Effects of physiotherapy and home-based training in parkinsonian syndromes: protocol for a randomised controlled trial (MobilityAPP).

INTRODUCTION: Gait and mobility impairment are pivotal signs of parkinsonism, and they are particularly severe in atypical parkinsonian disorders including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A pilot study demonstrated a significant improvement of gait in patients with MSA of parkinsonian type (MSA-P) after physiotherapy and matching home-based exercise, as reflected by sensor-based gait parameters. In this study, we aim to investigate whether a gait-focused physiotherapy (GPT) and matching home-based exercise lead to a greater improvement of gait performance compared with a standard physiotherapy/home-based exercise programme (standard physiotherapy, SPT). METHODS AND ANALYSIS: This protocol was deployed to evaluate the effects of a GPT versus an active control undergoing SPT and matching home-based exercise with regard to laboratory gait parameters, physical activity measures and clinical scales in patients with Parkinson's disease (PD), MSA-P and PSP. The primary outcomes of the trial are sensor-based laboratory gait parameters, while the secondary outcome measures comprise real-world derived parameters, clinical rating scales and patient questionnaires. We aim to enrol 48 patients per disease group into this double-blind, randomised-controlled trial. The study starts with a 1 week wearable sensor-based monitoring of physical activity. After randomisation, patients undergo a 2 week daily inpatient physiotherapy, followed by 5 week matching unsupervised home-based training. A 1 week physical activity monitoring is repeated during the last week of intervention. ETHICS AND DISSEMINATION: This study, registered as 'Mobility in Atypical Parkinsonism: a Trial of Physiotherapy (Mobility_APP)' at clinicaltrials.gov (NCT04608604), received ethics approval by local committees of the involved centres. The patient's recruitment takes place at the Movement Disorders Units of Innsbruck (Austria), Erlangen (Germany), Lausanne (Switzerland), Luxembourg (Luxembourg) and Bolzano (Italy). The data resulting from this project will be submitted to peer-reviewed journals, presented at international congresses and made publicly available at the end of the trial. TRIAL REGISTRATION NUMBER: NCT04608604.

Slowing gait during turning: how volition of modifying walking speed affects the gait pattern in healthy adults.

Background: Turning during walking and volitionally modulating walking speed introduces complexity to gait and has been minimally explored. Research question: How do the spatiotemporal parameters vary between young adults walking at a normal speed and a slower speed while making 90°, 180°, and 360° turns? Methods: In a laboratory setting, the spatiotemporal parameters of 10 young adults were documented as they made turns at 90°, 180°, and 360°. A generalized linear model was utilized to determine the effect of both walking speed and turning amplitude. Results: Young adults volitionally reducing their walking speed while turning at different turning amplitudes significantly decreased their cadence and spatial parameters while increasing their temporal parameters. In conditions of slower movement, the variability of certain spatial parameters decreased, while the variability of some temporal parameters increased. Significance: This research broadens the understanding of turning biomechanics in relation to volitionally reducing walking speed. Cadence might be a pace gait constant synchronizing the rhythmic integration of several inputs to coordinate an ordered gait pattern output. Volition might up-regulate or down-regulate this pace gait constant (i.e., cadence) which creates the feeling of modulating walking speed.

The paired-pulse TMS paradigm of short intracortical inhibition is mediated by a reduction of repetitive motor neuron discharges.

Transcranial magnetic stimulation (TMS) causes repetitive spinal motoneuron discharges (repMNDs), but the effects of short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) on repMNDs remain unknown. Triple stimulation technique (TST) and the extended TST-protocols that include a fourth and fifth stimulation, the Quadruple (QuadS) and Quintuple (QuintS) stimulation, respectively, offer a precise estimate of cortical and spinal motor neuron discharges, including repMNDs. The objective of our study was to explore the effects of SICI and ICF on repMNDs. We explored conventional paired-pulse TMS protocols of SICI and ICF with the TMS, TST, the QuadS, and the QuintS protocols, in a randomized study design in 20 healthy volunteers. We found significantly less repMNDs in the SICI paradigm compared with a single-pulse TMS (SP-TMS). No significant difference was observed in the ICF paradigm. There was a significant inter- and intrasubject variability in both SICI and ICF. We demonstrate a significant reduction of repMNDs in SICI, which may result from the suppression of later I-waves and mediate the inhibition of motor-evoked potential (MEP). There is no increase in repMNDs in ICF suggesting another mechanism underlying facilitation. This study provides the proof that a reduction of repMNDs mediates the inhibition seen in SICI.NEW & NOTEWORTHY Significant reduction of repetitive motor neuron discharges (repMNDs) in short-interval intracortical inhibition (SICI) may result from the suppression of later I-waves and mediate the inhibition of motor-evoked potential (MEP). There is no change in the number of repMNDs in intracortical facilitation (ICF). There was a significant variability in SICI and ICF in healthy subjects.

Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee.

The review provides a comprehensive update (previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119(3):504-32) on clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological diseases. Most TMS measures rely on stimulation of motor cortex and recording of motor evoked potentials. Paired-pulse TMS techniques, incorporating conventional amplitude-based and threshold tracking, have established clinical utility in neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain and functional diseases. Cortical hyperexcitability has emerged as a diagnostic aid in amyotrophic lateral sclerosis. Single-pulse TMS measures are of utility in stroke, and myelopathy even in the absence of radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced in Alzheimer's disease. The triple stimulation technique (TST) may enhance diagnostic utility of conventional TMS measures to detect upper motor neuron involvement. The recording of motor evoked potentials can be used to perform functional mapping of the motor cortex or in preoperative assessment of eloquent brain regions before surgical resection of brain tumors. TMS exhibits utility in assessing lumbosacral/cervical nerve root function, especially in demyelinating neuropathies, and may be of utility in localizing the site of facial nerve palsies. TMS measures also have high sensitivity in detecting subclinical corticospinal lesions in multiple sclerosis. Abnormalities in central motor conduction time or TST correlate with motor impairment and disability in MS. Cerebellar stimulation may detect lesions in the cerebellum or cerebello-dentato-thalamo-motor cortical pathways. Combining TMS with electroencephalography, provides a novel method to measure parameters altered in neurological disorders, including cortical excitability, effective connectivity, and response complexity.

Spatiotemporal parameters during turning gait maneuvers of different amplitudes in young and elderly healthy adults: A descriptive and comparative study.

BACKGROUND: Turning during walking adds complexity to gait and has been little investigated until now. Research question What are the differences in spatiotemporal parameters between young and elderly healthy adults performing quarter-turns (90°), half-turns (180°) and full-turns (360°)? METHODS: The spatiotemporal parameters of 10 young and 10 elderly adults were recorded in a laboratory while turning at 90°, 180° and 360°. Two-way mixed ANOVA were performed to determine the effect of age and turning amplitude. RESULTS: Elderly were slower and needed more steps and time to perform turns of larger amplitude than young adults. Cadence did not differ across age or across turning amplitude. Generally, in the elderly, the spatial parameters were smaller and the temporal parameters enhancing stability (i.e., double-support phase and stance/cycle ratio) were larger, especially for turns of larger amplitudes. In elderly adults, the variability of some spatial parameters was decreased, whereas the variability of some temporal parameters was increased. Stride width of the external leg showed the most substantial difference between groups. Most parameters differed between turning at 90° and turning at larger amplitudes (180°, 360°). Significance This study extends the characterization of turning biomechanics with respect to ageing. It also suggested paying particular attention to the turning amplitude. Finally, the age-related differences may pave the way for new selective rehabilitation protocols in the elderly.

Non-invasive brain stimulation for Parkinson's disease: Clinical evidence, latest concepts and future goals: A systematic review.

Parkinson's disease (PD) is becoming a major public-health issue in an aging population. Available approaches to treat advanced PD still have limitations; new therapies are needed. The non-invasive brain stimulation (NIBS) may offer a complementary approach to treat advanced PD by personalized stimulation. Although NIBS is not as effective as the gold-standard levodopa, recent randomized controlled trials show promising outcomes in the treatment of PD symptoms. Nevertheless, only a few NIBS-stimulation paradigms have shown to improve PD's symptoms. Current clinical recommendations based on the level of evidence are reported in Table 1 through Table 3. Furthermore, novel technological advances hold promise and may soon enable the non-invasive stimulation of deeper brain structures for longer periods.

Physical Therapy for Freezing of Gait and Gait Impairments in Parkinson Disease: A Systematic Review.

INTRODUCTION: Freezing of gait (FOG) is a major cause of falls and disability in Parkinson disease (PD). As FOG only partially improves in response to dopaminergic medication, physical therapy is an important element of its management. OBJECTIVE: To assess the evidence for the physical interventions for FOG and gait impairments and to establish recommendations for clinical practice. LITERATURE SURVEY: This review follows the guidelines for systematic reviews: the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Systematic search in PubMed, Embase, Physiotherapy Evidence Databases, and CINAHL for randomized controlled trials of PT interventions for FOG in PD patients until April 2018. SYNTHESIS: Twenty randomized controlled trials (RCTs) were reviewed. In 12 RCTs, PT for FOG was assessed, which was the primary outcome measure in nine of these RCTs. In eight RCTs, PT for gait impairment (not targeting specifically FOG) in PD was assessed. The following PT interventions reduce FOG with a good category A recommendation: cueing strategies (P < .05) (visual and auditory); treadmill walking (P < .05); aquatic obstacle training (P < .01); supervised slackline training (P < .05). These interventions can be combined and maintain their efficacy when being applied concurrently: though there is a lack of long-term follow-up studies. The following PT interventions show possible benefit and need further investigations: balance and coordination training; aquatic gait training; sensory (tactile) cues. The treadmill training and auditory and visual cues are effective also for other gait disturbances in PD and improve gait kinematics. CONCLUSIONS: Visual and auditory cueing and the treadmill training are effective interventions for FOG and gait impairments in PD patients (evidence level A- according to the European Federation of Neurological Societies). Tactile cues and other specific therapies targeting FOG are probably effective but need further studies.

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018).

A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance.

Gait events during turning can be detected using kinematic features originally proposed for the analysis of straight-line walking.

There is a growing interest for turning biomechanics notably because it is a more challenging task than straight-line walking during which some gait impairments are increased. Detecting heel-strike (HS) and toe-off (TO) events using the trajectory of markers attached to the feet is common in straight-line gait analysis and could reveal very useful to evaluate turning maneuvers. Yet, a comprehensive evaluation is missing, making difficult the selection of features for temporal analysis of turning. This study aimed to compare features of foot marker trajectories to detect HS and TO. Twenty healthy participants, 10 young (5 males, 23 ±â€¯1 years old, 21.3 ±â€¯2.2 kg/m2) and 10 elderly (4 males, 72 ±â€¯5 years old, 26.4 ±â€¯6.4 kg/m2), performed quarter, half, and full turns as well as straight-line walking in a gait lab. Fourteen features, adapted from straight-line walking literature, were used to detect HS and TO based on marker trajectories. Force plate measures served as reference. One HS and one TO feature were found particularly suitable. Overall, they detected more than 99% of the 1788 events recorded, with accuracies and precisions of -3.9 ms and 9.0 ms for HS and -7.8 ms and 10.7 ms for TO, respectively. Differences in accuracy and precision were observed among walking conditions and groups, but remained small, generally below 4.0 ms. In conclusion, this study identified kinematic features that can be used to analyze both turning and straight-line walking. Further assessment could be necessary with pathologies inducing severe degradation of gait patterns.

Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS).

A group of European experts was commissioned by the European Chapter of the International Federation of Clinical Neurophysiology to gather knowledge about the state of the art of the therapeutic use of transcranial direct current stimulation (tDCS) from studies published up until September 2016, regarding pain, Parkinson's disease, other movement disorders, motor stroke, poststroke aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimer's disease, tinnitus, depression, schizophrenia, and craving/addiction. The evidence-based analysis included only studies based on repeated tDCS sessions with sham tDCS control procedure; 25 patients or more having received active treatment was required for Class I, while a lower number of 10-24 patients was accepted for Class II studies. Current evidence does not allow making any recommendation of Level A (definite efficacy) for any indication. Level B recommendation (probable efficacy) is proposed for: (i) anodal tDCS of the left primary motor cortex (M1) (with right orbitofrontal cathode) in fibromyalgia; (ii) anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episode without drug resistance; (iii) anodal tDCS of the right DLPFC (with left DLPFC cathode) in addiction/craving. Level C recommendation (possible efficacy) is proposed for anodal tDCS of the left M1 (or contralateral to pain side, with right orbitofrontal cathode) in chronic lower limb neuropathic pain secondary to spinal cord lesion. Conversely, Level B recommendation (probable inefficacy) is conferred on the absence of clinical effects of: (i) anodal tDCS of the left temporal cortex (with right orbitofrontal cathode) in tinnitus; (ii) anodal tDCS of the left DLPFC (with right orbitofrontal cathode) in drug-resistant major depressive episode. It remains to be clarified whether the probable or possible therapeutic effects of tDCS are clinically meaningful and how to optimally perform tDCS in a therapeutic setting. In addition, the easy management and low cost of tDCS devices allow at home use by the patient, but this might raise ethical and legal concerns with regard to potential misuse or overuse. We must be careful to avoid inappropriate applications of this technique by ensuring rigorous training of the professionals and education of the patients.

Non-invasive brain stimulation for Parkinson's disease: Current concepts and outlook 2015.

BACKGROUND AND PURPOSE: In advanced Parkinson's disease (PD), the emergence of symptoms refractory to conventional therapy poses a therapeutic challenge. The success of deep brain stimulation (DBS) and advances in the understanding of the pathophysiology of PD have raised interest in non-invasive brain stimulation as an alternative therapeutic tool. The rationale for its use draws from the concept that reversing abnormalities in brain activity and physiology thought to cause the clinical deficits may restore normal functioning. Currently the best evidence in support of this concept comes from DBS, which improves motor deficits, and modulates brain activity and motor cortex physiology, though whether a causal interaction exists remains largely undetermined. CONCLUSION: Most trials of non-invasive brain stimulation in PD have applied repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex and cortical areas of the motor circuit. Published studies suggest a possible therapeutic potential of rTMS and transcranial direct current stimulation (tDCS), but clinical effects so far have been small and negligible regarding functional independence and quality of life. Approaches to potentiate the efficacy of rTMS, including increasing stimulation intensity and novel stimulation parameters, derive their rationale from studies of brain physiology. These novel parameters simulate normal firing patterns or act on the hypothesized role of oscillatory activity in the motor cortex and basal ganglia in motor control. There may also be diagnostic potential of TMS in characterizing individual traits for personalized medicine.

Transcranial Direct Current Stimulation for the Treatment of Chronic Tinnitus: A Randomized Controlled Study.

BACKGROUND: Tinnitus is an often disabling condition for which there is no effective therapy. Current research suggests that tinnitus may develop due to maladaptive plastic changes and altered activity in the auditory and prefrontal cortex. Transcranial direct current stimulation (tDCS) modulates brain activity and has been shown to transiently suppress tinnitus in trials. OBJECTIVE: To investigate the efficacy and safety of tDCS in the treatment of chronic subjective tinnitus. METHODS: In a randomized, parallel, double-blind, sham-controlled study, the efficacy and safety of cathodal tDCS to the auditory cortex with anode over the prefrontal cortex was investigated in five sessions over five consecutive days. Tinnitus was assessed after the last session on day 5, and at follow-up visits 1 and 3 months post stimulation using the Tinnitus Handicap Inventory (THI, primary outcome measure), Subjective Tinnitus Severity Scale, Hospital Anxiety and Depression scale, Visual Analogue Scale, and Clinical Global Impression scale. RESULTS: 42 patients were investigated, 21 received tDCS and 21 sham stimulation. There were no beneficial effects of tDCS on tinnitus as assessed by primary and secondary outcome measures. Effect size assessed with Cohen's d amounted to 0.08 (95% CI: -0.52 to 0.69) at 1 month and 0.18 (95% CI: -0.43 to 0.78) at 3 months for the THI. CONCLUSION: tDCS of the auditory and prefrontal cortices is safe, but does not improve tinnitus. Different tDCS protocols might be beneficial.

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS).

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.

Parkinson's disease.

In advanced Parkinson's disease (PD), the emergence of symptoms refractory to conventional therapy poses therapeutic challenges. The success of deep brain stimulation (DBS) and advances in the understanding of the pathophysiology of PD have raised interest in noninvasive brain stimulation as an alternative therapeutic tool. The rationale for its use draws from the concept that reversing abnormalities in brain activity and physiology thought to cause the clinical deficits may restore normal functioning. Currently the best evidence in support of this concept comes from DBS, which improves motor deficits, and modulates brain activity and motor cortex physiology, although whether a causal interaction exists remains largely undetermined. Most trials of noninvasive brain stimulation in PD have applied repetitive transcranial magnetic stimulation (rTMS), targeting the motor cortex. Current studies suggest a possible therapeutic potential for rTMS and transcranial direct current stimulation (tDCS), but clinical effects so far have been small and negligible with regard to functional independence and quality of life. Approaches to potentiate the efficacy of rTMS include increasing stimulation intensity and novel stimulation parameters that derive their rationale from studies on brain physiology. These novel parameters are intended to simulate normal firing patterns or to act on the hypothesized role of oscillatory activity in the motor cortex and basal ganglia with regard to motor control and its contribution to the pathogenesis of motor disorders. Noninvasive brain stimulation studies will enhance our understanding of PD pathophysiology and might provide further evidence for potential therapeutic applications.

Controlled study of 50-Hz repetitive transcranial magnetic stimulation for the treatment of Parkinson disease.

OBJECTIVE: To investigate the safety and efficacy of 50-Hz repetitive transcranial magnetic stimulation (rTMS) in the treatment of motor symptoms in Parkinson disease (PD). BACKGROUND: Progression of PD is characterized by the emergence of motor deficits that gradually respond less to dopaminergic therapy. rTMS has shown promising results in improving gait, a major cause of disability, and may provide a therapeutic alternative. Prior controlled studies suggest that an increase in stimulation frequency might enhance therapeutic efficacy. METHODS: In this randomized, double blind, sham-controlled study, the authors investigated the safety and efficacy of 50-Hz rTMS of the motor cortices in 8 sessions over 2 weeks. Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neurophysiological, and neuropsychological parameters. In addition, the safety of 50-Hz rTMS was tested with electromyography-electroencephalogram (EMG-EEG) monitoring during and after stimulation. RESULTS: The authors investigated 26 patients with mild to moderate PD: 13 received 50-Hz rTMS and 13 sham stimulation. The 50-Hz rTMS did not improve gait, bradykinesia, and global and motor UPDRS, but there appeared a short-lived "on"-state improvement in activities of daily living (UPDRS II). The 50-Hz rTMS lengthened the cortical silent period, but other neurophysiological and neuropsychological measures remained unchanged. EMG/EEG recorded no pathological increase of cortical excitability or epileptic activity. There were no adverse effects. CONCLUSION: It appears that 50-Hz rTMS of the motor cortices is safe, but it fails to improve motor performance and functional status in PD. Prolonged stimulation or other techniques with rTMS might be more efficacious but need to be established in future research.

Transcranial direct current stimulation for the treatment of focal hand dystonia.

The treatment of writer's cramp, a task-specific focal hand dystonia, needs new approaches. A deficiency of inhibition in the motor cortex might cause writer's cramp. Transcranial direct current stimulation modulates cortical excitability and may provide a therapeutic alternative. In this randomized, double-blind, sham-controlled study, we investigated the efficacy of cathodal stimulation of the contralateral motor cortex in 3 sessions in 1 week. Assessment over a 2-week period included clinical scales, subjective ratings, kinematic handwriting analysis, and neurophysiological evaluation. Twelve patients with unilateral dystonic writer's cramp were investigated; 6 received transcranial direct current and 6 sham stimulation. Cathodal transcranial direct current stimulation had no favorable effects on clinical scales and failed to restore normal handwriting kinematics and cortical inhibition. Subjective worsening remained unexplained, leading to premature study termination. Repeated sessions of cathodal transcranial direct current stimulation of the motor cortex yielded no favorable results supporting a therapeutic potential in writer's cramp.

Transcranial direct current stimulation for the treatment of Parkinson's disease.

BACKGROUND: Progression of Parkinson's disease (PD) is characterised by motor deficits which eventually respond less to dopaminergic therapy and thus pose a therapeutic challenge. Deep brain stimulation has proven efficacy but carries risks and is not possible in all patients. Non-invasive brain stimulation has shown promising results and may provide a therapeutic alternative. OBJECTIVE: To investigate the efficacy of transcranial direct current stimulation (tDCS) in the treatment of PD. DESIGN: Randomised, double blind, sham controlled study. SETTING: Research institution. METHODS: The efficacy of anodal tDCS applied to the motor and prefrontal cortices was investigated in eight sessions over 2.5 weeks. Assessment over a 3 month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, Unified Parkinson's Disease Rating Scale (UPDRS), Serial Reaction Time Task, Beck Depression Inventory, Health Survey and self-assessment of mobility. RESULTS: Twenty-five PD patients were investigated, 13 receiving tDCS and 12 sham stimulation. tDCS improved gait by some measures for a short time and improved bradykinesia in both the on and off states for longer than 3 months. Changes in UPDRS, reaction time, physical and mental well being, and self-assessed mobility did not differ between the tDCS and sham interventions. CONCLUSION: tDCS of the motor and prefrontal cortices may have therapeutic potential in PD but better stimulation parameters need to be established to make the technique clinically viable. This study was publicly registered (clinicaltrials.org: NCT00082342).

REM sleep behavior disorder is not linked to postural instability and gait dysfunction in Parkinson.

To evaluate a potential association of REM-sleep behavior disorder (RBD) with gait and postural impairment in Parkinson's disease (PD). Gait difficulties and postural impairment are frequent in PD and are a major cause of disability. Animal studies indicate a key role of the pedunculopontine nucleus (PPN) in gait, postural control, and REM sleep, and also in the pathophysiology of RBD. In humans, such an association has not been investigated. Twenty-six patients with mild-to-moderate PD (13 with polysomnography confirmed and 13 with excluded RBD), and 20 age-matched healthy controls were prospectively investigated. Gait assessment on a treadmill, and static and dynamic posturography were performed. PD patients with RBD do not differ from those without RBD in gait and postural control. Greater severity of PD or prevalence of gait and postural disturbances in the presence of RBD were not found. RBD was not associated with any particular motor phenotype. We found no association of RBD with gait disturbances and postural impairment. Human gait and postural control and RBD appear to depend upon different neuronal circuits.

Safety study of 50 Hz repetitive transcranial magnetic stimulation in patients with Parkinson's disease.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in treating Parkinson's disease (PD), but the best values for rTMS parameters are not established. Fifty Hertz rTMS may be superior to 25 Hz rTMS investigated so far. The objective of this study was to determine if 50 Hz rTMS could be delivered safely in PD patients since current safety limits are exceeded. METHODS: Fifty Hertz rTMS was applied with a circular coil on the primary motor cortex (M1). Stimulation intensity was first tested at 60% rest motor threshold [RMT] and 0.5 s train duration and then increased in 0.5 s steps to 2 s, and by 10% steps to 90% RMT. Multi-channel electromyography (EMG) was recorded to control for signs of increasing time-locked EMG activity including correlates of the spread of excitation and after-discharges, or an increase of M1 excitability. Pre- and post-50 Hz rTMS assessments included EEG, Unified Parkinson Disease Rating Scale (UPDRS), Grooved Pegboard Test, Serial Reaction Time Task (SRTT), Folstein Mini-Mental Status Examination (MMSE) and Verbal Fluency to control for motor and cognitive side effects. RESULTS: Ten PD patients were investigated. Multi-channel EMG showed no signs of increased time-locked EMG activity including correlates of the spread of excitation and after-discharges, or increased M1 excitability in 9 patients. A PD patient with bi-temporal spikes in the pre-testing EEG had clinical and EMG correlates of spread of excitation at 90% RMT, but no seizure activity. Pre- and post-50 Hz assessment showed no changes. No adverse events were observed. Fifty Hertz rTMS was well tolerated except by 1 patient who wished to terminate the study due to facial muscle stimulation. CONCLUSION: Fifty Hertz rTMS at an intensity of 90% RMT for 2 s appears safe in patients with PD, but caution should be taken for patients with paroxysmal EEG activity. For this reason, comprehensive screening should include EEG before higher-frequency rTMS is applied. SIGNIFICANCE: This is the first study to investigate safety of 50 Hz rTMS in humans.