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.

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.

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.

Apixaban versus Aspirin for Embolic StrokeIn a trial of 352 patients with embolic stroke of undetermined source, 5 mg of apixaban administered twice daily was compared with 100 mg of aspirin administered once daily for the prevention of recurrent ischemic strokes. At 12 months, 13.6% of patients given apixaban had new ischemic lesions on magnetic resonance imaging compared with 16.0% of patients given aspirin, and the rates of clinically relevant bleeding were also comparable.

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.

Evoked EEG Responses to TMS Targeting Regions Outside the Primary Motor Cortex and Their Test-Retest Reliability.

Transcranial magnetic stimulation (TMS)-evoked electroencephalography (EEG) potentials (TEPs) provide unique insights into cortical excitability and connectivity. However, confounding EEG signals from auditory and somatosensory co-stimulation complicate TEP interpretation. Our optimized sham procedure established with TMS of primary motor cortex (Gordon in JAMA 245:118708, 2021) differentiates direct cortical EEG responses to TMS from those caused by peripheral sensory inputs. Using this approach, this study aimed to investigate TEPs and their test-retest reliability when targeting regions outside the primary motor cortex, specifically the left angular gyrus, supplementary motor area, and medial prefrontal cortex. We conducted three identical TMS-EEG sessions one week apart involving 24 healthy participants. In each session, we targeted the three areas separately using a figure-of-eight TMS coil for active TMS, while a second coil away from the head produced auditory input for sham TMS. Masking noise and electric scalp stimulation were applied in both conditions to achieve matched EEG responses to peripheral sensory inputs. High test-retest reliability was observed in both conditions. However, reliability declined for the 'cleaned' TEPs, resulting from the subtraction of evoked EEG response to the sham TMS from those to the active, particularly for latencies > 100 ms following the TMS pulse. Significant EEG differences were found between active and sham TMS at latencies < 90 ms for all targeted areas, exhibiting distinct spatiotemporal characteristics specific to each target. In conclusion, our optimized sham procedure effectively reveals EEG responses to direct cortical activation by TMS in brain areas outside primary motor cortex. Moreover, we demonstrate the impact of peripheral sensory inputs on test-retest reliability of TMS-EEG responses.

Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis.

OBJECTIVE: Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state-of-the-art clinical settings and trials applying combined outcome parameters. METHODS: Serum GFAP and NfL (neurofilament light chain) were investigated in EmBioProMS participants with primary (PP) or secondary progressive MS. Six months confirmed disability progression (CDP) was defined using combined outcome parameters (EDSS, timed-25-foot walk test (T25FW), and nine-hole-peg-test (9HPT)). RESULTS: 243 subjects (135 PPMS, 108 SPMS, age 55.5, IQR [49.7-61.2], 135 female, median follow-up: 29.3 months [17.9-40.9]) were included. NfL (age-) and GFAP (age- and sex-) adjusted Z scores were higher in pwPMS compared to HC (p < 0.001 for both). 111 (32.8%) CDP events were diagnosed in participants with ≥3 visits (n = 169). GFAP Z score >3 was associated with higher risk for CDP in participants with low NfL Z score (i.e., ≤1.0) (HR: 2.38 [1.12-5.08], p = 0.025). In PPMS, GFAP Z score >3 was associated with higher risk for CDP (HR: 2.88 [1.21-6.84], p = 0.016). Risk was further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53-12.13], p = 0.006). INTERPRETATION: Blood GFAP may help identify pwPPMS at risk of progression. Combination of high GFAP and low NfL levels could distinguish non-active pwPMS with particularly high progression risk.

Computed tomography perfusion imaging-guided intravenous thrombolysis in acute minor ischemic stroke.

Background: Over 50% of acute ischemic stroke (AIS) patients present with minor neurological deficits, and optimal treatment is still debated. The randomized PRISMS trial did not show beneficial effects of intravenous thrombolysis (IVT) in unselected patients with minor stroke and non-disabling neurological deficits. Purpose: The study aimed to evaluate if AIS patients with minor stroke may benefit from computed-tomography-perfusion (CTP)-guided IVT. The primary endpoint was good functional outcomes, defined as a modified Rankin Scale score of 0-2 at 90 days. Methods: AIS patients with a NIHSS of ≤5 presenting within 4.5 h underwent multimodal CT-imaging including CTP. CTP mismatch was defined as hypoperfusion on CTP with time-to-peak delay >6 s without corresponding hypoperfusion in cerebral blood volume. IVT decision was left to the attending stroke physicians. Patients with large vessel occlusion (LVO) and absolute contraindications to IVT were excluded. Results: In total, 267 consecutive patients were included [mean age: 72 ± 14 years, 45.3% female patients, 75.3% received IVT, median NIHSS on admission: 3 (IQR 2, 4)]. CTP mismatch was detected in 41.8% of IVT- treated patients (IVT+) and 28.8% of standard treatment patients (IVT-) (p = 0.06). IVT+ had favorable outcomes at 90 days compared to IVT- (p = 0.006), but no interaction with an existing CTP mismatch was detected (ORadj: 1.676; 95% CI: 0.644-4.364). No symptomatic intracranial hemorrhage according to ECASS-III criteria occurred. Conclusion: Although selected AIS patients with minor stroke may benefit from IVT, CTP mismatch does not correlate with functional outcomes. No benefit from CTP mismatch in guiding IVT was detected in patients without LVO presenting with minor neurological deficits.

Testing spasticity mechanisms in chronic stroke before and after intervention with contralesional motor cortex 1 Hz rTMS and physiotherapy.

BACKGROUND: Previous studies showed that repetitive transcranial magnetic stimulation (rTMS) reduces spasticity after stroke. However, clinical assessments like the modified Ashworth scale, cannot discriminate stretch reflex-mediated stiffness (spasticity) from passive stiffness components of resistance to muscle stretch. The mechanisms through which rTMS might influence spasticity are also not understood. METHODS: We measured the effects of contralesional motor cortex 1 Hz rTMS (1200 pulses + 50 min physiotherapy: 3×/week, for 4-6 weeks) on spasticity of the wrist flexor muscles in 54 chronic stroke patients using a hand-held dynamometer for objective quantification of the stretch reflex response. In addition, we measured the excitability of three spinal mechanisms thought to be related to post-stroke spasticity: post-activation depression, presynaptic inhibition and reciprocal inhibition before and after the intervention. Effects on motor impairment and function were also assessed using standardized stroke-specific clinical scales. RESULTS: The stretch reflex-mediated torque in the wrist flexors was significantly reduced after the intervention, while no change was detected in the passive stiffness. Additionally, there was a significant improvement in the clinical tests of motor impairment and function. There were no significant changes in the excitability of any of the measured spinal mechanisms. CONCLUSIONS: We demonstrated that contralesional motor cortex 1 Hz rTMS and physiotherapy can reduce the stretch reflex-mediated component of resistance to muscle stretch without affecting passive stiffness in chronic stroke. The specific physiological mechanisms driving this spasticity reduction remain unresolved, as no changes were observed in the excitability of the investigated spinal mechanisms.

Targeting motor cortex high-excitability states defined by functional connectivity with real-time EEG-TMS.

We tested previous post-hoc findings indicating a relationship between functional connectivity (FC) in the motor network and corticospinal excitability (CsE), in a real-time EEG-TMS experiment in healthy participants. We hypothesized that high FC between left and right motor cortex predicts high CsE. FC was quantified in real-time by single-trial phase-locking value (stPLV), and TMS single pulses were delivered based on the current FC. CsE was indexed by motor-evoked potential (MEP) amplitude in a hand muscle. Possible confounding factors (pre-stimulus µ-power and phase, interstimulus interval) were evaluated post hoc. MEPs were significantly larger during high FC compared to low FC. Post hoc analysis revealed that the FC condition showed a significant interaction with µ-power in the stimulated hemisphere. Further, inter-stimulus interval (ISI) interacted with high vs. low FC conditions. In summary, FC was confirmed to be predictive of CsE, but should not be considered in isolation from µ-power and ISI. Moreover, FC was complementary to µ-phase in predicting CsE. Motor network FC is another marker of real-time accessible CsE beyond previously established markers, in particular phase and power of the µ rhythm, and may help define a more robust composite biomarker of high/low excitability states of human motor cortex.

Repetitive sensorimotor mu-alpha phase-targeted afferent stimulation produces no phase-dependent plasticity related changes in somatosensory evoked potentials or sensory thresholds.

Phase-dependent plasticity has been proposed as a neurobiological mechanism by which oscillatory phase-amplitude cross-frequency coupling mediates memory process in the brain. Mimicking this mechanism, real-time EEG oscillatory phase-triggered transcranial magnetic stimulation (TMS) has successfully induced LTP-like changes in corticospinal excitability in the human motor cortex. Here we asked whether EEG phase-triggered afferent stimulation alone, if repetitively applied to the peaks, troughs, or random phases of the sensorimotor mu-alpha rhythm, would be sufficient to modulate the strength of thalamocortical synapses as assessed by changes in somatosensory evoked potential (SEP) N20 and P25 amplitudes and sensory thresholds (ST). Specifically, we applied 100 Hz triplets of peripheral electrical stimulation (PES) to the thumb, middle, and little finger of the right hand in pseudorandomized trials, with the afferent input from each finger repetitively and consistently arriving either during the cortical mu-alpha trough or peak or at random phases. No significant changes in SEP amplitudes or ST were observed across the phase-dependent PES intervention. We discuss potential limitations of the study and argue that suboptimal stimulation parameter choices rather than a general lack of phase-dependent plasticity in thalamocortical synapses are responsible for this null finding. Future studies should further explore the possibility of phase-dependent sensory stimulation.