Involvement of muscarinic acetylcholine receptor-mediated cholinergic neurotransmission in TMS-EEG responses.

The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is emerging as a valuable tool for investigating brain functions in health and disease. However, the detailed neural mechanisms underlying TMS-EEG responses, including TMS-evoked EEG potentials (TEPs) and TMS-induced EEG oscillations (TIOs), remain largely unknown. Combining TMS-EEG with pharmacological interventions provides a unique opportunity to elucidate the roles of specific receptor-mediated neurotransmissions in these responses. Here, we investigated the involvement of muscarinic acetylcholine receptor (mAChR)-mediated cholinergic neurotransmission in TMS-EEG responses by evaluating the effects of mAChR antagonists on TEPs and TIOs in twenty-four healthy participants using a randomized, placebo-controlled crossover design. TEPs and TIOs were measured before and after administering a single oral dose of scopolamine (a non-selective mAChR antagonist), biperiden (an M1 mAChR antagonist), or placebo, with TMS targeting the left medial prefrontal cortex (mPFC), angular gyrus (AG), and supplementary motor area (SMA). The results indicated that mAChR-mediated cholinergic neurotransmission played a role in TEPs, but not TIOs, in a target-specific manner. Specifically, scopolamine significantly increased the amplitude of a local TEP component between approximately 40 and 63 ms post-stimulus when TMS was applied to the SMA, but not the mPFC or AG. Biperiden produced a similar but less pronounced effect. Importantly, the effects of these mAChR antagonists on TEPs were independent of those on sensory-evoked EEG potentials caused by TMS-associated sensory stimulation. These findings expand our understanding of TMS-EEG physiology, providing insights for its application in physiological and clinical research.

Continuous Blood Pressure Indices During the First 72 Hours and Functional Outcome in Patients with Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Management of intracerebral hemorrhage (ICH) is challenged by limited therapeutic options and a complex relationship between blood pressure (BP) dynamics, especially BP variability (BPV) and ICH outcome. METHODS: In an exploratory analysis of prospectively collected data on consecutive patients with nontraumatic ICH between 2015 and 2020, continuous BP accessed via an arterial line extracted from the Intellispace Critical Care and Anesthesia information system (Philips Healthcare) was analyzed over the first 72 h post admission. Arterial lines were used as part of standard clinical practice in the intensive care, ensuring high fidelity and real-time data essential for acute care settings. BPV was assessed through successive variation (SV), standard deviation (SD), and coefficient of variation using all available BP measurements. Multivariate regression models were applied to evaluate the association between BPV indices and functional outcome at 3 months. RESULTS: Among 261 patients (mean age 69.6 ± 15.2 years, 47.9% female, median National Institutes of Health Stroke Scale [NIHSS] score 6 [interquartile range 2-12]) analyzed, lower systolic BP upon admission (< 140 mm Hg) and lower systolic BPV were significantly associated with favorable outcome, whereas higher diastolic BPV correlated with improved outcomes. In the multivariate analysis, diastolic BPV (SD, SV) within the first 72 h post admission emerged as an independent predictor of good functional outcome (modified Rankin Scale score < 3; odds ratio 1.123, 95% confidence interval CI 1.008-1.184, p = 0.035), whereas systolic BPV (SD) showed a negative association. Patients with better outcomes also exhibited distinct clinical characteristics, including younger age, lower median NIHSS scores, and less prevalence of anticoagulation therapy upon admission. CONCLUSIONS: This study shows the prognostic value of BPV in the acute phase of ICH. Lower systolic BPV (SD) and higher diastolic BPV (SD, SV) were associated with better functional outcomes, challenging traditional BP management strategies. These findings might help to tailor a personalized BP management in ICH.

Brain state-dependent repetitive transcranial magnetic stimulation for motor stroke rehabilitation: a proof of concept randomized controlled trial.

Background: In healthy subjects, repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1) demonstrated plasticity effects contingent on electroencephalography (EEG)-derived excitability states, defined by the phase of the ongoing sensorimotor µ-oscillation. The therapeutic potential of brain state-dependent rTMS in the rehabilitation of upper limb motor impairment post-stroke remains unexplored. Objective: Proof-of-concept trial to assess the efficacy of rTMS, synchronized to the sensorimotor µ-oscillation, in improving motor impairment and reducing upper-limb spasticity in stroke patients. Methods: We conducted a parallel group, randomized double-blind controlled trial in 30 chronic stroke patients (clinical trial registration number: NCT05005780). The experimental intervention group received EEG-triggered rTMS of the ipsilesional M1 [1,200 pulses; 0.33 Hz; 100% of the resting motor threshold (RMT)], while the control group received low-frequency rTMS of the contralesional motor cortex (1,200 pulses; 1 Hz, 115% RMT), i.e., an established treatment protocol. Both groups received 12 rTMS sessions (20 min, 3× per week, 4 weeks) followed by 50 min of physiotherapy. The primary outcome measure was the change in upper-extremity Fugl-Meyer assessment (FMA-UE) scores between baseline, immediately post-treatment and 3 months' follow-up. Results: Both groups showed significant improvement in the primary outcome measure (FMA-UE) and the secondary outcome measures. This included the reduction in spasticity, measured objectively using the hand-held dynamometer, and enhanced motor function as measured by the Wolf Motor Function Test (WMFT). There were no significant differences between the groups in any of the outcome measures. Conclusion: The application of brain state-dependent rTMS for rehabilitation in chronic stroke patients is feasible. This pilot study demonstrated that the brain oscillation-synchronized rTMS protocol produced beneficial effects on motor impairment, motor function and spasticity that were comparable to those observed with an established therapeutic rTMS protocol. Clinical Trial Registration: ClinicalTrials.gov, identifier [NCT05005780].

Heart Rate Variability and Functional Outcomes of Patients with Spontaneous Intracerebral Hemorrhage.

BACKGROUND: The relationship between heart rate variability (HRV) changes potentially indicating autonomic dysregulation following spontaneous intracerebral hemorrhage (ICH) and functional outcome has not yet been fully elucidated. This study investigated the effects of HRV during the initial 96 h after admission on 90-day functional outcome in ICH patients. METHODS: We included patients with spontaneous ICH in a prospective cohort single-center study. Continuous HR data were retrieved from the Intellispace Critical Care and Anesthesia information system (Philips Healthcare) and analyzed within the following time intervals: 0-2, 0-8, 0-12, 0-24, 0-48, 0-72, and 8-16, 16-24, 24-48, 48-72, 72-96 h after admission. HRV was determined from all available HR values by calculating the successive variability (SV), standard deviation (SD), and coefficient of variation (CV). Low HRV was set as SD ≤ 11.4 ms, and high HRV as SD > 11.4 ms. The clinical severity of ICH was assessed using the National Institutes of Health Stroke Scale (NIHSS) and functional outcome using the modified Rankin Scale (mRS). Good functional outcome was defined as mRS 0-2. RESULTS: The cohort included 261 ICH patients (mean age ± SD 69.6 ± 16.5 years, 48.7% female, median NIHSS 6 (2, 12), median ICH score 1 (0, 2), of whom 106 (40.6%) had good functional outcome. All patients had the lowest HRV at admission, which increased during the first two days. Comparing ICH patients with low HRV (n = 141) and high HRV (n = 118), those with good outcome showed significantly lower HRV during the first three days (0-72 h: HRV SD good outcome 10.6 ± 3.5 ms vs. poor outcome 12.0 ± 4.0 ms; p = 0.004). Logistic regression revealed that advanced age, high premorbid mRS, and high NIHSS at admission were significant predictors of poor functional outcome, while reduced SD of HRV showed a non-significant trend towards good functional outcome (0-72 h: OR 0.898; CI 0.800-1.008; p = 0.067). CONCLUSIONS: Our results indicate autonomic dysfunction with sympathetic hyperactivity after spontaneous ICH, as reflected by the evidence of the lower HRV in the first days. Initially increased sympathetic tone appears to have a protective effect, as suggested by the comparatively lower HRV in patients with good functional outcome at the first days.

Local neuronal sleep after stroke: The role of cortical bistability in brain reorganization.

BACKGROUND: Acute cerebral ischemia triggers a number of cellular mechanisms not only leading to excitotoxic cell death but also to enhanced neuroplasticity, facilitating neuronal reorganization and functional recovery. OBJECTIVE: Transferring these cellular mechanisms to neurophysiological correlates adaptable to patients is crucial to promote recovery post-stroke. The combination of TMS and EEG constitutes a promising readout of neuronal network activity in stroke patients. METHODS: We used the combination of TMS and EEG to investigate the development of local signal processing and global network alterations in 40 stroke patients with motor deficits alongside neural reorganization from the acute to the chronic phase. RESULTS: We show that the TMS-EEG response reflects information about reorganization and signal alterations associated with persistent motor deficits throughout the entire post-stroke period. In the early post-stroke phase and in a subgroup of patients with severe motor deficits, TMS applied to the lesioned motor cortex evoked a sleep-like slow wave response associated with a cortical off-period, a manifestation of cortical bistability, as well as a rapid disruption of the TMS-induced formation of causal network effects. Mechanistically, these phenomena were linked to lesions affecting ascending activating brainstem fibers. Of note, slow waves invariably vanished in the chronic phase, but were highly indicative of a poor functional outcome. CONCLUSION: In summary, we found evidence that transient effects of sleep-like slow waves and cortical bistability within ipsilesional M1 resulting in excessive inhibition may interfere with functional reorganization, leading to a less favorable functional outcome post-stroke, pointing to a new therapeutic target to improve recovery of function.

Blindly separated spontaneous network-level oscillations predict corticospinal excitability.

Objective.The corticospinal responses of the motor network to transcranial magnetic stimulation (TMS) are highly variable. While often regarded as noise, this variability provides a way of probing dynamic brain states related to excitability. We aimed to uncover spontaneously occurring cortical states that alter corticospinal excitability.Approach.Electroencephalography (EEG) recorded during TMS registers fast neural dynamics-unfortunately, at the cost of anatomical precision. We employed analytic Common Spatial Patterns technique to derive excitability-related cortical activity from pre-TMS EEG signals while overcoming spatial specificity issues.Main results.High corticospinal excitability was predicted by alpha-band activity, localized adjacent to the stimulated left motor cortex, and suggesting a travelling wave-like phenomenon towards frontal regions. Low excitability was predicted by alpha-band activity localized in the medial parietal-occipital and frontal cortical regions.Significance.We established a data-driven approach for uncovering network-level neural activity that modulates TMS effects. It requires no prior anatomical assumptions, while being physiologically interpretable, and can be employed in both exploratory investigation and brain state-dependent stimulation.

Exploring Motor Network Connectivity in State-Dependent Transcranial Magnetic Stimulation: A Proof-of-Concept Study.

State-dependent non-invasive brain stimulation (NIBS) informed by electroencephalography (EEG) has contributed to the understanding of NIBS inter-subject and inter-session variability. While these approaches focus on local EEG characteristics, it is acknowledged that the brain exhibits an intrinsic long-range dynamic organization in networks. This proof-of-concept study explores whether EEG connectivity of the primary motor cortex (M1) in the pre-stimulation period aligns with the Motor Network (MN) and how the MN state affects responses to the transcranial magnetic stimulation (TMS) of M1. One thousand suprathreshold TMS pulses were delivered to the left M1 in eight subjects at rest, with simultaneous EEG. Motor-evoked potentials (MEPs) were measured from the right hand. The source space functional connectivity of the left M1 to the whole brain was assessed using the imaginary part of the phase locking value at the frequency of the sensorimotor µ-rhythm in a 1 s window before the pulse. Group-level connectivity revealed functional links between the left M1, left supplementary motor area, and right M1. Also, pulses delivered at high MN connectivity states result in a greater MEP amplitude compared to low connectivity states. At the single-subject level, this relation is more highly expressed in subjects that feature an overall high cortico-spinal excitability. In conclusion, this study paves the way for MN connectivity-based NIBS.

Modulation of dorsal premotor cortex differentially influences visuomotor adaptation in young and older adults.

The communication between dorsal premotor cortex (PMd) and primary motor cortex (M1) is important for visuomotor adaptation, but it is unclear how this relationship changes with advancing age. The present study recruited 21 young and 23 older participants for two experimental sessions during which intermittent theta burst stimulation (iTBS) or sham was applied over PMd. We assessed the effects of PMd iTBS on M1 excitability using motor evoked potentials (MEP) recorded from right first dorsal interosseous when single-pulse transcranial magnetic stimulation (TMS) was applied with posterior-anterior (PA) or anterior-posterior (AP) currents; and adaptation by quantifying error recorded during a visuomotor adaptation task (VAT). PMd iTBS potentiated PA (P < 0.0001) and AP (P < 0.0001) MEP amplitude in both young and older adults. PMd iTBS increased error in young adults during adaptation (P = 0.026), but had no effect in older adults (P = 0.388). Although PMd iTBS potentiated M1 excitability in both young and older adults, the intervention attenuated visuomotor adaptation specifically in young adults.

The effects of intermittent theta burst stimulation over dorsal premotor cortex on primary motor cortex plasticity in young and older adults.

Previous transcranial magnetic stimulation (TMS) research suggests that the dorsal premotor cortex (PMd) influences neuroplasticity within the primary motor cortex (M1) through indirect (I) wave interneuronal circuits. However, it is unclear how the influence of PMd on the plasticity of M1 I-waves changes with advancing age. This study therefore investigated the neuroplastic effects of intermittent theta burst stimulation (iTBS) to M1 early and late I-wave circuits when preceded by iTBS (PMd iTBS-M1 iTBS) or sham stimulation (PMd sham-M1 iTBS) to PMd in 15 young and 16 older adults. M1 excitability was assessed with motor evoked potentials (MEP) recorded from the right first dorsal interosseous using posterior-anterior (PA) and anterior-posterior (AP) current TMS at standard stimulation intensities (PA1mV, AP1mV) and reduced stimulation intensities (PA0.5mV, early I-waves; AP0.5mV, late I-waves). PMd iTBS-M1 iTBS lowered the expected facilitation of PA0.5mV (to M1 iTBS) in young and older adults (P = 0.009), whereas the intervention had no effect on AP0.5mV facilitation in either group (P = 0.305). The modulation of PA0.5mV following PMd iTBS-M1 iTBS may reflect a specific influence of PMd on different I-wave circuits that are involved in M1 plasticity within young and older adults.

A hybrid brain-muscle-machine interface for stroke rehabilitation: Usability and functionality validation in a 2-week intensive intervention.

Introduction: The primary constraint of non-invasive brain-machine interfaces (BMIs) in stroke rehabilitation lies in the poor spatial resolution of motor intention related neural activity capture. To address this limitation, hybrid brain-muscle-machine interfaces (hBMIs) have been suggested as superior alternatives. These hybrid interfaces incorporate supplementary input data from muscle signals to enhance the accuracy, smoothness and dexterity of rehabilitation device control. Nevertheless, determining the distribution of control between the brain and muscles is a complex task, particularly when applied to exoskeletons with multiple degrees of freedom (DoFs). Here we present a feasibility, usability and functionality study of a bio-inspired hybrid brain-muscle machine interface to continuously control an upper limb exoskeleton with 7 DoFs. Methods: The system implements a hierarchical control strategy that follows the biologically natural motor command pathway from the brain to the muscles. Additionally, it employs an innovative mirror myoelectric decoder, offering patients a reference model to assist them in relearning healthy muscle activation patterns during training. Furthermore, the multi-DoF exoskeleton enables the practice of coordinated arm and hand movements, which may facilitate the early use of the affected arm in daily life activities. In this pilot trial six chronic and severely paralyzed patients controlled the multi-DoF exoskeleton using their brain and muscle activity. The intervention consisted of 2 weeks of hBMI training of functional tasks with the system followed by physiotherapy. Patients' feedback was collected during and after the trial by means of several feedback questionnaires. Assessment sessions comprised clinical scales and neurophysiological measurements, conducted prior to, immediately following the intervention, and at a 2-week follow-up. Results: Patients' feedback indicates a great adoption of the technology and their confidence in its rehabilitation potential. Half of the patients showed improvements in their arm function and 83% improved their hand function. Furthermore, we found improved patterns of muscle activation as well as increased motor evoked potentials after the intervention. Discussion: This underscores the significant potential of bio-inspired interfaces that engage the entire nervous system, spanning from the brain to the muscles, for the rehabilitation of stroke patients, even those who are severely paralyzed and in the chronic phase.

Breakdown of effective information flow in disorders of consciousness: Insights from TMS-EEG.

BACKGROUND: The complexity of the neurophysiological mechanisms underlying human consciousness is widely acknowledged, with information processing and flow originating in cortex conceived as a core mechanism of consciousness emergence. Combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is considered as a promising technique to understand the effective information flow associated with consciousness. OBJECTIVES: To investigate information flow with TMS-EEG and its relationship to different consciousness states. METHODS: We applied an effective information flow analysis by combining time-varying multivariate adaptive autoregressive model and adaptive directed transfer function on TMS-EEG data of frontal, motor and parietal cortex in patients with disorder of consciousness (DOC), including 14 vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients, 21 minimally conscious state (MCS) patients, and 22 healthy subjects. RESULTS: TMS in DOC patients, particularly VS/UWS, induced a significantly weaker effective information flow compared to healthy subjects. The bidirectional directed information flow was lost in DOC patients with TMS of frontal, motor and parietal cortex. The interactive ROI rate of the information flow network induced by TMS of frontal and parietal cortex was significantly lower in VS/UWS than in MCS. The interactive ROI rate correlated with DOC clinical scales. CONCLUSIONS: TMS-EEG revealed a physiologically relevant correlation between TMS-induced information flow and levels of consciousness. This suggests that breakdown of effective cortical information flow serves as a viable marker of human consciousness. SIGNIFICANCE: Findings offer a unique perspective on the relevance of information flow in DOC, thus providing a novel way of understanding the physiological basis of human consciousness.

Adapted Beamforming: A Robust and Flexible Approach for Removing Various Types of Artifacts from TMS-EEG Data.

Electroencephalogram (EEG) recorded as response to transcranial magnetic stimulation (TMS) can be highly informative of cortical reactivity and connectivity. Reliable EEG interpretation requires artifact removal as the TMS-evoked EEG can contain high-amplitude artifacts. Several methods have been proposed to uncover clean neuronal EEG responses. In practice, determining which method to select for different types of artifacts is often difficult. Here, we used a unified data cleaning framework based on beamforming to improve the algorithm selection and adaptation to the recorded signals. Beamforming properties are well understood, so they can be used to yield customized methods for EEG cleaning based on prior knowledge of the artifacts and the data. The beamforming implementations also cover, but are not limited to, the popular TMS-EEG cleaning methods: independent component analysis (ICA), signal-space projection (SSP), signal-space-projection-source-informed-reconstruction method (SSP-SIR), the source-estimate-utilizing noise-discarding algorithm (SOUND), data-driven Wiener filter (DDWiener), and the multiple-source approach. In addition to these established methods, beamforming provides a flexible way to derive novel artifact suppression algorithms by considering the properties of the recorded data. With simulated and measured TMS-EEG data, we show how to adapt the beamforming-based cleaning to different data and artifact types, namely TMS-evoked muscle artifacts, ocular artifacts, TMS-related peripheral responses, and channel noise. Importantly, beamforming implementations are fast to execute: We demonstrate how the SOUND algorithm becomes orders of magnitudes faster via beamforming. Overall, the beamforming-based spatial filtering framework can greatly enhance the selection, adaptability, and speed of EEG artifact removal.

Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, the ProVal-MS study.

INTRODUCTION: In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. METHODS: ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing-Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing-Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. PERSPECTIVE: Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)-ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034.

Apixaban versus Aspirin for Embolic Stroke of Undetermined Source.

BACKGROUND: Rivaroxaban and dabigatran were not superior to aspirin in trials of patients with embolic stroke of undetermined source (ESUS). It is unknown whether apixaban is superior to aspirin in patients with ESUS and known risk factors for cardioembolism. METHODS: We conducted a multicenter, randomized, open-label, blinded-outcome trial of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within 28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban in case of atrial fibrillation detection. The primary outcome was any new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow-up. Secondary outcomes included major and clinically relevant nonmajor bleeding. RESULTS: A total of 352 patients were randomly assigned to receive apixaban (178 patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%) participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, 0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per 100 person-years in those given apixaban and 45.7 per 100 person-years in those given aspirin. The Apixaban for the Treatment of Embolic Stroke of Undetermined Source trial was terminated after a prespecified interim analysis as a result of futility. CONCLUSIONS: Apixaban treatment was not superior to cardiac monitoring-guided aspirin in preventing new ischemic lesions in an enriched ESUS population. (Funded by Bristol-Myers Squibb and Medtronic Europe; ClinicalTrials.gov number, NCT02427126.)

Pharmacological adjuncts and transcranial magnetic stimulation-induced synaptic plasticity: a systematic review.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation modality that has been used to study human synaptic plasticity. Leveraging work in ex vivo preparations, mechanistically informed pharmacological adjuncts to TMS have been used to improve our fundamental understanding of TMS-induced synaptic plasticity. METHODS: We systematically reviewed the literature pairing pharmacological adjuncts with TMS plasticity-induction protocols in humans. We searched MEDLINE, PsycINFO, and Embase from 2013 to Mar. 10, 2023. Studies published before 2013 were extracted from a previous systematic review. We included studies using repetitive TMS, theta-burst stimulation, paired associative stimulation, and quadripulse stimulation paradigms in healthy and clinical populations. RESULTS: Thirty-six studies met our inclusion criteria (28 in healthy and 8 in clinical populations). Most pharmacological agents have targeted the glutamatergic N-methyl-d-aspartate (NMDA; 15 studies) or dopamine receptors (13 studies). The NMDA receptor is necessary for TMS-induced plasticity; however, sufficiency has not been shown across protocols. Dopaminergic modulation of TMS-induced plasticity appears to be dose-dependent. The GABAergic, cholinergic, noradrenergic, and serotonergic neurotransmitter systems have small evidence bases supporting modulation of TMS-induced plasticity, as do voltage-gated calcium and sodium channels. Studies in clinical populations suggest that pharmacological adjuncts to TMS may rescue motor cortex plasticity, with implications for therapeutic applications of TMS and a promising clinical trial in depression. LIMITATIONS: This review is limited by the predominance in the literature of studies with small sample sizes and crossover designs. CONCLUSION: Pharmacologically enhanced TMS largely parallels findings from ex vivo preparations. As this area expands and novel targets are tested, adequately powered samples in healthy and clinical populations will inform the mechanisms of TMS-induced plasticity in health and disease.

Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter.

Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives.

Closed-Loop Brain Stimulation.

In the same way that beauty lies in the eye of the beholder, what a stimulus does to the brain is determined not simply by the nature of the stimulus but by the nature of the brain that is receiving the stimulus at that instant in time. Over the past decades, therapeutic brain stimulation has typically applied open-loop fixed protocols and has largely ignored this principle. Only recent neurotechnological advancements have enabled us to predict the nature of the brain (i.e., the electrophysiological brain state in the next instance in time) with sufficient temporal precision in the range of milliseconds using feedforward algorithms applied to electroencephalography time-series data. This allows stimulation exclusively whenever the targeted brain area is in a prespecified excitability or connectivity state. Preclinical studies have shown that repetitive stimulation during a particular brain state (e.g., high-excitability state), but not during other states, results in lasting modification (e.g., long-term potentiation) of the stimulated circuits. Here, we survey the evidence that this is also possible at the systems level of the human cortex using electroencephalography-informed transcranial magnetic stimulation. We critically discuss opportunities and difficulties in developing brain state-dependent stimulation for more effective long-term modification of pathological brain networks (e.g., in major depressive disorder) than is achievable with conventional fixed protocols. The same real-time electroencephalography-informed transcranial magnetic stimulation technology will allow closing of the loop by recording the effects of stimulation. This information may enable stimulation protocol adaptation that maximizes treatment response. This way, brain states control brain stimulation, thereby introducing a paradigm shift from open-loop to closed-loop stimulation.

Patient-reported outcome parameters and disability worsening in progressive multiple sclerosis.

OBJECTIVES: Detection and prediction of disability progression is a significant unmet need in people with progressive multiple sclerosis (PwPMS). Government and health agencies have deemed the use of patient-reported outcomes measurements (PROMs) in clinical practice and clinical trials a major strategic priority. Nevertheless, data documenting the clinical utility of PROMs in neurological diseases is scarce. This study evaluates if assessment of PROMs could track progression in PwPMS. METHODS: Emerging blood Biomarkers in Progressive Multiple Sclerosis (EmBioProMS) investigated PROMs (Beck depression inventory-II (BDI-II), multiple sclerosis impact scale-29 (MSIS-29), fatigue scale for motor and cognition (FSMC)) in PwPMS (primary [PPMS] and secondary progressive MS [SPMS]). PROMs were evaluated longitudinally and compared between participants with disability progression (at baseline; retrospective evidence of disability progression (EDP), and during follow up (FU); prospective evidence of confirmed disability progression (CDP)) and those without progression. In an independent cohort of placebo participants of the phase III ORATORIO trial in PPMS, the diagnostic and prognostic value of another PROMs score (36-Item Short Form Survey [SF-36]) regarding CDP was evaluated. RESULTS: EmBioProMS participants with EDP in the two years prior to inclusion (n = 136/227), or who suffered from CDP during FU (number of events= 88) had worse BDI-II, MSIS-29, and FSMC scores compared to PwPMS without progression. In addition, baseline MSIS29physical above 70th, 80th, and 90th percentiles predicted future CDP/ progression independent of relapse activity in EmBioProMS PPMS participants (HR of 3.7, 6.9, 6.7, p = 0.002, <0.001, and 0.001, respectively). In the placebo arm of ORATORIO (n = 137), the physical component score (PCS) of SF-36 worsened at week 120 compared to baseline, in cases who experienced progression over the preceding trial period (P = 0.018). Worse PCS at baseline was associated with higher hazard ratios of disability accumulation over the subsequent 120 weeks (HR: 2.01 [30th-], 2.11 [20th-], and 2.8 [10th percentile], P = 0.007, 0.012 and 0.005, respectively). CONCLUSIONS: PROMs could provide additional, practical, cost-efficient, and remotely accessible insight about disability progression in PMS through standardized, structured, and quantifiable patient feedback.