Temporally optimized patterned stimulation (TOPS®) as a therapy to personalize deep brain stimulation treatment of Parkinson's disease.

Deep brain stimulation (DBS) is a well-established therapy for the motor symptoms of Parkinson's disease (PD), but there remains an opportunity to improve symptom relief. The temporal pattern of stimulation is a new parameter to consider in DBS therapy, and we compared the effectiveness of Temporally Optimized Patterned Stimulation (TOPS) to standard DBS at reducing the motor symptoms of PD. Twenty-six subjects with DBS for PD received three different patterns of stimulation (two TOPS and standard) while on medication and using stimulation parameters optimized for standard DBS. Side effects and motor symptoms were assessed after 30 min of stimulation with each pattern. Subjects experienced similar types of side effects with TOPS and standard DBS, and TOPS were well-tolerated by a majority of the subjects. On average, the most effective TOPS was as effective as standard DBS at reducing the motor symptoms of PD. In some subjects a TOPS pattern was the most effective pattern. Finally, the TOPS pattern with low average frequency was found to be as effective or more effective in about half the subjects while substantially reducing estimated stimulation energy use. TOPS DBS may provide a new programing option to improve DBS therapy for PD by improving symptom reduction and/or increasing energy efficiency. Optimizing stimulation parameters specifically for TOPS DBS may demonstrate further clinical benefit of TOPS DBS in treating the motor symptoms of Parkinson's disease.

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

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 frequency 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.

Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation.

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.

Deep brain stimulation alleviates parkinsonian bradykinesia by regularizing pallidal activity.

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.

Myoclonus and tremor response to thalamic deep brain stimulation parameters in a patient with inherited myoclonus-dystonia syndrome.

We present a 74-year-old woman with inherited myoclonus-dystonia, with predominant myoclonus and a novel mutation in the epsilon-sarcoglycan gene. The patient reports a life-long history of rapid, jerking movements, most severe in the upper extremities as well as a postural and action tremor. Bilateral deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus was performed, and the patient demonstrated moderate clinical improvement in myoclonus. We studied the effects on myoclonus and tremor of varying DBS frequency and amplitude. The frequency tuning curve for myoclonus was similar to that of tremor, suggesting similar mechanisms by which DBS alleviates both disorders.

A model predicting optimal parameters for deep brain stimulation in essential tremor.

In nine patients with essential tremor (14 thalami), the authors varied frequency, voltage, and pulsewidth of thalamic deep brain stimulation, and quantified postural tremor. Low frequency stimulation aggravated tremor; the effect increased with increasing voltage. High frequency stimulation had a U-shaped relation to voltage, with minimum tremor at an optimal voltage characteristic of the individual thalamus and increases in voltage beyond the optimum reduced tremor suppression.Based on the hypothesis that tremor response to deep brain stimulation resulted from two competing processes, the authors successfully modeled the relationship of tremor to voltage and frequency of stimulation using a mathematical model. The optimum voltage predicted by the model agreed with the empirically measured value. Moreover, the model made accurate predictions at high stimulation frequency based on measurements made at low stimulation frequency.Our results indicate there is an optimal voltage for tremor suppression by thalamic deep brain stimulation in most patients with essential tremor. The optimum varies across patients, and this is related to electrode position. A mathematical model based on "competing processes" successfully predicts optimum voltage in individual patients. This supports a competing processes model of deep brain stimulation effects.

A method to estimate the spatial extent of activation in thalamic deep brain stimulation.

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 clinically-measured threshold amplitudes. RESULTS: The method enabled estimation of the amplitude-distance constant with a median squared error of 0.07-0.23V/mm2 and provided an estimate of the distance between the electrode and the Vc/Vim border with a median squared error of 0.01-0.04mm. Application of the method to clinically-measured threshold amplitudes to elicit paresthesias estimated the amplitude-distance constant to be 0.22V/mm2. CONCLUSIONS: The method enabled robust quantification of the spatial extent of activation in thalamic DBS and predicted that stimulation amplitudes of 1-3.5V would produce a mean effective radius of activation of 2.0-3.9mm. SIGNIFICANCE: Knowing the spatial extent of activation may improve methods of electrode placement and stimulation parameter selection in DBS.

Tremor varies as a function of the temporal regularity of deep brain stimulation.

The frequency of stimulation is one of the primary factors determining the effectiveness of deep brain stimulation (DBS) in relieving tremor. DBS efficacy, however, may depend not only on the average frequency of stimulation, but also on the temporal pattern of stimulation. We conducted intraoperative measurements of the effect of temporally irregular DBS (nonconstant interpulse intervals) on tremor. As the coefficient of variation of irregular high frequency DBS trains increased, they became less effective at reducing tremor (mixed effects regression model, P<0.04). These data provide evidence that the effects of DBS are dependent not only on the average frequency of DBS, but also on the regularity of the temporal spacing of DBS pulses.

Amplitude- and frequency-dependent changes in neuronal regularity parallel changes in tremor With thalamic deep brain stimulation.

The mechanisms by which deep brain stimulation (DBS) alleviates tremor remain unclear, but successful treatment can be achieved with properly selected frequency and amplitude. The clinical tremor response to thalamic DBS for essential tremor is dependent on the stimulation frequency and amplitude, and for high frequencies (> or = 90 Hz), increasing amplitude suppressed tremor, whereas for low frequencies (< 60 Hz), increasing amplitude aggravated tremor. We studied the effects of stimulation frequency and amplitude on the output of a population of intrinsically active model neurons to test the hypothesis that regularization of neuronal firing patterns is responsible for the clinical effectiveness of DBS. The firing patterns of model thalamocortical neurons were dependent on stimulation frequency and amplitude in a manner similar to the clinical tremor response. Above a critical frequency, increasing amplitude reduced the coefficient of variation (CV) of the neuronal firing pattern, whereas for low frequencies, increasing the amplitude increased the CV of neuronal activity. The correlation between the changes in tremor and the changes in the CV of neuronal firing supports the hypothesis that regularization of neuronal firing pattern during DBS is one of the mechanisms underlying the suppression of tremor.

Clinical response to varying the stimulus parameters in deep brain stimulation for essential tremor.

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.

Selection of stimulus parameters for deep brain stimulation.

OBJECTIVE: To provide an analysis of stimulation parameters for deep brain stimulation (DBS). METHODS: Synthesis of theoretical and empirical findings is used to provide guidance for the selection of stimulus parameters. Finite element modeling is used to investigate the effects of contact location and electrode geometry on the electric field, and to estimate the effects of current density distribution on the limit for non-damaging stimulation. RESULTS: Anatomical targeting of DBS electrodes is complicated by the uncertainty of which neural elements are targeted and differences in the electric field distribution in fiber tracts and nuclei. Electrical targeting by selection of electrode geometry and stimulus waveform can alter the distribution of the electric field and control neural activation. The recommended charge density limit for DBS represents a liberal estimate for non-damaging stimulation. Short duration stimulus pulses reduce charge injection and increase the therapeutic window between therapeutic effects and side effects. CONCLUSIONS: There are several challenges to developing rational methods of selecting stimulus parameters including a large number of degrees of freedom, the unknown effects of stimulation, and the complexity of the responses. SIGNIFICANCE: Understanding the fundamentals of electrical stimulation of the nervous system enables rational selection of stimulus parameters.