Mapping of subthalamic nucleus using microelectrode recordings during deep brain stimulation.

Alongside stereotactic magnetic resonance imaging, microelectrode recording (MER) is frequently used during the deep brain stimulation (DBS) surgery for optimal target localization. The aim of this study is to optimize subthalamic nucleus (STN) mapping using MER analytical patterns. 16 patients underwent bilateral STN-DBS. MER was performed simultaneously for 5 microelectrodes in a setting of Ben's-gun pattern in awake patients. Using spikes and background activity several different parameters and their spectral estimates in various frequency bands including low frequency (2-7 Hz), Alpha (8-12 Hz), Beta (sub-divided as Low_Beta (13-20 Hz) and High_Beta (21-30 Hz)) and Gamma (31 to 49 Hz) were computed. The optimal STN lead placement with the most optimal clinical effect/side-effect ratio accorded to the maximum spike rate in 85% of the implantation. Mean amplitude of background activity in the low beta frequency range was corresponding to right depth in 85% and right location in 94% of the implantation respectively. MER can be used for STN mapping and intraoperative decisions for the implantation of DBS electrode leads with a high accuracy. Spiking and background activity in the beta range are the most promising independent parameters for the delimitation of the proper anatomical site.

Screening for Platelet Dysfunction and Use of Prophylactic Tranexamic Acid in Patients Undergoing Deep Brain Stimulation: A Retrospective Analysis of Incidence and Outcome of Intracranial Hemorrhage.

INTRODUCTION: The rate of intracranial hemorrhage (ICH) after deep brain stimulation (DBS) is between 1.5 and 6.1%, with prolonged deficits occurring in 0.4-2.5% of the patients. This retrospective study investigates whether the prophylactic administration of tranexamic acid (TA) to patients with abnormal platelet function detected preoperatively by platelet function analyzer (PFA) lowered the risk for an ICH event. METHODS: We performed a systematic review of the medical records of 485 consecutively admitted patients who underwent bilateral DBS surgery in a single-center university hospital setting between 2009 and 2018. The cohort was split into two groups. In one group, preoperative PFA screening was performed (n = 156, patients recruited from 2014 to 2018), and TA was administered if platelet function was abnormal. No preoperative PFA was performed in the second group (n = 359, patients recruited from 2009 to 2013). Both cohorts were analyzed for the occurrence of ICH, defined by (i) detection of ICH in routine postoperative magnetic resonance/computed tomography imaging or (ii) in non-routine imaging for the onset of new neurological symptoms. RESULTS: Fourteen of the 156 screened patients (9%) showed reproducible PFA-100 closure abnormalities (3 with von Willebrand disease, 11 with no identifiable cause of platelet dysfunction). Two of the 156 patients (1.3%) in this cohort revealed an ICH on imaging, 1 of whom (0.6%) exhibited a prolonged neurological deficit as a result of ICH. In the cohort without platelet testing, 11 of the 329 patients (3.3%) demonstrated ICH on imaging, of whom 5 (1.5%) suffered from a prolonged neurological deficit. CONCLUSION: In this retrospective study, the screening and the administration of TA appeared to lower the risk of an ICH by 1.8%. One patient with von Willebrand disease suffered an ICH despite TA treatment. A prospective study is needed to clarify the impact of platelet testing and TA administration on the of incidence ICH.

Do Adaptors Shorten the Battery Life of Nonrechargeable Generators for Deep Brain Stimulation?

OBJECTIVE: Generators implanted for deep brain stimulation must be replaced after several years. If a Kinetra generator is replaced by the Activa-PC, an adaptor will be required to attach it to the original extension cables. On the basis of our clinical impression that the battery life of the Active-PC generator was shorter when an adaptor was used, we performed this retrospective study. METHODS: We determined the battery lifetimes of deep brain stimulation generators that had been implanted in our department. The inclusion criterion was the initial implantation of a Kinetra generator that was later replaced by an Activa-PC with adaptor, which itself was subsequently also replaced. These patients were compared with an Activa-PC control group without an adaptor but identical with regard to number of battery exchanges, disease, and target. RESULTS: There were 28 patients in the study group and 14 in the control group. Battery lifetime of the Activa-PC with adaptor (32.4 ± 7.7 months) was significantly shorter than that of the Kinetra (53.5 ± 15.7 months, P = 0.000006). The battery life of Activa-PC without an adaptor (35.3 ± 8.2 months) did not differ significantly from that of the Activa-PC with an adaptor (P = 0.333). CONCLUSIONS: The battery lifetime in a replacement Activa-PC is shorter than that in the original Kinetra generator. Adaptors have no significant effect on battery life. Patients should be informed that the battery in their new generator must be checked more frequently than before.

Evaluation of a programming algorithm for deep brain stimulation in dystonia used in a double-blind, sham-controlled multicenter study.

BACKGROUND: Programming deep brain stimulation in dystonia is difficult because of the delayed benefits and absence of evidence-based guidelines. Therefore, we evaluated the efficacy of a programming algorithm applied in a double-blind, sham-controlled multicenter study of pallidal deep brain stimulation in dystonia. METHODS: A standardized monopolar review to identify the contact with the best acute antidystonic effect was applied in 40 patients, who were then programmed 0.5 V below the adverse effect threshold and maintained on these settings for at least 3 months, if tolerated. If no acute effects were observed, contact selection was based on adverse effects or anatomical criteria. Three-year follow-up data was available for 31 patients, and five-year data for 32 patients. The efficacy of the algorithm was based on changes in motor scores, adverse events, and the need for reprogramming. RESULTS: The mean (±standard deviation) dystonia motor score decreased by 73 ± 24% at 3 years and 63 ± 38% at 5 years for contacts that exhibited acute improvement of dystonia (n = 17) during the monopolar review. Contacts without acute benefit improved by 58 ± 30% at 3 years (n = 63) and 53 ± 31% at 5 years (n = 59). Interestingly, acute worsening or induction of dystonia/dyskinesia (n = 9) correlated significantly with improvement after 3 years, but not 5 years. CONCLUSIONS: Monopolar review helped to detect the best therapeutic contact in approximately 30% of patients exhibiting acute modulation of dystonic symptoms. Acute improvement, as well as worsening of dystonia, predicted a good long-term outcome, while induction of phosphenes did not correlate with outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT00142259.

White Matter Changes Along the Electrode Lead in Patients Treated With Deep Brain Stimulation.

Introduction: Deep brain stimulation (DBS) is an established treatment for various movement disorders. There is little data available about the potential damage to brain parenchyma through DBS treatment. The objective of this study was to investigate the occurrence of signal changes on magnetic resonance imaging (MRI) in patients treated with DBS. Methods: We retrospectively analyzed MRI scans of 30 DBS patients (21 patients with Parkinson's disease, 3 patients with dystonia and 6 patients with tremor) that had undergone additional MRI scans after DBS surgery (ranging from 2 months to 8 years). Axial T2 sequences were analyzed by two raters using a standardized lesion mapping procedure. Results: 26 out of 30 analyzed patients showed hyperintense white matter changes surrounding the DBS lead (mean volume = 2.43 ml). Lesions were prominent along the upper half of the electrode lead within the subcortical white matter, with no abnormalities along the lower lead. Their volume was significantly correlated to the time from surgery to MRI and to the number of microelectrodes used in surgery, but was independent from underlying disease (Parkinson's disease, dystonia, tremor), target structure (STN, GPi, VIM), demographical data, or cardiovascular risk factors. Discussion: White matter changes along the electrode leads in DBS patients are a frequent finding. These changes seem to evolve with certain latency after surgery and might be radiologically classified as a gliosis. Our findings identify the number of intraoperatively used microelectrodes as a risk factor in the formation of gliosis. Therefore, mechanical damage at the time of surgery and an individual tissue response might contribute to their evolution. Further studies are needed to define the exact mechanisms and their clinical impact.

Neurostimulation in tardive dystonia/dyskinesia: A delayed start, sham stimulation-controlled randomized trial.

INTRODUCTION: Growing evidence suggests that pallidal deep brain stimulation represents a potential new therapeutic avenue in tardive dystonia/dyskinesia, but controlled and blinded randomized studies (RCT) are missing. The present RCT compares dystonia/dyskinesia severity of pallidal neurostimulation in patients with tardive dystonia using a delayed-start design paradigm. METHODS: Dystonia/dyskinesia severity was assessed via blinded videos following pallidal neurostimulation at 3 (blinded phase) and 6 months (open extension phase). Primary endpoint was the percentage change of dystonia severity (Burke-Fahn-Marsden-Dystonia-Rating-Scale, BFMDRS) at 3 months between active vs. sham neurostimulation using blinded-video assessment. Secondary endpoints comprised clinical rating scores for movement disorders. Clinicaltrials.gov NCT00331669. RESULTS: Twenty-five patients were randomized (1:1) to active (n = 12) or sham neurostimulation (n = 13). In the intention-to-treat analyses the between group difference of dystonia severity (BFMDRS) between active vs. sham stimulation was not significant at 3 months. Three months post-randomisation dystonia severity improved significantly within the neurostimulation by 22.8% and non-significantly within the sham group (12.0%) compared to their respective baseline severity. During the open-label extension with both groups being actively treated, significant and pronounced improvements of 41.5% were observed via blinded evaluation. Adverse events (n = 10) occurred in 10/25 of patients during the 6 months, mostly related to surgical implantation of the device; all resolved without sequelae. CONCLUSION: The primary endpoint of this randomized trial was not significant, most likely due to incomplete recruitment. However, pronounced improvements of most secondary endpoints at 3 and 6 months provide evidence for efficacy and safety of pallidal neurostimulation in tardive dystonia.

Complications of Impulse Generator Exchange Surgery for Deep Brain Stimulation: A Single-Center, Retrospective Study.

BACKGROUND: Nonrechargeable deep brain stimulation impulse generators (IGs) with low or empty battery status require surgical IG exchange several years after initial implantation. The aim of this study was to investigate complication rates after IG exchange surgery and identify risk factors. METHODS: We retrospectively analyzed complications following IG exchange surgery from 2008 to 2015 in our department. Medical records of all patients who underwent IG exchange surgery were systematically reviewed. The shortest follow-up time was 19 months. RESULTS: From 2008 to 2015, 438 IGs were exchanged in 319 patients. Overall complication rate was 8.90%. Infection developed in 12 patients (2.74%). Six patients (1.37%) experienced local wound erosions. Hardware malfunctions were present in 11 patients (2.51%), and local hemorrhage was observed in 3 cases (0.68%). Repeated fixation of the IG was required in 2 patients (0.46%). Traction of the connecting cables necessitated surgical revision in 2 patients (0.46%). In 2 cases (0.46%), the IG was placed abdominally or exchanged for a smaller device owing to patient discomfort resulting from the initial positioning. One 80-year-old patient (0.23%) had severely worsening heart failure and died 4 days after IG exchange surgery. CONCLUSIONS: IG exchange surgery, although often considered a minor surgery, was associated with a complication rate of approximately 9% in our center. Patients and physicians should understand the complication rates associated with IG exchange surgery because this information might facilitate selection of a rechargeable IG.

Comparison of the Battery Life of Nonrechargeable Generators for Deep Brain Stimulation.

OBJECTIVE: Nonrechargeable deep brain stimulation (DBS) generators must be replaced when the battery capacity is exhausted. Battery life depends on many factors and differs between generator models. A new nonrechargeable generator model replaced the previous model in 2008. Our clinical impression is that the earlier model had a longer battery life than the new one. We conducted this study to substantiate this. METHODS: We determined the battery life of every DBS generator that had been implanted between 2005 and 2012 in our department for the treatment of Parkinson's disease, and compared the battery lives of the both devices. We calculated the current used by estimating the total electrical energy delivered (TEED) based on the stimulation parameters in use one year after electrode implantation. RESULTS: One hundred ninety-two patients were included in the study; 105 with the old and 86 with the new model generators. The mean battery life in the older model was significantly longer (5.44 ± 0.20 years) than that in the new model (4.44 ± 0.17 years) (p = 0.023). The mean TEED without impedance was 219.9 ± 121.5 mW * Ω in the older model and 145.1 ± 72.7 mW * Ω in the new one, which indicated significantly lower stimulation parameters in the new model (p = 0.00038). CONCLUSION: The battery life of the new model was significantly shorter than that of the previous model. A lower battery capacity is the most likely reason, since current consumption was similar in both groups.

Movement-Related Activity of Human Subthalamic Neurons during a Reach-to-Grasp Task.

The aim of the study was to record movement-related single unit activity (SUA) in the human subthalamic nucleus (STN) during a standardized motor task of the upper limb. We performed microrecordings from the motor region of the human STN and registered kinematic data in 12 patients with Parkinson's disease (PD) undergoing deep brain stimulation surgery (seven women, mean age 62.0 ± 4.7 years) while they intraoperatively performed visually cued reach-to-grasp movements using a grip device. SUA was analyzed offline in relation to different aspects of the movement (attention, start of the movement, movement velocity, button press) in terms of firing frequency, firing pattern, and oscillation. During the reach-to-grasp movement, 75/114 isolated subthalamic neurons exhibited movement-related activity changes. The largest proportion of single units showed modulation of firing frequency during several phases of the reach and grasp (polymodal neurons, 45/114), particularly an increase of firing rate during the reaching phase of the movement, which often correlated with movement velocity. The firing pattern (bursting, irregular, or tonic) remained unchanged during movement compared to rest. Oscillatory single unit firing activity (predominantly in the theta and beta frequency) decreased with movement onset, irrespective of oscillation frequency. This study shows for the first time specific, task-related, SUA changes during the reach-to-grasp movement in humans.

Intraoperative Thresholds for Capsular Stimulation Are Reliable for Chronic Pallidal Deep Brain Stimulation in Dystonia.

BACKGROUND: The threshold current for inducing muscle contractions by stimulation of pyramidal tract fibres adjacent to the globus pallidus internus (GPi) is, besides microelectrode recordings for the determination of nuclear boundaries, currently the only neurophysiological marker for intraoperative refinement of the anatomically planned target point for pallidal deep brain stimulation (GPi-DBS) in dystonia. OBJECTIVES: To determine the relationship between intraoperative thresholds for muscle contractions under general anaesthesia and postoperative thresholds in GPi-DBS. METHODS: Intraoperatively, current amplitude thresholds (120 µs, 130 Hz) were determined in 6 dystonic patients under general anaesthesia (through the uninsulated tip of the microelectrode guide tube). Postoperative localization of chronic stimulation electrodes by MRI and image fusion with the stereotactic planning determined the stimulation contact for comparing thresholds with intraoperative values. RESULTS: Current thresholds were 3.3 ± 0.8 mA intraoperatively (follow-up 0, FU0; n = 12), 2.9 ± 1.2 mA within 1 week after surgery (FU1; n = 12), and 3.5 ± 1.6 mA after 6-17 months (FU2; n = 8). FU0 and FU1 differed by trend, and FU1 and FU2 were significantly different (Friedman test, p = 0.0048; post hoc Dunn multiple comparison test, p < 0.05). FU0 and FU2 were not different. DISCUSSION: The threshold amplitude to induce tonic muscular contractions may constitute a valid approach of functionally refining the anatomically guided electrode placement in GPi-DBS for dystonia, because intraoperative values are predictive for postoperative thresholds with the chronically implanted neurostimulation system.

Uncoupling of dopaminergic and subthalamic stimulation: Life-threatening DBS withdrawal syndrome.

BACKGROUND: Deep brain stimulation (DBS) in therapy for advanced Parkinson's disease (PD) is an accepted treatment. Infections of the system and other complications occasionally result in hardware removal and subsequent medical treatment alone for months. METHODS: We have analyzed the clinical course of 15 patients requiring removal of at least parts of the DBS system, resulting in a cessation of stimulation. RESULTS: Most had an uncomplicated return to medical treatment. Three had an unfavorable course during withdrawal, including two deaths. These patients had suffered from PD for more than 18 y and had had DBS for more than 8 y. CONCLUSIONS: We conclude that DBS withdrawal can be life-threatening, because the whole range of dopaminergic and nondopaminergic medical treatments may be ineffective at this stage. The lack of response to medical treatment might be attributable to advanced disease and long-term changes of the basal ganglia loop in PD.

Subthalamic nucleus stimulation improves Parkinsonian gait via brainstem locomotor centers.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) can ameliorate gait disturbances in Parkinson's disease (PD). Using motor imagery and positron emission tomography (PET), we investigated how STN-DBS interacts with supraspinal locomotor centers in PD. METHODS: Ten PD patients with bilateral STN-DBS actually walked or stood still under STN-DBS ON or OFF conditions. Directly thereafter, subjects imagined walking or standing while changes in regional cerebral blood flow were measured by PET. RESULTS: Independent of STN-DBS, imagined walking distance correlated with imagery duration. Compared with STN-DBS OFF, STN-DBS ON improved actual gait and increased imagined walking distance. Imagery of gait (vs. stance) induced activity in the supplementary motor area and the right superior parietal lobule for both STN-DBS conditions. The improvement of imagined gait during STN-DBS ON led to activity changes in the pedunculopontine nucleus/mesencephalic locomotor region (PPN/MLR). CONCLUSIONS: Data suggest that STN-DBS improves Parkinsonian gait by modulating PPN/MLR activity.

Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial.

BACKGROUND: Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment. METHODS: In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18-75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 µs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889. FINDINGS: Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0 to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. INTERPRETATION: Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. FUNDING: Medtronic.

Physiological and anatomical decomposition of subthalamic neurostimulation effects in essential tremor.

Postural tremor is the leading symptom in essential tremor, but in some cases intention tremor and limb ataxia emerge and can become highly disabling features. Deep brain stimulation of the thalamus or subthalamic white matter improve tremor and ataxia; however, the underlying network mechanisms are enigmatic. To elucidate the mechanisms of deep brain stimulation in essential tremor, we pursued a multimodal approach combining kinematic measures of reach-to-grasp movements, clinical assessments, physiological measures of neuronal excitability and probabilistic tractography from diffusion tensor imaging. Seven patients with essential tremor (age 62.9 ± 10.3 years, two females) received thalamic deep brain stimulation and a clinical examination of severity of limb tremor and ataxia at off stimulation, using therapeutic and supratherapeutic stimulation parameters. A reach-to-grasp task based on acoustic cues was also performed. To examine the electrical properties of target structures, we determined the chronaxie of neural elements modulated. A control group of 13 healthy subjects (age 56 ± 7.6 years, five females) underwent whole-brain diffusion tensor imaging at 3 T. Probabilistic tractography was applied in healthy subjects from seeds in cerebellum and midbrain to reconstruct the connectivity pattern of the subthalamic area. The positions of stimulation electrodes in patients were transferred into probability maps and connectivity values were correlated to clinical outcome measures. Therapeutic stimulation improved ataxia and tremor mainly during the target period of the reaching paradigm (63% reduction compared with off stimulation). Notably the acceleration (29%) and deceleration periods (41%) were improved. By contrast, supratherapeutic stimulation worsened ataxia during the deceleration period with a 55% increase of spatial variability, while maintaining near complete suppression of tremor. Chronaxie measures were in the range of rapidly-conducting myelinated fibres with significantly different values for the anti-tremor effect of therapeutic stimulation (27 s) and the pro-ataxic effect of supratherapeutic stimulation (52 s). The degree of connectivity to the dentato-thalamic tract at the stimulating electrode correlated significantly with the reduction of tremor in the therapeutic condition. Our data suggest that stimulation induced tremor reduction and induction of ataxia by supratherapeutic stimulation are mediated by different fibre systems. Probalistic tractography identified the dentato-thalamic tract as a likely target of tremor suppression. Stimulation-induced ataxia may be caused by additional recruitment of adjacent fibre systems at higher amplitudes. Stimulation with short pulse duration may help to increase the therapeutic window and focus on the anti-tremor effect.

The subthalamic nucleus influences visuospatial attention in humans.

Spatial attention is a lateralized feature of the human brain. Whereas the role of cortical areas of the nondominant hemisphere on spatial attention has been investigated in detail, the impact of the BG, and more precisely the subthalamic nucleus, on signs and symptoms of spatial attention is not well understood. Here we used unilateral deep brain stimulation of the subthalamic nucleus to reversibly, specifically, and intraindividually modify the neuronal BG outflow and its consequences on signs and symptoms of visuospatial attention in patients suffering from Parkinson disease. We tested 13 patients with Parkinson disease and chronic deep brain stimulation in three stimulation settings: unilateral right and left deep brain stimulation of the subthalamic nucleus as well as bilateral deep brain stimulation of the subthalamic nucleus. In all three stimulation settings, the patients viewed a set of pictures while an eye-tracker system recorded eye movements. During the exploration of the visual stimuli, we analyzed the time spent in each visual hemispace, as well as the number, duration, amplitude, peak velocity, acceleration peak, and speed of saccades. In the unilateral left-sided stimulation setting, patients show a shorter ipsilateral exploration time of the extrapersonal space, whereas number, duration, and speed of saccades did not differ between the different stimulation settings. These results demonstrated reduced visuospatial attention toward the side contralateral to the right subthalamic nucleus that was not being stimulated in a unilateral left-sided stimulation. Turning on the right stimulator, the reduced visuospatial attention vanished. These results support the involvement of the subthalamic nucleus in modulating spatial attention. Therefore, the subthalamic nucleus is part of the subcortical network that subserves spatial attention.

Motor outcome of dystonic camptocormia treated with pallidal neurostimulation.

BACKGROUND: Deep brain stimulation of the internal pallidum (GPi-DBS) is effective for various types of drug-refractory primary dystonias. Rare clinical forms as dystonic camptocormia may profit but available data are scarce. METHODS: We here report on a retrospective clinical assessment of three patients with primary dystonic camptocormia treated with GPi-DBS. RESULTS: All three patients showed marked response to bilateral GPi-DBS within days to weeks after surgery which was preserved in the long-term (38-45 months after implantation: mean improvement 82% as rated on the Burke Fahn Marsden Dystonia Rating Scale, 89% in the subitem "trunk"). Two patients developed mild stimulation induced speech problems (stuttering or dysarthria) which resolved with reprogramming or were acceptable in return for the control of dystonic symptoms. CONCLUSIONS: The diagnosis and treatment of camptocormia will continue to require expert knowledge in movement and neuromuscular disorders, but DBS may expand treatment options in this difficult patient population.

Relation of lead trajectory and electrode position to neuropsychological outcomes of subthalamic neurostimulation in Parkinson's disease: results from a randomized trial.

Deep brain stimulation of the subthalamic nucleus improves motor functions in patients suffering from advanced Parkinson's disease but in some patients, it is also associated with a mild decline in cognitive functioning about one standard deviation from the preoperative state. We assessed the impact of the cortical lead entry point, the subcortical electrode path and the position of the active electrode contacts on neuropsychological changes after subthalamic nucleus-deep brain stimulation compared to a control group of patients receiving best medical treatment. Sixty-eight patients with advanced Parkinson's disease were randomly assigned to have subthalamic nucleus-deep brain stimulation or best medical treatment for Parkinson's disease. All patients had a blinded standardized neuropsychological exam (Mattis Dementia Rating scale, backward digit span, verbal fluency and Stroop task performance) at baseline and after 6 months of treatment. Patients with subthalamic nucleus-deep brain stimulation were defined as impaired according to a mild decline of one or more standard deviations compared to patients in the best medical treatment group. The cortical entry point of the electrodes, the electrode trajectories and the position of the active electrode contact were transferred into a normalized brain volume by an automated, non-linear registration algorithm to allow accurate statistical group analysis using pre- and postoperative magnetic resonance imaging data. Data of 31 patients of the subthalamic nucleus-deep brain stimulation group and 31 patients of the best medical treatment group were analysed. The subthalamic nucleus-deep brain stimulation group showed impaired semantic fluency compared with the best medical treatment group 6 months after surgery (P = 0.02). Electrode trajectories intersecting with caudate nuclei increased the risk of a decline in global cognition and working memory performance. Statistically, for every 0.1 ml overlap with a caudate nucleus, the odds for a decline >1 standard deviation increased by a factor of 37.4 (odds ratio, confidence interval 2.1-371.8) for the Mattis Dementia Rating Scale and by a factor of 8.8 (odds ratio, confidence interval 1.0-70.9) for the backward digit span task. Patients with subthalamic nucleus-deep brain stimulation who declined in semantic verbal fluency, Stroop task and the backward digit span task performance showed a position of the active electrode outside the volume built by the active electrodes of stable performers. Passage of the chronic stimulation lead through the head of the caudate increases the risk of global cognitive decline and working memory performance after subthalamic nucleus-deep brain stimulation in Parkinson's disease. Therefore the electrode path should be planned outside the caudate nuclei, whenever possible. This study also stresses the importance of precise positioning of the active stimulating contact within the subthalamic volume to avoid adverse effects on semantic verbal fluency and response inhibition.

Lower limb joints kinematics in essential tremor and the effect of thalamic stimulation.

Following the hypothesis that thalamic deep brain stimulation improves ataxia in patients with essential tremor by modulating the cerebello-thalamo-cortical pathway, we examined the joint kinematics of lower limbs during uninterrupted gait in eleven patients who have been treated with bilateral thalamic stimulation for 24.7±20.3 months. Patients were assessed under routine chronic stimulation, supra-therapeutic amplitude, and off stimulation by means of an infrared movement analysis system while walking on a treadmill. Chronic thalamic DBS normalized the highly variable excursion throughout the gait cycle that characterized the subgroup of patients with longest disease duration. Supratherapeutic thalamic DBS amplitude did not reproduce such improvements while, more importantly, it induced ataxic changes of joint excursion. The normalization of kinematic abnormalities argues against the hypothesis of a cerebellar neurodegeneration in ET. Moreover, these results suggest that the beneficial effect of thalamic DBS on ataxic symptoms is limited to a narrow therapeutic window.