A Statistical Framework for Visualization of Positional Uncertainty in Deep Brain Stimulation Electrodes

Introduction: Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (slMFB) is currently being researched in clinical trials and open case series as a therapeutic option for treatment-resistant major depressive disorder and treatment-resistant obsessive-compulsive disorder (TR-OCD). There are numerous publications describing stimulation in such proximity to the ventral tegmental area (VTA) and open questions remain concerning the stimulation target and its functional environment. As of right now, we are not aware of any publications that compare the typical electrode placements with the histologically supported tractographic depiction of the target structure. Methods: We used three cadaver midbrain samples with presumed unaltered anatomy. After fixation, staining and slicing, the histological samples were warped to the Montreal Neurological Institute (MNI) big brain environment. Utilizing a tractographic atlas, a qualitative analysis of the typical slMFB stimulation site in the lateral VTA utilizing a subset of clinically implanted DBS electrodes in n = 12 patients, successfully implanted for TR-OCD was performed. Results: A joint qualitative overlay analysis of predominantly tyrosine hydroxylase stained histology at different resolutions in an anatomical common space was achieved. Localization of the DBS lead bodies was found in the typical positions in front of the red nuclei in the lateral VTA. DBS lead tip region positions explained the oculomotor side effects of stimulation related to paranigral or parabrachial pigmented sub-nuclei of the VTA, respectively. The location of active electrode contacts suggests downstream and antidromic effects on the greater VTA related medial forebrain bundle system. Conclusion: This is the first dedicated joint histopathological overlay analysis of DBS electrodes targeting the slMFB and lateral VTA in a common anatomical space. This analysis might serve to better understand the DBS target region for this procedure. Introduction: Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (slMFB) is currently being researched in clinical trials and open case series as a therapeutic option for treatment-resistant major depressive disorder and treatment-resistant obsessive-compulsive disorder (TR-OCD). There are numerous publications describing stimulation in such proximity to the ventral tegmental area (VTA) and open questions remain concerning the stimulation target and its functional environment. As of right now, we are not aware of any publications that compare the typical electrode placements with the histologically supported tractographic depiction of the target structure. Methods: We used three cadaver midbrain samples with presumed unaltered anatomy. After fixation, staining and slicing, the histological samples were warped to the Montreal Neurological Institute (MNI) big brain environment. Utilizing a tractographic atlas, a qualitative analysis of the typical slMFB stimulation site in the lateral VTA utilizing a subset of clinically implanted DBS electrodes in n = 12 patients, successfully implanted for TR-OCD was performed. Results: A joint qualitative overlay analysis of predominantly tyrosine hydroxylase stained histology at different resolutions in an anatomical common space was achieved. Localization of the DBS lead bodies was found in the typical positions in front of the red nuclei in the lateral VTA. DBS lead tip region positions explained the oculomotor side effects of stimulation related to paranigral or parabrachial pigmented sub-nuclei of the VTA, respectively. The location of active electrode contacts suggests downstream and antidromic effects on the greater VTA related medial forebrain bundle system. Conclusion: This is the first dedicated joint histopathological overlay analysis of DBS electrodes targeting the slMFB and lateral VTA in a common anatomical space. This analysis might serve to better understand the DBS target region for this procedure.

Patients with chronically implanted deep brain stimulator (DBS) electrodes can encounter complications requiring hardware removal. We assessed the safety and efficacy of using implanted DBS electrodes to create a therapeutic lesion before their removal. Revision or removal of the DBS electrodes was required in two patients who had previously undergone DBS implantation. We conducted a series of in vitro experiments to confirm that the DBS electrodes could be used to generate radiofrequency lesions and to assess the relationship between radiofrequency parameters and lesion size. With this information, and with the approval of the hospital ethical review board, implanted electrodes were used to create incremental radiofrequency lesions in the thalamus in one patient and in the subthalamic nucleus in another. The procedures were performed under local anesthesia with contiguous contacts of the DBS lead connected to the active and reference sites of the RF generator to create a bipolar lesion. A 51-year-old man with essential tremor and a thalamic DBS required repeated battery changes secondary to tolerance and high voltage demands. Rather than replacing the battery, a radiofrequency thalamotomy was performed by using the existing left DBS electrode. At the 6-month follow-up examination, successful lesioning provided near complete tremor control. A second patient, a 50-year-old man with Parkinson's disease who had undergone bilateral subthalamic deep brain stimulation, developed skin erosion over the DBS hardware. A subthalamic nucleus lesion was made through the right DBS electrode. Lesion position and size were confirmed with magnetic resonance imaging. Lesions can be made through chronically implanted DBS electrodes in a safe, graded fashion and can produce therapeutic benefit.

Deep brain stimulation (DBS) of the centromedian thalamic nucleus has been reportedly used to treat severe Tourette syndrome, yielding promising outcomes. However, it remains unclear how DBS electrode position and stimulation parameters modulate the specific area and related networks. The authors aimed to evaluate the relationships between the anatomical location of stimulation fields and clinical responses, including therapeutic and side effects. The authors collected data from 8 patients with Tourette syndrome who were treated with DBS. The authors selected the active contact following threshold tests of acute side effects and gradually increased the stimulation intensity within the therapeutic window such that acute and chronic side effects could be avoided at each programming session. The patients were carefully interviewed, and stimulation-induced side effects were recorded. Clinical outcomes were evaluated using the Yale Global Tic Severity Scale, the Yale-Brown Obsessive-Compulsive Scale, and the Hamilton Depression Rating Scale. The DBS lead location was evaluated in the normalized brain space by using a 3D atlas. The volume of tissue activated was determined, and the associated normative connective analyses were performed to link the stimulation field with the therapeutic and side effects. The mean follow-up period was 10.9 ± 3.9 months. All clinical scales showed significant improvement. Whereas the volume of tissue activated associated with therapeutic effects covers the centromedian and ventrolateral nuclei and showed an association with motor networks, those associated with paresthesia and dizziness were associated with stimulation of the ventralis caudalis and red nucleus, respectively. Depressed mood was associated with the spread of stimulation current to the mediodorsal nucleus and showed an association with limbic networks. This study addresses the importance of accurate implantation of DBS electrodes for obtaining standardized clinical outcomes and suggests that meticulous programming with careful monitoring of clinical symptoms may improve outcomes.

The use of multiple trajectories microelectrode recording (MER) during implantation of deep brain stimulation (DBS) electrodes into the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) is discussed controversially because of possible risks and unclear benefits. The aim of the study is to investigate whether MER combined with intraoperative evaluation of stimulation effects improve clinical outcome in PD patients undergoing STN DBS surgery. Prior to final DBS electrode implantation, we performed multiple trajectories MER and intraoperative test stimulations after magnetic resonance imaging (MRI)-guided planning in 32 PD patients. In further 10 patients no MER (only intraoperative test stimulation) was used. We found a significantly better clinical outcome (Unified Parkinson's Disease Rating Scale [UPDRS] III) in patients undergoing MER compared with non-MER patients. In MER patients, DBS electrode placement was performed using the central trajectory in 73%. Another than the central trajectory was taken in 27% of the patients. No difference in clinical outcome between DBS electrodes implanted on the central or a decentral trajectory was observed. DBS surgery based on intraoperative multiple trajectories MER and test stimulation improves clinical outcome if compared with intraoperative test stimulation alone. The data suggest that DBS surgery solely based on MRI and intraoperative test stimulation without MER may lead to nonoptimal placement of DBS electrodes and consequently poorer clinical outcome.

Increased electrode impedance as an indicator for early detection of deep brain stimulation (DBS) hardware Infection: Clinical experience and in vitro study

Background: Although there are few reports of radiofrequency lesions performed through deep brain stimulation (DBS) electrodes in patients with movement disorders, experience with this method is scarce. Methods: We present 2 patients who had been previously treated with DBS of subthalamic nuclei (STN) and the ventral intermediate (VIM) nucleus of the thalamus for Parkinson's disease and essential tremor, respectively, and underwent a radiofrequency lesion through their DBS electrodes after developing a hardware infection. The authors conduct a review of the literature regarding this method. Results: Both patients had a good clinical outcome after 20 and 8 months, respectively, as assessed by a reduction in Fahn-Tolosa-Marin Scale and Unified Parkinson's Disease Rating Scale scores. The second patient underwent a second DBS system implantation surgery after his radiofrequency treatment to optimize his management, achieving optimal clinical control with lower current and drug requirements than before the radiofrequency intervention. No adverse effects were observed. Conclusions: Radiofrequency lesions through DBS electrodes allow the creation of small and localized lesions. Its effectiveness and low-risk profile, in addition to its low cost, make this procedure suitable and a possible alternative in the therapeutic repertoire for the surgical treatment of movement disorders.

The objective of this study was to determine the incidence of seizures following deep brain stimulation (DBS) electrode implantation and to evaluate factors associated with postoperative seizures. The authors performed a single-center retrospective case-control study. The outcome of interest was seizure associated with DBS implantation. Univariate analyses were performed using the Student t-test for parametric continuous outcomes. The authors used the Kruskal-Wallis test or Wilcoxon rank-sum test for nonparametric continuous outcomes, chi-square statistics for categorical outcomes, and multivariate logistic regression for binomial variables. A total of 814 DBS electrode implantations were performed in 645 patients (478 [58.7%] in men and 520 [63.9%] in patients with Parkinson's disease). In total, 22 (3.4%) patients who had undergone 23 (2.8%) placements experienced seizure. Of the 23 DBS implantation-related seizures, 21 were new-onset seizures (3.3% of 645 patients) and 2 were recurrence or worsening of a prior seizure disorder. Among the 23 cases with postimplantation-related seizure, epilepsy developed in 4 (17.4%) postoperatively; the risk of DBS-associated epilepsy was 0.50% per DBS electrode placement and 0.63% per patient. Nine (39.1%) implantation-related seizures had associated postoperative radiographic abnormalities. Multivariate analyses suggested that age at surgery conferred a modest increased risk for postoperative seizures (OR 1.06, 95% CI 1.02-1.10). Sex, primary diagnosis, electrode location and sidedness, and the number of trajectories were not significantly associated with seizures after DBS surgery. Seizures associated with DBS electrode placement are uncommon, typically occur early within the postoperative period, and seldom lead to epilepsy. This study suggests that patient characteristics, such as age, may play a greater role than perioperative variables in determining seizure risk. Multiinstitutional studies may help better define and mitigate the risk of seizures after DBS surgery.

Direct testing of deep brain stimulation (DBS) mechanisms in humans is needed to assess therapy and to understand stimulation effects. We developed an innovative paradigm for investigation of DBS on human movement disorders. Temporary connection to the DBS electrode during implantable pulse generator (IPG) replacement permitted analysis of novel patterns of stimulation on motor symptoms, which could enhance efficacy and improve battery life. Patients enrolled in this prospective, Institutional Review Board-approved study underwent IPG replacement using local (monitored) anesthesia. Following device explant, the DBS electrode was connected to an external, isolated electrical stimulator using a sterile adapter cable. Different temporal patterns of stimulation were delivered while quantifying upper-extremity tremor (tri-axial accelerometry) or bradykinesia (finger-tapping). Upon experiment completion, the new IPG was implanted. Among 159 IPG replacements from 2005 to 2011, 56 patients agreed to the research study (16 essential tremor [ET], 31 Parkinson's disease [PD], 5 mixed ET/PD tremor, 3 multiple sclerosis, 1 tremor/myoclonus). Surgical procedures were extended by 42 ± 8.2 min in 37 patients completing the study. Motor symptoms varied with stimulation pattern, with some patterns showing improved tremor or bradykinesia control. No postoperative infections or complications were observed in the 159 patients. IPG replacement occurs when the DBS/brain interface is stable and patients demonstrate symptom reduction with known stimulation parameters. Conducting research at this time point avoids DBS implant issues, including temporary microlesion effects, fluctuating electrode impedances, and technical limitations of contemporary IPGs, providing advantageous conditions to conduct translational DBS research with minimal additional risk to research subjects.

Many previous studies have shown that placement of deep brain stimulation (DBS) electrodes carries a considerable risk of hemorrhage. To date, no studies have evaluated the incidence of intracranial hemorrhage after removal of DBS electrodes. The authors performed a retrospective chart review to identify the incidence and trends in hemorrhage after DBS electrode removal. A retrospective chart review of all DBS electrodes removed at the Cleveland Clinic between October 2000 and May 2010 was performed. All patients underwent postoperative CT scanning. Each patient was evaluated for age, sex, side of placement, target, duration of lead placement, reason for removal, and medical comorbidities. A total of 78 lead removals were performed in the 10-year period (1300 leads were implanted during the same period). Of the 78 leads removed, 10 (12.8%) resulted in hemorrhages seen on postoperative CT scans. The hemorrhages were superficial cortical in 6 cases of lead removal (60%) and deep in 4 cases (40%). No statistically significant correlation to any of the factors evaluated was found. All hemorrhages were asymptomatic. The authors' retrospective study of 78 DBS lead removals revealed a high risk of intracranial hemorrhage (12.8% per lead). The risk of hemorrhage during removal is significantly greater than the risk of hemorrhage during implantation (2.0% per lead at the authors' center during the same period). There were more superficial hemorrhages, and all hemorrhages were asymptomatic. Removal of DBS leads carries a significantly higher risk of postoperative hemorrhages that are seen on images but are not clinically symptomatic.

The different peaks of somatosensory-evoked potentials (SEP) originate from a variety of anatomical sites in the central nervous system. The origin of the median nerve subcortical N18 SEP has been studied under various conditions, but the exact site of its generation is still unclear. While it has been claimed to be located in the thalamic region, other studies indicated its possible origin below the pontomedullary junction. Here, we scrutinized and compared SEP recordings from median nerve stimulation through deep brain stimulation (DBS) electrodes implanted in various subcortical targets. We studied 24 patients with dystonia, Parkinson's disease, and chronic pain who underwent quadripolar electrode implantation for chronic DBS and recorded median nerve SEPs from globus pallidus internus (GPi), subthalamic nucleus (STN), thalamic ventral intermediate nucleus (Vim), and ventral posterolateral nucleus (VPL) and the centromedian-parafascicular complex (CM-Pf). The largest amplitude of the triphasic potential of the N18 complex was recorded in Vim. Bipolar recordings confirmed the origin to be close to Vim electrodes (and VPL/CM-Pf) and less close to STN electrodes. GPi recorded only far-field potentials in unipolar derivation. Recordings from DBS electrodes located in different subcortical areas allow determining the origin of certain subcortical SEP waves more precisely. The subcortical N18 of the median nerve SEP-to its largest extent-is generated ventral to the Vim in the region of the prelemniscal radiation/ zona incerta.

The degree to which deep brain stimulation (DBS) therapy can effectively treat various brain disorders depends on how well one can selectively stimulate one or more axonal pathways within the brain. There is rapidly growing clinical interest in DBS lead implant designs with electrode arrangements that can better target axonal pathways of interest, especially in cases where the optimal target is immediately adjacent to a pathway that when stimulated will elicit adverse side effects. Numerical modeling has demonstrated that DBS leads with four radially segmented electrodes provide the best balance of directional targeting capability while minimizing the overall number of electrode contacts [1]. Here, we present a novel 4×4 DBS lead (16-channel electrode array) with the same form factor and materials as current 4 or 8-channel FDA-approved DBS leads. Electrode impedance spectroscopy was performed for three of these 4×4 DBS leads showing reliable electrode impedances before and after implantation within the brain.

for the next 5 min. At this point, 1.5 g/kg dexmedetomidine was administered as a loading dose over 20 min. The patient’s dyskinesias subsided within 18 –20 min of dexmedetomidine infusion. The dexmedetomidine infusion rate was then reduced to 1.2 g kg 1 h 1 for another 10 min, after which it was continued at a rate of 0.2– 0.5 g kg 1 h 1 . When the infusion was stopped just before the microelectrode recordings, dyskinesias recurred. The dexmedetomidine infusion was restarted with good control of dyskinetic movements and titrated to keep the patient sufficiently awake to answer questions. Specifically, during microstimulation at the end of microelectrode recording for each tract, the patient was asked whether he experienced paresthesias or pulling in the muscles of his face, arms, or legs. During macrostimulation at the time of placement of the DBS electrodes, he was asked to move his fingers or toes. This allowed satisfactory placement of bilateral subthalamic nucleus DBS electrodes. Approximately an hour after surgery, the patient had another brief episode of dyskinesias that subsided spontaneously while he was in the postoperative care unit. The patient was off dexmedetomidine infusion at this time. The patient did well postoperatively and was discharged home without further problems. During his follow-up visit at 5 weeks, he reported improvement of all symptoms, indicating satisfactory DBS function.

Introduction: Obsessive-compulsive disorder (OCD) and treatment-resistant bipolar depression (TRBD) constitute some of the most challenging psychiatric disorders to treat, as a significant proportion of patients demonstrate poor response to pharmacological strategies alone or in combination with psychoterapeutic approaches.1 Deep brain stimulation (DBS) is a potential therapeutic approach for select patients, although clinical outcomes remain inconsistent. To improve treatment efficacy, clinicians need to gain a deeper understanding of the neural activity and associated behavioral outcomes that correspond to distinct symptom profiles.2 One of the major hurdles in any effort to explore psychiatric neuromodulation is linking neural activity with behavior that we can observe. Examining correlated neural features with behaviorial information may provide biomarkers to inform DBS interventions.3-5 The present study introduces a platform that integrates video, audio, and neural data, including theta-band activity and spectrograms, all collected during real-world observations. This multimodal data approach enables clinicians to examine brain-behavior interactions with greater precision, facilitating the development of more individualized and effective treatment strategies. Objective: to validate the feasibility of frame-level synchronization of video, audio, and intracranial signals during real-world clinical sessions, and to demonstrate its potential to support behavioral–neural biomarker discovery for DBS in OCD and TRBD.Method: We implemented a hardware-based synchronization system designed for ecological clinical environments, that interfaces continuous high-definition video (FLIR Blackfly), high-fidelity audio, and direct neural recordings from implanted DBS systems. As shown in Figure 1, an Arduino-based controller generates a unique frame ID that increases sequentially, embedding it into one audio channel. This ID serves as the common temporal reference to align video and audio streams, which are later synchronized with the neural recordings. This platform aligns: Patient video recordings capturing spontaneous behavior and facial expressions; multichannel audio, including verbal responses and environmental context; intracranial electrophysiology from DBS electrodes. By extracting the frame ID from the audio channel, all modalities can be aligned with sub-frame accuracy. This approach remains robust to environmental noise and brief recording outages, which is crucial for long term clinical monitoring. The resulting output is processed and merged into a single synchronized outputs for subsequent behavioral annotation and biomarker analysis.Results: In recent recordings, the system was able to constantly align continuous video, audio, and neural signals over sessions lasting up to one hour. The system was validated across five patient sessions, consistently achieving stable synchronization throughout. Each dataset contained thousands of precisely matched frame identifiers, ensuring accurate temporal alignment across all modalities. The resulting synchronized outputs (Figure 2) allowed frame-by-frame correlation of patient behavior, speech patterns, and neural activity without perceptible desynchronization. Across recordings, alignment error remained below one frame (<33 ms), ensuring temporal precision sufficient for clinical and research analysis.Discussion: Synchronizing neural, behavioral, and contextual data enables real-time insight into brain–behavior relationships, helping identify biomarkers that can inform and refine DBS treatment. In the future, synchronized datasets could be integrated into clinical routines by allowing physicians to review neural activity alongside patient behavior and speech, providing a more objective complement to standard psychiatric assessments. One limitation is that the system has so far been validated in sessions of about one hour, which is well suited for proof-of-concept but more challenging to scale to recordings lasting several hours.Conclusions: This platform demonstrates the feasibility of precise multimodal synchronization in DBS patients, providing clinicians with richer, time-aligned datasets to link behavior and neural activity. These results lay the groundwork for future clinical studies aimed at validating multimodal biomarkers and testing whether such data can inform adaptive DBS programming.

Background:The centromedian (CM) region of the thalamus is a common target for deep brain stimulation (DBS) treatment for Tourette Syndrome (TS). However, there are currently no standard microelectrode recording or macrostimulation methods to differentiate CM thalamus from other nearby structures and nuclei.Case Report:Here we present a case of failed conventional stereotactic targeting in TS DBS. Postoperative local field potential recordings (LFPs) showed features including beta power desynchronization during voluntary movement and thalamo-cortical phase amplitude coupling at rest. These findings suggested that the DBS lead was suboptimally placed in the ventral intermediate (VIM) nucleus of the thalamus rather than the intended CM region. Due to a lack of clinical improvement in tic severity scales three months following the initial surgery, the patient underwent lead revision surgery. Slight repositioning of the DBS leads resulted in a remarkably different clinical outcome. Afterwards, LFPs revealed less beta desynchronization and disappearance of the thalamo-cortical phase amplitude coupling. Follow-up clinical visits documented improvement of the patient’s global tic scores.Discussion:This case provides preliminary evidence that combining physiology with atlas based targeting may possibly enhance outcomes in some cases of Tourette DBS. A larger prospective study will be required to confirm these findings.Highlight:This report demonstrates a case of failed centromedian nucleus region deep brain stimulation (DBS). We observed suboptimal tic improvement several months following DBS surgery and subsequent lead revision improved the outcome. The neurophysiology provided an important clue suggesting the possibility of suboptimally placed DBS leads. Repeat LFPs during lead revision revealed less beta desynchronization and disappearance of the thalamo-cortical phase amplitude coupling. There was improvement in tic outcome following slight repositioning during bilateral DBS lead revision. This case provides preliminary evidence supporting the use of physiology to augment the atlas based targeting of Tourette DBS cases.

Thalamic recordings and stimulation in myoclonic dystonia