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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.

BackgroundOne of the experimental neuromodulation techniques being researched for the treatment of Alzheimer's disease (AD) is deep brain stimulation (DBS). To evaluate the effectiveness of DBS in AD, we performed a systematic review and meta-analysis of the available evidence.MethodsFrom the inception through December 2021, the following databases were searched: Medline via PubMed, Scopus, Embase, Cochrane Library, and Web of Science. The search phrases used were “Alzheimer's disease,” “AD,” “deep brain stimulation,” and “DBS.” The information from the included articles was gathered using a standardized data-collecting form. In the included papers, the Cochrane Collaboration methodology was used to evaluate the risk of bias. A fixed-effects model was used to conduct the meta-analysis.ResultsOnly five distinct publications and 6 different comparisons (one study consisted of two phases) were included out of the initial 524 papers that were recruited. DBS had no impact on the cognitive ability in patients with AD [0.116 SMD, 95% confidence interval (CI), −0.236 to 0.469, p = 0.518]. The studies' overall heterogeneity was not significant (κ2 = 6.23, T2 = 0.053, df = 5, I2 = 19.76%, p = 0.284). According to subgroup analysis, the fornix-DBS did not improve cognitive function in patients with AD (0.145 SMD, 95%CI, −0.246 to 0.537, p = 0.467). Unfavorable neurological and non-neurological outcomes were also reported.ConclusionThe inconsistencies and heterogeneity of the included publications in various target and age groups of a small number of AD patients were brought to light by this meta-analysis. To determine if DBS is useful in the treatment of AD, further studies with larger sample sizes and randomized, double-blinded, sham-controlled designs are required.

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.

Abstract Deep brain stimulation (DBS) in the bed nucleus of the stria terminalis (BST), a region implicated in the expression of anxiety, shows promise in psychiatric patients, but its effects throughout the limbic system are largely unknown. In male Wistar rats, we first evaluated the neural signature of contextual fear (N = 16) and next, of the anxiolytic effects of high-frequency electrical stimulation in the BST (N = 31), by means of c-Fos protein expression. In non-operated animals, we found that the left medial anterior BST displayed increased c-Fos expression in anxious (i.e., context-conditioned) versus control subjects. Moreover, control rats showed asymmetric expression in the basolateral amygdala (BLA) (i.e., higher intensities in the right hemisphere), which was absent in anxious animals. The predominant finding in rats receiving bilateral BST stimulation was a striking increase in c-Fos expression throughout much of the left hemisphere, which was not confined to the predefined regions of interest. To conclude, we found evidence for lateralized c-Fos expression during the expression of contextual fear and anxiolytic high-frequency electrical stimulation of the BST, particularly in the medial anterior BST and BLA. In addition, we observed an extensive and unexpected left-sided c-Fos spread following bilateral stimulation in the BST.

Neurosurgery for psychiatric disorders (NPD), also sometimes referred to as psychosurgery, is rapidly evolving, with new techniques and indications being investigated actively. Many within the field have suggested that some form of guidelines or regulations are needed to help ensure that a promising field develops safely. Multiple countries have enacted specific laws regulating NPD. This article reviews NPD-specific laws drawn from North and South America, Asia and Europe, in order to identify the typical form and contents of these laws and to set the groundwork for the design of an optimal regulation for the field. Key challenges for this design that are revealed by the review are how to define the scope of the law (what should be regulated), what types of regulations are required (eligibility criteria, approval procedures, data collection, and oversight mechanisms), and how to approach international harmonization given the potential migration of researchers and patients.

BackgroundSome patients suffer from persistent and severely disabling Obsessive-Compulsive Disorder (OCD) symptoms that cannot be alleviated by conventional treatments or neuroablative interventions targeting cortico-striatal loop circuits. Currently, it is unclear how to manage the clinical symptoms of these unique patients. We reasoned that deep brain stimulation (DBS) of the habenula (HB) could be a valuable subsequent treatment option for these otherwise medically intractable cases of severe OCD. The HB is an epithalamic structure critically involved in the encoding and responding to aversive stimulus events, cognitive and brain processes known to be impaired in many patients with OCD. Similarly, HB DBS can alleviate depression and anxiety, which often co-occur with OCD. Here, we explore the clinical benefits and risks of HB DBS treatment in a patient with severe and refractory OCD.Case PresentationA 30-year-old male patient presented with persistent and severely disabling OCD symptoms that were refractory to previous psychological and pharmacological treatments as well as to neuroablative surgical interventions involving both capsulotomy and cingulotomy. After HB DBS, however, the severity of the patient's OCD symptoms was markedly reduced at 1-month follow-up, which was sustained until the final (at 12-month) follow-up. The patient also reported enduring improvements in depression, anxiety, and health-related quality of life after several months of HB DBS treatment.ConclusionsThis case report provides the first clinical evidence suggesting that HB DBS could serve as a safe and effective alternative neurosurgical intervention for severe and refractory OCD. The present findings are promising and warrant further research into the role of the HB in pathophysiology and treatment of OCD.

Exaggerated activity in the beta band (13–35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment.

Background: Neural injury to the motor cortex may result in long-term impairments. As a model for human impairments, rodents are often used to study deficits related to reaching and grasping, using the single-pellet reach-to-grasp task. Current assessments of this test capture mostly endpoint outcome. While qualitative features have been proposed, they usually involve manual scoring.Objective: To detect three phases of movement during the single-pellet reach-to-grasp test and assess completion of each phase. To automatically monitor rat forelimb trajectory so as to extract kinematics and classify phase outcome.Methods: A top-view camera is used to monitor three rats during training, healthy and impaired testing, over 33 days. By monitoring the coordinates of the forelimb tip along with the position of the pellet, the algorithm divides a trial into reaching, grasping and retraction. Unfulfilling any of the phases results in one of three possible errors: miss, slip or drop. If all phases are complete, the outcome label is success. Along with endpoints, movement kinematics are assessed: variability, convex hull, mean and maximum reaching speed, length of trajectory and peak forelimb extension.Results: The set of behavior endpoints was extended to include miss, slip, drop and success rate. The labeling algorithm was tested on pre- and post-lesion datasets, with overall accuracy rates of 86% and 92%, respectively. These endpoint features capture a drop in skill after motor cortical lesion as the success rate of 59.6 ± 11.8% pre-lesion decreases to 13.9 ± 8.2% post-lesion, along with a significant increase in miss rate from 7.2 ± 6.7% pre-lesion to 50.2 ± 18.7% post-lesion. Kinematics reveals individual-specific strategies of improvement during training, with a common trend of trajectory variability decreasing with success. Correlations between kinematics and endpoints reveal a more complex pattern of relationships during rehabilitation (18 significant pairs of features) than during training (nine correlated pairs).Conclusion: Extended endpoint outcomes and kinematics of reaching and grasping are captured automatically with a robust computer program. Both endpoints and kinematics capture intra-animal drop in skill after a motor cortical lesion. Correlations between kinematics and endpoints change from training to rehabilitation, suggesting different mechanisms that underlie motor improvement.

In the quest for chronically reliable and bio-tolerable brain interfaces there has been a steady evolution towards the use of highly flexible, polymer-based electrode arrays. The reduced mechanical mismatch between implant and brain tissue has shown to reduce the evoked immune response, which in turn has a positive effect on signal stability and noise. Unfortunately, the low stiffness of the implants also has practical repercussions, making surgical insertion extremely difficult. In this work we explore the use of dextran as a coating material that temporarily stiffens the implant, preventing buckling during insertion. The mechanical properties of dextran coated neural probes are characterized, as well as the different parameters which influence the dissolution rate. Tuning parameters, such as coating thickness and molecular weight of the used dextran, allows customization of the stiffness and dissolution time to precisely match the user’s needs. Finally, the immunological response to the coated electrodes was analyzed by performing a histological examination after four months of in vivo testing. The results indicated that a very limited amount of glial scar tissue was formed. Neurons have also infiltrated the area that was initially occupied by the dissolving dextran coating. There was no noticeable drop in neuron density around the site of implantation, confirming the suitability of the coating as a temporary aid during implantation of highly flexible polymer-based neural probes.

Previous research suggests that anodal transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) modulates NMDA receptor dependent processes that mediate synaptic plasticity. Here we test this proposal by applying anodal versus sham tDCS while subjects practiced to flex the thumb as fast as possible (ballistic movements). Repetitive practice of this task has been shown to result in performance improvements that reflect use-dependent plasticity resulting from NMDA receptor mediated, long-term potentiation (LTP)-like processes. Using a double-blind within-subject cross-over design, subjects (n=14) participated either in an anodal or a sham tDCS session which were at least 3 months apart. Sham or anodal tDCS (1 mA) was applied for 20 min during motor practice and retention was tested 30 min, 24 hours and one week later. All subjects improved performance during each of the two sessions (p < 0.001) and learning gains were similar. Our main result is that long term retention performance (i.e. 1 week after practice) was significantly better when practice was performed with anodal tDCS than with sham tDCS (p < 0.001). This effect was large (Cohen's d=1.01) and all but one subject followed the group trend. Our data strongly suggest that anodal tDCS facilitates long-term memory formation reflecting use-dependent plasticity. Our results support the notion that anodal tDCS facilitates synaptic plasticity mediated by an LTP-like mechanism, which is in accordance with previous research.

BackgroundDeep brain stimulation (DBS) has been proposed as an alternative to ablative neurosurgery for severe treatment-resistant Obsessive-Compulsive Disorder (OCD), although with partially discrepant results probably related to differences in anatomical targetting and stimulation conditions. We sought to determine the efficacy and tolerability of DBS in OCD and the existence of clinical predictors of response using meta-analysis.MethodsWe searched the literature on DBS for OCD from 1999 through January 2014 using PubMed/MEDLINE and PsycINFO. We performed fixed and random-effect meta-analysis with score changes (pre-post DBS) on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) as the primary-outcome measure, and the number of responders to treatment, quality of life and acceptability as secondary measures.FindingsThirty-one studies involving 116 subjects were identified. Eighty-three subjects were implanted in striatal areas--anterior limb of the internal capsule, ventral capsule and ventral striatum, nucleus accumbens and ventral caudate--27 in the subthalamic nucleus and six in the inferior thalamic peduncle. Global percentage of Y-BOCS reduction was estimated at 45.1% and global percentage of responders at 60.0%. Better response was associated with older age at OCD onset and presence of sexual/religious obsessions and compulsions. No significant differences were detected in efficacy between targets. Five patients dropped out, but adverse effects were generally reported as mild, transient and reversible.ConclusionsOur analysis confirms that DBS constitutes a valid alternative to lesional surgery for severe, therapy-refractory OCD patients. Well-controlled, randomized studies with larger samples are needed to establish the optimal targeting and stimulation conditions and to extend the analysis of clinical predictors of outcome.