Clinical neurophysiology in the treatment of movement disorders: IFCN handbook chapter.

In this review, different aspects of the use of clinical neurophysiology techniques for the treatment of movement disorders are addressed. First of all, these techniques can be used to guide neuromodulation techniques or to perform therapeutic neuromodulation as such. Neuromodulation includes invasive techniques based on the surgical implantation of electrodes and a pulse generator, such as deep brain stimulation (DBS) or spinal cord stimulation (SCS) on the one hand, and non-invasive techniques aimed at modulating or even lesioning neural structures by transcranial application. Movement disorders are one of the main areas of indication for the various neuromodulation techniques. This review focuses on the following techniques: DBS, repetitive transcranial magnetic stimulation (rTMS), low-intensity transcranial electrical stimulation, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), and focused ultrasound (FUS), including high-intensity magnetic resonance-guided FUS (MRgFUS), and pulsed mode low-intensity transcranial FUS stimulation (TUS). The main clinical conditions in which neuromodulation has proven its efficacy are Parkinson's disease, dystonia, and essential tremor, mainly using DBS or MRgFUS. There is also some evidence for Tourette syndrome (DBS), Huntington's disease (DBS), cerebellar ataxia (tDCS), and axial signs (SCS) and depression (rTMS) in PD. The development of non-invasive transcranial neuromodulation techniques is limited by the short-term clinical impact of these techniques, especially rTMS, in the context of very chronic diseases. However, at-home use (tDCS) or current advances in the design of closed-loop stimulation (tACS) may open new perspectives for the application of these techniques in patients, favored by their easier use and lower rate of adverse effects compared to invasive or lesioning methods. Finally, this review summarizes the evidence for keeping the use of electromyography to optimize the identification of muscles to be treated with botulinum toxin injection, which is indicated and widely performed for the treatment of various movement disorders.

Plasticity-Induced Effects of Theta Burst Transcranial Ultrasound Stimulation in Parkinson's Disease.

BACKGROUND: Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD). OBJECTIVE: The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. METHODS: We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60. RESULTS: tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. CONCLUSIONS: tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Utility of Neurophysiological Evaluation in Movement Disorders Clinical Practice.

Background: Quantitative and objective neurophysiological assessment can help to define the predominant phenomenology and provide diagnoses that have prognostic and therapeutic implications for movement disorders. Objectives: Evaluate the agreement between initial indications and final diagnoses after neurophysiological evaluations in a specialized movement disorders center. Methods: Electrophysiological studies conducted for movement disorders from 2003 to 2021 were reviewed. The indications were classified according to predominant phenomenology and the diagnoses categorized in subgroups of phenomenology. Results: A total of 509 studies were analyzed. 51% (259) of patients were female, with a mean age of 51 years (ranges 5 to 89 years). The most common reasons for referral were evaluation of functional movement disorders (FMD), followed by jerky movements, tremor and postural instability. Regarding FMD referrals, there was a diagnostic change in 13% of the patients after electrophysiological assessment. The patients with jerky movements as indication had a diagnosis other than myoclonus in 27% of them, and tremor was not confirmed in 20% of the cases. In patients with an electrophysiological diagnosis of FMD, it was not suspected in 30% of the referrals. Similarly, tremor was not mentioned in the referral of 17% of the patients with this electrophysiological diagnosis and myoclonus was not suspected in 13% of the cases. Conclusions: Electrophysiological assessment has utility in the evaluation of movement disorders, even in patients evaluated by movement disorders neurologists. More studies are needed to standardize the protocols between centers and to promote the availability and use of these techniques among movement disorders clinics.

Accelerated Transcranial Ultrasound Neuromodulation in Parkinson's Disease: A Pilot Study.

OBJECTIVE: Low-intensity transcranial focused ultrasound (TUS) is a novel method for neuromodulation. We aimed to study the feasibility of stimulating the bilateral primary motor cortices (M1) with accelerated theta-burst TUS (a-tbTUS) on neurophysiologic and clinical outcomes in Parkinson's disease (PD). METHODS: Patients were randomly assigned to receive active or sham a-tbTUS for the first visit and the alternate condition on the second visit, at least 10 days apart. a-tbTUS was administered in three consecutive sonications at 30-minute intervals. We used an accelerated protocol to produce an additive effect of stimulation. Patients were studied in the OFF-medication state. Transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) were used to assess motor cortical excitability before and after TUS. Clinical outcomes after a-tbTUS administration were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III. RESULTS: A total of 20 visits were conducted in 10 PD patients. Compared to the baseline, TMS-elicited MEP amplitudes significantly increased following active but not sham sonication (P = 0.0057). MEP amplitudes were also higher following a-tbTUS than sham sonication (P = 0.0064). There were no statistically significant changes in MDS-UPDRS-III scores with active or sham a-tbTUS. CONCLUSIONS: a-tbTUS increases motor cortex excitability and is a feasible non-invasive neuromodulation strategy in PD. Future studies should determine optimal dosing parameters and the durability of neurophysiologic and clinical outcomes in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Botulinum toxin in the management of parkinsonian disorders.

Many studies have shown that botulinum toxin (BoNT) can be an option to treat motor and non-motor symptoms in Parkinson's disease (PD) and parkinsonian syndromes. The advantages of BoNT compared to oral medications include localized action and low incidence of systemic side effects, which is important in treating neurodegenerative disease. Motor symptoms that can be treated with BoNT include blepharospasm, apraxia of eyelid opening, tremor, cervical dystonia and limb dystonia. Other indications with less evidence include camptocormia, freezing of gait and dyskinesia. Non-motor symptoms that may improve with BoNT include sialorrhea, pain, overreactive bladder, dysphagia and constipation. However, the current evidence for use of BoNT in parkinsonism is mostly based on open-label studies and there are few randomized, controlled trials. BoNT can be a valuable tool to treat certain symptoms of PD and parkinsonian syndromes to improve the patient's quality of life. However, many of the uses are not supported by high quality studies and further studies are needed to provide further evidence of efficacy, define the optimal injection protocols such as doses and muscle selection.

Mechanisms of theta burst transcranial ultrasound induced plasticity in the human motor cortex.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique with high depth penetrance and spatial resolution. Theta-burst TUS (tbTUS) is a plasticity-inducing protocol which increases motor cortical excitability for up to 30 min following 80s of sonication. While this protocol may have therapeutic potential for the treatment of psychiatric and neurological disorders, the mechanisms of action of TUS remain unclear. OBJECTIVE: We conducted the first pharmacological study to examine the mechanisms of TUS in human primary motor cortex. By administering brain-active drugs with known mechanisms of action, we aimed to elucidate the mechanisms of tbTUS. METHODS: Fourteen healthy subjects participated in a within-subjects randomized, double-blind, cross-over study with five visits. At each visit, one of four study drugs (carbamazepine - Na+ channel blocker, nimodipine - L-type Ca2+ channel blocker, lorazepam - positive allosteric modulator of gamma-aminobutyric acid (GABA) type A receptor, dextromethorphan - N-methyl-d-aspartate receptor antagonist) or placebo was administered in random order, followed by tbTUS. RESULTS: The plasticity effects of tbTUS on motor cortex excitability measured by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation were reduced by all study drugs compared to placebo. CONCLUSION: tbTUS may induce NMDA-dependent synaptic plasticity since the effects are blocked by increased GABAA receptor activities and voltage-gated Na+ and Ca2+ channels blockers. These results are consistent with the hypotheses that tbTUS induced long-term potentiation-like mechanisms and that TUS involves activation of mechanosensitive Na+ and Ca2+ channels. Alternatively, non-specific pharmacologically induced changes in excitatory/inhibitory balance might have interfered with the effects of tbTUS.

Different types of tremor and myoclonus in an atypical case of shaking upon standing.

Shaking upon standing is associated with a spectrum of different conditions. We describe an unusual case with a combination of slow orthostatic tremor, orthostatic myoclonus, and parkinsonism. The case illustrates the utility of electrophysiology for precise characterization of physical findings to establish the diagnosis.

Parkinson's Disease-Cognitive Rating Scale (PD-CRS): Normative Data and Mild Cognitive Impairment Assessment in Brazil.

Background: The Parkinson's Disease-Cognitive Rating Scale (PD-CRS) assesses posterior-cortical and frontal-subcortical cognitive functioning and distinguishes mild cognitive impairment in Parkinson's disease (PD-MCI); however, it was not evaluated in Brazil. Objectives: To investigate PD-CRS's reliability, validity, normative data, and accuracy for PD-MCI screening in Brazil. Methods: The effects of age, education, and sex on PD-CRS scores were explored. The instrument was tested in 714 individuals (53% female, 21-94 years), with a broad range of education and no neurodegenerative disorder. Trail Making, Consonant Trigrams, Five-Point, and semantic fluency tests were administered for comparison. A second study enrolled patients with PD and intact cognition (n = 44, 59.75 ± 10.79 years) and with PD-MCI (n = 25, 65.76 ± 10.33 years) to investigate criterion validity. PD-CRS subtests were compared with the Cambridge Automated Neuropsychological Battery memory and executive tasks. Results: PD-CRS was unidimensional and reliable (McDonald's ω = 0.83). Using robust multiple regressions, age, and education predicted the total and derived scores in the normative sample. At the 85-point cutoff, PD-MCI was detected with 68% sensitivity and 86% specificity (area under the curve = 0.870). PD-CRS scores strongly correlated with executive and verbal/visual memory tests in both normative and clinical samples. Conclusions: This study investigated the applicability of PD-CRS in the Brazilian context. The scale seems helpful in screening for PD-MCI, with adequate internal consistency and construct validity. The PD-CRS variance is influenced by age and educational level, a critical issue for cognitive testing in countries with educational and cultural heterogeneity.

Evaluation of the Cutaneous Silent Period in a Healthy Brazilian Population.

PURPOSE: To establish cutaneous silent period (CSP) normative values and investigate the variables that may influence them. METHODS: We tested 41 healthy subjects. All subjects underwent nerve conduction studies, and we evaluated the CSP in both arms. RESULTS: Four subjects did not have CSP and were excluded. The analyses were performed in the healthy group composed of 23 women and 14 men, with a mean age of 35 (range, 19-64) years. The CSP median duration was 23.2 milliseconds (ms), with 2 to 98th percentile at 11.3 and 48.7 ms. The median onset latency was 87.9 (range, 72.9-109) ms, and the median end latency was 112 (range, 93.8-138) ms. The CSP onset latency positively correlated with height, whereas CSP end latency and duration were weakly but significantly associated with age. Some measurements of ulnar nerve conduction study also correlated with CSP measures. The interrater coefficients for the primary measures of onset and end latency demonstrates the reproducibility of the method. CONCLUSIONS: The CSP with the fifth digit stimulation and recording from the abductor digiti minimi muscle is a valid diagnostic tool that can be used in clinical practice.

Long-Term Recording of Subthalamic Aperiodic Activities and Beta Bursts in Parkinson's Disease.

BACKGROUND: Local field potentials (LFPs) represent the summation of periodic (oscillations) and aperiodic (fractal) signals. Although previous studies showed changes in beta band oscillations and burst characteristics of the subthalamic nucleus (STN) in Parkinson's disease (PD), how aperiodic activity in the STN is related to PD pathophysiology is unknown. OBJECTIVES: The study aimed to characterize the long-term effects of STN-deep brain stimulation (DBS) and dopaminergic medications on aperiodic activities and beta bursts. METHODS: A total of 10 patients with PD participated in this longitudinal study. Simultaneous bilateral STN-LFP recordings were conducted in six separate visits during a period of 18 months using the Activa PC + S device in the off and on dopaminergic medication states. We used irregular-resampling auto-spectral analysis to separate oscillations and aperiodic components (exponent and offset) in the power spectrum of STN-LFP signals in beta band. RESULTS: Our results revealed a systematic increase in both the exponent and the offset of the aperiodic spectrum over 18 months following the DBS implantation, independent of the dopaminergic medication state of patients with PD. In contrast, beta burst durations and amplitudes were stable over time and were suppressed by dopaminergic medications. CONCLUSIONS: These findings indicate that oscillations and aperiodic activities reflect at least partially distinct yet complementary neural mechanisms, which should be considered in the design of robust biomarkers to optimize adaptive DBS. Given the link between increased gamma-aminobutyric acidergic (GABAergic) transmission and higher aperiodic activity, our findings suggest that long-term STN-DBS may relate to increased inhibition in the basal ganglia. © 2022 International Parkinson and Movement Disorder Society.

Use of non-invasive neurostimulation for rehabilitation in functional movement disorders.

Functional movement disorders (FMD) are a subtype of functional neurological disorders which involve abnormal movements and include multiple phenomenologies. There is a growing interest in the mechanism, diagnosis, and treatment of these disorders. Most of the current therapeutic approaches rely on psychotherapy and physiotherapy conducted by a multidisciplinary team. Although this approach has shown good results in some cases, FMD cause a great burden on the health system and other treatment strategies are urgently needed. In this review, we summarize past studies that have applied non-invasive neurostimulation techniques, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and peripheral nerve stimulation as a treatment for FMD. There is an increasing number of studies related to TMS including randomized controlled trials; however, the protocols amongst studies are not standardized. There is only preliminary evidence for the efficacy of non-invasive neuromodulation in reducing FMD symptoms, and further studies are needed. There is insufficient evidence to allow implementation of these techniques in clinical practice.

Human Studies of Transcranial Ultrasound neuromodulation: A systematic review of effectiveness and safety.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is gaining traction as a safe and non-invasive technique in human studies. There has been a rapid increase in TUS human studies in recent years, with more than half of studies to date published after 2020. This rapid growth in the relevant body of literature necessitates comprehensive reviews to update clinicians and researchers. OBJECTIVE: The aim of this work is to review human studies with an emphasis on TUS devices, sonication parameters, outcome measures, results, and adverse effects, as well as highlight future directions of investigation. METHODS: A systematic review was conducted by searching the Web of Science and PubMed databases on January 12, 2022. Human studies of TUS were included. RESULTS: A total of 35 studies were identified using focused/unfocused ultrasound devices. A total of 677 subjects belonging to diverse cohorts (i.e., healthy, chronic pain, dementia, epilepsy, traumatic brain injury, depression) were enrolled. The stimulation effects vary in a sonication parameter-dependant fashion. Clinical, neurophysiological, radiological and histological outcome measures were assessed. No severe adverse effects were reported in any of the studies surveyed. Mild symptoms were observed in 3.4% (14/425) of the subjects, including headache, mood deterioration, scalp heating, cognitive problems, neck pain, muscle twitches, anxiety, sleepiness and pruritis. CONCLUSIONS: Although increasingly being used, TUS is still in its early phases. TUS can change short-term brain excitability and connectivity, induce long-term plasticity, and modulate behavior. New techniques should be used to further elucidate its underlying mechanisms and identify its application in novel populations.

Epidemiological and clinical aspects of Guillain-Barré syndrome and its variants.

BACKGROUND: Guillain-Barré syndrome (GBS), an acute polyradiculoneuropathy that occurs because of an abnormal inflammatory response in the peripheral nervous system, is clinically characterized by acute flaccid paresis and areflexia with or without sensory symptoms. This syndrome can lead to disabling or even life-threatening sequelae. OBJECTIVE: This study aimed to present the clinical and epidemiological aspects of GBS in patients admitted to a tertiary-level hospital in the Federal District between January 2013 and June 2019. METHODS: In this observational, cross-sectional and retrospective study, medical records of patients diagnosed with acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy or acute axonal motor-sensitive neuropathy based on electromyographic findings were included, and clinical data were collected retrospectively. RESULTS: A total of 100 patients (63 males and 37 females; ratio, 1.7:1) aged 2-86 years (mean, 36.4 years) were included. The mean annual incidence rate of GBS was 0.54 cases/100,000 inhabitants, with 52 and 49% of the cases occurring between October and March (rainy season) and between April and September (dry season), respectively. The proportions of patients showing each GBS variant were as follows: demyelinating forms, 57%; axonal forms, 39%; and undetermined, 4%. The mean duration of hospitalization was 8-15 days for most patients (38%). During hospitalization, 14% of the patients required mechanical ventilation and 20% experienced infectious complications. CONCLUSION: The findings indicate that there was an increase in the incidence of GBS during the rainy season. Moreover, we did not observe the typical bimodal distribution regarding age at onset.

New-Onset Movement Disorders Associated with COVID-19.

Introduction: Movement disorders are increasingly described in hospitalized and milder cases of SARS-CoV-2 infection, despite a very low prevalence compared to the total patients. Methods: We reviewed the scientific literature published in English, spanning from the initial descriptions of COVID-19 until January 25, 2021, in the PubMed/MEDLINE database. Results: We identified 93 new-onset movement disorders cases (44 articles) from 200 papers screened in the database or reference lists. Myoclonus was present in 63.4% (n = 59), ataxia in 38.7% (n = 36), action/postural tremor in 10.8% (n = 10), rigid-akinetic syndrome in 5.38% (n = 5), oculomotor abnormalities in 20.4% (n = 19), catatonia in 2.1% (n = 2), dystonia in 1.1% (n = 1), chorea in 1.1% (n = 1), functional (psychogenic) movement disorders in 3.2% (n = 3) of the reported COVID-19 cases with any movement disorder. Encephalopathy was a common association (n = 37, 39.78%). Discussion: Comprehensive neurophysiological, clinical, and neuroimaging descriptions of movement disorders in the setting of SARS-CoV-2 infection are still lacking, and their pathophysiology may be related to inflammatory, postinfectious, or even indirect mechanisms not specific to SARS-CoV-2, such as ischemic-hypoxic brain insults, drug effects, sepsis, kidney failure. Cortical/subcortical myoclonus, which the cited secondary mechanisms can largely cause, seems to be the most common hyperkinetic abnormal movement, and it might occur in association with encephalopathy and ataxia. Conclusion: This brief review contributes to the clinical description of SARS-CoV-2 potential neurological manifestations, assisting clinical neurologists in identifying features of these uncommon syndromes as a part of COVID-19 symptomatology. Highlights: - Movement disorders are probably uncommon neurological manifestations in SARS-CoV-2 infection;- Myoclonus is the most reported movement disorder associated with COVID-19, its clinical complications or pharmacological management;- The pathophysiology is yet not well-understood but can include systemic inflammation, autoimmune mechanisms, or hypoxia.