, 2005] and increasing evidence suggests that long pauses during stimulation (≥50 ms) reduce tremor suppression during Vim thalamic DBS [Birdno et al, 2012; Kuncel et al, 2012]. Pauses during stimulation can lead to rebound burst firing in thalamic neurons following a release from inhibition, mediated by a T-Type Ca 2+ current [Jahnsen and Llinás, 1984; Person and Perkel, 2005], and this phenomenon is hypothesized to exacerbate tremor.…”

High Frequency Stimulation Extends the Refractory Period and Generates Axonal Block in the Rat Hippocampus

“…Recently, in order to search for optimal effects of DBS and to save battery power of the implanted pulse generator, various patterns of stimulation including pauses with tens to hundreds milliseconds have been tested in DBS for animals, patients and computer simulation models [8,9,30]. The results have shown that continuous stimulation without pauses is most effective therapeutics in suppressing tremor with thalamic DBS, while inconsistent intervals between DBS pulses could induce burst firings of neurons [31,32]. The present study sheds light on an important mechanism of extended refractory period induced by HFS to explain these phenomena.…”