Transcutaneous Spinal Direct Current Stimulation (tsDCS) Modulates Human Corticospinal System Excitability

This study aimed to assess the effects of thoracic anodal and cathodal transcutaneous spinal direct current stimulation (tsDCS) on upper- and lower-limb corticospinal excitability. Yet, despite studies assessing thoracic tsDCS influences the spinal ascending tract and reflexes, none assessed the effects of this technique over upper- and lower-limb corticomotorneuronal connections. In 14 healthy subjects we recorded motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) from abductor hallucis (AH) and hand abductor digiti minimi (ADM) muscles before (baseline, B), and at a different time-points (0 and 30 minutes) after anodal or cathodal tsDCS (2.5 mA, 20 minutes, T9-T11 level). In 8 of the 14 subjects we also tested the soleus H-reflex, the F-waves from AH and ADM before and after tsDCS. Both anodal and cathodal tsDCS left the upper-limb MEPs and F-wave unchanged. Conversely, while leaving lower-limb H-reflex unchanged, they oppositely affected lower-limb MEPs: whereas anodal tsDCS increased resting motor threshold (mean\ub1SEM 107.33 \ub1 3.3%, increase immediately after tsDCS, and 108.37 \ub1 3.2% increase 30 min after tsDCS compared to baseline), and had no effects on MEP area and latency, cathodal tsDCS increased MEP area (139.71 \ub1 12.9% increase immediately after tsDCS and 132.74 \ub122.0% increase 30 min after tsDCS compared to baseline) without affecting resting motor threshold and MEP latency. Our results show that tsDCS induces polarity specific changes in corticospinal excitability that last for more than 30 min after tsDCS offset and selectively affect responses in lower-limb muscles innervated by lumbar and sacral motorneurons

Effects of rituximab in two patients with dysferlin-deficient muscular dystrophy

Background. The administration of rituximab (RTX) in vivo results in B-cell depletion, but evidence for multiple mechanisms of action have been reported. Surprisingly, B cell depletion produced a response in patients with polymyositis, which is characterized as a T cell-mediated autoimmune disorder with biopsy findings similar to Miyoshi myopathy (MM). Indeed, in dysferlinopathies, there is evidence of immune system involvement including the presence of muscle inflammation and a down regulation of the complement inhibitory factor, CD55. Methods. Two patients were treated with four weekly infusions of RTX 375 mg/m2. To measure the improvement in muscle strength after treatment, the isometric hand grip maximal voluntary contraction (MVC) was measured by load cell four times during treatment, and again after one year. In order to assess the reproducibility of our grip assessment, we determined the hand MVC analysis in 16 healthy subjects. Moreover, we measured the number of B cells present in patients by flow cytometric analysis during the course of treatment. Results. The analysis of B cell number during the course of treatment showed that CD20- and CD19-positive cells were depleted to 0-0.01%. The decrease in B cells was followed by an improvement in the mobility of the pelvic and shoulder girdles as shown by the MRC%. The MVC values of both patients began at values lower than normal whereas during treatment patients had improved percentage of muscle strength. The strength peak in both patients coincided with the minimum B cell values. There were no severe adverse events associated with an infusion of RTX. Conclusion. We consider the increase in muscle strength observed in both treated patients to be a consequence of their treatment with RTX. To our knowledge, these are the first cases of increased muscle strength in patients with MM. Furthermore, the results of this study indicate that B cell depletion with RTX may be useful in the treatment of patients affected by MM, suggesting a possible role for B cells in the pathophysiology of this muscle disorder

Ethical safety of deep brain stimulation: A study on moral decision-making in Parkinson's disease

INTRODUCTION: The possibility that deep brain stimulation (DBS) in Parkinson's disease (PD) alters patients' decisions and actions, even temporarily, raises important clinical, ethical and legal questions. Abnormal moral decision-making can lead to ethical rules violations. Previous experiments demonstrated the subthalamic (STN) activation during moral decision-making. Here we aim to study whether STN DBS can affect moral decision-making in PD patients. METHODS: Eleven patients with PD and bilateral STN DBS implant performed a computerized moral task in ON and OFF stimulation conditions. A control group of PD patients without DBS implant performed the same experimental protocol. All patients underwent motor, cognitive and psychological assessments. RESULTS: STN stimulation was not able to modify neither reaction times nor responses to moral task both when we compared the ON and the OFF state in the same patient (reaction times, p = .416) and when we compared DBS patients with those treated only with the best medical treatment (reaction times: p = .408, responses: p = .776). CONCLUSIONS: Moral judgment is the result of a complex process, requiring cognitive executive functions, problem-solving, anticipations of consequences of an action, conflict processing, emotional evaluation of context and of possible outcomes, and involving different brain areas and neural circuits. Our data show that STN DBS leaves unaffected moral decisions thus implying relevant clinical and ethical implications for DBS consequences on patients' behavior, on decision-making and on judgment ability. In conclusion, the technique can be considered safe on moral behavior

Web-based telemonitoring and delivery of caregiver support for patients with Parkinson disease after deep brain stimulation: protocol

The increasing number of patients, the high costs of management, and the chronic progress of the disease that prevents patients from performing even simple daily activities make Parkinson disease (PD) a complex pathology with a high impact on society. In particular, patients implanted with deep brain stimulation (DBS) electrodes face a highly fragile stabilization period, requiring specific support at home. However, DBS patients are followed usually by untrained personnel (caregivers or family), without specific care pathways and supporting systems

Adaptive deep brain stimulation in a freely moving parkinsonian patient

The future of deep brain stimulation (DBS) for Parkinson\u2019s disease (PD) lies in new closed-loop systems that continuously supply the implanted stimulator with new settings obtained by analyzing a feedback signal related to the patient\u2019s current clinical condition

Peri-lead edema and local field potential correlation in post-surgery subthalamic nucleus deep brain stimulation patients

Implanting deep brain stimulation (DBS) electrodes in patients with Parkinson's disease often results in the appearance of a non-infectious, delayed-onset edema that disappears over time. However, the time window between the DBS electrode and DBS stimulating device implant is often used to record local field potentials (LFPs) which are used both to better understand basal ganglia pathophysiology and to improve DBS therapy. In this work, we investigated whether the presence of post-surgery edema correlates with the quality of LFP recordings in eight patients with advanced Parkinson's disease implanted with subthalamic DBS electrodes. The magnetic resonance scans of the brain after 8.5 +/- 1.5 days from the implantation surgery were segmented and the peri-electrode edema volume was calculated for both brain hemispheres. We found a correlation (rho = -0.81, p < 0.0218, Spearman's correlation coefficient) between left side local field potentials of the low beta band (11-20 Hz) and the edema volume of the same side. No other significant differences between the hemispheres were found. Despite the limited sample size, our results suggest that the effect on LFPs may be related to the edema localization, thus indicating a mechanism involving brain networks instead of a simple change in the electrode-tissue interface

Adaptive deep brain stimulation controls levodopa-induced side effects in Parkinsonian patients

The potential superior benefits of adaptive deep brain stimulation (aDBS) approaches compared to classical, constantparameters DBS were already proven by scientific evidence from different research groups. aDBS provides better symptoms control in Parkinson\u2019s disease patients by adapting the stimulation parameters to the patient\u2019s clinical state estimated through the analysis of subthalamic neuronal oscillations (ie, local field potentials) in the beta band (13-30 Hz)

Interaction between rhythms in the human basal ganglia: application of bispectral analysis to local field potentials

IEEE Transactions on Neural Systems and Rehabilitation Engineering, 15(4): pp. 483-492.The application of deep brain stimulation (DBS) for the treatment of Parkinson’s disease offered a direct “insight” into the human electrical activity in subcortical structures. The analysis of the oscillatory activity [local field potentials (LFPs)] disclosed the importance of rhythms and of interactions between rhythms in the human basal ganglia information processing. The aim of this study wasto investigate the existence of possible nonlinear interactions between LFP rhythms characterizing the output structure of the basal ganglia, the globus pallidus internus, by means of bispectral analysis. The results of this study disclosed that the rhythms expressed in the globus pallidus internus of the untreated parkinsonian patient are not independent and, in particular, the low-beta (13–20Hz)band generates harmonics that are included in the high-beta (20–35 Hz) band. Conversely, in the dystonic globus pallidus, as well as in the parkinsonian globus pallidus afterdopaminergic medication (i.e., in the more “normal” condition), the rhythms are substantially independent and characterized by a strong activity in the low-frequency band that generates a second harmonic (4–14 Hz), mostly included in the same band. The interactions between rhythms in the human globus pallidus are therefore different in different pathologies and in different patient’s states. The interpretation of these interactions is likely critical for fully understanding the role of LFP rhythms in the pathophysiology of human basal ganglia

Case report: Clinical and molecular characterization of two siblings affected by Brody myopathy

Exercise-induced muscle stiffness is the hallmark of Brody disease, an autosomal recessive myopathy due to biallelic pathogenic variants in ATP2A1, encoding the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase SERCA1. About 40 patients have been reported so far. Our knowledge about the natural history of this disorder, genotype–phenotype correlations and the effect of symptomatic treatment is partial. This results in incomplete recognition and underdiagnosis of the disease. Here, we report the clinical, instrumental, and molecular features of two siblings presenting childhood-onset exercise-induced muscle stiffness without pain. Both the probands display difficulty in climbing stairs and running, frequent falls, delayed muscle relaxation after exertion. Cold temperatures worsen these symptoms. No myotonic discharges were observed at electromyography. Whole Exome Sequencing analysis in the probands revealed the presence of two ATP2A1 variants: the previously reported frameshift microdeletion c.2464delC and the likely pathogenic novel splice-site variant c.324 + 1G &gt; A, whose detrimental effect was demonstrated in ATP2A1 transcript analysis. The bi-allelic inheritance was verified by Sanger sequencing in the unaffected parents. This study expands the molecular defects associated with Brody myopathy

Eight-hours adaptive deep brain stimulation in patients with Parkinson disease

To assess the feasibility and clinical efficacy of local field potentials (LFPs)-based adaptive deep brain stimulation (aDBS) in patients with advanced Parkinson disease (PD) during daily activities in an open-label, nonblinded study. METHODS: We monitored neurophysiologic and clinical fluctuations during 2 perioperative experimental sessions lasting for up to 8 hours. On the first day, the patient took his/her daily medication, while on the second, he/she additionally underwent subthalamic nucleus aDBS driven by LFPs beta band power. RESULTS: The beta band power correlated in both experimental sessions with the patient's clinical state (Pearson correlation coefficient r = 0.506, p < 0.001, and r = 0.477, p < 0.001). aDBS after LFP changes was effective (30% improvement without medication [3-way analysis of variance, interaction day 7 medication p = 0.036; 30.5 \ub1 3.4 vs 22.2 \ub1 3.3, p = 0.003]), safe, and well tolerated in patients performing regular daily activities and taking additional dopaminergic medication. aDBS was able to decrease DBS amplitude during motor "on" states compared to "off" states (paired t test p = 0.046), and this automatic adjustment of STN-DBS prevented dyskinesias. CONCLUSIONS: The main findings of our study are that aDBS is technically feasible in everyday life and provides a safe, well-tolerated, and effective treatment method for the management of clinical fluctuations. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with advanced PD, aDBS is safe, well tolerated, and effective in controlling PD motor symptoms