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Background: Subthalamic deep brain stimulation (STN-DBS) is a well-established therapy to treat Parkinson's disease (PD). However, the STN-DBS sub-target remains debated. Recently, a white matter tract termed the hyperdirect pathway (HDP), directly connecting the motor cortex to STN, has gained interest as HDP stimulation is hypothesized to drive DBS therapeutic effects. Previously, we have investigated EEG-based evoked potentials (EPs) to better understand the neuroanatomical origins of the DBS clinical effect. We found a 3-ms peak (P3) relating to clinical benefit, and a 10-ms peak (P10) suggesting nigral side effects. Here, we aimed to investigate the neuroanatomical origins of DBS EPs using probabilistic mapping. Methods: EPs were recorded using EEG whilst low-frequency stimulation was delivered at all DBS-contacts individually. Next, EPs were mapped onto the patients’ individual space and then transformed to MNI standard space. Using voxel-wise and fiber-wise probabilistic mapping, we determined hotspots/hottracts and coldspots/coldtracts for P3 and P10. Topography analysis was also performed to determine the spatial distribution of the DBS EPs. Results: In all 13 patients (18 hemispheres), voxel- and fiber-wise probabilistic mapping resulted in a P3-hotspot/hottract centered on the posterodorsomedial STN border indicative of HDP stimulation, while the P10-hotspot/hottract covered large parts of the substantia nigra. Conclusion: This study investigated EP-based probabilistic mapping in PD patients during STN-DBS, revealing a P3-hotspot/hottract in line with HDP stimulation and P10-hotspot/hottract related to nigral stimulation. Results from this study provide key evidence for an electrophysiological measure of HDP and nigral stimulation.

Background: To maximize clinical benefit and minimize stimulation-induced side effects, optimising deep brain stimulation (DBS) parameters is paramount. Recent literature suggests a potential benefit of short pulse width DBS (spDBS; ≤40 μs) over conventional pulse width DBS (cDBS; ≥60 μs) in movement disorders. Objective: To compare therapeutic window (TW), therapeutic and side effects and energy consumption of spDBS and cDBS in movement disorders. Methods: We systematically searched Medline, Embase, Cochrane Library and Web of Science. Appropriate paired analyses were performed. Results: Nine Parkinson's disease (PD) (143 patients), 4 essential tremor (ET) (26 patients) and no dystonia studies were included in the meta-analysis. TW defined as therapeutic amplitude range was larger with spDBS vs. cDBS in PD (standardized mean difference (SMD) = -1.04, p

IntroductionSymmetric biphasic pulses have been shown to increase the therapeutic window compared to standard cathodic pulses in ET Vim-DBS patients. Furthermore, three hours of stimulation with biphasic pulses caused less stimulation-induced ataxia compared to cathodic pulses. Therefore, an investigation of the longer-term safety of biphasic pulses is warranted.MethodsSeven ET patients were included in a randomized double-blind, cross-over design of one week home-use of symmetric biphasic stimulation (anodic phase first) versus cathodic stimulation. Amplitude was set in a double-blinded way, at the tremor arrest threshold. The primary outcome was safety assessed by documenting the adverse events. Secondary outcome parameters were stimulation amplitude, tremor (Fahn-Tolosa-Marin Tremor Rating Scale) and ataxia (International Cooperative Ataxia Rating Scale) severity, quality of life (Quality of Life in Essential Tremor Questionnaire) and cognition (Montreal Cognitive Assessment). Three patients continued in the open-label extension phase for 3 months, during which biphasic stimulation-only was further assessed by the same outcome parameters.ResultsDuring the 1 week testing, no adverse effects were reported. To obtain equivalent tremor control, the amplitude of the biphasic pulse was significantly higher compared to that of the cathodic pulse (p = 0.003). The other outcome parameters were not significantly different. During the open-label study, one patient used the remote control to increase the amplitude, leading to two falls caused by stimulation-induced ataxia. No other adverse effects occurred.Discussion and conclusionIn a small cohort, when tested for one week, symmetric biphasic pulses suggest to be safe, but require higher stimulation amplitudes. Further follow-up studies are needed to investigate long-term effects and safety.

ObjectiveSubthalamic deep brain stimulation (STN-DBS) is a neurosurgical therapy to treat Parkinson’s disease (PD). Optimal therapeutic outcomes are not achieved in all patients due to increased DBS technological complexity; programming time constraints; and delayed clinical response of some symptoms. To streamline the programming process, biomarkers could be used to accurately predict the most effective stimulation configuration. Therefore, we investigated if DBS-evoked potentials (EPs) combined with imaging to perform prediction analyses could predict the best contact configuration.MethodsIn 10 patients, EPs were recorded in response to stimulation at 10 Hz for 50 s on each DBS-contact. In two patients, we recorded from both hemispheres, resulting in recordings from a total of 12 hemispheres. A monopolar review was performed by stimulating on each contact and measuring the therapeutic window. CT and MRI data were collected. Prediction models were created to assess how well the EPs and imaging could predict the best contact configuration.ResultsEPs at 3 ms and at 10 ms were recorded. The prediction models showed that EPs can be combined with imaging data to predict the best contact configuration and hence, significantly outperformed random contact selection during a monopolar review.ConclusionEPs can predict the best contact configuration. Ultimately, these prediction tools could be implemented into daily practice to ease the DBS programming of PD patients.

BackgroundSubthalamic deep brain stimulation (DBS) is an established therapy to treat Parkinson’s disease (PD). To maximize therapeutic outcome, optimal DBS settings must be carefully selected for each patient. Unfortunately, this is not always achieved because of: (1) increased technological complexity of DBS devices, (2) time restraints, or lack of expertise, and (3) delayed therapeutic response of some symptoms. Biomarkers to accurately predict the most effective stimulation settings for each patient could streamline this process and improve DBS outcomes.ObjectiveTo investigate the use of evoked potentials (EPs) to predict clinical outcomes in PD patients with DBS.MethodsIn ten patients (12 hemispheres), a monopolar review was performed by systematically stimulating on each DBS contact and measuring the therapeutic window. Standard imaging data were collected. EEG-based EPs were then recorded in response to stimulation at 10 Hz for 50 s on each DBS-contact. Linear mixed models were used to assess how well both EPs and image-derived information predicted the clinical data.ResultsEvoked potential peaks at 3 ms (P3) and at 10 ms (P10) were observed in nine and eleven hemispheres, respectively. Clinical data were well predicted using either P3 or P10. A separate model showed that the image-derived information also predicted clinical data with similar accuracy. Combining both EPs and image-derived information in one model yielded the highest predictive value.ConclusionEvoked potentials can accurately predict clinical DBS responses. Combining EPs with imaging data further improves this prediction. Future refinement of this approach may streamline DBS programming, thereby improving therapeutic outcomes.Clinical trial registrationClinicalTrials.gov, identifier NCT04658641.

Background: Since the inception of DBS, cathodic pulses have been used. Objective: To investigate the effect of anodic and symmetric biphasic pulses on the therapeutic window (TW) in essential tremor (ET) patients. Methods: A randomized, doubled-blinded, cross-over design was used to test the effect of cathodic, anodic and symmetric biphasic pulses (cathode-first and anode-first) on the TW in an acute clinical setting. TW was defined as the difference between the minimal stimulation amplitude provoking side effects and minimal stimulation amplitude inducing tremor arrest. Results: 9 ET patients (10 hemispheres) were included. Anodic stimulation induced a significantly larger TW compared to cathodic stimulation (p = 0.008). Symmetric biphasic stimulation also widened the TW compared to cathodic stimulation for both cathode- (p = 0.047) and anode-first (p = 0.008) biphasic pulses. For both anodic and biphasic pulses, the effect on TW was mainly driven by the change in side effect threshold. The order of the phases in the biphasic pulse had a significant effect on the side effect threshold (p = 0.039), with biphasic-anode first having the highest value. All pulse shapes were safe in the acute setting. Conclusion: Anodic and symmetric biphasic pulses increase TW in ET patients.

BackgroundDeep brain stimulation (DBS) is an effective neuromodulation therapy to treat people with medication-refractory Parkinson’s disease (PD). However, the neural networks affected by DBS are not yet fully understood. Recent studies show that stimulating on different DBS-contacts using a single current source results in distinct EEG-based evoked potentials (EPs), with a peak at 3 ms (P3) associated with dorsolateral subthalamic nucleus stimulation and a peak at 10 ms associated with substantia nigra stimulation. Multiple independent current control (MICC) technology allows the center of the electric field to be moved in between two adjacent DBS-contacts, offering a potential advantage in spatial precision.ObjectiveDetermine if MICC precision targeting results in distinct neurophysiological responses recorded via EEG.Materials and MethodsWe recorded cortical EPs in five hemispheres (four PD patients) using EEG whilst employing MICC to move the electric field from the most dorsal DBS-contact to the most ventral in 15 incremental steps.ResultsThe center of the electric field location had a significant effect on both the P3 and P10 amplitude in all hemispheres where a peak was detected (P3, detected in 4 of 5 hemispheres, p < 0.0001; P10, detected in 5 of 5 hemispheres, p < 0.0001). Post hoc analysis indicated furthermore that MICC technology can significantly refine the resolution of steering.ConclusionUsing MICC to incrementally move the center of the electric field to locations between adjacent DBS-contacts resulted in significantly different neurophysiological responses that may allow further precision of the programming of individual patients.