No abstract

Deep brain stimulation (DBS) of the basal ganglia can alleviate the motor symptoms of Parkinson's disease although the therapeutic mechanisms are unclear. We hypothesize that DBS relieves symptoms by minimizing pathologically disordered neuronal activity in the basal ganglia. In human participants with parkinsonism and clinically effective deep brain leads, regular (i.e., periodic) high-frequency stimulation was replaced with irregular (i.e., aperiodic) stimulation at the same mean frequency (130 Hz). Bradykinesia, a symptomatic slowness of movement, was quantified via an objective finger tapping protocol in the absence and presence of regular and irregular DBS. Regular DBS relieved bradykinesia more effectively than irregular DBS. A computational model of the relevant neural structures revealed that output from the globus pallidus internus was more disordered and thalamic neurons made more transmission errors in the parkinsonian condition compared with the healthy condition. Clinically therapeutic, regular DBS reduced firing pattern disorder in the computational basal ganglia and minimized model thalamic transmission errors, consistent with symptom alleviation by clinical DBS. However, nontherapeutic, irregular DBS neither reduced disorder in the computational basal ganglia nor lowered model thalamic transmission errors. Thus we show that clinically useful DBS alleviates motor symptoms by regularizing basal ganglia activity and thereby improving thalamic relay fidelity. This work demonstrates that high-frequency stimulation alone is insufficient to alleviate motor symptoms: DBS must be highly regular. Descriptive models of pathophysiology that ignore the fine temporal resolution of neuronal spiking in favor of average neural activity cannot explain the mechanisms of DBS-induced symptom alleviation.

Deep brain stimulation (DBS) provides dramatic tremor relief when delivered at high-stimulation frequencies (more than ∼100 Hz), but its mechanisms of action are not well-understood. Previous studies indicate that high-frequency stimulation is less effective when the stimulation train is temporally irregular. The purpose of this study was to determine the specific characteristics of temporally irregular stimulus trains that reduce their effectiveness: long pauses, bursts, or irregularity per se. We isolated these characteristics in stimulus trains and conducted intraoperative measurements of postural tremor in eight volunteers. Tremor varied significantly across stimulus conditions (P < 0.015), and stimulus trains with pauses were significantly less effective than stimulus trains without (P < 0.002). There were no significant differences in tremor between trains with or without bursts or between trains that were irregular or periodic. Thus the decreased effectiveness of temporally irregular DBS trains is due to long pauses in the stimulus trains, not the degree of temporal irregularity alone. We also conducted computer simulations of neuronal responses to the experimental stimulus trains using a biophysical model of the thalamic network. Trains that suppressed tremor in volunteers also suppressed fluctuations in thalamic transmembrane potential at the frequency associated with cerebellar burst-driver inputs. Clinical and computational findings indicate that DBS suppresses tremor by masking burst-driver inputs to the thalamus and that pauses in stimulation prevent such masking. Although stimulation of other anatomic targets may provide tremor suppression, we propose that the most relevant neuronal targets for effective tremor suppression are the afferent cerebellar fibers that terminate in the thalamus.

Objective-The goal of this study was to develop, evaluate, and apply a method to quantify the unknown spatial extent of activation in deep brain stimulation (DBS) of the ventral intermedius nucleus (Vim) of the thalamus.Methods-The amplitude-distance relationship and the threshold amplitudes to elicit clinical responses were combined to estimate the unknown amplitude-distance constant and the distance between the electrode and the border between the Vim and the ventrocaudal nucleus (Vc) of the thalamus. We tested the sensitivity of the method to errors in the input parameters, and subsequently, applied the method to estimate the amplitude-distance constant from clinicallymeasured threshold amplitudes.Results-The method enabled estimation of the amplitude-distance constant with a median squared error of 0.07-0.23 V/mm 2 and provided an estimate of the distance between the electrode and the Vc/Vim border with a median squared error of 0.01-0.04 mm. Application of the method to clinically-measured threshold amplitudes to elicit paresthesias estimated the amplitude-distance constant to be 0.22 V/mm 2 .Conclusions-The method enabled robust quantification of the spatial extent of activation in thalamic DBS and predicted that stimulation amplitudes of 1-3.5 V would produce a mean effective radius of activation of 2.0-3.9 mm.Significance-Knowing the spatial extent of activation may improve methods of electrode placement and stimulation parameter selection in DBS.

Deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus for essential tremor is sometimes limited by side effects. The mechanisms by which DBS alleviates tremor or causes side effects are unclear; thus, it is difficult to select stimulus parameters that maximize the width of the therapeutic window. The goal of this study was to quantify the impact on side effect intensity (SE), tremor amplitude, and the therapeutic window of varying stimulus parameters. Tremor amplitude and SE were recorded at 40 to 90 combinations of pulse width, frequency, and voltage across 14 thalami. Posterior variable inclusion probabilities indicated that frequency and voltage were the most important predictors of both SE and tremor amplitude. The amount of tremor suppression achieved at frequencies of 90 to 100 Hz was not different from that at 160 to 170 Hz. However, the width of the therapeutic window decreased significantly and power consumption increased as frequency was increased above 90 to 100 Hz. Improved understanding of the relationships between stimulus parameters and clinical responses may lead to improved techniques of stimulus parameter adjustment.