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Recent evidence suggests that beta bursts in subthalamic nucleus (STN) play an important role in Parkinsonian pathophysiology. We studied the spatio-temporal relationship between STN beta bursts and cortical activity in 26 Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery. Postoperatively, we simultaneously recorded STN local field potentials (LFP) from externalized DBS leads and cortical activity using whole-brain magnetoencephalography. Event-related magnetic fields (ERF) were averaged time-locked to STN beta bursts and subjected to source localization. Our results demonstrate that ERF exhibiting activity significantly different from baseline activity were localized within areas functionally related to associative, limbic, and motor systems as well as regions pertinent for visual and language processing. Our data suggest that STN beta bursts are involved in network formation between STN and cortex. This interaction is in line with the idea of parallel processing within the basal ganglia-cortex loop, specifically within the functional subsystems of the STN (i.e., associative, limbic, motor, and the related cortical areas). ERFs within visual and language-related cortical areas indicate involvement of beta bursts in STN-cortex networks beyond the associative, limbic, and motor loops. In sum, our results highlight the involvement of STN beta bursts in the formation of multiple STN - cortex loops in patients with PD.

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. 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. 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. 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. Medtronic.

Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m2 temozolomide, given on days 1–7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6–7 weeks in 30 fractions of 1·8–2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3–10·2) in the temozolomide group versus 9·6 months (8·2–10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84–1·42, pnon-inferiority=0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2–4·1] vs 4·7 [4·2–5·2]; HR 1·15, 95% CI 0·92–1·43, pnon-inferiority=0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0–10·0]; HR 0·62, 95% CI 0·42–0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5–11·7] vs 4·6 [4·2–5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0–3·5] vs 4·6 months [3·7–6·3]). The most frequent grade 3–4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. Merck Sharp & Dohme.

In Parkinson’s disease (PD), subthalamic nucleus (STN) beta burst activity is pathologically elevated. These bursts are reduced by dopamine and deep brain stimulation (DBS). Therefore, these bursts have been tested as a trigger for closed-loop DBS. To provide better targeted parameters for closed-loop stimulation, we investigate the spatial distribution of beta bursts within the STN and if they are specific to a beta sub-band. Local field potentials (LFP) were acquired in the STN of 27 PD patients while resting. Based on the orientation of segmented DBS electrodes, the LFPs were classified as anterior, postero-medial, and postero-lateral. Each recording lasted 30 min with (ON) and without (OFF) dopamine. Bursts were detected in three frequency bands: ±3 Hz around the individual beta peak frequency, low beta band (lBB), and high beta band (hBB). Medication reduced the duration and the number of bursts per minute but not the amplitude of the beta bursts. The burst amplitude was spatially modulated, while the burst duration and rate were frequency dependent. Furthermore, the hBB burst duration was positively correlated with the akinetic-rigid UPDRS III subscore. Overall, these findings on differential dopaminergic modulation of beta burst parameters suggest that hBB burst duration is a promising target for closed-loop stimulation and that burst parameters could guide DBS programming.

Pathological oscillations including elevated beta activity in the subthalamic nucleus (STN) and between STN and cortical areas are a hallmark of neural activity in Parkinson’s disease (PD). Oscillations also play an important role in normal physiological processes and serve distinct functional roles at different points in time. We characterised the effect of dopaminergic medication on oscillatory whole-brain networks in PD in a time-resolved manner by employing a hidden Markov model on combined STN local field potentials and magnetoencephalography (MEG) recordings from 17 PD patients. Dopaminergic medication led to coherence within the medial and orbitofrontal cortex in the delta/theta frequency range. This is in line with known side effects of dopamine treatment such as deteriorated executive functions in PD. In addition, dopamine caused the beta band activity to switch from an STN-mediated motor network to a frontoparietal-mediated one. In contrast, dopamine did not modify local STN–STN coherence in PD. STN–STN synchrony emerged both on and off medication. By providing electrophysiological evidence for the differential effects of dopaminergic medication on the discovered networks, our findings open further avenues for electrical and pharmacological interventions in PD.

The role of beta band activity in cortico-basal ganglia interactions during motor control has been studied extensively in resting-state and for simple movements, such as button pressing. However, little is known about how beta oscillations change and interact in more complex situations involving rapid changes of movement in various contexts. To close this knowledge gap, we combined magnetoencephalography (MEG) and local field potential recordings from the subthalamic nucleus (STN) in Parkinson’s disease patients to study beta dynamics during initiation, stopping, and rapid reversal of rotational movements. The action prompts were manipulated to be predictable vs. unpredictable. We observed movement-related beta suppression at motor sequence start, and a beta rebound after motor sequence stop in STN power, motor cortical power, and STN-cortex coherence. Despite involving a brief stop of movement, no clear rebound was observed during reversals of turning direction. At the cortical level, beta power decreased bilaterally following reversals, but more so in the hemisphere ipsilateral to movement, due to a floor effect on the contralateral side. In the STN, power modulations varied across patients, with patients displaying brief increases or decreases of high-beta power. Importantly, cue predictability affected these modulations. Event-related increases of STN-cortex beta coherence were generally stronger in the unpredictable than in the predictable condition. In summary, this study reveals the influence of movement context on beta oscillations in basal ganglia-cortex loops when humans change ongoing movements according to external cues. We find that movement scenarios requiring higher levels of caution involve enhanced modulations of subthalamo-cortical beta synchronization. Furthermore, our results confirm that beta oscillations reflect the start and end of motor sequences better than movement changes within a sequence.

In this sham-controlled trial of neurostimulation of the internal globus pallidus for primary dystonia, neurostimulation improved movement, disability, and quality-of-life scores. Adverse events were common; 18% of patients had infections at the stimulator site, seroma, or lead breakage or dislodgment, and 12% had dysarthria. In patients with primary dystonia, neurostimulation of the internal globus pallidus improved movement, disability, and quality-of-life scores. Adverse events were common. Primary dystonia comprises a group of idiopathic, incurable movement disorders that vary with respect to age at onset, body distribution, and genetic association. 1 All these disorders are characterized by twisting, repetitive movements or abnormal postures caused by involuntary muscle contractions. 2 The mainstay of treatment for focal or segmental dystonia is the injection of botulinum toxin to denervate the affected muscles. 3 When this approach fails (because too many muscles are involved, the movement pattern is too complex, or neutralizing antibodies develop 4 ), the management of dystonia becomes difficult. Drug therapy is often unsatisfactory, 5 which leaves many patients with a profound incapacity . . .

Aberrant information processing in the basal ganglia and connected cortical areas are key to many neurological movement disorders such as Parkinson’s disease. Investigating the electrophysiology of this system is difficult in humans because non-invasive methods, such as electroencephalography or magnetoencephalography, have limited sensitivity to deep brain areas. Recordings from electrodes implanted for therapeutic deep brain stimulation, in contrast, provide clear deep brain signals but are not suited for studying cortical activity. Therefore, we combine magnetoencephalography and local field potential recordings from deep brain stimulation electrodes in individuals with Parkinson’s disease. Here, we make these data available, inviting a broader scientific community to explore the dynamics of neural activity in the subthalamic nucleus and its functional connectivity to cortex. The dataset encompasses resting-state recordings, plus two motor tasks: static forearm extension and self-paced repetitive fist clenching. Most patients were recorded both in the medicated and the unmedicated state. Along with the raw data, we provide metadata on channels, events and scripts for pre-processing to help interested researchers get started.

Background Neurostimulation is a highly effective therapy for the treatment of chronic Intractable pain, however, due to the complexity of pain, measuring a subject’s long-term response to the therapy remains difficult. Frequent measurement of patient-reported outcomes (PROs) to reflect multiple aspects of subjects’ pain is a crucial step in determining therapy outcomes. However, collecting full-length PROs is burdensome for both patients and clinicians. The objective of this work is to identify the reduced set of questions from multiple validated PROs that can accurately characterize chronic pain patients’ responses to neurostimulation therapies. Methods Validated PROs were used to capture pain, physical function and disability, as well as psychometric, satisfaction, and global health metrics. PROs were collected from 509 patients implanted with Spinal Cord Stimulation (SCS) or Dorsal Root Ganglia (DRG) neurostimulators enrolled in the prospective, international, post-market REALITY study (NCT03876054, Registration Date: March 15, 2019). A combination of linear regression, Pearson’s correlation, and factor analysis were used to eliminate highly correlated questions and find the minimal meaningful set of questions within the predefined domains of each scale. Results The shortened versions of the questionnaires presented almost identical accuracy for classifying the therapy outcomes as compared to the validated full-length versions. In addition, principal component analysis was performed on all the PROs and showed a robust clustering of pain intensity, psychological factors, physical function, and sleep across multiple PROs. A selected set of questions captured from multiple PROs can provide adequate information for measuring neurostimulation therapy outcomes. Conclusions PROs are important subjective measures to evaluate the physiological and psychological aspects of pain. However, these measures are cumbersome to collect. These shorter and more targeted PROs could result in better patient engagement, and enhanced and more frequent data collection processes for digital health platforms that minimize patient burden while increasing therapeutic benefits for chronic pain patients.

Chronic lower back pain (CLBP) is a debilitating condition, and a leading cause of disability associated with significant negative impacts on patients' quality of life (QoL) and mental health. In both Persistent Spinal Pain Syndrome Types 1 and 2 (PSPS-T1/2) patients, spinal cord stimulation (SCS) therapy has shown favorable outcomes including improved QoL and patient satisfaction, reductions in opioid use, and an acceptable safety profile. This consensus aimed to define the PSPS-T1 patient profile for SCS to maximize its benefits in clinical settings and allow budget holders to quantify the patient population and allocate budget accordingly. This study used a modified Delphi methodology. A literature review was conducted, followed by multidisciplinary steering group discussions that resulted in the development of 32 statements under five key domains. These statements, along with a four-point Likert scale, were incorporated into a survey distributed across seven European countries to 144 healthcare professionals experienced in pain management. The respondents included orthopedic surgeons (n=50), pain specialists (n=48), and neurosurgeons (n=46). The consensus agreement threshold was set at 75%. Consensus was achieved for 30 of the 32 statements, with 11 statements (34%) reaching ≥90% agreement. Two statements did not achieve consensus. Based on the consensus achieved in the study, an algorithm is proposed to assist in patient selection for SCS. This consensus provides recommendations on optimal patient profiles, referral processes, diagnostic procedures, and a decision-making algorithm for PSPS-T1 patients who are ineligible for spine surgery in Europe.