Deep Brain Stimulation For Essential Tremor Research Articles

Overlapping stimulation of subthalamic nucleus and dentato-rubro-thalamic tract in Parkinson's disease after deep brain stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces tremor, rigidity, and akinesia. According to the literature, the dentato-rubro-thalamic tract (DRTt) is verified target for DBS in essential tremor; however, its role in the treatment of Parkinson's disease is only vaguely described. The aim of our study was to identify the relationship between symptom alleviation in PD patients and the distance of the DBS electrode electric field (EF) to the DRTt. A single-center retrospective analysis of patients (N = 30) with idiopathic Parkinson's disease (PD) who underwent DBS between November 2018 and January 2020 was performed. DRTt and STN were visualized using diffusion-weighted imaging (DWI) and tractography protocol of magnetic resonance (MR). The EF was calculated and compared with STN and course of DRTt. Evaluation of patients before and after surgery was performed with use of UPDRS-III scale. The association between distance from EF to DRTt and clinical outcomes was examined. To confirm the anatomical variation between DRTt and STN observed in tractography, white matter dissection was performed with the Klingler technique on ten human brains. Patients with EF overlapping STN and DRTt benefited from significant motor symptoms improvement. Anatomical findings confirmed the presence of population differences in variability of the DRTt course and were consistent with the DRTt visualized by MR. DRTt proximity to STN, the main target in PD DBS surgery, confirmed by DWI with tractography protocol of MR combined with proper predefined stimulation parameters may improve efficacy of DBS-STN.

Management of essential tremor deep brain stimulation-induced side effects.

Deep brain stimulation (DBS) is an effective surgical therapy for carefully selected patients with medication refractory essential tremor (ET). The most popular anatomical targets for ET DBS are the ventral intermedius nucleus (VIM) of the thalamus, the caudal zona incerta (cZI) and the posterior subthalamic area (PSA). Despite extensive knowledge in DBS programming for tremor suppression, it is not uncommon to experience stimulation induced side effects related to DBS therapy. Dysarthria, dysphagia, ataxia, and gait impairment are common stimulation induced side effects from modulation of brain tissue that surround the target of interest. In this review, we explore current evidence about the etiology of stimulation induced side effects in ET DBS and provide several evidence-based strategies to troubleshoot, reprogram and retain tremor suppression.

Optimizing Deep Brain Stimulation in Essential Tremor: A Randomized Controlled Trial for Target Consideration.

The thalamic ventral intermediate nucleus (VIM) is a well-established target for deep brain stimulation (DBS) in the treatment of essential tremor (ET). Increasing data indicate that the posterior subthalamic area (PSA) may be superior, but high-level evidence is limited. We aimed at further comparing the intraindividual efficacy and side effect profile of PSA vs VIM DBS in ET. In this randomized, double-blind, crossover trial, 4-contact DBS leads were bilaterally implanted with single-trajectory covering the VIM and PSA. Patients were randomized postsurgery to 2 groups, receiving VIM stimulation (4-7 months) and then PSA stimulation (8-11 months) or vice versa. The primary end point was the difference in improvement from baseline to the end of the VIM vs PSA DBS period in the total score of the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS). Ten patients with medically refractory ET were enrolled, and 9 completed the study. The difference between reduction of FTM-TRS total score in the PSA vs VIM DBS period was -7.4 (95% CI: -28.5 to 13.7, P = .328). Clinical benefit was achieved at significantly lower stimulation intensity under PSA DBS. Furthermore, PSA DBS provided greater improvement in head tremor subscore of FTM-TRS (PSA vs VIM: -2.2, P = .020) and disease-specific quality of life (PSA vs VIM: -13.8, P = .046) and induced fewer speech (Dysphonia Severity Index score: P = .043; diadochokinetic rate: P = .007; VDI score: P = .005) and gait disturbances compared with VIM DBS. Seven patients remained with PSA DBS after the crossover phase. Our study confirms that PSA-DBS is comparable with VIM-DBS in suppressing tremors, superior in improving disease-specific quality of life, and possibly more effective in reducing head tremor.

Active contact proximity to the cerebellothalamic tract predicts initial therapeutic current requirement with DBS for ET: an application of 7T MRI.

To characterize how the proximity of deep brain stimulation (DBS) active contact locations relative to the cerebellothalamic tract (CTT) affect clinical outcomes in patients with essential tremor (ET). DBS is an effective treatment for refractory ET. However, the role of the CTT in mediating the effect of DBS for ET is not well characterized. 7-Tesla (T) MRI-derived tractography provides a means to measure the distance between the active contact and the CTT more precisely. A retrospective review was conducted of 12 brain hemispheres in 7 patients at a single center who underwent 7T MRI prior to ventral intermediate nucleus (VIM) DBS lead placement for ET following failed medical management. 7T-derived diffusion tractography imaging was used to identify the CTT and was merged with the post-operative CT to calculate the Euclidean distance from the active contact to the CTT. We collected optimized stimulation parameters at initial programing, 1- and 2-year follow up, as well as a baseline and postoperative Fahn-Tolosa-Marin (FTM) scores. The therapeutic DBS current mean (SD) across implants was 1.8 mA (1.8) at initial programming, 2.5 mA (0.6) at 1 year, and 2.9 mA (1.1) at 2-year follow up. Proximity of the clinically-optimized active contact to the CTT was 3.1 mm (1.2), which correlated with lower current requirements at the time of initial programming (R2 = 0.458, p = 0.009), but not at the 1- and 2-year follow up visits. Subjects achieved mean (SD) improvement in tremor control of 77.9% (14.5) at mean follow-up time of 22.2 (18.9) months. Active contact distance to the CTT did not predict post-operative tremor control at the time of the longer term clinical follow up (R2 = -0.073, p = 0.58). Active DBS contact proximity to the CTT was associated with lower therapeutic current requirement following DBS surgery for ET, but therapeutic current was increased over time. Distance to CTT did not predict the need for increased current over time, or longer term post-operative tremor control in this cohort. Further study is needed to characterize the role of the CTT in long-term DBS outcomes.

Neuropsychological assessment protocol in an ongoing randomized controlled trial on posterior subthalamic area vs. ventral intermediate nucleus deep brain stimulation for essential tremor.

Patients with essential tremor (ET) may experience cognitive-affective impairment. Deep brain stimulation (DBS) of different targets, such as the ventral intermediate nucleus (VIM) of the thalamus or the posterior subthalamic area (PSA), has been shown to be beneficial for refractory ET. However, there is little evidence regarding the possible neuropsychological effects of PSA-DBS on patients with ET, and there are few studies comparing it with VIM-DBS in this population.In this study, we aim to present the evaluation protocol and neuropsychological battery as used in an ongoing trial of DBS for ET comparing the already mentioned targets. As part of a randomized, double-blind, crossover clinical trial comparing the effectiveness and safety of PSA-DBS vs. VIM-DBS, 11 patients with refractory ET will undergo a multi-domain neuropsychological battery assessment. This will include a pre-/post-implantation assessment (3 months after the stimulation of each target and 6 months after an open stage of DBS on the most optimal target). Evidence on the neuropsychological effects of DBS in patients with refractory ET is very scarce, particularly in lesser-explored targets such as PSA. This study could contribute significantly in this field, particularly on pre-procedure safety analysis for tailored patient/technique selection, and to complete the safety analysis of the procedure. Moreover, if proven useful, this proposed neuropsychological assessment protocol could be extensible to other surgical therapies for ET.

10 Years Follow-Up of Deep Brain Stimulation in the Caudal Zona Incerta/Posterior Subthalamic Area for Essential Tremor.

Long-term data on the effects of deep brain stimulation (DBS) for essential tremor (ET) is scarce, especially regarding DBS in the caudal Zona incerta (cZi) and the posterior subthalamic area (PSA). The aim of this prospective study was to evaluate the effect of cZi/PSA DBS in ET at 10 years after surgery. Thirty-four patients were included. All patients received cZi/PSA DBS (5 bilateral/29 unilateral) and were evaluated at regular intervals using the essential tremor rating scale (ETRS). One year after surgery, there was a 66.4% improvement of total ETRS and 70.7% improvement of tremor (items 1-9) compared with the preoperative baseline. Ten years after surgery, 14 patients had died and 3 were lost to follow-up. In the remaining 17 patients, a significant improvement was maintained (50.8% for total ETRS and 55.8% for tremor items). On the treated side the scores of hand function (items 11-14) had improved by 82.6% at 1 year after surgery, and by 66.1% after 10 years. Since off-stimulation scores did not differ between year 1 and 10, this 20% deterioration of on-DBS scores was interpreted as a habituation. There was no significant increase in stimulation parameters beyond the first year. This 10 year follow up study, found cZi/PSA DBS for ET to be a safe procedure with a mostly retained effect on tremor, compared to 1 year after surgery, and in the absence of increase in stimulation parameters. The modest deterioration of effect of DBS on tremor was interpreted as habituation.

Thalamic Segmentation and Neural Activation Modeling Based on Individual Tissue Microstructure in Deep Brain Stimulation for Essential Tremor

ObjectiveThalamic deep brain stimulation (DBS) is the primary surgical therapy for essential tremor (ET). Thalamic DBS traditionally uses an atlas-based targeting approach, which, although nominally accurate, may obscure individual anatomic differences from population norms. The objective of this study was to compare this traditional atlas-based approach with a novel quantitative modeling methodology grounded in individual tissue microstructure (N-of-1 approach). Materials and MethodsThe N-of-1 approach uses individual patient diffusion tensor imaging (DTI) data to perform thalamic segmentation and volume of tissue activation (VTA) modeling. For each patient, the thalamus was individually segmented into 13 nuclei using DTI-based k-means clustering. DBS-induced VTAs associated with tremor suppression and side effects were then computed for each patient with finite-element electric-field models incorporating DTI microstructural data. Results from N-of-1 and traditional atlas-based modeling were compared for a large cohort of patients with ET treated with thalamic DBS. ResultsThe size and shape of individual N-of-1 thalamic nuclei and VTAs varied considerably across patients (N = 22). For both methods, tremor-improving therapeutic VTAs showed similar overlap with motor thalamic nuclei and greater motor than sensory nucleus overlap. For VTAs producing undesirable sustained paresthesia, 94% of VTAs overlapped with N-of-1 sensory thalamus estimates, whereas 74% of atlas-based segmentations overlapped. For VTAs producing dysarthria/motor contraction, the N-of-1 approach predicted greater spread beyond the thalamus into the internal capsule and adjacent structures than the atlas-based method. ConclusionsThalamic segmentation and VTA modeling based on individual tissue microstructure explain therapeutic stimulation equally well and side effects better than a traditional atlas-based method in DBS for ET. The N-of-1 approach may be useful in DBS targeting and programming, particularly when patient neuroanatomy deviates from population norms.

Suppression of Axial Tremor by Deep Brain Stimulation in Patients with Essential Tremor: Effects on Gait and Balance Measures.

Background:Deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus has been successful in mitigating upper limb tremor, but the effect on gait and balance performance is unclear. Here, we aim to examine the effectiveness of VIM DBS on stride length variability, sway path length, and task-relevant tremor of various body segments in essential tremor (ET).Methods:Seventeen ET individuals treated with DBS (ET DBS) and 17 age-and sex-matched healthy controls (HC) performed a postural balance and overground walking task. In separate and consecutive visits, ET DBS performed gait and balance tasks with DBS ON or OFF. The main outcome measures were sway path length, stride length variability, and tremor quantified from upper limb, lower limb, upper and lower trunk (axial) during the gait and balance tasks.Results:With DBS OFF, ET DBS exhibited significantly greater stride length variability, sway path length, and tremor during gait and balance task relative to HC. Relative to DBS OFF, DBS ON reduced stride length variability and sway path length in ET DBS. The DBS-induced reduction in stride length variability was associated with the reduction in both upper trunk tremor and upper limb tremor. The DBS-induced reduction in sway path length was associated with the reduction in upper trunk tremor.Discussion:The findings of this study revealed that VIM DBS was effective in improving gait and balance in ET DBS and that improvements in gait and postural balance were associated with a reduction of axial tremor during the tasks.Highlights:ET patients exhibit tremor in various body locations during gait and balance.DBS reduced stride length variability and sway path length.DBS-induced improvements in gait and balance were associated with reduction in axial tremor.

Benefits and Risks of a Staged‐Bilateral VIM Versus Unilateral VIM DBS for Essential Tremor

ABSTRACTBackgroundDespite over 30 years of clinical experience, high‐quality studies on the efficacy of bilateral versus unilateral deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus for medically refractory essential tremor (ET) remain limited.ObjectivesTo compare benefits and risks of bilateral versus unilateral VIM DBS using the largest ET DBS clinical trial dataset available to date.MethodsParticipants from the US St. Jude/Abbott pivotal ET DBS trial who underwent staged‐bilateral VIM implantation constituted the primary cohort in this sub‐analysis. Their assessments “on” DBS at six months after second‐side VIM DBS implantation were compared to the assessments six months after unilateral implantation. Two control cohorts of participants with unilateral implantation only were also used for between‐group comparisons.ResultsThe primary cohort consisted of n = 38 ET patients (22M/16F; age of 65.3 ± 9.5 years). The second side VIM‐DBS resulted in a 29.6% additional improvement in the total motor CRST score (P < 0.001), with a 64.1% CRST improvement in the contralateral side (P < 0.001). An added improvement was observed in the axial tremor score (21.4%, P = 0.005), and CRST part B (24.8%, P < 0.001) score. Rate of adverse events was slightly higher after bilateral stimulation.ConclusionsIn the largest ET DBS study to date, staged‐bilateral VIM DBS was a highly effective treatment for ET with bilateral implantation resulting in greater reduction in total motor tremor scores when compared to unilateral stimulation alone.

P 57 Markerless, video-based kinematic Tremor Analysis: machine vision in movement disorders

Introduction: Clinimetrics of movement disorders relies on scales such as the Fahn-Tolosa-Marin Tremor Rating Scale for Essential Tremor (ET). However, these rating scales are prone to rater bias. Quantitative measurements of tremor kinematics, which are proxy measures of clinical outcome, can be achieved with gold standard tremor analyses using reflective markers and several special cameras. Due to their resource-intensiveness, broad availability is lacking. We therefore asked whether new developments in the field of machine vision can close the gap between granular clinimetrics and simplicity. Patients & Methods: Using the open-source software DeepLabCut (DLC), we tuned a recurrent convolutional neural network (RCNN) to track anatomic landmarks of the upper body by annotating a total of 1.878 frames from 234 videos of 51 ET patients who had undergone deep brain stimulation for ET and 10 healthy subjects. In a retrospective subcohort of 43 patients, tremor amplitudes were derived using the RCNN predictions. We probed the influence of DBS condition on tremor kinematics and expert annotated tremor rating scores (TRS) using repeated measures (rm-)ANOVA and Wilcoxon signed-ranked tests. Then, we assessed correlation of tremor metrics with TRS. To prospectively validate the method, we calculated the correlation of tremor metrics derived from both the video-based RCNN and the marker-based gold standard approach in 7 patients. The videos for validation were not used for training and were unknown to the network. To test for precision, we assessed relative errors and equivalence of both methods using two one sided T-Tests (TOST). Results: The RCNN achieved a mean Euclidean train/test error of 3.56/10.74 pixels corresponding to the average pixel size of a fingertip. In the retrospective analysis, DBS exerted a significant effect on the mean tremor amplitudes (Friedman test: χ2(3)=45.3, p<.001) and TRS (right: W=7.0, p<.001; left: W=37.5, p<.001). RCNN-derived maximum amplitudes correlated strongly with TRS (right: rs=.789, p<.001; left: rs=.640, p<.001). In the prospective analysis, mean amplitudes derived from both methods were strongly correlated (DBS off: rs=.982, p<.001; DBS on: rs=.824, p<.001). Relative errors of RCNN-derived mean amplitudes from goldstandard measurements did not significantly deviate from zero (p>.06). TOST revealed RCNN-derived measurements to be partially (DBS off: upper bound T(13)=0.5, p=.7; lower bound T(13)=3.9, p<.001) and fully (DBS on: T(13)=-15.2, p<.001; T(13)=14.52, p<.001) located within 90% CI equivalence bounds. Conclusion: We demonstrate the utility of video-based markerless tremor analysis using an RCNN for both retrospective and prospective settings. Our method allows sufficiently accurate measurements of tremor characteristics to assess the severity of the disease and to map individual disease progression.

Personalizing Deep Brain Stimulation Using Advanced Imaging Sequences.

With a growing appreciation for interindividual anatomical variability and patient-specific brain connectivity, advanced imaging sequences offer the opportunity to directly visualize anatomical targets for deep brain stimulation (DBS). The lack of quantitative evidence demonstrating their clinical utility, however, has hindered their broad implementation in clinical practice. Using fast gray matter acquisition T1 inversion recovery (FGATIR) sequences, the present study identified a thalamic hypointensity that holds promise as a visual marker in DBS. To validate the clinical utility of the identified hypointensity, we retrospectively analyzed 65 patients (26 female, mean age=69.1 ± 12.7 years) who underwent DBS in the treatment of essential tremor. We characterized its neuroanatomical substrates and evaluated the hypointensity's ability to predict clinical outcome using stimulation volume modeling and voxelwise mapping. Finally, we determined whether the hypointensity marker could predict symptom improvement on a patient-specific level. Anatomical characterization suggested that the identified hypointensity constituted the terminal part of the dentatorubrothalamic tract. Overlap between DBS stimulation volumes and the hypointensity in standard space significantly correlated with tremor improvement (R2 =0.16, p=0.017) and distance to hotspots previously reported in the literature (R2 =0.49, p=7.9e-4). In contrast, the amount of variance explained by other anatomical atlas structures was reduced. When accounting for interindividual neuroanatomical variability, the predictive power of the hypointensity increased further (R2 =0.37, p=0.002). Our findings introduce and validate a novel imaging-based marker attainable from FGATIR sequences that has the potential to personalize and inform targeting and programming in DBS for essential tremor. ANN NEUROL 2022;91:613-628.

Evaluating and Optimizing Dentato-Rubro-Thalamic-Tract Deterministic Tractography in Deep Brain Stimulation for Essential Tremor.

Dentato-rubro-thalamic tract (DRT) deep brain stimulation (DBS) suppresses tremor in essential tremor (ET) patients. However, DRT depiction through tractography can vary depending on the included brain regions. Moreover, it is unclear which section of the DRT is optimal for DBS. To evaluate deterministic DRT tractography and tremor control in DBS for ET. After DBS surgery, DRT tractography was conducted in 37 trajectories (20 ET patients). Per trajectory, 5 different DRT depictions with various regions of interest (ROI) were constructed. Comparison resulted in a DRT depiction with highest correspondence to intraoperative tremor control. This DRT depiction was subsequently used for evaluation of short-term postoperative adverse and beneficial effects. Postoperative optimized DRT tractography employing the ROI motor cortex, posterior subthalamic area (PSA), and ipsilateral superior cerebellar peduncle and dentate nucleus best corresponded with intraoperative trajectories (92%) and active DBS contacts (93%) showing optimal tremor control. DRT tractography employing a red nucleus or ventral intermediate nucleus of the thalamus (VIM) ROI often resulted in a more medial course. Optimal stimulation was located in the section between VIM and PSA. This optimized deterministic DRT tractography strongly correlates with optimal tremor control. This technique is readily implementable for prospective evaluation in DBS target planning for ET.

Comparative connectivity correlates of dystonic and essential tremor deep brain stimulation

The pathophysiology of dystonic tremor and essential tremor remains partially understood. In patients with medication-refractory dystonic tremor or essential tremor, deep brain stimulation (DBS) targeting the thalamus or posterior subthalamic area has evolved into a promising treatment option. However, the optimal DBS targets for these disorders remains unknown. This retrospective study explored the optimal targets for DBS in essential tremor and dystonic tremor using a combination of volumes of tissue activated estimation and functional and structural connectivity analyses. We included 20 patients with dystonic tremor who underwent unilateral thalamic DBS, along with a matched cohort of 20 patients with essential tremor DBS. Tremor severity was assessed preoperatively and approximately 6 months after DBS implantation using the Fahn-Tolosa-Marin Tremor Rating Scale. The tremor-suppressing effects of DBS were estimated using the percentage improvement in the unilateral tremor-rating scale score contralateral to the side of implantation. The optimal stimulation region, based on the cluster centre of gravity for peak contralateral motor score improvement, for essential tremor was located in the ventral intermediate nucleus region and for dystonic tremor in the ventralis oralis posterior nucleus region along the ventral intermediate nucleus/ventralis oralis posterior nucleus border (4 mm anterior and 3 mm superior to that for essential tremor). Both disorders showed similar functional connectivity patterns: a positive correlation between tremor improvement and involvement of the primary sensorimotor, secondary motor and associative prefrontal regions. Tremor improvement, however, was tightly correlated with the primary sensorimotor regions in essential tremor, whereas in dystonic tremor, the correlation was tighter with the premotor and prefrontal regions. The dentato-rubro-thalamic tract, comprising the decussating and non-decussating fibres, significantly correlated with tremor improvement in both dystonic and essential tremor. In contrast, the pallidothalamic tracts, which primarily project to the ventralis oralis posterior nucleus region, significantly correlated with tremor improvement only in dystonic tremor. Our findings support the hypothesis that the pathophysiology underpinning dystonic tremor involves both the cerebello-thalamo-cortical network and the basal ganglia-thalamo-cortical network. Further our data suggest that the pathophysiology of essential tremor is primarily attributable to the abnormalities within the cerebello-thalamo-cortical network. We conclude that the ventral intermediate nucleus/ventralis oralis posterior nucleus border and ventral intermediate nucleus region may be a reasonable DBS target for patients with medication-refractory dystonic tremor and essential tremor, respectively. Uncovering the pathophysiology of these disorders may in the future aid in further improving DBS outcomes.

Lateralized Effect of Thalamic Deep Brain Stimulation Location on Verbal Abstraction.

Regionalized thalamic activity has been implicated in language function, and yet the effect of thalamic deep brain stimulation (DBS) on language-related clinical outcomes is underexplored. The objective of this study was to determine if the location of stimulation within the thalamus correlates with changes in language-related neuropsychological outcomes following DBS for essential tremor. Thirty patients with essential tremor underwent comprehensive neuropsychological evaluations before and after DBS surgery targeting the ventral intermediate nucleus of the thalamus. Changes in neuropsychological functions were evaluated. The relationships between language-related outcomes and stimulation location were assessed using both categorical and linear methods. Any significant results were further validated using linear discriminant analysis. Most neuropsychological functions remained unchanged at the group level. However, outcome on a measure of verbal abstraction was significantly dependent on stimulation location along the anterior-posterior axis within the left ventral lateral thalamus, with anterior stimulation associated with reduced verbal abstraction performance. This result was supported by linear discriminant analysis, which showed that stimulation locations with improved and reduced verbal abstraction function were best separated by a vector nearly parallel to the anterior-posterior axis. No stimulation location dependence was found for verbal abstraction outcome in the right thalamus or for outcomes of other language functions in either hemisphere. We demonstrate an effect of thalamic DBS on verbal abstraction as a function of left thalamic topography. This finding provides clinical evidence for the lateralization and regionalization of thalamic language function that may be relevant for understanding nonmotor effects of stimulation. © 2021 International Parkinson and Movement Disorder Society.

Connectivity correlates to predict essential tremor deep brain stimulation outcome: Evidence for a common treatment pathway

Background and purposeDeep brain stimulation (DBS) is the most common surgical treatment for essential tremor (ET), yet there is variation in outcome and stimulation targets. This study seeks to consolidate proposed stimulation “sweet spots,” as well as assess the value of structural connectivity in predicting treatment outcomes. Materials and methodsNinety-seven ET individuals with unilateral thalamic DBS were retrospectively included. Using normative brain connectomes, structural connectivity measures were correlated with the percentage improvement in contralateral tremor, based on the Fahn-Tolosa-Marin tremor rating scale (TRS), after parameter optimization (range 3.1–12.9 months) using a leave-one-out cross-validation in 83 individuals. The predictive feature map was used for cross-validation in a separate cohort of 14 ET individuals treated at another center. Lastly, estimated volumes of tissue activated (VTA) were used to assess a treatment “sweet spot,” which was compared to seven previously reported stimulation sweet spots and their relationship to the tract identified by the predictive feature map. ResultsIn the training cohort, structural connectivity between the VTA and dentato-rubro-thalamic tract (DRTT) correlated with contralateral tremor improvement (R = 0.41; p < 0.0001). The same connectivity profile predicted outcomes in a separate validation cohort (R = 0.59; p = 0.028). The predictive feature map represented the anatomical course of the DRTT, and all seven analyzed sweet spots overlapped the predictive tract (DRTT). ConclusionsOur results strongly support the possibility that structural connectivity is a predictor of contralateral tremor improvement in ET DBS. The results suggest the future potential for a patient-specific functionally based surgical target. Finally, the results showed convergence in “sweet spots” suggesting the importance of the DRTT to the outcome.

Cognitive Outcomes for Essential Tremor Patients Selected for Thalamic Deep Brain Stimulation Surgery Through Interdisciplinary Evaluations.

Objective: Deep brain stimulation (DBS) targeted to the ventral intermediate (VIM) nucleus of the thalamus is effective for motor symptoms in essential tremor (ET), but there is limited data on cognitive outcomes. We examined cognitive outcomes in a large cohort of ET DBS patients (pre-DBS and 1+ year after DBS).Methods: In a retrospective analysis, we used repeated-measures ANOVA testing to examine whether the age of tremor onset, age at DBS surgery, hemisphere side implanted with lead, unilateral vs. bilateral implantations, and presence of surgical complications influenced the cognitive outcomes. Neuropsychological outcomes of interest were verbal memory, executive functioning, working memory, language functioning, visuospatial functioning, and general cognitive function.Results: We identified 50 ET DBS patients; 29 (58%) males; the mean age of tremor onset was 35.84 (±21.50) years with a median age of 38 years. The mean age at DBS was 68.18 (±10.07) years. There were 37 unilateral 30 left, seven right, and 13 bilateral brain implantations. In the subgroup analysis, there was a significant interaction between assessment (pre vs. post) and age of tremor onset (<38 vs. >38 years); F(1,30) = 4.47; p = 0.043 for working memory. The post hoc testing found improvements for younger onset ET. Similarly, there was a significant interaction between assessment (pre vs. post) and complications vs. no complications subgroups; F(1,45) = 4.34; p = 0.043 for verbal memory with worsening scores seen for ET patients with complications. The remaining tests were not significant.Conclusion: In this large cohort of ET patients with (>30% improvements), DBS was not accompanied by a significant decline in many cognitive domains. These outcomes were possibly related to the selection of patients with normal cognitive functioning before surgery, unilateral DBS implantations for the majority, and selection of patients with optimal response to DBS.

Deep-Brain Stimulation for Essential Tremor and Other Tremor Syndromes: A Narrative Review of Current Targets and Clinical Outcomes.

Tremor is a prevalent symptom associated with multiple conditions, including essential tremor (ET), Parkinson’s disease (PD), multiple sclerosis (MS), stroke and trauma. The surgical management of tremor evolved from stereotactic lesions to deep-brain stimulation (DBS), which allowed safe and reversible interference with specific neural networks. This paper reviews the current literature on DBS for tremor, starting with a detailed discussion of current tremor targets (ventral intermediate nucleus of the thalamus (Vim), prelemniscal radiations (Raprl), caudal zona incerta (Zi), thalamus (Vo) and subthalamic nucleus (STN)) and continuing with a discussion of results obtained when performing DBS in the various aforementioned tremor syndromes. Future directions for DBS research are then briefly discussed.

Comprehensive Evaluation of Voice-Specific Outcomes in Patients With Essential Tremor Before and After Deep Brain Stimulation

Deep brain stimulation (DBS) is a treatment for medically refractory essential tremor (ET), but there is a paucity of literature examining the effects of DBS on voice in patients with ET pre-DBS and post-DBS. This study aimed to report a comprehensive evaluation of voice in patients with ET pre-DBS and 6-months post-DBS. Case series. Five patients receiving DBS for ET underwent voice evaluations pre-DBS and 6-months post-DBS. One patient had concurrent ET of the vocal tract (ETVT). The evaluation included patient-reported, perceptual, acoustic, and phonatory aerodynamic analyses of voice. Voice Handicap Index-10, Grade, Roughness, Breathiness, Asthenia, Strain Scale, perturbation measures, cepstral spectral index of dysphonia, cepstral peak prominence, and mean phonatory airflow measures were also among the data collected. Patients with ET presented with minimal changes in perceptual, acoustic, and phonatory aerodynamic parameters. Perceived vocal roughness significantly increased 6-months post-DBS (P = 0.047). The patient with ETVT presented with clinically significant improvement in almost all collected voice parameters 6-months post-DBS. This is the first study to provide data encompassing auditory perceptual voice analysis, voice-specific patient-reported quality of life measures, acoustic, and phonatory aerodynamic outcomes in patients pre-DBS and 6-months post-DBS for ET. The results of our preliminary study have implications for the use of a comprehensive voice assessment to identify and measure change in voice outcomes in patients with ET and ETVT pre- and postsurgery.

Predictors of second-sided deep brain stimulation for Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological movement disorder that is commonly treated with deep brain stimulation (DBS) surgery in advanced stages. The purpose of this study was to investigate factors that affect time to placement of a second-sided DBS lead for PD when a unilateral lead is initially placed for asymmetrical presentation. The decision whether to initially perform unilateral or bilateral DBS is largely based on physician and/or patient preference. This study was a retrospective cohort analysis of patients with PD undergoing initial unilateral DBS for asymmetrical disease between January 1999 and December 2017 at the authors' institution. Patients treated with DBS for essential tremor or other conditions were excluded. Variables collected included demographics at surgery, time since diagnosis, Unified Parkinson's Disease Rating Scale motor scores (UPDRS-III), patient-reported quality-of-life outcomes, side of operation, DBS target, intraoperative complications, and date of follow-up. Paired t-tests were used to assess mean changes in UPDRS-III. Cox proportional hazards analysis and the Kaplan-Meier method were used to determine factors associated with time to second lead insertion over 5 years. The final cohort included 105 patients who underwent initial unilateral DBS for asymmetrical PD; 59% of patients had a second-sided lead placed within 5 years with a median time of 34 months. Factors found to be significantly associated with early second-sided DBS included patient age 65 years or younger, globus pallidus internus (GPi) target, and greater off-medication reduction in UPDRS-III score following initial surgery. Older age was also found to be associated with a smaller preoperative UPDRS-III levodopa responsiveness score and with a smaller preoperative to postoperative medication-off UPDRS-III change. Younger patients, those undergoing GPi-targeted unilateral DBS, and patients who responded better to the initial DBS were more likely to undergo early second-sided lead placement. Therefore, these patients, and patients who are more responsive to medication preoperatively (as a proxy for DBS responsiveness), may benefit from consideration of initial bilateral DBS.

Deep brain stimulation in the caudal zona incerta modulates the sensorimotor cerebello-cerebral circuit in essential tremor

Essential tremor is effectively treated with deep brain stimulation (DBS), but the neural mechanisms underlying the treatment effect are poorly understood. Essential tremor is driven by a dysfunctional cerebello-thalamo-cerebral circuit resulting in pathological tremor oscillations. DBS is hypothesised to interfere with these oscillations at the stimulated target level, but it is unknown whether the stimulation modulates the activity of the cerebello-thalamo-cerebral circuit during different task states (with and without tremor) in awake essential tremor patients. To address this issue, we used functional MRI in 16 essential tremor patients chronically implanted with DBS in the caudal zona incerta. During scanning, the patients performed unilateral tremor-inducing postural holding and pointing tasks as well as rest, with contralateral stimulation turned On and Off.We show that DBS exerts both task-dependent as well as task-independent modulation of the sensorimotor cerebello-cerebral regions (p ​≤ ​0.05, FWE cluster-corrected for multiple comparisons). Task-dependent modulation (DBS ​× ​task interaction) resulted in two patterns of stimulation effects. Firstly, activity decreases (blood oxygen level-dependent signal) during tremor-inducing postural holding in the primary sensorimotor cortex and cerebellar lobule VIII, and activity increases in the supplementary motor area and cerebellar lobule V during rest (p ​≤ ​0.05, post hoc two-tailed t-test). These effects represent differences at the effector level and may reflect DBS-induced tremor reduction since the primary sensorimotor cortex, cerebellum and supplementary motor area exhibit less motor task-activity as compared to the resting condition during On stimulation. Secondly, task-independent modulation (main effect of DBS) was observed as activity increase in the lateral premotor cortex during all motor tasks, and also during rest (p ​≤ ​0.05, post hoc two-tailed t-test). This task-independent effect may mediate the therapeutic effects of DBS through the facilitation of the premotor control over the sensorimotor circuit, making it less susceptible to tremor entrainment.Our findings support the notion that DBS in essential tremor is modulating the sensorimotor cerebello-cerebral circuit, distant to the stimulated target, and illustrate the complexity of stimulation mechanisms by demonstrating task-dependent as well as task-independent actions in cerebello-cerebral regions.