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.

A transdiagnostic group exercise intervention for mental health outpatients in Germany (ImPuls): results of a pragmatic, multisite, block-randomised, phase 3 controlled trial.

BACKGROUND: Globally, mental health conditions pose a substantial burden of disease. Despite the availability of evidence-based pharmacological and psychological treatments, the symptoms of a substantial subgroup of patients do not respond to these interventions, and only a minority of patients have access to them. This study aimed to assess the efficacy of ImPuls, a 6-month transdiagnostic group exercise intervention, plus treatment-as-usual, compared with treatment-as-usual alone in outpatients with various mental disorders. METHODS: In this pragmatic, two-arm, multisite, randomised controlled trial in Germany, ten outpatient rehabilitative and medical care facilities were involved as study sites. Participants were outpatients diagnosed according to ICD-10 with one or more of the following disorders based on structured clinical interviews: moderate or severe depression, primary insomnia, post-traumatic stress disorder (PTSD), panic disorder, or agoraphobia. Participants were required to be aged between 18 years and 65 years, insured by the health insurers Allgemeine Ortskrankenkasse Baden-Württemberg or Techniker Krankenkasse, fluent in German, and without medical contraindications for exercise. Blocks of six participants were randomly allocated to ImPuls plus treatment-as-usual or treatment-as-usual alone (allocation ratio: 1:1), stratified by study site. The randomisation sequence was generated by an external data manager. The team responsible for data collection and management was masked to the randomisation sequence. The ImPuls intervention comprised evidence-based outdoor exercises lasting 30 min, and aimed at achieving at least moderate intensity. It also incorporated behavioural change techniques targeting motivational and volitional determinants of exercise behaviour. Treatment-as-usual was representative of typical outpatient health care in Germany, allowing patients access to any standard treatments. The primary outcome was global symptom severity at 6 months after randomisation, measured using self-report on the Brief Symptom Inventory (BSI-18) and analysed in the intention-to-treat sample. No individuals with lived experience of mental illness were involved in conducting the study or writing the final publication. Safety was assessed in all participants. The trial was registered with the German Clinical Trials Register (DRKS00024152) with a completion date of June 30, 2024. FINDINGS: 600 patients provided informed consent, were recruited to the study, and underwent a diagnostic interview between Jan 1, 2021, and May 31, 2022. Following this, 199 were excluded on the basis of inclusion and exclusion criteria and one withdrew consent during the baseline assessment. Of the 400 eligible participants, 284 (71%) self-identified as female, 106 (27%) self-identified as male, and nine (2%) self-identified as other. The mean age was 42·20 years (SD 13·23; range 19-65). Ethnicity data were not assessed. 287 (72%) participants met the criteria for moderate or severe depression, 81 (20%) for primary insomnia, 37 (9%) for agoraphobia, 46 (12%) for panic disorder, and 72 (18%) for PTSD. 199 participants were allocated to the intervention group of ImPuls plus treatment-as-usual and 201 to the control group of treatment-as-usual alone. 38 (19%) participants did not receive the minimum ImPuls intervention dose. ImPuls plus treatment-as-usual demonstrated superior efficacy to treatment-as-usual alone in reducing global symptom severity, with an adjusted difference on BSI-18 of 4·11 (95% CI 1·74-6·48; d=0·35 [95% CI 0·14-0·56]; p=0·0007) at 6 months. There were no significant differences in the total number of adverse events or serious adverse events between the two groups. There was one serious adverse event (male, torn ligament) related to the intervention. INTERPRETATION: ImPuls is an efficacious transdiagnostic adjunctive treatment in outpatient mental health care. Our findings suggest that exercise therapy should be implemented in outpatient mental health care as an adjunctive transdiagnostic treatment for mental disorders such as depression, insomnia, panic disorder, agoraphobia, and PTSD. Transdiagnostic group exercise interventions might ameliorate the existing disparity in care provision between the many individuals in need of evidence-based treatment and the few who are receiving it. FUNDING: The German Innovation Fund of the Federal Joint Committee of Germany.

Challenges of neural interfaces for stroke motor rehabilitation.

More than 85% of stroke survivors suffer from different degrees of disability for the rest of their lives. They will require support that can vary from occasional to full time assistance. These conditions are also associated to an enormous economic impact for their families and health care systems. Current rehabilitation treatments have limited efficacy and their long-term effect is controversial. Here we review different challenges related to the design and development of neural interfaces for rehabilitative purposes. We analyze current bibliographic evidence of the effect of neuro-feedback in functional motor rehabilitation of stroke patients. We highlight the potential of these systems to reconnect brain and muscles. We also describe all aspects that should be taken into account to restore motor control. Our aim with this work is to help researchers designing interfaces that demonstrate and validate neuromodulation strategies to enforce a contingent and functional neural linkage between the central and the peripheral nervous system. We thus give clues to design systems that can improve or/and re-activate neuroplastic mechanisms and open a new recovery window for stroke patients.

Concept and study protocol of the process evaluation of a pragmatic randomized controlled trial to promote physical activity in outpatients with heterogeneous mental disorders-the ImPuls study.

BACKGROUND: Evidence suggests that patients suffering from different mental disorders benefit from exercise programs combined with behavior change techniques. Based on this evidence, we have developed an exercise program (ImPuls) specifically designed to provide an additional treatment option in the outpatient mental health care system. The implementation of such complex programs into the outpatient context requires research that goes beyond the evaluation of effectiveness, and includes process evaluation. So far, process evaluation related to exercise interventions has rarely been conducted. As part of a current pragmatic randomized controlled trial evaluating ImPuls treatment effects, we are therefore carrying out comprehensive process evaluation according to the Medical Research Council (MRC) framework. The central aim of our process evaluation is to support the findings of the ongoing randomized controlled trial. METHODS: The process evaluation follows a mixed-methods approach. We collect quantitative data via online-questionnaires from patients, exercise therapists, referring healthcare professionals and managers of outpatient rehabilitative and medical care facilities before, during, and after the intervention. In addition, documentation data as well as data from the ImPuls smartphone application are collected. Quantitative data is complemented by qualitative interviews with exercise therapists as well as a focus-group interview with managers. Treatment fidelity will be assessed through the rating of video-recorded sessions. Quantitative data analysis includes descriptive as well as mediation and moderation analyses. Qualitative data will be analyzed via qualitative content analysis. DISCUSSION: The results of our process evaluation will complement the evaluation of effectiveness and cost-effectiveness and will, for example, provide important information about mechanisms of impact, structural prerequisites, or provider qualification that may support the decision-making process of health policy stakeholders. It might contribute to paving the way for exercise programs like ImPuls to be made successively available for patients with heterogeneous mental disorders in the German outpatient mental health care system. TRIAL REGISTRATION: The parent clinical study was registered in the German Clinical Trials Register (ID: DRKS00024152, registered 05/02/2021, https://drks.de/search/en/trial/DRKS00024152 ).

A real-time fMRI neurofeedback system for the clinical alleviation of depression with a subject-independent classification of brain states: A proof of principle study.

Most clinical neurofeedback studies based on functional magnetic resonance imaging use the patient's own neural activity as feedback. The objective of this study was to create a subject-independent brain state classifier as part of a real-time fMRI neurofeedback (rt-fMRI NF) system that can guide patients with depression in achieving a healthy brain state, and then to examine subsequent clinical changes. In a first step, a brain classifier based on a support vector machine (SVM) was trained from the neural information of happy autobiographical imagery and motor imagery blocks received from a healthy female participant during an MRI session. In the second step, 7 right-handed female patients with mild or moderate depressive symptoms were trained to match their own neural activity with the neural activity corresponding to the "happiness emotional brain state" of the healthy participant. The training (4 training sessions over 2 weeks) was carried out using the rt-fMRI NF system guided by the brain-state classifier we had created. Thus, the informative voxels previously obtained in the first step, using SVM classification and Effect Mapping, were used to classify the Blood-Oxygen-Level Dependent (BOLD) activity of the patients and converted into real-time visual feedback during the neurofeedback training runs. Improvements in the classifier accuracy toward the end of the training were observed in all the patients [Session 4-1 Median = 6.563%; Range = 4.10-27.34; Wilcoxon Test (0), 2-tailed p = 0.031]. Clinical improvement also was observed in a blind standardized clinical evaluation [HDRS CE2-1 Median = 7; Range 2 to 15; Wilcoxon Test (0), 2-tailed p = 0.016], and in self-report assessments [BDI-II CE2-1 Median = 8; Range 1-15; Wilcoxon Test (0), 2-tailed p = 0.031]. In addition, the clinical improvement was still present 10 days after the intervention [BDI-II CE3-2_Median = 0; Range -1 to 2; Wilcoxon Test (0), 2-tailed p = 0.50/ HDRS CE3-2 Median = 0; Range -1 to 2; Wilcoxon Test (0), 2-tailed p = 0.625]. Although the number of participants needs to be increased and a control group included to confirm these findings, the results suggest a novel option for neural modulation and clinical alleviation in depression using noninvasive stimulation technologies.

Efficacy and cost-effectiveness of a Transdiagnostic group-based exercise intervention: study protocol for a pragmatic multi-site randomized controlled trial.

BACKGROUND: Mental disorders are prevalent and cause considerable burden of disease. Exercise has been shown to be efficacious to treat major depressive disorders, insomnia, panic disorder with and without agoraphobia and post traumatic stress disorder (PTSD). METHODS: This pragmatic, two arm, multi-site randomised controlled trial will evaluate the efficacy and cost-effectiveness of the manualized, group-based six-months exercise intervention "ImPuls", among physically inactive patients with major depressive disorders, insomnia, panic disorder, agoraphobia and PTSD within a naturalistic outpatient context in Germany. A minimum of 375 eligible outpatients from 10 different study sites will be block-randomized to either ImPuls in addition to treatment as usual (TAU) or TAU only. ImPuls will be conducted by trained exercise therapists and delivered in groups of six patients. The program will combine (a) moderate to vigorous aerobic exercise carried out two-three times a week for at least 30 min with (b) behavior change techniques for sustained exercise behavior change. All outcomes will be assessed pre-treatment, post-treatment (six months after randomization) and at follow-up (12 months after randomization). Primary outcome will be self-reported global symptom severity assessed with the Brief Symptom Inventory (BSI-18). Secondary outcomes will be accelerometry-based moderate to vigorous physical activity, self-reported exercise, disorder-specific symptoms, quality-adjusted life years (QALY) and healthcare costs. Intention-to-treat analyses will be conducted using mixed models. Cost-effectiveness and cost-utility analysis will be conducted using incremental cost-effectiveness and cost-utility ratios. DISCUSSION: Despite its promising therapeutic effects, exercise programs are currently not provided within the outpatient mental health care system in Germany. This trial will inform service providers and policy makers about the efficacy and cost-effectiveness of the group-based exercise intervention ImPuls within a naturalistic outpatient health care setting. Group-based exercise interventions might provide an option to close the treatment gap within outpatient mental health care settings. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (ID: DRKS00024152 , 05/02/2021).

Brain oscillatory activity as a biomarker of motor recovery in chronic stroke.

In the present work, we investigated the relationship of oscillatory sensorimotor brain activity to motor recovery. The neurophysiological data of 30 chronic stroke patients with severe upper-limb paralysis are the basis of the observational study presented here. These patients underwent an intervention including movement training based on combined brain-machine interfaces and physiotherapy of several weeks recorded in a double-blinded randomized clinical trial. We analyzed the alpha oscillations over the motor cortex of 22 of these patients employing multilevel linear predictive modeling. We identified a significant correlation between the evolution of the alpha desynchronization during rehabilitative intervention and clinical improvement. Moreover, we observed that the initial alpha desynchronization conditions its modulation during intervention: Patients showing a strong alpha desynchronization at the beginning of the training improved if they increased their alpha desynchronization. Patients showing a small alpha desynchronization at initial training stages improved if they decreased it further on both hemispheres. In all patients, a progressive shift of desynchronization toward the ipsilesional hemisphere correlates significantly with clinical improvement regardless of lesion location. The results indicate that initial alpha desynchronization might be key for stratification of patients undergoing BMI interventions and that its interhemispheric balance plays an important role in motor recovery.

Movement-related brain oscillations vary with lesion location in severely paralyzed chronic stroke patients.

In the past few years, innovative upper-limb rehabilitation methods have been proposed for chronic stroke patients. These methods aim at functional motor rehabilitation using Brain-machine interfaces to constitute an alternate pathway from the brain to the muscles. Even in patients with absence of residual finger movements, recovery could be achieved. The extent to which these interventions are affected by individual lesion topology is yet to be understood. In this study EEG was measured in 30 chronic stroke patients during movement attempts of the paretic arm. We show that the magnitude of the event-related desynchronization was smaller in patients presenting lesions with involvement of the motor cortex. This could have important implications on the design of new rehabilitation schemes for these patients, which might benefit from carefully tailored interventions.

Stroke lesion location influences the decoding of movement intention from EEG.

Recent studies have demonstrated the efficacy of brain-machine interfaces (BMI) for motor rehabilitation after stroke, especially for those patients with severe paralysis. However, a cerebro-vascular accident can affect the brain in many different manners, and lesions in diverse areas, even from significantly different volumes, can lead to similar or equal motor deficits. The location of the insult influences the way the brain activates when moving or attempting to move a paralyzed limb. Since the essence of a rehabilitative BMI is to precisely decode motor commands from the brain, it is crucial to characterize how lesion location affects the measured signals and if and how it influences BMI performance. This paper compares the performances of an electroencephalography (EEG)-based movement intention decoder in two groups of severely paralyzed chronic stroke patients: 14 with subcortical lesions and 14 with mixed (i.e., cortical and subcortical) lesions. We show that the lesion location influences the performance of the BMI when decoding the movement attempts of the paretic arm. The obtained results underline the need for further developments for a better individualization of BMI-based rehabilitative therapies for stroke patients.

A subject-independent pattern-based Brain-Computer Interface.

While earlier Brain-Computer Interface (BCI) studies have mostly focused on modulating specific brain regions or signals, new developments in pattern classification of brain states are enabling real-time decoding and modulation of an entire functional network. The present study proposes a new method for real-time pattern classification and neurofeedback of brain states from electroencephalographic (EEG) signals. It involves the creation of a fused classification model based on the method of Common Spatial Patterns (CSPs) from data of several healthy individuals. The subject-independent model is then used to classify EEG data in real-time and provide feedback to new individuals. In a series of offline experiments involving training and testing of the classifier with individual data from 27 healthy subjects, a mean classification accuracy of 75.30% was achieved, demonstrating that the classification system at hand can reliably decode two types of imagery used in our experiments, i.e., happy emotional imagery and motor imagery. In a subsequent experiment it is shown that the classifier can be used to provide neurofeedback to new subjects, and that these subjects learn to "match" their brain pattern to that of the fused classification model in a few days of neurofeedback training. This finding can have important implications for future studies on neurofeedback and its clinical applications on neuropsychiatric disorders.