NIMBUS is a clinical study evaluating a new, non-invasive brain stimulation treatment to improve arm and hand function in people with long-term effects of stroke. The treatment uses a personalized method to stimulate deeper areas of the brain through the scalp, without surgery, while participants undergo intensive physiotherapy rehabilitation. Physiotherapy in combination with the brain stimulation will occur three times a day over the course of a week. In the study, participants are randomly assigned to receive either the active treatment or a sham (inactive) version, so researchers can compare the outcomes fairly. The study will assess whether the treatment is safe, feasible, and effective by measuring changes in arm movement, daily activities, and brain function before and after the treatment. The goal is to determine whether this approach can enhance recovery after stroke and support the development of improved rehabilitation therapies.
* The burden of stroke.\*\* Stroke is a major cause of acquired disabilities, with a growing number of survivors due to an aging society and improved acute management. Still, persistent motor impairment is highly common in stroke patients and is associated with a poor level of reintegration in normal life. Effective novel neurorehabilitation strategies are thus urgently required to enhance recovery rates and decrease the burden of stroke for patients, the healthcare systems and society. * Neuroplasticity and brain networks.\*\* To improve the efficacy of therapeutic strategies for stroke patients, a clear understanding of the neuronal mechanisms underlying post-stroke recovery is essential. Stroke lesions initiate a cascade of changes in brain metabolism, functional activation, neuronal excitability, and structural integrity. Recent neuroimaging studies, including structural and functional analyses, have highlighted dynamic network changes that are particularly important in the process of successful recovery. For upper extremity (UE) motor function, the recovery network notably includes the primary and secondary motor cortices, as well as core deep brain structures such as the striatum. Neuroplastic changes in these areas are critical elements for successful functional reorganization and recovery after a stroke. An important aspect is the enhanced plasticity observed during the acute and subacute phases after a stroke-specifically, the first 12 weeks, known as the "hyper-plastic phase." This period corresponds to a sensitive window during which the brain responds optimally to external stimuli, activity, rehabilitative treatments, and interventional strategies. Intensive interventional approaches during this time are most effective in promoting brain plasticity and recovery. However, spontaneous brain reorganization after a stroke often fails to achieve substantial and satisfactory functional recovery independently. * Promising but unsatisfactory results from NIBS.\*\* Among various innovative neurorehabilitation strategies, non-invasive brain stimulation (NIBS) is associated with promising results to neuromodulate brain activity and enhance neuroplasticity and motor recovery by potentiating the response to behavioural training. The safe and easy application of NIBS makes the technique particularly interesting for clinicians and scientists. However, despite this exciting potential, the application is so far limited to cortical areas (e.g., motor cortex) and has revealed heterogeneous results regarding motor recovery. This heterogeneity might be due to the so far 'one suits all non-personalized' application of NIBS. Historically, the motor cortex has been the primary target for interventions, despite the possibility that the motor cortex may not be as crucial as other brain regions in motor skill acquisition and consolidation-key components of neurorehabilitation and recovery. However, core deep brain structures, such as the basal ganglia, particularly the striatum, which are critically involved in (re-)learning, reorganization, and recovery processes after stroke, have remained inaccessible to non-invasive interventions. * Role of the basal ganglia/striatum under physiological conditions.\*\* Deep subcortical structures such as the basal ganglia are relay nodes representing a critical hub in the motor network. In particular, the striatum plays a substantial role in key aspects of sensorimotor processing and learning, essentially important for the execution and (re-)acquisition of motor skills. Lesion studies in animal models demonstrated the significant role of the striatum in the acquisition and the retention of motor behavior. For example, lesions of the dorsal striatum in primates resulted in significant motor impairment, e.g., slowness of movement and altered acquisition of motor skills while lesions of the dorsolateral striatum in rats led to the disruption of motor habit formation. In humans, the classical studies of patients with neurological disorders affecting the striatum (as Parkinson's Disease) demonstrated striatal involvement not only in movement performance but also in the acquisition of new motor skills. This was further underlined in non-human primate models of Parkinsonism. Furthermore, imaging data were able to delineate the involvement of basal ganglia in the motor learning network in healthy humans. In sum, the striatum is a key structure of motor control and (re-)learning. The striatum contributes to multiple levels including initiation of movements, facilitation of goal-directed actions, habit formation and especially motor skill acquisition, consolidation and retention. This makes the striatum a very promising target for interventional strategies based on striatal neuromodulation combined with motor (re-)learning after brain lesions. This concept is further supported by current evidence that the striatum is a highly neuroplastic area given the striatum's composition and known associations with critical neurotransmitter systems. * Striatum in stroke - animal and human models.\*\* Emerging evidence from both animal and human studies underscores the pivotal role of the striatum in post-stroke recovery mechanisms, highlighting the striatum as a promising target for neuromodulation therapies. In animal stroke models, a consistent regenerative response has been observed after focal strokes, resulting in the replacement of lost striatal neurons. Despite disturbances in movement-related neuronal activity following motor cortical strokes, the striatum continues to play a substantial role in controlling residual motor functions. During rehabilitation, reorganization of striatal activity strongly correlates with improvements in animals' motor abilities. Moreover, optogenetic stimulation of striatal activity promotes neurogenesis and long-term functional recovery, demonstrating a causal relationship between striatal activity and motor function restoration. In human studies, neuroimaging has revealed that lesions in the basal ganglia are associated with abnormal interaction patterns with cortical areas after a stroke. Structural connectivity with the basal ganglia two weeks post-stroke significantly contributes to predicting motor recovery at three months. A large-scale study involving over 800 individuals found that reduced volume of the ipsilesional striatum is strongly associated with poorer outcomes in the chronic phase. Collectively, these findings suggest that neuroplastic changes in the striatum are crucial for supporting motor recovery. Interestingly, the striatum is also involved in reward processing and motivation as well as visuospatial attention-aspects that play significant roles in the relearning and reacquisition of motor skills following a stroke. Deficits in reward processing among stroke patients have been linked to reduced activity in the ventral striatum, independent of structural damage. Furthermore, individuals with lesions in the basal ganglia exhibit poorer reward sensitivity, higher levels of apathy, and impaired visuospatial attention. Therefore, the basal ganglia, particularly the striatum, serve as key nodes within brain networks that facilitate motor recovery and influence critical aspects of motor skill reacquisition-such as reward, motivation, and attention-which are fundamental mechanisms underpinning neurorehabilitation. * Striatum and LTP-like plasticity.\*\* Approximately 95% of striatal cells are GABAergic medium spiny neurons (MSNs), which receive glutamatergic inputs from the cortex and dopaminergic inputs from the substantia nigra. MSNs have the capacity to undergo long-term potentiation (LTP) or long-term depression (LTD)-key neuroplasticity mechanisms-in response to high-frequency stimulation. Theta burst stimulation, initially demonstrated in hippocampal slices, can induce LTP- and LTD-like plasticity in the striatum, particularly when delivered in patterns that mirror natural striatal activation. This underscores the significance of activity-dependent effects linked to physiological striatal firing in enhancing behavioral outcomes. Importantly, LTP at corticostriatal synapses is associated with motor behavior and may constitute a key cellular substrate for motor learning and skill acquisition. These attributes make the striatum an excellent target for neuromodulatory interventions, especially for LTP-inducing theta-burst stimulation. Collectively, this evidence reinforces the view that the striatum is a highly neuroplastic structure playing a crucial role in motor skill acquisition-two essential aspects for functional reorganization and motor recovery after stroke. * Transcranial temporal interference stimulation (tTIS).\*\* The aforementioned animal and human studies have highlighted the critical role of the striatum in motor learning, recovery processes, and neuroplasticity. These findings strongly support the striatum as a novel, promising target for neuromodulation-based interventions to effectively support recovery, particularly during the subacute, hyperplastic phase following a stroke. However, traditional NIBS techniques, such as transcranial direct current stimulation (tDCS), alternating current stimulation (tACS), and transcranial magnetic stimulation (TMS), are unable to reach deep brain structures like the striatum due to the inherent trade-off between focality and depth. The recent introduction of transcranial temporal interference stimulation (tTIS) presents an exciting, implementable, and promising non-invasive approach. tTIS enables targeted, non-invasive modulation of striatal activity with an excellent balance between depth and focality. Striatal tTIS represents a groundbreaking, novel interventional strategy to enhance motor recovery following brain injury. In first-in-human proof-of-concept studies, \*\*the investigators demonstrated\*\* that striatal neuromodulation by tTIS is feasible and safe. Applying theta burst patterned tTIS (iTBS-tTIS) to the striatum led to a significant, improvement in motor skill acquisition and increased activity changes in the striatum and the connected network. The behavioral improvement was most pronounced in healthy old adults, typically in comparable age as stroke patients. Additional proof-of-concept studies further support the feasibility and efficacy of tTIS in brain lesioned patient cohorts. For instance, \*\*the investigators conducted\*\* a study involving 15 patients with traumatic brain injury (TBI) and, demonstrating that tTIS significantly improved motor learning and retention, with clinically meaningful effects observed for at least 24 hours after stimulation. Moreover, a study in patients with Parkinson's disease demonstrated that tTIS can improve motor symptoms, particularly bradykinesia and tremor. Collectively, these results highlight that tTIS is a safe and well-tolerated technique, demonstrating strong potential for improving motor outcomes in various neurological conditions. To achieve not only the demonstrated shorter-lasting, but long-lasting effects in the present project, \*\*the investigators will significantly enhance the dosage and apply an accelerated stimulation protocol with three stimulation sessions per day for one week.\*\* * Accelerated stimulation protocols for neurorehabilitation.\*\* Recent clinical guidelines from leading organizations such as the National Institute for Health and Care Excellence (NICE), the Intercollegiate Stroke Working Party (ISWP), and the European Stroke Organisation (ESO) emphasize the critical importance of increasing the intensity of upper limb motor rehabilitation in stroke recovery. Accelerated protocols-entailing multiple therapy sessions per day-have emerged as an effective strategy to significantly enhance functional outcomes and improve the quality of life for stroke survivors. Studies have highlighted the benefits and safety of accelerated brain stimulation protocols across various conditions, including stroke, depression, Parkinson's disease and Alzheimer's disease. These protocols, which deliver multiple stimulation sessions per day over consecutive days, have demonstrated equal or greater effectiveness compared to traditional, longer treatment paradigms. Moreover, accelerated protocols reduce the overall time commitment for patients, minimizing the impact on \*\*patients' professional responsibilities and transportation demands\*\*. Building on this evidence, \*\*the investigators propose\*\* to implement an accelerated striatal tTIS protocol, aiming to achieve more rapid, intensive, and effective motor rehabilitation. * Primary research question.\*\* Current evidence highlights that (a) the striatum is a core structure involved in post-stroke motor recovery, and (b) there is an innovative opportunity to neuromodulate the striatum non-invasively, safely, and with precise depth-focality. This breakthrough could pave the way for novel and disruptive treatment strategies to enhance stroke recovery. \*\*The investigators hypothesize\*\* that personalized, accelerated striatal tTIS, combined with upper extremity rehabilitative training, will be feasible, safe, and lead to greater behavioral improvement and recovery than placebo stimulation with rehabilitative training in chronic stroke patients. The primary endpoints are composite upper extremity motor functions, feasibility and safety. To test this hypothesis, \*\*the investigators will conduct\*\* a double-blind, placebo-controlled, multicenter clinical trial. \*\*The investigators will apply\*\* intermittent theta-burst tTIS to the striatum (iTBS-tTISStriatum), with individualized electrode positioning based on each patient's anatomy, alongside intensive rehabilitation therapy. This will be the first clinical trial to non-invasively target deep brain structures (striatum) to enhance stroke recovery in humans. \*\*Secondary research questions.\*\* The core aspect of the present project is to determine the behavioral effects of the suggested transformative interventional strategy on motor recovery. However, \*\*the present project also requires personalized electrode placement and assessment of the impact of the intervention on daily life activities, higher order cognitive functions, brain activity and long-term effects. The project should further allow evaluation of factors that impact the degree of individual treatment response, paving the way to biomarkers.\*\* * Changes in daily life-oriented behavior - the Smart Kitchen Assessment:.\*\* Therapy-induced changes in functional upper-limb performance in daily-life-like tasks will be quantified using objective, instrumented measures before (week 1) and after (week 3) the therapy. The outcomes will include: change in movement speed and smoothness of the paretic upper limb, change in movement efficiency during functional tasks, change in bimanual coordination, change in task success rate. These outcomes reflect clinically meaningful improvements in dexterity and functional task performance in an ecologically valid environment, and enable the discrimination between true motor improvement and compensatory strategies. * Changes in daily life-oriented behavior - Questionnaires.\*\* Changes in daily functioning and perceived health will be evaluated from before the therapy (week 1) to after the therapy (week 3) using validated clinical questionnaires and observation scales. Outcomes will include: change in independence in activities of daily living, change in upper-limb performance during daily activities, change in patient-reported global health and well-being. \*\*Treatment-induced changes in sensory, psycho-social and cognitive domains.\*\* Non-motor effects of the therapy will be assessed through changes from before (week 1) to after (week 3) the intervention in: mood and motivation, fatigue and sleep quality, sensory function, attention, executive functions, and spatial awareness. These outcomes provide a concise characterization of therapy-related changes beyond motor performance. \*\*Treatment-induced changes in network properties (Multi-modal MRI and electrophysiology).\*\* Neurobiological effects of the therapy will be evaluated through changes in: structural and functional brain connectivity, global network efficiency and integration, cortical excitability and excitation-inhibition balance. These outcomes will support interpretation of clinical effects and mechanisms of recovery. \*\*Long-lasting treatment-induced changes in behavior:\*\* To determine whether the achieved effects of the proposed interventional strategy persist, \*\*the investigators will invite the patients\*\* for a clinical, behavioral follow-up evaluation (FU) 3 months after the end of the treatment. Outcomes of interest will be similar to the primary outcomes, and to those established to assess changes in daily-life behavior (questionnaires and Smart Kitchen assessment) and in sensory, psycho-social, and cognitive domains.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
84
Transcranial Temporal Interference Stimulation (tTIS) is a non-invasive neuromodulation technique that applies multiple high-frequency electrical currents via scalp electrodes to generate an amplitude-modulated electric field in deep brain regions without surgery. The technique allows targeting of different deep brain structures depending on electrode configuration and current parameters. In this study, stimulation is individualized to target the striatum using subject-specific electrode placement based on anatomical information. The stimulation is delivered in a theta-burst-patterned protocol designed to induce plasticity-related effects. tTIS is applied concurrently with upper-limb rehabilitative training during each session. The intervention is administered over five consecutive days, with three sessions per day within an accelerated protocol.
Participants undergo intensive, task-oriented upper-limb rehabilitation training focused on improving motor function of the affected arm and hand following stroke. Training is delivered in a structured and personalized manner, adapted to the participant's level of impairment and functional capacity. Each session includes approximately 30 minutes of physiotherapy involving repetitive, goal-directed movements and functional tasks targeting upper-limb use. The rehabilitation is provided concurrently with stimulation (active or sham) and follows an accelerated schedule of three sessions per day over five consecutive days.
Sham Transcranial Temporal Interference Stimulation (tTIS) is a non-invasive neuromodulation procedure that applies two identical high-frequency electrical currents via scalp electrodes. Because the currents have the same frequency, no low-frequency amplitude-modulated electric field is generated in deep brain regions. The sham stimulation uses the same individualized electrode placement based on anatomical information and follows the same stimulation schedule and device settings as the active intervention, while not delivering the temporal interference pattern intended to modulate striatal activity. Sham tTIS is applied concurrently with upper-limb rehabilitative training during each session. The intervention is administered over five consecutive days, with three sessions per day within an accelerated protocol.
CRR SUVA
Sion, Valais, Switzerland
Change in Upper-Limb Motor Function (Composite Motor Score)
Upper-limb motor performance assessed using a composite motor score including the Fugl-Meyer Assessment Upper Limb, Pinch \& Grip, Box\&Blocks, Nine-Hole Peg Test, and Action Research Arm Test (ARAT). The primary endpoint is defined as the change from baseline to post-intervention.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Barthel Index Score
Independence in basic activities of daily living will be assessed using the Barthel Index. The instrument evaluates feeding, bathing, grooming, dressing, bowel and bladder control, toilet use, transfers, mobility, and stair use. The total score ranges from 0 to 100, with higher scores indicating greater independence. The outcome will be the change in total score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Changes in daily life-oriented behavior - Questionnaires.
Changes in daily functioning and perceived health will be evaluated from before the therapy (week 1) to after the therapy (week 3) using validated clinical questionnaires and observation scales. Outcomes will include: change in independence in activities of daily living, change in upper-limb performance during daily activities, change in patient-reported global health and well-being.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Modified Rankin Scale Score
Global disability will be assessed using the Modified Rankin Scale. Scores range from 0 to 5 in the study CRF, with 0 indicating no symptoms and 5 indicating severe disability requiring constant nursing care and attention. The outcome will be the change in score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Functional Independence Measure Total Score
Functional independence will be assessed using the Functional Independence Measure (FIM), covering self-care, sphincter control, transfers, locomotion, communication, and social cognition. Individual items are rated from 1 (total assistance) to 7 (complete independence), and the total FIM score will be used as the outcome measure. Higher scores indicate greater functional independence. The outcome will be the change in total score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1) and post-intervention (Week 3, ±3 days)
Change in Modified Upper Limb Lucerne ICF-Based Multidisciplinary Observation Scale Score
Daily-life upper-limb function will be assessed using the Modified Upper Limb Lucerne ICF-Based Multidisciplinary Observation Scale (LIMOS). The scale evaluates lifting and carrying objects, fine hand use, hand and arm use, washing, and dressing. The summed score ranges from 0 to 20, with higher scores indicating greater independence in upper-limb-related activities. The outcome will be the change in total score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in PROMIS Global Health Score
Patient-reported global physical, mental, and social health will be assessed using the PROMIS Global Health questionnaire. Scores will be calculated according to the standardized PROMIS scoring procedure, with higher scores indicating better self-reported health. The outcome will be the change in score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Hospital Anxiety and Depression Scale - Anxiety Subscale Score
Anxiety symptoms will be assessed using the Anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A). The subscale consists of 7 items scored from 0 to 3, yielding a total score from 0 to 21. Higher scores indicate greater anxiety symptom severity. The outcome will be the change in HADS-A score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Hospital Anxiety and Depression Scale - Depression Subscale Score
Depressive symptoms will be assessed using the Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). The subscale consists of 7 items scored from 0 to 3, yielding a total score from 0 to 21. Higher scores indicate greater depressive symptom severity. The outcome will be the change in HADS-D score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in State-Trait Anxiety Inventory - State Anxiety Score
Current anxiety will be assessed using the State subscale of the State-Trait Anxiety Inventory (STAI-S). The STAI-S consists of 20 items assessing anxiety experienced at the time of assessment. The total score ranges from 20 to 80, with higher scores indicating greater state anxiety. The outcome will be the change in total score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in State-Trait Anxiety Inventory - Trait Anxiety Score
General anxiety tendency will be assessed using the Trait subscale of the State-Trait Anxiety Inventory (STAI-T). The STAI-T consists of 20 items and yields a total score ranging from 20 to 80, with higher scores indicating greater trait anxiety. The outcome will be the change in total score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Multidimensional Fatigue Inventory Score
Fatigue will be assessed using the Multidimensional Fatigue Inventory. The questionnaire contains 20 items rated on a 5-point response scale and assesses general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. Scores will be calculated according to the standardized scoring procedure, with higher scores indicating greater fatigue. The outcome will be the change in fatigue score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Pittsburgh Sleep Quality Index Global Score
Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI). The PSQI assesses sleep quality and disturbances during the preceding month and generates a global score ranging from 0 to 21. Higher scores indicate poorer sleep quality. The outcome will be the change in global PSQI score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Apathy Evaluation Scale Self-Rated Score
Motivation and apathy will be assessed using the self-rated Apathy Evaluation Scale. The instrument contains 18 items assessing interest, initiative, engagement, and motivation. The total score will be calculated according to the standardized scoring procedure, with higher scores indicating greater apathy. The outcome will be the change in total score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Revised Nottingham Sensory Assessment Score
Somatosensory function will be assessed using the Revised Nottingham Sensory Assessment. The assessment evaluates tactile sensation, proprioception, and stereognosis. Sensory responses are scored according to the standardized assessment criteria, with higher scores reflecting better sensory function. The outcome will be the change in sensory performance from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Sensitive Neglect Test Single-Task Total Omissions
Spatial attention will be assessed using the single-task condition of the Sensitive Neglect Test (SNT). The outcome measure will be the total number of omitted targets. Higher numbers of omissions indicate greater impairment of visuospatial attention. The outcome will be the change in total omissions from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Sensitive Neglect Test Dual-Task Total Omissions
Spatial attention under dual-task conditions will be assessed using the dual-task condition of the Sensitive Neglect Test (SNT). The outcome measure will be the total number of omitted targets. Higher numbers of omissions indicate greater impairment of visuospatial attention under dual-task conditions. The outcome will be the change in total omissions from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Long-Line Bisection Error
Visuospatial attention will be assessed using a line-bisection task. Participants bisect two 20-cm horizontal lines, and the deviation from the true midpoint is measured in millimeters. Deviations to the right of the midpoint are recorded as positive values and deviations to the left as negative values. The mean deviation across the two 20-cm lines will be used as the outcome measure. Values closer to zero indicate more accurate spatial midpoint estimation.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in TAP Phasic Alertness Index
Phasic alertness will be assessed using the alertness module of the Test of Attentional Performance (TAP). Median reaction time is measured in conditions with and without an auditory warning signal. The phasic alertness index is calculated as the difference between median reaction time without and with the warning signal, divided by the overall median reaction time. The outcome will be the change in the phasic alertness index from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Color Trails Test Interference Index
Divided attention and cognitive flexibility will be assessed using the Color Trails Test. Performance time and errors are recorded for Parts 1 and 2, and an interference index is derived from performance across the two parts. The outcome will be the change in the Color Trails Test interference index from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Stroop Victoria Test Interference Index
Inhibitory control will be assessed using the Stroop Victoria Test. Completion times are recorded for the Color, Word, and Interference cards. The primary Stroop outcome will be the interference index calculated as completion time for the Interference Card divided by completion time for the Color Card. The outcome will be the change in the interference index from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Five-Point Test Correct Designs
Nonverbal executive functioning and design fluency will be assessed using the Five-Point Test. The outcome measure will be the number of correct unique designs produced within the standardized task period. Higher values indicate greater design fluency. The outcome will be the change in the number of correct designs from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Phonological Verbal Fluency Score
Phonological verbal fluency will be assessed by asking participants to generate words beginning with a specified letter during a 1-minute period. Repetitions and errors will be excluded. The outcome measure will be the number of correct words generated, with higher values indicating better verbal fluency. The outcome will be the change from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Digit Span Forward Total Score
Auditory attention and short-term verbal memory will be assessed using the Digit Span Forward condition. The outcome will be the total number of correctly completed sequences according to the study scoring procedure. Higher scores indicate better performance. The outcome will be the change from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Digit Span Backward Total Score
Verbal working memory will be assessed using the Digit Span Backward condition. The outcome will be the total number of correctly completed sequences according to the study scoring procedure. Higher scores indicate better working-memory performance. The outcome will be the change from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Digit Span Sequencing Total Score
Working-memory manipulation will be assessed using the Digit Span Sequencing condition. Participants reproduce orally presented digit sequences in ascending numerical order. The outcome will be the total score according to the study scoring procedure, with higher scores indicating better performance. The outcome will be the change from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Token Test Total Score
Auditory language comprehension will be assessed using the Token Test. Participants execute increasingly complex verbal commands using colored geometric tokens. Responses are scored according to the study scoring procedure, yielding a maximum total score of 36. Higher scores indicate better auditory comprehension. The outcome will be the change in total score from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Paretic Upper-Limb Movement Speed During the Smart Kitchen Assessment
Upper-limb movement speed during standardized daily-life-like tasks in the Smart Kitchen Assessment will be quantified using instrumented movement recordings. Movement speed will be calculated as the time to complete each subtask and reported in seconds. The outcome will be the change from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Paretic Upper-Limb Movement Smoothness During the Smart Kitchen Assessment
Movement smoothness of the paretic upper limb during standardized daily-life-like tasks will be quantified using tortuosity of the active wrist in linear movements (such as reaching or placing) and cycle consistency in periodic movements (such as peeling or grating). Both measures are dimensionless. Lower values of Tortuosity and Higher values of cycle consistency indicate smoother movement. The outcome will be the change from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Movement Efficiency During the Smart Kitchen Assessment
Movement efficiency during standardized Smart Kitchen tasks will be quantified using using the jerk of the upper limb kinematics and reported in m/s\^3. Lower values indicate greater movement efficiency. The outcome will be the change from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Bimanual Coordination During the Smart Kitchen Assessment
Bimanual coordination during standardized Smart Kitchen tasks will be quantified using using the time needed to perform bimanual tasks and reported in seconds. Lower values indicate better bimanual coordination. The outcome will be the change from baseline to post-intervention and follow-up.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days), and follow-up (Week 14, ±10 days)
Change in Static Resting-State Functional Connectivity Measured With fMRI
Static resting-state functional connectivity will be assessed using functional MRI and quantified from the temporal correlation of resting-state BOLD signals between brain regions. Correlation-based connectivity values will be used to characterize functional coupling within and between brain networks. The outcome will assess changes in static functional connectivity from baseline to post-intervention.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days)
Change in Dynamic Resting-State Functional Connectivity Measured With fMRI
Dynamic resting-state functional connectivity will be assessed using functional MRI by quantifying temporal variability in functional coupling between brain regions. Dynamic connectivity will be characterized using the variability of time-resolved functional connections, expressed as the standard deviation of connectivity-related time series. The outcome will assess changes in dynamic functional connectivity from baseline to post-intervention.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days)
Association Between Structural Connectivity and Treatment Response
Structural brain connectivity will be assessed at baseline and post-intervention using diffusion-weighted MRI and quantified using streamline-based connectivity between brain regions. Structural connectivity measures will characterize the strength or preservation of anatomical connections and will be examined for association with the magnitude of behavioral response to the intervention.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days)
Change in Resting-State EEG Functional Connectivity
Resting-state EEG will be recorded under standardized eyes-open and/or eyes-closed conditions. Functional connectivity will be quantified using Debiased Weighted Phase Lag Index (dwPLI) within the oscillatory bands of interest. The outcome will be the change in dwPLI from baseline to post-intervention.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days)
Change in Cortical Excitability Measured With TMS-EEG
Cortical excitability will be assessed using TMS combined with EEG. The outcome measure will be TEP amplitude at predefined components, electrodes, and time intervals, reported in mV. The outcome will be the change from baseline to post-intervention.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days)
Change in Excitation-Inhibition Balance Measured With TMS-EEG
Cortical excitation-inhibition balance will be assessed using TMS-EEG and quantified using the amplitude of induced TEPs in response to Paired-pulse Short intracortical inhibition (SICI) and intracortical facilitation (ICF). The measure will be reported in mV. The outcome will be the change in waveform from baseline to post-intervention.
Time frame: Baseline (Week 1), post-intervention (Week 3, ±3 days)
Incidence of Adverse Events, Serious Adverse Events, Adverse Device Effects, and Device Deficiencies
Safety will be assessed by recording adverse events, serious adverse events, anticipated and unanticipated adverse device effects, and device deficiencies occurring during the intervention period. The number and proportion of participants experiencing each category of event will be reported together with event type and severity.
Time frame: From the first intervention session through completion of the intervention period at the end of Week 2
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