Towards an electroencephalographic measure of awareness based on the reactivity of oscillatory macrostates to hearing a subject's own name.

We proposed that the brain's electrical activity is composed of a sequence of alternating states with repeating topographic spectral distributions on scalp electroencephalogram (EEG), referred to as oscillatory macrostates. The macrostate showing the largest decrease in the probability of occurrence, measured as a percentage (reactivity), during sensory stimulation was labelled as the default EEG macrostate (DEM). This study aimed to assess the influence of awareness on DEM reactivity (DER). We included 11 middle cerebral artery ischaemic stroke patients with impaired awareness having a median Glasgow Coma Scale (GCS) of 6/15 and a group of 11 matched healthy controls. EEG recordings were carried out during auditory 1 min stimulation epochs repeating either the subject's own name (SON) or the SON in reverse (rSON). The DEM was identified across three SON epochs alternating with three rSON epochs. Compared with the patients, the DEM of controls contained more posterior theta activity reflecting source dipoles that could be mapped in the posterior cingulate cortex. The DER was measured from the 1 min quiet baseline preceding each stimulation epoch. The difference in mean DER between the SON and rSON epochs was measured by the salient EEG reactivity (SER) theoretically ranging from -100% to 100%. The SER was 12.4 ± 2.7% (Mean ± standard error of the mean) in controls and only 1.3 ± 1.9% in the patient group (P < 0.01). The patient SER decreased with the Glasgow Coma Scale. Our data suggest that awareness increases DER to SON as measured by SER.

The relationship between pathological brain activity and functional network connectivity in glioma patients.

PURPOSE: Glioma is associated with pathologically high (peri)tumoral brain activity, which relates to faster progression. Functional connectivity is disturbed locally and throughout the entire brain, associating with symptomatology. We, therefore, investigated how local activity and network measures relate to better understand how the intricate relationship between the tumor and the rest of the brain may impact disease and symptom progression. METHODS: We obtained magnetoencephalography in 84 de novo glioma patients and 61 matched healthy controls. The offset of the power spectrum, a proxy of neuronal activity, was calculated for 210 cortical regions. We calculated patients' regional deviations in delta, theta and lower alpha network connectivity as compared to controls, using two network measures: clustering coefficient (local connectivity) and eigenvector centrality (integrative connectivity). We then tested group differences in activity and connectivity between (peri)tumoral, contralateral homologue regions, and the rest of the brain. We also correlated regional offset to connectivity. RESULTS: As expected, patients' (peri)tumoral activity was pathologically high, and patients showed higher clustering and lower centrality than controls. At the group-level, regionally high activity related to high clustering in controls and patients alike. However, within-patient analyses revealed negative associations between regional deviations in brain activity and clustering, such that pathologically high activity coincided with low network clustering, while regions with 'normal' activity levels showed high network clustering. CONCLUSION: Our results indicate that pathological activity and connectivity co-localize in a complex manner in glioma. This insight is relevant to our understanding of disease progression and cognitive symptomatology.

Relationship between the interlimb transfer of a visuomotor learning task and interhemispheric inhibition in healthy humans.

The "interlimb transfer" phenomenon consists of improved performance of the trained and untrained contralateral limbs after unilateral motor practice. We here assessed whether a visuomotor learning task can be transferred from one hemisphere to the other, whether this occurs symmetrically, and the cortical neurophysiological correlates of this phenomenon, focusing on interhemispheric connectivity measures. We enrolled 33 healthy subjects (age range: 24-73 years). Participants underwent two randomized sessions, which investigated the transfer from the dominant to the nondominant hand and vice versa. Measures of cortical and intracortical excitability and interhemispheric inhibition were assessed through transcranial magnetic stimulation before and after a visuomotor task. The execution of the visuomotor task led to an improvement in motor performance with the dominant and nondominant hands and induced a decrease in intracortical inhibition in the trained hemisphere. Participants were also able to transfer the visuomotor learned skill. The interlimb transfer, however, only occurred from the dominant to the nondominant hand and positively correlated with individual learning-related changes in interhemispheric inhibition. We here demonstrated that the "interlimb transfer" of a visuomotor task occurs asymmetrically and relates to the modulation of specific inhibitory interhemispheric connections. The study results have pathophysiological, clinical, and neuro-rehabilitative implications.

Long Latency Reflexes in Clinical Neurology: A Systematic Review.

BACKGROUND: Long latency reflexes (LLRs) are impaired in a wide array of clinical conditions. We aimed to illustrate the clinical applications and recent advances of LLR in various neurological disorders from a systematic review of published literature. METHODS: We reviewed the literature using appropriately chosen MeSH terms on the database platforms of MEDLINE, Web of Sciences, and Google Scholar for all the articles from 1st January 1975 to 2nd February 2021 using the search terms "long loop reflex", "long latency reflex" and "C-reflex". The included articles were analyzed and reported using synthesis without meta-analysis (SWiM) guidelines. RESULTS: Based on our selection criteria, 40 articles were selected for the systematic review. The various diseases included parkinsonian syndromes (11 studies, 217 patients), Huntington's disease (10 studies, 209 patients), myoclonus of varied etiologies (13 studies, 127 patients) including progressive myoclonic epilepsy (5 studies, 63 patients) and multiple sclerosis (6 studies, 200 patients). Patients with parkinsonian syndromes showed large amplitude LLR II response. Enlarged LLR II was also found in myoclonus of various etiologies. LLR II response was delayed or absent in Huntington's disease. Delayed LLR II response was present in multiple sclerosis. Among the other diseases, LLR response varied according to the location of cerebellar lesions while the results were equivocal in patients with essential tremor. CONCLUSIONS: Abnormal LLR is observed in many neurological disorders. However, larger systematic studies are required in many neurological disorders in order to establish its role in diagnosis and management.

Being a technician during COVID-19: a qualitative cross-sectional survey on the experiences of clinical neurophysiology technicians.

BACKGROUND: During the Sars-CoV-2 virus pandemic, Italy faced an unrivaled health emergency. Its impact has been significant on the hospital system and personnel. Clinical neurophysiology technicians played a central role (but less visibly so compared to other healthcare workers) in managing the COVID-19 pandemic. This research aims to explore the experiences of clinical neurophysiology technicians during the pandemic and contribute to the debate on the well-being of healthcare workers on the front line. METHODS: We implemented a cross-sectional survey across Italy. It contained questions that were open-ended for participants to develop their answers and acquire a fuller perspective. The responses were analyzed according to the framework method. RESULTS: One hundred and thirty-one responses were valid, and the following themes were generated: technicians' experiences in their relationship with patients, technicians' relationship with their workgroup and directors, and technicians' relationship with the context outside of their work. The first theme included sub-themes: fear of infection, empathy, difficulty, a sense of obligation and responsibility, anger, and sadness. The second theme contained selfishness/solidarity in the workgroup, lack of protection/collaboration from superiors, stress, and distrust. The last theme included fear, stress/tiredness, serenity, sadness, and anger. CONCLUSION: This study contributes to building a humanized perspective for personnel management, bringing attention to the technical work of healthcare professionals in an emergency and the emotional and relational dimensions. These are the starting points to define proper, contextually adequate support.

Variability in electrodiagnostic findings associated with neurogenic thoracic outlet syndrome.

INTRODUCTION/AIMS: Neurogenic thoracic outlet syndrome (NTOS) is a heterogeneous and often disputed entity. An electrodiagnostic pattern of T1 > C8 axon involvement is considered characteristic for the diagnosis of NTOS. However, since the advent of high-resolution nerve ultrasound (US) imaging, we have encountered several patients with a proven entrapment of the lower brachial plexus who showed a different, variable electrodiagnostic pattern. METHODS: In this retrospective case series, 14 patients with an NTOS diagnosis with a verified source of compression of the lower brachial plexus and abnormal findings on their electrodiagnostic testing were included. Their medical records were reviewed to obtain clinical, imaging, and electrodiagnostic data. RESULTS: Seven patients showed results consistent with the "classic" T1 axon > C8 pattern of involvement. Less typical findings included equally severe involvement of T1 and C8 axons, more severe C8 involvement, pure motor abnormalities, neurogenic changes on needle electromyography in the flexor carpi radialis and biceps brachii muscles, and one patient with an abnormal sensory nerve action potential (SNAP) amplitude for the median sensory response recorded from the third digit. Patients with atypical findings on electrodiagnostic testing underwent nerve imaging more often compared to patients with classic findings (seven of seven patients vs. five of seven respectively), especially nerve ultrasound. DISCUSSION: When there is a clinical suspicion of NTOS, an electrodiagnostic finding other than the classic T1 > C8 pattern of involvement does not rule out the diagnosis. High resolution nerve imaging is valuable to diagnose additional patients with this treatable condition.

Efficacy of rituximab in anti-myelin-associated glycoprotein demyelinating polyneuropathy: Clinical, hematological and neurophysiological correlations during 2 years of follow-up.

BACKGROUND AND PURPOSE: We evaluated the clinical and neurophysiological efficacy of rituximab (RTX) in a neurophysiologically homogeneous group of patients with monoclonal gammopathy and immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody (anti-MAG) demyelinating polyneuropathy. METHODS: Twenty three anti-MAG-positive polyneuropathic patients were prospectively evaluated before and for 2 years after treatment with RTX 375 mg/m2 . The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (INCAT-ds), modified INCAT sensory score (mISS), Medical Research Council sum score, Patients' Global Impression of Change scale were used, IgM levels were assessed and extensive electrophysiological examinations were performed before (T0) and 1 year (T1) and 2 years (T2) after RTX treatment. RESULTS: At T1 and T2 there was a significant reduction from T0 both in mISS and in INCAT-ds, with a p value < 0.001 in the inferential Friedman's test overall analysis. Ulnar nerve Terminal Latency Index and distal motor latency significantly changed from T0 to T1 and in the overall analysis (p = 0.001 and p = 0.002), and ulnar nerve sensory nerve action potential (SNAP) amplitude was significantly increased at T2 from T1, with a p value < 0.001 in the overall analysis. Analysis of the receiver-operating characteristic curves showed that a 41.8% increase in SNAP amplitude in the ulnar nerve at T2 from T0 was a fair predictor of a mISS reduction of ≥2 points (area under the curve 0.85; p = 0.005; sensitivity: 90.9%, specificity: 83.3%). CONCLUSIONS: This study suggests that RTX is effective in patients with clinically active demyelinating anti-MAG neuropathy over 2 years of follow-up, and that some neurophysiological variables might be useful for monitoring this efficacy.

Deep brain stimulation of the brainstem.

Deep brain stimulation (DBS) of the subthalamic nucleus, pallidum, and thalamus is an established therapy for various movement disorders. Limbic targets have also been increasingly explored for their application to neuropsychiatric and cognitive disorders. The brainstem constitutes another DBS substrate, although the existing literature on the indications for and the effects of brainstem stimulation remains comparatively sparse. The objective of this review was to provide a comprehensive overview of the pertinent anatomy, indications, and reported stimulation-induced acute and long-term effects of existing white and grey matter brainstem DBS targets. We systematically searched the published literature, reviewing clinical trial articles pertaining to DBS brainstem targets. Overall, 164 studies describing brainstem DBS were identified. These studies encompassed 10 discrete structures: periaqueductal/periventricular grey (n = 63), pedunculopontine nucleus (n = 48), ventral tegmental area (n = 22), substantia nigra (n = 9), mesencephalic reticular formation (n = 7), medial forebrain bundle (n = 8), superior cerebellar peduncles (n = 3), red nucleus (n = 3), parabrachial complex (n = 2), and locus coeruleus (n = 1). Indications for brainstem DBS varied widely and included central neuropathic pain, axial symptoms of movement disorders, headache, depression, and vegetative state. The most promising results for brainstem DBS have come from targeting the pedunculopontine nucleus for relief of axial motor deficits, periaqueductal/periventricular grey for the management of central neuropathic pain, and ventral tegmental area for treatment of cluster headaches. Brainstem DBS has also acutely elicited numerous motor, limbic, and autonomic effects. Further work involving larger, controlled trials is necessary to better establish the therapeutic potential of DBS in this complex area.

A nationwide survey on clinical neurophysiology education in Italian schools of specialization in neurology.

INTRODUCTION: Clinical neurophysiology deals with nervous system functions assessed with electrophysiological and ultrasound-based imaging techniques. Even though the need for highly specialized neurophysiologists has increased, residency training rarely takes today's requirements into account. This study aimed to snapshot the neurophysiological training provided by Italian specialization schools in neurology. METHODS: A single-page web-based survey comprising 13 multiple-choice categorical and interval scale questions was sent via e-mail to neurology specialization school directors. The survey addressed the programs' structural neurophysiology organization, time dedicated to each clinical neurophysiology subspecialty, and descriptors assessing the discipline's importance (e.g., residents who attempted residential courses, gained certifications, or awards gained). RESULTS: The most studied neurophysiological techniques were electroencephalography (EEG) and electromyography (EMG). Most specialization schools devoted less than 3 months each to multimodal evoked potentials (EPs), ultrasound sonography (US), and intra-operative monitoring. Of the 35 specialization schools surveyed, 77.1% reported that four students, or fewer, participated in the Italian Society of Clinical Neurophysiology Examination in Neurophysiology. Of the 35 specialization centers surveyed, 11.4% declared that the final evaluation required students to discuss a neurophysiological test. DISCUSSION: Our survey underlined the poorly standardized technical requirements in postgraduate neurology specialization schools, wide variability among training programs, and limited training on multi-modal evoked potentials, intraoperative monitoring, and sonography. These findings underline the need to reappraise and improve educational and training standards for clinical neurophysiology during postgraduate specialization schools in neurology with an international perspective.

Intracerebral electrical stimulations of the temporal lobe: A stereoelectroencephalography study.

The functional anatomy of the anteromesial portion of the temporal lobe and its involvement in epilepsy can be explored by means of intracerebral electrical stimulations. Here, we aimed to expand the knowledge of its physiological and pathophysiological symptoms by conducting the first large-sample systematic analysis of 1529 electrical stimulations of this anatomical region. We retrospectively analysed all clinical manifestations induced by intracerebral electrical stimulations in 173 patients with drug-resistant focal epilepsy with at least one electrode implanted in this area. We found that high-frequency stimulations were more likely to evoke electroclinical manifestations (p < .0001) and also provoked 'false positive' seizures. Multimodal symptoms were associated with EEG electrical modification (after discharge) (p < .0001). Visual symptoms were not associated with after discharge (p = .0002) and were mainly evoked by stimulation of the hippocampus (p = .009) and of the parahippocampal gyrus (p = .0212). 'False positive seizures' can be evoked by stimulation of the hippocampus, parahippocampal gyrus and amygdala, likely due to their intrinsic low epileptogenic threshold. Visual symptoms evoked in the hippocampus and parahippocampal gyrus, without EEG changes, are physiological symptoms and suggest involvement of these areas in the visual ventral stream. Our findings provide meaningful guidance in the interpretation of intracranial EEG studies of the temporal lobe.

Neurophysiological patterns of acute and post-acute foodborne botulism.

INTRODUCTION/AIMS: Neurophysiological patterns in patients with foodborne botulism are rarely described after the acute phase. We report data from a large Italian outbreak of botulism, with patients evaluated at different timepoints after poisoning. METHODS: Eighteen male patients (mean age 47 ± 8.4 y) underwent 22 clinical and neurophysiological evaluations (4 patients were re-evaluated). The resting compound muscle action potential (CMAP) amplitude, postexercise CMAP amplitude, CMAP change after high-frequency (50 Hz) repetitive nerve stimulation (HFRNS), and motor unit action potentials (MUAPs) were assessed in the acute (4-8 days after poisoning; 5 patients), early post-acute (32-39 days after poisoning; 5 patients), and late post-acute (66-80 days after poisoning; 12 patients) phases. RESULTS: In the acute, early post-acute, and late post-acute phases, respectively, reduced CMAP amplitudes were found in 100%, 20%, and 17% of patients; abnormal postexercise CMAP facilitation was observed in 100%, 40%, and 0% of patients; and pathological incremental responses to HFRNS were found in 80%, 50%, and 8% of patients. Baseline CMAP amplitudes, postexercise CMAP facilitation, and CMAP increases in response to HFRNS differed significantly between the acute and post-acute phases. Small MUAPs were found in 100% of patients in the acute and early post-acute phases and in 50% of patients in the late post-acute phase. DISCUSSION: The neurophysiological findings of foodborne botulism vary considerably according to the evaluation time point. In the post-acute phase, different neurophysiological techniques must be applied to support a diagnosis of botulism.

Utility of neuromuscular ultrasound in the investigation of common mononeuropathies in everyday neurophysiology practice.

INTRODUCTION: In everyday clinical neurophysiology practice, mononeuropathies are evaluated primarily by traditional electrodiagnostic testing. We sought to assess the additional benefit of neuromuscular ultrasound (US) in this scenario. METHODS: All consecutive mononeuropathies undergoing combined US and electrodiagnostic evaluation over a 23-mo period at a single neurophysiology practice were reviewed. Three independent examiners assessed how often US was: (a) "contributory" - enabling a definite diagnosis not made by electrophysiology alone and/or impacting on the therapeutic decision, (b) "confirmatory" of the electrodiagnostic findings, but not adding further diagnostic or therapeutic information, or (c) "negative" - missed the diagnosis. RESULTS: There were 385 studies included. US was "contributory" in 36%, "confirmatory" in 61% and "negative" in 3%. DISCUSSION: In this study of everyday neurophysiology practice, neuromuscular US contributed significant diagnostic or therapeutic information in over 1/3 of the investigations for common mononeuropathies. False negative US studies were uncommon in this setting.

Standard procedures for the diagnostic pathway of sleep-related epilepsies and comorbid sleep disorders: an EAN, ESRS and ILAE-Europe consensus review.

BACKGROUND AND PURPOSE: Some epilepsy syndromes (sleep-related epilepsies, SREs) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life. Our purpose was to define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2). METHODS: The project was conducted under the auspices of the European Academy of Neurology, the European Sleep Research Society and the International League Against Epilepsy Europe. The framework entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For the literature search a stepwise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine's MEDLINE database and Cochrane Library. RESULTS: Scenario 1: Despite a low quality of evidence, recommendations on anamnestic evaluation and tools for capturing the event at home or in the laboratory are provided for specific SREs. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizure control. CONCLUSIONS: Definitive procedures for evaluating patients with SRE are lacking. Advice is provided that could be of help for standardizing and improving the diagnostic approach of specific SREs. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined.

Evolving concepts on bradykinesia.

Bradykinesia is one of the cardinal motor symptoms of Parkinson's disease and other parkinsonisms. The various clinical aspects related to bradykinesia and the pathophysiological mechanisms underlying bradykinesia are, however, still unclear. In this article, we review clinical and experimental studies on bradykinesia performed in patients with Parkinson's disease and atypical parkinsonism. We also review studies on animal experiments dealing with pathophysiological aspects of the parkinsonian state. In Parkinson's disease, bradykinesia is characterized by slowness, the reduced amplitude of movement, and sequence effect. These features are also present in atypical parkinsonisms, but the sequence effect is not common. Levodopa therapy improves bradykinesia, but treatment variably affects the bradykinesia features and does not significantly modify the sequence effect. Findings from animal and patients demonstrate the role of the basal ganglia and other interconnected structures, such as the primary motor cortex and cerebellum, as well as the contribution of abnormal sensorimotor processing. Bradykinesia should be interpreted as arising from network dysfunction. A better understanding of bradykinesia pathophysiology will serve as the new starting point for clinical and experimental purposes.

Risk factors for psychological distress in electroencephalography technicians during the COVID-19 pandemic: A national-level cross-sectional survey in Japan.

OBJECTIVE: To identify the risk factors for psychological distress in electroencephalography (EEG) technicians during the coronavirus disease 2019 (COVID-19) pandemic. METHOD: In this national-level cross-sectional survey initiated by Japan Young Epilepsy Section (YES-Japan), which is a national chapter of The Young Epilepsy Section of the International League Against Epilepsy (ILAE-YES), a questionnaire was administered to 173 technicians engaged in EEG at four clinics specializing in epilepsy care and 20 hospitals accredited as (quasi-) epilepsy centers or epilepsy training facilities in Japan from March 1 to April 30, 2021. We collected data on participants' profiles, information about work, and psychological distress outcome measurements, such as the K-6 and Tokyo Metropolitan Distress Scale for Pandemic (TMDP). Linear regression analysis was used to identify the risk factors for psychological distress. Factors that were significantly associated with psychological distress in the univariate analysis were subjected to multivariate analysis. RESULTS: Among the 142 respondents (response rate: 82%), 128 were included in the final analysis. As many as 35.2% of EEG technicians have been under psychological distress. In multivariate linear regression analysis for K-6, female sex, examination for patients (suspected) with COVID-19, and change in salary or bonus were independent associated factors for psychological distress. Contrastingly, in multivariate linear regression analysis for TMDP, female sex, presence of cohabitants who had to be separated from the respondent due to this pandemic, and change in salary or bonus were independent associated factors for psychological distress. CONCLUSION: We successfully identified the risk factors associated with psychological distress in EEG technicians during the COVID-19 pandemic. Our results may help in understanding the psychological stress in EEG technicians during the COVID-19 pandemic and improving the work environment, which is necessary to maintain the mental health of EEG technicians.

Electroencephalography Attenuations in Adults: Clinical Correlates.

Spontaneous intermittent generalized attenuations (SIGAs) are defined as a transient decrease in amplitude of electroencephalography (EEG) activity in response to a physiologic process, external stimuli, or as a result of a pathologic condition. We seek to investigate their relationship to clinical outcomes. Demographic information, modified Rankin Scale (mRS), and clinical information were noted on 22 consecutive patients with SIGAs on their EEG. 12 of the 22 patients (54.5%) died, and 12 patients (54.5%) were admitted to the intensive care unit or coronary care unit. Future studies should attempt to prospectively compare outcomes among patients with SIGAs against a control group.

How to Identify Responders and Nonresponders to Dorsal Root Ganglion-Stimulation Aimed at Eliciting Motor Responses in Chronic Spinal Cord Injury: Post Hoc Clinical and Neurophysiological Tests in a Case Series of Five Patients.

OBJECTIVE: While integrity of spinal pathways below injury is generally thought to be an important factor in the success-rate of neuromodulation strategies for spinal cord injury (SCI), it is still unclear how the integrity of these pathways conveying the effects of stimulation should be assessed. In one of our institutional case series of five patients receiving dorsal root ganglion (DRG)-stimulation for elicitation of immediate motor response in motor complete SCI, only two out of five patients presented as responders, showing immediate muscle activation upon DRG-stimulation. The current study focuses on post hoc clinical-neurophysiological tests performed within this patient series to illustrate their use for prediction of spinal pathway integrity, and presumably, responder-status. MATERIALS AND METHODS: In a series of three nonresponders and two responders (all male, American Spinal Injury Association [ASIA] impairment scale [AIS] A/B), a test-battery consisting of questionnaires, clinical measurements, as well as a series of neurophysiological measurements was performed less than eight months after participation in the initial study. RESULTS: Nonresponders presented with a complete absence of spasticity and absence of leg reflexes. Additionally, nonresponders presented with close to no compound muscle action potentials (CMAPs) or Hofmann(H)-reflexes. In contrast, both responders presented with clear spasticity, elicitable leg reflexes, CMAPs, H-reflexes, and sensory nerve action potentials, although not always consistent for all tested muscles. CONCLUSIONS: Post hoc neurophysiological measurements were limited in clearly separating responders from nonresponders. Clinically, complete absence of spasticity-related complaints in the nonresponders was a distinguishing factor between responders and nonresponders in this case series, which mimics prior reports of epidural electrical stimulation, potentially illustrating similarities in mechanisms of action between the two techniques. However, the problem remains that explicit use and report of preinclusion clinical-neurophysiological measurements is missing in SCI literature. Identifying proper ways to assess these criteria might therefore be unnecessarily difficult, especially for nonestablished neuromodulation techniques.

Phase-Dependent Suppression of Beta Oscillations in Parkinson's Disease Patients.

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain.SIGNIFICANCE STATEMENT In Parkinson's disease (PD), movement impairment is correlated with exaggerated beta frequency oscillations in the cerebral cortex and subthalamic nucleus (STN). Using a novel method of stimulation in PD patients undergoing neurosurgery, we demonstrate that STN beta oscillations can be suppressed when consecutive electrical pulses arrive at a specific phase of the oscillation. This effect is likely because of interrupting the timing of neuronal activity rather than excitability, as stimulation altered the firing pattern of STN spiking without changing overall rate. These findings show the potential of oscillation phase as an input for "closed-loop" stimulation, which could provide a valuable neuromodulation strategy for the treatment of brain disorders and for elucidating the role of neuronal oscillations in the healthy brain.

Differential effects of motor skill acquisition on the primary motor and sensory cortices in healthy humans.

KEY POINTS: We explored the large variability in motor skill acquisition-related effects on the primary and sensory cortices. Namely, we tested whether this variability depends on interindividual variance or the type of motor task investigated. We compared different motor-learning tasks, i.e. model-free vs. model-based learning tasks, and their possible differential effects on the primary motor and sensory cortices by using transcranial magnetic stimulation techniques. The model-free learning task induced an increase in corticospinal excitability and a reduction in the amplitude of somatosensory-evoked potentials. Conversely, the model-based learning tasks induced a decrease in intracortical inhibition. No correlations were found between neurophysiological changes and motor performance, indicating that this differential modulation may be secondary to the motor skill acquisition. The study results suggest differential motor skill acquisition-related effects on cortical parameters, possibly due to the engagement of specific neurophysiological substrates. ABSTRACT: A large variability in learning-related neurophysiological changes in the primary motor and sensory cortices has been observed. It is unclear whether these differential effects are due to the different tasks investigated or to interindividual variance. Only a few studies have assessed different motor-learning tasks and their effects on neurophysiological features within the same group of participants, and several issues are unclear. Here, we compared the effects of different tasks within each individual. We investigated the effects on motor and sensory cortex parameters after a model-free learning task, i.e. a ballistic motor task, compared with model-based learning tasks, i.e. visuomotor-learning tasks. Motor- and sensory-evoked potentials, intracortical excitability as assessed by short-interval intracortical inhibition, and sensorimotor interaction, i.e. short-latency afferent inhibition, were recorded from 15 healthy subjects before and after the tasks. The ballistic motor task induced an increase in corticospinal excitability but did not change motor cortex intracortical inhibition or sensorimotor integration. In addition, it decreased the amplitude of cortical components of the somatosensory-evoked potentials. The visuomotor-learning tasks induced a reduction in motor cortex intracortical inhibition but did not modulate corticospinal and sensory cortex excitability or sensorimotor integration. This differential modulation is likely to be secondary to the motor skill acquisition, since no correlation was observed between neurophysiological changes and motor performance. Our results demonstrate differential motor skill acquisition-related effects on cortical parameters, possibly reflecting the engagement of specific neurophysiological substrates, and contribute in-depth knowledge of the mechanisms involved in different types of motor skill acquisition in humans.

Re-emergent Tremor in Parkinson's Disease: The Role of the Motor Cortex.

BACKGROUND: Parkinson's disease patients may show a tremor that appears after a variable delay while the arms are kept outstretched (re-emergent tremor). The objectives of this study were to investigate re-emergent tremor pathophysiology by studying the role of the primary motor cortex in this tremor and making a comparison with rest tremor. METHODS: We enrolled 10 Parkinson's disease patients with both re-emergent and rest tremor. Tremor was assessed by spectral analysis, corticomuscular coherence and tremor-resetting produced by transcranial magnetic stimulation over the primary motor cortex. We also recorded transcranial magnetic stimulation-evoked potentials generated by motor cortex stimulation during rest tremor, tremor suppression during wrist extension, and re-emergent tremor. Spectral analysis, corticomuscular coherence, and tremor resetting were compared between re-emergent tremor and rest tremor. RESULTS: Re-emergent tremor showed significant corticomuscular coherence, causal relation between motor cortex activity and tremor muscle and tremor resetting. The P60 component of transcranial magnetic stimulation-evoked potentials reduced in amplitude during tremor suppression, recovered before re-emergent tremor, was facilitated at re-emergent tremor onset, and returned to values similar to those of rest tremor during re-emergent tremor. Compared with rest tremor, re-emergent tremor showed similar corticomuscular coherence and tremor resetting, but slightly higher frequency. CONCLUSIONS: Re-emergent tremor is causally related with the activity of the primary motor cortex, which is likely a convergence node in the network that generates re-emergent tremor. Re-emergent tremor and rest tremor share common pathophysiological mechanisms in which the motor cortex plays a crucial role. © 2020 International Parkinson and Movement Disorder Society.