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Epilepsy treatment trials typically rely on seizure diaries to determine seizure frequency, but these are time-consuming and difficult to maintain accurately. Fast, reliable, and objective biomarkers of treatment response are needed, particularly in Lennox-Gastaut syndrome (LGS), where high seizure frequency and comorbid cognitive and behavioral issues are additional obstacles to accurate diary-keeping. Here, we measured generalized paroxysmal fast activity (GPFA), a key interictal electrographic feature of LGS, and correlated GPFA burden with seizure diaries during a thalamic deep brain stimulation (DBS) treatment trial (Electrical Stimulation of the Thalamus in Epilepsy of Lennox-Gastaut Phenotype [ESTEL]).GPFA and electrographic seizure counts from intermittent, 24-h electroencephalograms (EEGs) were compared to 3-month diary-recorded seizure counts in 17 young adults with LGS (mean age ± SD = 24.9 ± 6.6) in the ESTEL study, a randomized clinical trial of DBS lasting 12 months (comprising a 3-month baseline and 9 months of postimplantation follow-up).Baseline median seizures measured by diaries numbered 2.6 (interquartile range [IQR] = 1.4-5) per day, compared to 284 (IQR = 120.5-360) electrographic seizures per day, confirming that diaries capture only a small fraction of seizure burden. Across all patient EEGs, the average number of GPFA discharges per hour of sleep was 138 (IQR =72-258). GPFA duration and frequency, quantified over 2-h windows of sleep EEG, were significantly associated with diary-recorded seizure counts over 3-month intervals (p .001, ηWhen seeking to optimize treatment in patients with LGS, monitoring changes in GPFA may allow rapid titration of treatment parameters, rather than waiting for feedback from seizure diaries.

We previously reported seizure and EEG outcomes of the ESTEL study (Electrical Stimulation of Thalamus for Epilepsy of Lennox-Gastaut phenotype). To assess potential cognitive and behavioral changes during chronic, duty-cycle stimulation of bilateral thalamic centromedian nucleus, we compared standardized cognitive and behavioral measurements, as well as caregiver assessments of disability/severity, before implantation and after 3-months stimulation.Twenty patients with LGS (17-37 years;13 females) were studied; one participant was not randomized due to DBS device removal, with outcomes of 19 remaining participants reported here. Cognitive and behavioral measurements were performed at baseline (i.e., before DBS implantation), at the end of the blinded stimulation phase, and at study exit. Instruments measured cognition (NIH toolbox cognitive battery, NIHTB-CB), adaptive skills (ABAS-3), epilepsy severity (GASE) and disability (GAD), quality of life (QOLIE-31), and depression (PHQ-9). Changes in scores after 3-months of stimulation relative to baseline were explored using Wilcoxon matched-pairs signed rank tests.After 3-months of stimulation, caregiver-reported epilepsy severity (GASE) and disability (GAD) improved (p0.05). No other instrument showed a significant change from baseline. Measurements that required direct participant involvement, rather than caregivers, was completed by only a subset of higher-functioning individuals (NIHTB-CB, n = 13; QOLIE-31, n = 3; and PHQ-9, n = 6). In addition to cognitive impairments, behavioral and physical limitations were common obstacles to instrument completion. Standardized scores were hindered by 'floor effects'; however, raw scores better reflected clinical impressions of participants' functioning and were more sensitive to caregiver-reported changes following treatment.DBS treatment is associated with reduced epilepsy severity and disability in young adults with LGS. Performing cognitive and behavioral outcome measurement in patients with cognitive impairment is challenging but possible and requires careful selection of instruments and modifications of score interpretation to avoid floor effects.

Deep brain stimulation (DBS) can reduce seizures in Lennox-Gastaut syndrome (LGS). However, little is known about the optimal target and whether efficacy depends on connectivity of the stimulation site. Using outcome data from the ESTEL trial, we aimed to determine the optimal target and connectivity for DBS in LGS.A total of 20 patients underwent bilateral DBS of the thalamic centromedian nucleus (CM). Outcome was percentage seizure reduction from baseline after 3 months of DBS, defined using three measures (monthly seizure diaries, 24-hour scalp electroencephalography [EEG], and a novel diary-EEG composite). Probabilistic stimulation mapping identified thalamic locations associated with higher/lower efficacy. Two substitute diffusion MRI datasets (a normative dataset from healthy subjects and a "disease-matched" dataset from a separate group of LGS patients) were used to calculate structural connectivity between DBS sites and a map of areas known to express epileptic activity in LGS, derived from our previous EEG-fMRI research.Results were similar across the three outcome measures. Stimulation was most efficacious in the anterior and inferolateral "parvocellular" CM border, extending into the ventral lateral nucleus (posterior subdivision). There was a positive association between diary-EEG composite seizure reduction and connectivity to areas of a priori EEG-fMRI activation, including premotor and prefrontal cortex, putamen, and pontine brainstem. In contrast, outcomes were not associated with baseline clinical variables.Efficacious CM-DBS for LGS is linked to stimulation of the parvocellular CM and the adjacent ventral lateral nucleus, and is associated with connectivity to, and thus likely modulation of, the "secondary epileptic network" underlying the shared electroclinical manifestations of LGS. ANN NEUROL 2022;92:61-74.

Selecting the ideal contact to apply subthalamic nucleus deep brain stimulation in Parkinson’s disease can be an arduous process, with outcomes highly dependent on clinician expertise. This study aims to assess whether neuronal signals recorded intraoperatively in awake patients, and the anatomical location of contacts, can assist programming. In a cohort of 14 patients with Parkinson’s disease, implanted with subthalamic nucleus deep brain stimulation, the four contacts on each lead in the 28 hemispheres were ranked according to proximity to a nominated ideal anatomical location and power of the following neuronal signals: evoked resonant neural activity, beta oscillations and high-frequency oscillations. We assessed how these rankings predicted, on each lead: (i) the motor benefit from deep brain stimulation applied through each contact and (ii) the ‘ideal’ contact to apply deep brain stimulation. The ranking of contacts according to each factor predicted motor benefit from subthalamic nucleus deep brain stimulation, as follows: evoked resonant neural activity; r2 = 0.50, Akaike information criterion 1039.9, beta; r2 = 0.50, Akaike information criterion 1041.6, high-frequency oscillations; r2 = 0.44, Akaike information criterion 1057.2 and anatomy; r2 = 0.49, Akaike information criterion 1048.0. Combining evoked resonant neural activity, beta and high-frequency oscillations ranking data yielded the strongest predictive model (r2 = 0.61, Akaike information criterion 1021.5). The ‘ideal’ contact (yielding maximal benefit) was ranked first according to each factor in the following proportion of hemispheres; evoked resonant neural activity 18/28, beta 17/28, anatomy 16/28, high-frequency oscillations 7/28. Across hemispheres, the maximal available deep brain stimulation benefit did not differ from that yielded by contacts chosen by clinicians for chronic therapy or contacts ranked first according to evoked resonant neural activity. Evoked resonant neural activity, beta oscillations and anatomy similarly predicted how motor benefit from subthalamic nucleus deep brain stimulation varied across contacts on each lead. This could assist programming by providing a probability ranking of contacts akin to a ‘monopolar survey’. However, these factors identified the ‘ideal’ contact in only a proportion of hemispheres. More advanced signal processing and anatomical techniques may be needed for the full automation of contact selection.

Prior uncontrolled studies have reported seizure reductions following deep brain stimulation (DBS) in patients with Lennox-Gastaut syndrome (LGS), but evidence from randomized controlled studies is lacking. We aimed to formally assess the efficacy and safety of DBS to the centromedian thalamic nucleus (CM) for the treatment of LGS.We conducted a prospective, double-blind, randomized study of continuous, cycling stimulation of CM-DBS, in patients with LGS. Following pre- and post-implantation periods, half received 3 months of stimulation (blinded phase), then all received 3 months of stimulation (unblinded phase). The primary outcome was the proportion of participants with ≥50% reduction in diary-recorded seizures in stimulated versus control participants, measured at the end of the blinded phase. A secondary outcome was the proportion of participants with a ≥50% reduction in electrographic seizures on 24-hour ambulatory electroencephalography (EEG) at the end of the blinded phase.Between November 2017 and December 2019, 20 young adults with LGS (17-37 years;13 women) underwent bilateral CM-DBS at a single center in Australia, with 19 randomized (treatment, n = 10 and control, n = 9). Fifty percent of the stimulation group achieved ≥50% seizure reduction, compared with 22% of controls (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 0.44-21.45, p = 0.25). For electrographic seizures, 59% of the stimulation group had ≥50% reduction at the end of the blinded phase, compared with none of the controls (OR= 23.25, 95% CI = 1.0-538.4, p = 0.05). Across all patients, median seizure reduction (baseline vs study exit) was 46.7% (interquartile range [IQR] = 28-67%) for diary-recorded seizures and 53.8% (IQR = 27-73%) for electrographic seizures.CM-DBS in patients with LGS reduced electrographic rather than diary-recorded seizures, after 3 months of stimulation. Fifty percent of all participants had diary-recorded seizures reduced by half at the study exit, providing supporting evidence of the treatment effect. ANN NEUROL 2022;91:253-267.

IntroductionSelecting the ideal contact to apply subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease is time-consuming and reliant on clinical expertise. The aim of this cohort study was to assess whether neuronal signals (beta oscillations and evoked resonant neural activity (ERNA)), and the anatomical location of electrodes, can predict the contacts selected by long-term, expert-clinician programming of STN-DBS.MethodsWe evaluated 92 hemispheres of 47 patients with Parkinson’s disease receiving chronic monopolar and bipolar STN-DBS. At each contact, beta oscillations and ERNA were recorded intraoperatively, and anatomical locations were assessed. How these factors, alone and in combination, predicted the contacts clinically selected for chronic deep brain stimulation at 6 months postoperatively was evaluated using a simple-ranking method and machine learning algorithms.ResultsThe probability that each factor individually predicted the clinician-chosen contact was as follows: ERNA 80%, anatomy 67%, beta oscillations 50%. ERNA performed significantly better than anatomy and beta oscillations. Combining neuronal signal and anatomical data did not improve predictive performance.ConclusionThis work supports the development of probability-based algorithms using neuronal signals and anatomical data to assist programming of deep brain stimulation.

Introduction The efficacy of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson’s disease (PD) depends on how closely electrodes are implanted relative to an individual’s ideal stimulation location. Yet, previous studies have assessed how closely electrodes are implanted relative to the planned location, after homogenizing data to a reference. Thus here, we measured how accurately electrodes are implanted relative to an ideal, dorsal STN stimulation location, assessed on each individual’s native imaging. This measure captures not only the technical error of stereotactic implantation but also constraints imposed by planning a suitable trajectory. Methods This cross-sectional study assessed 226 electrodes in 113 consecutive PD patients implanted with bilateral STN-DBS by experienced clinicians utilizing awake, microelectrode guided, surgery. The error (Euclidean distance) between the actual electrode trajectory versus a nominated ideal, dorsal STN stimulation location was determined in each hemisphere on native imaging and predictive factors sought. Results The median electrode location error was 1.62 mm (IQR = 1.23 mm). This error exceeded 3 mm in 28/226 electrodes (12.4%). Location error did not differ between hemispheres implanted first or second, suggesting brain shift was minimised. Location error did not differ between electrodes positioned with (48/226), or without, a preceding microelectrode trajectory shift (suggesting such shifts were beneficial). There was no relationship between location error and case order, arguing against a learning effect. Discussion/Conclusion The proximity of STN-DBS electrodes to a nominated ideal, dorsal STN, stimulation location is highly variable, even when implanted by experienced clinicians with brain shift minimized, and without evidence of a learning effect. Using this measure, we found that assessments on awake patients (microelectrode recordings and clinical examination) likely yielded beneficial intraoperative decisions to improve positioning. In many patients the error is likely to have reduced therapeutic efficacy. More accurate methods to implant STN-DBS electrodes relative to the ideal stimulation location are needed.

OBJECTIVE Deep brain stimulation (DBS) surgery is commonly performed with the patient awake to facilitate assessments of electrode positioning. However, awake neurosurgery can be a barrier to patients receiving DBS. Electrode implantation can be performed with the patient under general anesthesia (GA) using intraoperative imaging, although such techniques are not widely available. Electrophysiological features can also aid in the identification of target neural regions and provide functional evidence of electrode placement. Here we assess the presence and positional variation under GA of spontaneous beta and high-frequency oscillation (HFO) activity, and evoked resonant neural activity (ERNA), a novel evoked response localized to the subthalamic nucleus. METHODS ERNA, beta, and HFO were intraoperatively recorded from DBS leads comprising four individual electrodes immediately after bilateral awake implantation into the subthalamic nucleus of 21 patients with Parkinson’s disease (42 hemispheres) and after subsequent GA induction deep enough to perform pulse generator implantation. The main anesthetic agent was either propofol (10 patients) or sevoflurane (11 patients). RESULTS GA reduced the amplitude of ERNA, beta, and HFO activity (p < 0.001); however, ERNA amplitudes remained large in comparison to spontaneous local field potentials. Notably, a moderately strong correlation between awake ERNA amplitude and electrode distance to an “ideal” therapeutic target within dorsal STN was preserved under GA (awake: ρ = −0.73, adjusted p value [padj] < 0.001; GA: ρ = −0.69, padj < 0.001). In contrast, correlations were diminished under GA for beta (awake: ρ = −0.45, padj < 0.001; GA: ρ = −0.13, padj = 0.12) and HFO (awake: ρ = −0.69, padj < 0.001; GA: ρ = −0.33, padj < 0.001). The largest ERNA occurred at the same electrode (awake vs GA) for 35/42 hemispheres (83.3%) and corresponded closely to the electrode selected by the clinician for chronic therapy at 12 months (awake ERNA 77.5%, GA ERNA 82.5%). The largest beta amplitude occurred at the same electrode (awake vs GA) for only 17/42 (40.5%) hemispheres and 21/42 (50%) for HFO. The electrode measuring the largest awake beta and HFO amplitudes corresponded to the electrode selected by the clinician for chronic therapy at 12 months in 60% and 70% of hemispheres, respectively. However, this correspondence diminished substantially under GA (beta 20%, HFO 35%). CONCLUSIONS ERNA is a robust electrophysiological signal localized to the dorsal subthalamic nucleus subregion that is largely preserved under GA, indicating it could feasibly guide electrode implantation, either alone or in complementary use with existing methods.

Objective We aimed to assess the roles of the cortex and thalamus (centromedian nucleus [CM]) during epileptic activity in Lennox-Gastaut syndrome (LGS) patients undergoing deep brain stimulation (DBS) surgery as part of the ESTEL (Electrical Stimulation of the Thalamus for Epilepsy of Lennox-Gastaut Phenotype) trial. Methods Twelve LGS patients (mean age = 26.8 years) underwent bilateral CM-DBS implantation. Intraoperatively, simultaneous electroencephalogram (EEG) was recorded (range = 10-34 minutes) from scalp electrodes and bilateral thalamic DBS electrodes. Temporal onsets of epileptic discharges (generalized paroxysmal fast activity [GPFA] and slow spike-and-wave [SSW]) were manually marked on recordings from scalp (ie, "cortex") and thalamus (ie, CM-DBS electrodes). Phase transfer entropy (PTE) analysis quantified the degree of information transfer from cortex to thalamus within different frequency bands around GPFA events. Results GPFA was captured in eight of 12 patients (total event number across patients = 168, cumulative duration = 358 seconds). Eighty-six percent of GPFA events were seen in both scalp and thalamic recordings. In most events (83%), onset occurred first at scalp, with thalamic onset lagging by a median of 98 milliseconds (interquartile range = 78.5 milliseconds). Results for SSW were more variable and seen in 11 of 12 patients; 25.4% of discharges were noted in both scalp and thalamus. Of these, 74.5% occurred first at scalp, with a median lag of 75 milliseconds (interquartile range = 228 milliseconds). One to 0.5 seconds and 0.5-0 seconds before GPFA onset, PTE analysis showed significant energy transfer from scalp to thalamus in the delta (1-3 Hz) frequency band. For alpha (8-12 Hz) and beta (13-30 Hz) frequencies, PTE was greatest 1-0.5 seconds before GPFA onset. Significance Epileptic activity is detectable in CM of thalamus, confirming that this nucleus participates in the epileptic network of LGS. Temporal onset of GPFA mostly occurs earlier at the scalp than in the thalamus. This supports our prior EEG-functional magnetic resonance imaging results and provides further evidence for a cortically driven process underlying GPFA in LGS.

Background: The use of alternate frequencies, amplitudes, and pulse widths to manage motor symptoms in Parkinson's disease (PD) patients with subthalamic nucleus deep brain stimulation (STN-DBS) is of clinical interest, but currently lacks systematic evidence. Objective/Hypothesis: Systematically review whether alternate STN-DBS settings influence the therapy's efficacy for managing PD motor symptoms. Methods: Systematic searches identified studies that; involved bilateral STN-DBS PD patients; manipulated ≥ 1 STN-DBS parameter (e.g., amplitude); assessed ≥ 1 motor symptom (e.g., tremor); and contrasted the experimental and chronic stimulation settings. A Mantel-Haenszel random-effects meta-analysis compared the UPDRS-III sub-scores at low (60-Hz) and high frequencies (≥ 130 Hz). Inter-study heterogeneity was assessed with the Cohen's χ and I index, while the standard GRADE evidence assessment examined strength of evidence. Results: Of the 21 included studies, 17 investigated the effect of alternate stimulation frequencies, five examined alternate stimulation amplitudes, and two studied changes in pulse width. Given the available data, meta-analyses were only possible for alternate stimulation frequencies. Analysis of the heterogeneity amongst the included studies indicated significant variability between studies and, on the basis of the GRADE framework, the pooled evidence from the meta-analysis studies was of very low quality due to the significant risks of bias. Conclusions: The meta-analysis reported a very low quality of evidence for the efficacy of low-frequency STN-DBS for managing PD motor symptoms. Furthermore, it highlighted that lower amplitudes lead to the re-emergence of motor symptoms and further research is needed to understand the potential benefits of alternate STN-DBS parameters for PD patients.

Pedunculopontine nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone pedunculopontine nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic nucleus or internal pallidum. Both rostral and caudal pedunculopontine nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20-80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether pedunculopontine nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of pedunculopontine nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. © 2017 International Parkinson and Movement Disorder Society.

ObjectivesDeep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) is an emerging treatment for multiple brain diseases, including the drug-resistant epilepsy Lennox-Gastaut syndrome (LGS). We aimed to improve neurosurgical targeting of the CM by (i) developing a structural MRI approach for CM visualisation, (ii) identifying the CM’s neurophysiological characteristics, and (iii) mapping connectivity from CM-DBS sites using functional MRI (fMRI).MethodsNineteen patients with LGS (mean age=28 years) underwent pre-surgical 3 tesla MRI using magnetisation-prepared 2 rapid acquisition gradient echoes (MP2RAGE) and fMRI sequences; 16 proceeded to bilateral CM-DBS implantation and intraoperative microelectrode recordings (MERs) from the thalamus. CM visualisation was achieved by highlighting intrathalamic borders on MP2RAGE using Sobel edge-detection. Mixed-effects analysis compared two MER features (spike firing rate, background noise) between ventrolateral, CM, and parafasicular nuclei. Resting-state fMRI connectivity was assessed using implanted CM-DBS electrode positions as regions-of-interest.ResultsThe CM appeared as a hyperintense region bordering the comparatively hypointense pulvinar, mediodorsal, and parafasicular nuclei. At the group-level, reduced spike firing and background noise distinguished CM from the ventrolateral nucleus; however, these trends were not found in 20-25% of individual MER trajectories. Areas of fMRI connectivity included basal ganglia, brainstem, cerebellum, sensorimotor/premotor and limbic cortex.ConclusionsIn the largest clinical trial cohort of LGS patients undergoing CM-DBS reported to date, we show that accurate targeting of the CM is achievable using 3 tesla MP2RAGE MRI. MERs may provide additional localising features in some cases, however their utility is limited by inter-patient variability. Therapeutic effects of CM-DBS may be mediated via connectivity with brain networks that support diverse arousal, cognitive, and sensorimotor processes.

Impairment of postural reflexes, termed postural instability, is a common and disabling deficit in Parkinson's disease. To assess postural reflexes, clinicians typically employ the pull test to grade corrective responses to a backward perturbation at the shoulders. However, the pull test is prone to issues with reliability and scaling (score/4). Here, we present an instrumented version of the pull test to more precisely quantify postural responses. Akin to the clinical test, pulls are manually administered except pull force is also recorded. Displacements of the trunk and feet are captured by a semi-portable motion tracking system. Raw data represent distance traveled (in millimeter units), making subsequent interpretation and analysis intuitive. The instrumented pull test also detects variabilities influencing pull test administration, such as pull force, thereby identifying and quantifying potential confounds that can be accounted for by statistical techniques. The instrumented pull test could have application in studies seeking to capture early abnormalities in postural responses, track postural instability over time, and detect responses to therapy.

Contains fulltext : 168033.pdf (Publisher’s version ) (Open Access) The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all patients treated. We evaluated the available data on the surgical anatomy and terminology of the PPN region in a companion paper. Here we focus on issues concerning surgical technique, imaging, and early side effects of surgery. The aim of this paper was to gain more insight into the reasoning for choosing specific techniques and to discuss shortcomings of available studies. Our data demonstrate the wide range in almost all fields which were investigated. There are a number of important challenges to be resolved, such as identification of the optimal target, the choice of the surgical approach to optimize electrode placement, the impact on the outcome of specific surgical techniques, the reliability of intraoperative confirmation of the target, and methodological differences in postoperative validation of the electrode position. There is considerable variability both within and across groups, the overall experience with PPN DBS is still limited, and there is a lack of controlled trials. Despite these challenges, the procedure seems to provide benefit to selected patients and appears to be relatively safe. One important limitation in comparing studies from different centers and analyzing outcomes is the great variability in targeting and surgical techniques, as shown in our paper. The challenges we identified will be of relevance when designing future studies to better address several controversial issues. We hope that the data we accumulated may facilitate the development of surgical protocols for PPN DBS.

Postural reflexes are impaired in conditions such as Parkinson’s disease, leading to difficulty walking and falls. In clinical practice, postural responses are assessed using the “pull test,” where an examiner tugs the prewarned standing patient backward at the shoulders and grades the response. However, validity of the pull test is debated, with issues including scaling and variability in administration and interpretation. It is unclear whether to assess the first trial or only subsequent repeated trials. The ecological relevance of a forewarned backward challenge is also debated. We therefore developed an instrumented version of the pull test to characterize responses and clarify how the test should be performed and interpreted. In 33 healthy participants, “pulls” were manually administered and pull force measured. Trunk and step responses were assessed with motion tracking. We probed for the StartReact phenomenon (where preprepared responses are released early by a startling stimulus) by delivering concurrent normal or “startling” auditory stimuli. We found that the first pull triggers a different response, including a larger step size suggesting more destabilization. This is consistent with “first trial effects,” reported by platform translation studies, where movement execution appears confounded by startle reflex-like activity. Thus, first pull test trials have clinical relevance and should not be discarded as practice. Supportive of ecological relevance, responses to repeated pulls exhibited StartReact, as previously reported with a variety of other postural challenges, including those delivered with unexpected timing and direction. Examiner pull force significantly affected the postural response, particularly the size of stepping.NEW & NOTEWORTHY We characterized postural responses elicited by the clinical “pull test” using instrumentation. The first pull triggers a different response, including a larger step size suggesting more destabilization. Thus, first trials likely have important clinical and ecological relevance and should not be discarded as practice. Responses to repeated pulls can be accelerated with a startling stimulus, as reported with a variety of other challenges. Examiner pull force was a significant factor influencing the postural response.

Deep brain stimulation (DBS) is a rapidly expanding treatment for neurological and psychiatric conditions; however, a target-specific biomarker is required to optimize therapy. Here, we show that DBS evokes a large-amplitude resonant neural response focally in the subthalamic nucleus. This response is greatest in the dorsal region (the clinically optimal stimulation target for Parkinson disease), coincides with improved clinical performance, is chronically recordable, and is present under general anesthesia. These features make it a readily utilizable electrophysiological signal that could potentially be used for guiding electrode implantation surgery and tailoring DBS therapy to improve patient outcomes. Ann Neurol 2018;83:1027-1031.

Impaired balance is a major contributor to falls and diminished quality of life in Parkinson's disease, yet the pathophysiology is poorly understood. Here, we assessed if patients with Parkinson's disease and severe clinical balance impairment have deficits in the intermittent and continuous control systems proposed to maintain upright stance, and furthermore, whether such deficits are potentially reversible, with the experimental therapy of pedunculopontine nucleus deep brain stimulation. Two subject groups were assessed: (i) 13 patients with Parkinson's disease and severe clinical balance impairment, implanted with pedunculopontine nucleus deep brain stimulators; and (ii) 13 healthy control subjects. Patients were assessed in the OFF medication state and blinded to two conditions; off and on pedunculopontine nucleus stimulation. Postural sway data (deviations in centre of pressure) were collected during quiet stance using posturography. Intermittent control of sway was assessed by calculating the frequency of intermittent switching behaviour (discontinuities), derived using a wavelet-based transformation of the sway time series. Continuous control of sway was assessed with a proportional-integral-derivative (PID) controller model using ballistic reaction time as a measure of feedback delay. Clinical balance impairment was assessed using the 'pull test' to rate postural reflexes and by rating attempts to arise from sitting to standing. Patients with Parkinson's disease demonstrated reduced intermittent switching of postural sway compared with healthy controls. Patients also had abnormal feedback gains in postural sway according to the PID model. Pedunculopontine nucleus stimulation improved intermittent switching of postural sway, feedback gains in the PID model and clinical balance impairment. Clinical balance impairment correlated with intermittent switching of postural sway (rho = - 0.705, P < 0.001) and feedback gains in the PID model (rho = 0.619, P = 0.011). These results suggest that dysfunctional intermittent and continuous control systems may contribute to the pathophysiology of clinical balance impairment in Parkinson's disease. Clinical balance impairment and their related control system deficits are potentially reversible, as demonstrated by their improvement with pedunculopontine nucleus deep brain stimulation.

Objective: Deep brain stimulation can be a remarkably effective treatment for Parkinson's disease and other conditions; however, an electrophysiological feedback signal is needed to improve surgical accuracy and for optimising therapy according to patient needs. Evoked responses may provide such a signal, although it is crucial to determine that recorded potentials are of neural origin and not a consequence of stimulation artefacts. Here, we use several in vitro and in vivo methods to establish the neural basis of resonant deep brain stimulation evoked activity. Approach: Recordings were obtained from deep brain stimulation electrodes in saline, in feline brain regions not expected to produce resonant neural responses, and in fourteen subthalamic nuclei in people with Parkinson's disease following stimulation with 60 μs per phase biphasic current pulses with different polarities. Main results: Electrodes in saline did not exhibit stimulation artefacts beyond 1 ms. Changing the pulse polarity reversed the stimulation artefact. Electrodes in feline brain elicited early latency activity (

Patients with congestive myelopathy due to spinal dural arteriovenous fistula (SDAVF) typically present with progressive sensory and motor disturbance in association with sphincter dysfunction. Spinal MRI usually shows longitudinally extensive T2 signal change. Here, we report four patients with progressive myelopathy due to SDAVF who also presented with findings on cerebrospinal fluid (CSF) examination suggestive of an inflammatory aetiology. Such CSF findings in SDAVF are important to recognise, to avoid the erroneous diagnosis of an inflammatory myelitis and inappropriate treatment with immunosuppression. SDAVF can be difficult to detect and may require repeated investigation, with formal angiography as the gold standard.

IntroductionDBS can improve motor deficit in Parkinson’s disease (PD) patients. Existing devices have limitations due to electrode positioning errors, fallible manual programming and delivery of continuous ‘open-loop’ stimulation despite fluctuating patient state. This results in partial efficacy, adverse effects and increased cost. One solution is to use an electrical feedback signal or ‘biomarker’ recorded from DBS electrodes. The most widely studied signal has been spontaneous local field potentials (LFPs), particularly beta band (13–30 Hz) and high frequency oscillations (HFO) (200–400 Hz). Here, we report a novel biomarker in the form of a large amplitude, evoked potential, with a characteristic oscillatory decay, termed evoked resonant neural activity (ERNA).1MethodsLFPs and ERNA were recorded in 14 patients with PD (28 hemispheres) undergoing STN DBS surgery. The four contacts in each electrode array were ranked according to ERNA amplitude, beta power, HFO power and proximity to the anatomically ideal stimulation location. At least 3 months after surgery, motor scores (UPDRS III, reaction time) were evaluated off-DBS and during stimulation delivered through each electrode contact in a randomised order.ResultsERNA amplitude, beta power and contact proximity to the anatomically ideal stimulation location predicted magnitude of therapeutic response to DBS. However, after exclusion of covariance, ERNA amplitude remained the only significant predictor of DBS response.ConclusionERNA is a readily recordable, large amplitude signal that accurately correlates with motor response to DBS. It holds significant potential as a biomarker for guiding electrode implantation, ideal contact selection, automated parameter fitting and delivery of closed-loop DBS.ReferenceSinclair NC, McDermott HJ, Bulluss KJ, Fallon JB, Perera T, Xu SS, et al. Subthalamic nucleus deep brain stimulation evokes resonant neural activity. Annals of neurology 2018;83(5).

Contains fulltext : 168032.pdf (Publisher’s version ) (Open Access) Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues.

Tremor is characterized commonly through subjective clinical rating scales. Accelerometer-based techniques for objective tremor measurement have been developed in the past, yet these measures are usually presented as an unintuitive dimensionless index without measurement units. Here we have developed a tool (TREMBAL) to provide quantifiable and objective measures of tremor severity using electromagnetic motion tracking. We aimed to compare TREMBAL's objective measures with clinical tremor ratings and determine the test-retest reliability of our technique. Eight participants with ET receiving deep brain stimulation (DBS) therapy were consented. Tremor was simultaneously recorded using TREMBAL and video during DBS adjustment. After each adjustment, participants performed a hands-outstretched task (for postural tremor) and a finger-nose task (for kinetic tremor). Video recordings were de-identified, randomized, and shown to a panel of movement disorder specialists to obtain their ratings. Regression analysis and Pearson's correlations were used to determine agreement between datasets. Subsets of the trial were repeated to assess test-retest reliability. Tremor amplitude and velocity measures were in close agreement with mean clinical ratings (r > 0.90) for both postural and kinetic tremors. Test-retest reliability for both translational and rotational components of tremor showed intra-class correlations >0.80. TREMBAL assessments showed that tremor gradually improved with increasing DBS therapy-this was also supported by clinical observation. TREMBAL measurements are a sensitive, objective and reliable assessment of tremor severity. This tool may have application in clinical trials and in aiding automated optimization of deep brain stimulation.

Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral. © 2012 The Author.

The pedunculopontine nucleus, a component of the reticular formation, is topographically organized in animal models and implicated in locomotor control. In Parkinson's disease, pedunculopontine nucleus stimulation is an emerging treatment for gait freezing. Local field potentials recorded from pedunculopontine nucleus electrodes in such patients have demonstrated oscillations in the alpha and beta frequency bands, reactive to self-paced movement. Whether these oscillations are topographically organized or relevant to locomotion is unknown. Here, we recorded local field potentials from the pedunculopontine nucleus in parkinsonian patients during rest and unconstrained walking. Relative gait speed was assessed with trunk accelerometry. Peaks of alpha power were present at rest and during gait, when they correlated with gait speed. Gait freezing was associated with attenuation of alpha activity. Beta peaks were less consistently observed across rest and gait, and did not correlate with gait speed. Alpha power was maximal in the caudal pedunculopontine nucleus region and beta power was maximal rostrally. These results indicate a topographic distribution of neuronal activity in the pedunculopontine nucleus region and concur with animal data suggesting that the caudal subregion has particular relevance to gait. Alpha synchronization, proposed to suppress 'task irrelevant' distraction, has previously been demonstrated to correlate with performance of cognitive tasks. Here, we demonstrate a correlation between alpha oscillations and improved gait performance. The results raise the possibility that stimulation of caudal and rostral pedunculopontine nucleus regions may differ in their clinical effects. © 2011 The Author.

Gait freezing and postural instability are disabling features of Parkinsonian disorders, treatable with pedunculopontine nucleus stimulation. Both features are considered deficits of proximal and axial musculature, innervated predominantly by reticulospinal pathways and tend to manifest when gait and posture require adjustment. Adjustments to gait and posture are amenable to pre-preparation and rapid triggered release. Experimentally, such accelerated release can be elicited by loud auditory stimuli--a phenomenon known as 'StartReact'. We observed StartReact in healthy and Parkinsonian controls. However, StartReact was absent in Parkinsonian patients with severe gait freezing and postural instability. Pedunculopontine nucleus stimulation restored StartReact proximally and proximal reaction times to loud stimuli correlated with gait and postural disturbance. These findings suggest a relative block to triggered, pre-prepared movement in gait freezing and postural instability, relieved by pedunculopontine nucleus stimulation.

Objectives Attentional augmentation and enhanced motor function are potential mechanisms by which stimulation of the region of the pedunculopontine nucleus (PPN) may improve gait in parkinsonism. Here, the authors assess the impact of stimulation of this region on attentional and motor aspects of reaction task performance in patients with parkinsonism. Methods Eleven patients implanted with PPN stimulators underwent computerised assessment of simple, choice and digit vigilance reaction tasks. Patients were assessed ‘off medication’ during stimulation at different frequencies (0 Hz, 5 Hz, 10 Hz and ‘therapeutic’ 20–35 Hz). There were two primary endpoints: ‘Speed of Reaction’ (sum of the mean task reaction times) and ‘Accuracy of Reaction’ (reflecting omissions and percentage of correct responses). Baseline performance was compared with age- and sex-matched healthy controls. Clinical effects of stimulation were assessed using the Unified Parkinson9s Disease Rating Scale and a falls frequency scale. Results Compared with healthy controls, subjects had significant deficits in ‘Speed of Reaction’ and in all mean task reaction times. ‘Accuracy of Reaction’ was not different from healthy controls and did not improve with stimulation. ‘Speed of Reaction’ significantly improved with stimulation at therapeutic frequencies (20–35 Hz). Of the individual tasks, only simple reaction time improved significantly. Simple reaction time distribution analysis revealed a general speeding of responses rather than a selective reduction in outliers. Acute PPN stimulation improved gait and balance but not akinesia scores. Chronic PPN stimulation significantly improved falls frequency. Falls score improvement significantly correlated with changes to simple reaction time with therapeutic stimulation. Conclusion The pattern of reaction time improvement with stimulation of the PPN area suggests a benefit on motor performance, rather than augmentation of attention.

Deep brain stimulation is now considered a routine treatment option for selected patients with advanced Parkinson's disease, primary segmental and generalised dystonia, and essential tremor. The neurosurgeon is responsible for the accurate and safe placement of the electrodes and the neurologist for the careful selection of patients and titration of medication against the effects of stimulation. A multidisciplinary team approach involving specialist nurses, neuropsychologists and neurophysiologists is required for a successful outcome. In this article we will summarise the key points in patient selection, provide an overview of the surgical technique, and discuss the beneficial and adverse outcomes that can occur.

In this study we investigate how the basal ganglia (BG) may process the behavioural relevance of environmental cues by recording local field potentials (LFPs) in the subthalamic nucleus of patients with Parkinson's disease who had undergone implantation of electrodes for deep brain stimulation. Fourteen patients were recorded as they performed a paradigm dissociating warning cue presentation from programming related to execution of specific tasks. Target and non-target warning cues of differing behavioural relevance were contrasted, and we evaluated if warning cue-evoked activities varied according to whether the eventual task to be performed was motor or cognitive and whether patients were receiving or withdrawn from dopaminergic therapy. Warning cues evoked a complex temporal sequence of activities with three epochs over the 760 ms following the onset of the warning cue. In contrast to the initial evoked LFP, evoked activities over two later periods were significantly influenced by behavioural relevance and by treatment state. The early activity was likely related to the initial orientating of attention induced by a novel target, while the delayed responses in our paradigm may reflect processing related to the non-motor resource implications of cues. The results suggest that the BG are intimately involved in the evaluation of changes in the environment and of their behavioural significance. The latter process is partly modulated by dopamine. Weakness in this function might contribute to the behavioural impairment that can follow BG lesions and surgery.

This paper presents the Brisbane experience of pedunculopontine nucleus (PPN) deep brain stimulation (DBS) in Parkinson’s disease (PD). Clinical outcomes along with studies of the mechanisms and neurophysiology of PPN in PD patients with severe freezing of gait (FoG) and postural imbalance (PI) are summarised and presented. Our results indicate that PPN DBS improves FoG and falls in the relatively uncommon group of PD patients who respond well to medication other than for continuing on time FoG and falls. Our studies indicate that bilateral DBS is more beneficial than unilateral DBS, and that the more caudal region of the PPN seems preferable for stimulation. There is evidence that rapid-release programs for initiation and correction of gait and posture are modulated by the PPN, possibly to some extent independently of the cerebral cortex. These functions were found to be impaired in PD patients with severe FoG/PI, but to some extent corrected by bilateral PPN DBS.

Objectives: Rest tremor is a cardinal symptom of Parkinson's disease (PD), and is readily suppressed by deep brain stimulation (DBS) of the subthalamic nucleus (STN). The therapeutic effect of the latter on bradykinesia and rigidity has been associated with the suppression of exaggerated beta (13-30 Hz) band synchronization in the vicinity of the stimulating electrode, but there is no correlation between beta suppression and tremor amplitude. In the present study, we investigate whether tremor suppression is related to suppression of activities at other frequencies.Materials and Methods: We recorded hand tremor and contralateral local field potential (LFP) activity from DBS electrodes during stimulation of the STN in 15 hemispheres in 11 patients with PD. DBS was applied with increasing voltages starting at 0.5 V until tremor suppression was achieved or until 4.5 V was reached.Results: Tremor was reduced to 48.9% +/- 10.9% of that without DBS once stimulation reached 2.5-3 V (t14 = -4.667, p Conclusions: Our findings support a relationship between low gamma oscillations and PD tremor, and reinforce the principle that the subthalamic LFP is a rich signal that may contain information about the severity of multiple different Parkinsonian features.

Dorsal column spinal stimulation in dopamine-depleted rodents was recently reported to disrupt pathologic corticostriatal synchronization, alleviate akinesia, and restore locomotion.1 This claim has prompted consideration that spinal stimulation “might become an efficient and less invasive alternative for treatment of Parkinson disease (PD) in the future.” In this study, we investigated whether dorsal column stimulation was of therapeutic benefit in 2 patients with PD. ### Level of evidence. This study provides Class II evidence that for patients with moderate to severe motor impairment from PD, high-frequency epidural cervical spinal cord stimulation does not significantly improve motor function as measured by the motor subsection of the Unified Parkinson's Disease Rating Scale (UPDRS). ### Methods. Two patients with PD had spinal stimulators (Medtronic models 3487a or 3898) implanted surgically into the high cervical epidural space without complication, as described previously.2 Patient 1, 75 years old, had moderate motor impairment (off/on medication motor UPDRS = 30/18). Patient 2, 77 years old, had more severe motor impairment (off/on medication UPDRS = 51/38) and was unable to walk without dopaminergic medication. Both patients met UK Brain Bank criteria for PD.3 Ten days postoperatively, both patients participated in a double-blind crossover study of the motor effects of spinal stimulation. In an initial exploratory phase, an antiparkinsonian effect of spinal stimulation was sought over a range of frequencies (30–300 Hz) and intensities (up to 4.0 V and 240 μs). Having failed to establish a clear benefit for any particular set of parameters, for the purposes of the study, patient 1 was …

This scientific commentary refers to ‘The integrative role of the pedunculopontine nucleus in human gait’, by Lau et al. (doi:10.1093/brain/awv047). Parkinson’s disease is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity and tremor, and dopamine replacement with levodopa remains the mainstay of treatment. In recent years, deep brain stimulation of the subthalamic nucleus (STN) has been widely used to treat tremor, rigidity and akinesia (Benabid et al. , 2009). However as the disease progresses, axial symptoms such as postural instability and gait disturbances often emerge, in particular freezing of gait (FOG). These gait disturbances are poorly responsive to dopamine therapy and to deep brain stimulation of the STN (Ferraye et al. , 2010). FOG is very debilitating, often leading to falls and having a severe impact on quality of life. Patients describe FOG as ‘like having feet that are glued to the floor’ and a 2010 workshop on FOG described it as ‘brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk’. Moreover, these disturbances of gait are responsive to sensory stimuli. For example, FOG is accentuated when approaching doorways and can be alleviated by …

BACKGROUND: Pedunculopontine nucleus (PPN) stimulation is a novel therapy for Parkinson disease. However, controversies remain regarding the clinical application of this new therapy, including patient selection, electrode positioning, and how best to assess outcomes. OBJECTIVE: To clarify the clinical application of PPN stimulation in Parkinson disease. METHODS: Five consecutive patients with Parkinson disease complicated by severe gait freezing, postural instability, and frequent falls (all persisting even while the patient was on medication) received bilateral stimulation of the mid-lower PPN without costimulation of other brain targets. Outcomes were assessed prospectively over 2 years with gait-specific questionnaires and the Unified Parkinson Disease Rating Scale (part III). RESULTS: The primary outcome, the Gait and Falls Questionnaire score, improved significantly with stimulation. Benefits were maintained over 2 years. Unified Parkinson Disease Rating Scale (part III) items assessing gait and posture were relatively insensitive to these treatment effects. Beneficial effects often appeared to outlast stimulation for hours or longer. Thus, single-session on- vs off-stimulation assessments may be susceptible to "delayed washout effects." Stimulation of the PPN did not change akinesia scores or dopaminergic medication requirements. CONCLUSION: Bilateral stimulation of the mid-lower PPN (more caudal than previous reports) without costimulation of other brain targets may be beneficial for the subgroup of patients with Parkinson disease who experience severe gait freezing and postural instability with frequent falls, which persist even while on medication. Choosing appropriate outcome measures and accounting for the possibility of prolonged stimulation washout effects appear to be important for detecting the clinical benefits.

Oculopharyngodistal myopathy is an uncommon myopathy characterised clinically by cranial and distal limb muscle weakness. Here we describe two siblings with autosomal dominant oculopharyngodistal myopathy apparently associated with dilated cardiomyopathy, which in one case progressed to ventricular hypertrabeculation/non-compaction. Electrocardiographic screening was normal and the cardiomyopathy was detected only with echocardiography. Our findings suggest that patients with oculopharyngodistal myopathy should be screened for cardiomyopathy (with both electrocardiography and echocardiography).

The pedunculopontine nucleus (PPN) is a reticular collection of neurons at the junction of midbrain and pons. The PPN in animal models appears topographically organised and functionally related to locomotion and arousal. In Parkinson’s disease, the PPN degenerates and is susceptible to abnormal basal ganglia output. In patients with Parkinson’s disease, low frequency PPN stimulation is proposed to improve gait freezing and postural instability. However, the therapeutic mechanisms, optimal clinical application and precise effects on gait and posture of PPN stimulation are unclear.Here, a topographic arrangement of the PPN was supported by local field potential recordings in parkinsonian patients. In the PPN region, beta oscillations were recorded rostrally and alpha oscillations caudally. Alpha oscillations, consistent with their putative role in allocating attention, correlated with gait performance and attenuated with gait freezing. Thus the caudal PPN subregion may be the most relevant target for gait disorders.Accordingly, an unblinded clinical study suggested that stimulation of the caudal PPN subregion was beneficial for gait freezing, postural instability and falls. In a double-blinded study using spatiotemporal gait analysis, caudal PPN stimulation reduced triggered gait freezing, with bilateral stimulation more effective than unilateral. However, akinesia including akinetic gait did not improve with PPN stimulation. Accordingly, dopaminergic medication requirements did not change.Mechanisms underlying gait freezing and PPN stimulation were explored with reaction time experiments. Parkinsonian patients with severe gait freezing and postural instability demonstrated a ‘block’ to pre-programmed movement. This was evidenced by prolonged simple reaction times and the absence of ‘StartReact’, whereby pre-prepared responses are normally accelerated by loud acoustic stimuli. PPN stimulation improved simple reaction time and restored Startreact. The relief of this ‘motor block’ with PPN stimulation may therefore explain the associated improvement in gait freezing and postural instability, as these tend to occur in circumstances requiring triggered, pre-prepared adjustments.

BACKGROUND: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective therapeutic intervention in severe Parkinson's disease, its mechanism of action remains unclear. One possibility is that DBS suppresses local pathologically synchronised oscillatory activity. METHODS: To explore this, the authors recorded from DBS electrodes implanted in the STN of 16 patients with Parkinson's disease during simultaneous stimulation (pulse width 60 μs; frequency 130 Hz) of the same target using a specially designed amplifier. The authors analysed data from 25 sides. RESULTS: The authors found that DBS progressively suppressed peaks in local field potential activity at frequencies between 11 and 30 Hz as voltage was increased beyond a stimulation threshold of 1.5 V. Median peak power had fallen to 54% of baseline values by a stimulation intensity of 3.0 V. CONCLUSION: The findings suggest that DBS can suppress pathological 11-30 Hz activity in the vicinity of stimulation in patients with Parkinson's disease. This suppression occurs at stimulation voltages that are clinically effective.

International audience; Background: Unlike thalamic lesioning, thalamic stimulation is considered a reversible treatment for tremor. However, tremor in Multiple Sclerosis (MS) can sometimes permanently improve during thalamic stimulation. Such 'permanent tremor reduction' (PTR) has been attributed to limb weakness preventing tremor expression. In this study, eleven consecutive patients with MS tremor treated with thalamic stimulation were assessed for PTR. Eighteen upper limbs had tremor, of which sixteen received contralateral stimulation. Methods: Tremor severity and limb strength were assessed preoperatively, early postoperatively (within one year) and late postoperatively (after three years). Tremor severity was rated using validated clinical scales both on and off stimulation. Following explantation, the parenchyma surrounding three electrode tracts was examined with MRI. Results: At final review (mean 5.2 years) PTR was evident in eleven of the eighteen upper limbs with tremor. PTR often rendered stimulation redundant. PTR could occur when limb strength was conserved and could arise remotely from the initial surgery. PTR was significant (and universal) in limbs that received long term (>2 years), effective (tremor suppressing) stimulation. PTR was not a significant finding in limbs that had not received long term, effective stimulation. Contralateral to a limb with PTR, MRI revealed a thalamic lesion adjacent to the electrode tract. Thalamic lesions were not identified contralateral to two limbs without PTR. Conclusions: MS tremor often permanently improves during thalamic stimulation, even when limb strength is conserved. PTR may simply reflect natural history. Alternatively, our findings appear consistent with the recent proposal that thalamic stimulation in MS might promote local 'demyelinative lesioning'.