Pallidal deep brain stimulation modulates cortical excitability and plasticity.

OBJECTIVE: Internal globus pallidus (GPi) deep brain stimulation (DBS) relieves symptoms in dystonia patients. However, the physiological effects produced by GPi DBS are not fully understood. In particular, how a single-pulse GPi DBS changes cortical circuits has never been investigated. We studied the modulation of motor cortical excitability and plasticity with single-pulse GPi DBS in dystonia patients with bilateral implantation of GPi DBS. METHODS: The cortical evoked potentials from DBS were recorded with electroencephalography. Transcranial magnetic stimulation with a conditioning test paired-pulse paradigm was used to investigate the effect of GPi DBS on the primary motor cortex. How GPi DBS might modulate the motor cortical plasticity was tested using a paired associative stimulation paradigm with repetitive pairs of GPi DBS and motor cortical stimulation at specific time intervals. RESULTS: GPi stimulation produced 2 peaks of cortical evoked potentials with latencies of ∼10 and ∼25 milliseconds in the motor cortical area. Cortical facilitation was observed at ∼10 milliseconds after single-pulse GPi DBS, and cortical inhibition was observed after a ∼25-millisecond interval. Repetitive pairs of GPi stimulation with cortical stimulation at these 2 time intervals produced long-term potentiation-like effects in the motor cortex. INTERPRETATION: Single-pulse DBS modulates cortical excitability and plasticity at specific time intervals. These effects may be related to the mechanism of action of DBS. Combination of DBS with cortical stimulation with appropriate timing has therapeutic potential and could be explored in the future as a method to enhance the effects of neuromodulation for neurological and psychiatric diseases. Ann Neurol 2018;83:352-362.

A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia.

As of mid-2016, 231 cases of variant Creutzfeldt-Jakob disease-the human form of a prion disease of cattle, bovine spongiform encephalopathy-have been reported from 12 countries. With few exceptions, the affected individuals had histories of extended residence in the UK or other Western European countries during the period (1980-96) of maximum global risk for human exposure to bovine spongiform encephalopathy. However, the possibility remains that other geographic foci of human infection exist, identification of which may help to foreshadow the future of the epidemic. We report results of a quantitative analysis of country-specific relative risks of infection for three individuals diagnosed with variant Creutzfeldt-Jakob disease in the USA and Canada. All were born and raised in Saudi Arabia, but had histories of residence and travel in other countries. To calculate country-specific relative probabilities of infection, we aligned each patient's life history with published estimates of probability distributions of incubation period and age at infection parameters from a UK cohort of 171 variant Creutzfeldt-Jakob disease cases. The distributions were then partitioned into probability density fractions according to time intervals of the patient's residence and travel history, and the density fractions were combined by country. This calculation was performed for incubation period alone, age at infection alone, and jointly for incubation and age at infection. Country-specific fractions were normalized either to the total density between the individual's dates of birth and symptom onset ('lifetime'), or to that between 1980 and 1996, for a total of six combinations of parameter and interval. The country-specific relative probability of infection for Saudi Arabia clearly ranked highest under each of the six combinations of parameter × interval for Patients 1 and 2, with values ranging from 0.572 to 0.998, respectively, for Patient 2 (age at infection × lifetime) and Patient 1 (joint incubation and age at infection × 1980-96). For Patient 3, relative probabilities for Saudi Arabia were not as distinct from those for other countries using the lifetime interval: 0.394, 0.360 and 0.378, respectively, for incubation period, age at infection and jointly for incubation and age at infection. However, for this patient Saudi Arabia clearly ranked highest within the 1980-96 period: 0.859, 0.871 and 0.865, respectively, for incubation period, age at infection and jointly for incubation and age at infection. These findings support the hypothesis that human infection with bovine spongiform encephalopathy occurred in Saudi Arabia.

Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic.

BACKGROUND: Recently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson's Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist withdrawal syndrome (DAWS). OBJECTIVES: The objective of this study was to establish the frequency, predictors, and outcomes of DAWS in a movement disorders clinic. METHODS: We conducted a retrospective chart review of a sample of patients with a clinical diagnosis of PD treated with DA in whom withdrawal or attempted withdrawal of DA was carried out because of adverse effects, or for any other reason. Out of 487 PD patient charts reviewed, 84 were withdrawn from the agonists and were evaluable. RESULTS: Thirteen patients (15.5%) met criteria for DAWS (DAWS+) and 71 did not (DAWS-). DAWS developed upon withdrawal from pergolide, pramipexole and ropinirole, and did not respond to levodopa. DAWS outcomes included recovery in less than 6 months in 61%, in more than a year in 23%, and an inability to discontinue DA in 15% of patients. Development of impulse control disorders was the reason for DA withdrawal in all DAWS+, but only in 41% of DAWS- patients (p<0.0001). DAWS+ and DAWS- patients did not differ in other variables. CONCLUSION: DAWS is a disabling complication of DA use. Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa. Further studies are required to characterise those at risk as well as to define an effective treatment.

Quantified Striatal Dopaminergic Denervation as Predictor for Motor Outcomes in Parkinson's Disease.

Background: A hallmark of Parkinson's disease (PD) is progressive loss of dopamine terminals in the basal ganglia, with clinical symptoms including motor and non-motor manifestations such as bradykinesia, rigidity, and cognitive impairment. Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can be used to assess dopaminergic denervation by detecting loss of striatal dopamine transporters (DaT). Objective: We examined DaT binding scores' (DaTbs) association with motor outcomes in PD and explored its usefulness as a predictor of disease progression. Faster dopaminergic denervation in the basal ganglia was hypothesized to have stronger correlation and predictive value for poor motor outcomes. Methods: Data was analyzed from the Parkinson's Progression Markers Initiative. DaTbs in the putamen and caudate nucleus were correlated with Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores for walking and balance difficulties, gait difficulties, and presence of dyskinesias. A predictive model using baseline speed of drop in DaT binding score was performed for each motor outcome. Results: All motor outcomes had mild, significantly negative correlation with DaTbs in the putamen and caudate nucleus, with similar degree of correlation per region. Speed of drop was predictive of only substantial gait difficulties when evaluated in the putamen but not the caudate. Conclusions: These findings suggest that analyzing speed of drop in DaTbs, which occurs early in the motor phase of the disease, may be helpful for predicting clinical outcomes in PD. Longer observation of this cohort may provide further data to investigate DaTbs as a prognostic marker in PD.

N-Methyl-D-Aspartate antagonists in levodopa induced dyskinesia: a meta-analysis.

BACKGROUND: Levodopa-induced dyskinesias (LID) are amongst the most disabling side-effects of levodopa therapy for Parkinson's disease (PD). It has been suggested that that N-Methyl-D-Aspartate (NMDA)-receptor antagonist may reduce peak-dose dyskinesia in PD patients and may lead to motor improvement. In this study, we compared the efficacy of NMDA receptor antagonists versus placebo in the treatment of LID in PD through a meta-analysis of controlled trials. METHODS: Electronic search of Pubmed (1990 - 2010), Medline (1966-2010), EMBASE (1974-2010) and other databases for relevant studies were performed. Controlled clinical trials of the effects of NMDA antagonists on LID that fulfill the study protocol were selected. Pooled data from included studies was then used to perform random and fixed effect models meta-analysis. RESULTS: The search resulted in 11 randomized, placebo controlled clinical trials that involved a total of 253 PD patients with peak-dose LID. The outcome measures were various dyskinesia rating scales and the Unified Parkinson Disease Rating Scale (UPDRS) subscales III and IV. The analysis showed significant reduction in Standard Mean Difference (SMD) for UPDRS IV (SMD -1.45; 95%CI -2.28 to -0.63) and UPDRS III (SMD -0.41; 95%CI -0.69 to -0.12) after treatment with amantadine. Other included drugs did not show significant change in the outcomes measured. CONCLUSION: This meta-analysis provides an update on the clinical trials and confirms the short-term benefits of amantadine therapy in the treatment of dyskinesia. The effects of other NMDA receptor antagonists need to be evaluated further in clinical trials.

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. Objective: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. Design, Setting, and Participants: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. Interventions: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. Main Outcomes and Measures: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies. Results: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001). Conclusions and Relevance: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02450552.

Two-year clinical outcomes associated with robotic-assisted subthalamic lead implantation in patients with Parkinson's disease.

Few centers have routinely implemented robotic stereotactic systems for deep brain stimulator (DBS) placement. The present study compares clinical outcomes associated with robotic-assisted subthalamic nucleus (STN)-targeted DBS surgery in patients with Parkinson's disease (PD) to those of the traditional frame-based method. A retrospective chart review was performed (February 2013-June 2017). Thirty-three patients were implanted using the Cosman-Roberts-Wells (CRW) frame and 27 patients were implanted using the ROSA robot. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) or UPDRS part III motor scores and levodopa equivalent daily doses (LEDD) were examined preoperatively and at 6, 12, and 24 months of follow-up. Operative times and complication rates were recorded. For the frame-based group, the reduction in the mean MDS-UPDRS part III motor score compared to baseline was 27% both at 6 and 12 months, and 36.7% at 24 months. For the robotic-assisted group, the reduction in the mean motor score from baseline was 17.6% at 6 months, 19% at 12 months and 21.4% at 24 months. The mean LEDD for the frame-based group decreased by 48.7% at 6 months, 56.7% at 12 months, and 29.7% at 24 months. For the robotic-assisted group, the mean LEDD decreased by 42% at 6 months, 45% at 12 months and 50% at 24 months. There were no significant differences in the mean motor scores and the LEDD reduction between the two groups. Operative times tended to be longer for robotic-assisted DBS surgery. Clinical outcomes associated with robotic-assisted surgery are comparable to those with frame-based surgery.

Safety of repetitive transcranial magnetic stimulation in patients with implanted cortical electrodes. An ex-vivo study and report of a case.

OBJECTIVE: To evaluate the safety of repetitive transcranial magnetic stimulation (rTMS) in patients with implanted subdural cortical electrodes. METHODS: We performed ex-vivo experiments to test the temperature, displacement and current induced in the electrodes with single pulse transcranial magnetic stimulation (TMS) from 10 to 100% of stimulator output and tested a typical rTMS protocol used in a clinical setting. We then used rTMS to the motor cortex to treat a patient with refractory post-herpetic neuralgia who had previously been implanted with a subdural motor cortical electrode for pain management. The rTMS protocol consisted of ten sessions of 2000 stimuli at 20Hz and 90% of resting motor threshold. RESULTS: The ex-vivo study showed an increase in the coil temperature of 2°C, a maximum induced charge density of 30.4µC/cm2/phase, and no electrode displacement with TMS. There was no serious adverse effect associated with rTMS treatment of the patient. Cortical tremor was observed in the intervals between trains of stimuli during one treatment session. CONCLUSIONS: TMS was safe in a patient with implanted Medtronic Resume II electrode (model 3587A) subdural cortical electrode. SIGNIFICANCE: TMS may be used as a therapeutic, diagnostic or research tool in patients this type of with implanted cortical electrodes.

Frameless Stereotactic Robot-Assisted Subthalamic Nucleus Deep Brain Stimulation: Case Report.

BACKGROUND: Electrode implantation for deep brain stimulation (DBS) can be performed in numerous ways, but the current "gold standard" is the use of frame-based systems for accuracy. Robotic stereotactic procedures, however, have gained increased interest because of their ease of use and reliability, but there could be concern about their safety in the United States as the result of recent lawsuits (e.g., the da Vinci Surgical System). We report the first DBS implantation performed using a robot (ROSA robotic device) approved by Food and Drug Administration for use in North America. CASE DESCRIPTION: A 56-year-old, right-handed woman with a 12-year history of Parkinson disease is described. She was offered bilateral subthalamic nucleus DBS placement to address motor fluctuations and dyskinesias. DBS electrode implantation was implemented successfully with ROSA robotic stereotactic assistance. Using preoperative magnetic resonance imaging scan acquisitions, we targeted the patient's subthalamic nucleus bilaterally. Bone fiducials were placed and intraoperative computed tomography (CT) imaging was obtained. The magnetic resonance imaging and CT were fused, and the patient was registered to the ROSA software. Trajectories were obtained and a microdrive device was fixed to the robotic arm to advance the electrode to the correct location. Electrodes were then placed bilaterally. Intraoperative CT showed good placement with no complications encountered. CONCLUSIONS: The advantages of robotic assistance in stereotactic procedures are as follows: 1) improved accuracy, 2) "arc-less" approach, and 3) minor adjustments can be made in multiple planes to the entry point without adjustment of a frame. The case demonstrates robotic stereotactic assistance viability as an alternative to traditional frame-based or frameless systems in U.S. hospitals.

What is a clinically important change in the Unified Dyskinesia Rating Scale in Parkinson's disease?

INTRODUCTION: Dyskinesia remain a significant problem in Parkinson Disease (PD). The translation process of novel drug targets for dyskinesia has proven difficult with several failures at phase III level. Determining the 'clinically important change' (CIC) for dyskinesia rating scales in phase II clinical trials may assist in optimizing drug development of new anti-dyskinetic treatments. We used a standard phase IIa acute levodopa infusion paradigm to determine for the first time the CIC for dyskinesia using the new UDysRS. METHODS: We performed a randomized, double-blind, placebo-controlled crossover study with eleven PD patients with stable bothersome dyskinesia. We used the following patient-reported clinically important events as CIC anchors: onset, maximum intensity, remission of dyskinesia. Objective dyskinesia scores using the UDysRS part III Impairment were determined at these same events by blinded video-rating. The CIC was determined using the 'within-patient' score change and a sensitivity- and specificity-based approach. RESULTS: Patients were most aware of 'onset of dyskinesia', followed by 'remission of dyskinesia'. An 11.1-point median change (UDysRS Part III Impairment, p < 0.0001) was the CIC for patient-reported remission of dyskinesia from a practically defined-OFF state. A 2.32-point change (UDysRS Part III Impairment) had the best specificity and sensitivity to distinguish between patient-reported remission and perception of dyskinesia. CONCLUSIONS: In this study, we provide the first report of a CIC for the UDysRS Part III Impairment. Early knowledge of a CIC may help inform the decision to advance into phase III trials and contribute for a higher yield of success in finding new anti-dyskinetic treatments.