Feasibility, Safety, and Preliminary Efficacy of Median Nerve Stimulation for Cognitive Dysfunction in Patients With Acute Traumatic Brain Injury

The MMSE will be used to evaluate global cognitive function. Assessments will be conducted by two trained occupational researchers who are blinded to group allocation and not involved in the intervention.

Global cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA), a 30-point screening tool evaluating multiple cognitive domains including attention, memory, language, executive function, and visuospatial ability. Higher scores indicate better cognitive performance, and a score below 26 suggests cognitive impairment.

Verbal fluency will be assessed using the Verbal Fluency Test, in which participants are asked to generate as many words as possible within 1 minute. The test evaluates language production and executive control, with higher word counts indicating better performance.

Language ability will be assessed using the Boston Naming Test, which requires participants to name a series of visually presented objects. Higher scores reflect better confrontation naming ability and language function.

Visuospatial ability will be assessed using the Rey-Osterrieth Complex Figure Test (RCFT), which evaluates visuospatial construction and visual memory through figure copying and recall tasks. Higher scores indicate better visuospatial performance.

Verbal learning and memory will be assessed using the Rey Auditory Verbal Learning Test (RAVLT), a verbal learning task involving a 15-item word list learned over five trials. The delayed recall score represents the number of correctly recalled words (range: 0-15) after a 30-minute delay, with higher scores indicating better memory performance.

Executive function will be assessed using the Stroop Test and Trail Making Test A/B. The Stroop Test evaluates inhibitory control and cognitive flexibility, while the Trail Making Test assesses processing speed (Part A) and set-shifting ability (Part B). Better executive function is reflected by higher accuracy and shorter completion time.

Attention and working memory will be assessed using the Digit Symbol Test and Digit Span Test. The Digit Symbol Test evaluates attention and processing speed, whereas the Digit Span Test assesses working memory capacity through forward and backward recall tasks. Higher scores indicate better cognitive performance.

Neuropsychiatric symptoms will be assessed using the Neuropsychiatric Inventory (NPI), which evaluates 12 neuropsychiatric symptom domains based on caregiver interviews, including both the caregiver's observations of patient behaviors and the associated caregiver distress. The total patient symptom score ranges from 0 to 144, and the caregiver distress score ranges from 0 to 60, with higher scores indicating greater symptom frequency, severity, and caregiver burden; a score of 0 represents the absence of symptoms or distress.

Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI), which consists of 19 self-rated items measuring seven domains of sleep: (1) subjective sleep quality, (2) sleep latency, (3) sleep duration, (4) habitual sleep efficiency, (5) sleep disturbances, (6) use of sleep medication, and (7) daytime dysfunction. The 19 items are aggregated into seven component scores, each ranging from 0 to 3, where 0 indicates no difficulty and 3 indicates severe difficulty. The component scores are summed to generate a global PSQI score ranging from 0 to 21, with higher scores indicating poorer overall sleep quality.

Anxiety symptoms will be assessed using the Hamilton Anxiety Scale (HAMA), a clinician-rated scale where higher scores indicate more severe anxiety symptoms.

Depressive symptoms will be assessed using the Hamilton Depression Scale (HAMD), where higher scores indicate more severe depressive symptoms.

Apathy will be assessed using the Modified Apathy Evaluation Scale (MAES), a questionnaire evaluating motivational and emotional engagement. The total score ranges from 0 to 42, with scores greater than 14 indicating apathy; higher scores represent more severe apathetic symptoms.

Agitation will be assessed using the Cohen-Mansfield Agitation Inventory (CMAI), a 29-item observational scale designed to assess agitation behaviors related to dementia and delirium. The CMAI measures the frequency of agitated behaviors across multiple categories, with total scores ranging from 29 to 116; higher scores indicate more severe agitation.

Neurological status will be assessed using the Glasgow Coma Scale (GCS), a 15-point scale ranging from 3 to 15, where higher scores indicate better level of consciousness.

Functional neurological outcome will be assessed using the Modified Rankin Scale (mRS), which ranges from 0 to 6, where higher scores indicate worse functional outcome. A score of 0 indicates normal daily functioning, and a score of 6 indicates death.

Activities of daily living will be assessed using the Modified Barthel Index (MBI), a 100-point scale evaluating functional independence in basic daily activities. Higher scores indicate greater independence. Scores <20 indicate very severe functional dependence with complete reliance on others; scores of 20-40 indicate severe dependence requiring substantial assistance; scores of 41-60 indicate moderate dependence; and scores >60 indicate basic independence in daily living.

Health-related quality of life will be assessed using the Short Form-36 Health Survey (SF-36), which evaluates physical and mental health domains, where higher scores indicate better quality of life.

Functional activities will be assessed using the Functional Activities Questionnaire (FAQ; range 0-30), with higher scores indicating worse functional performance. Scores ≤5 are considered normal, whereas scores ≥5 suggest impaired independence in home and community functioning.

Functional connectivity of brain networks will be assessed using magnetoencephalography (MEG), with quantification of connectivity within the default mode network and executive control network.

Serum tau concentration will be measured as a biomarker of neuronal injury, where higher levels may indicate greater neuronal damage.

Serum amyloid-β (Aβ) concentration will be measured as a biomarker related to cognitive impairment, where higher levels may indicate increased pathological burden.

Serum GFAP concentration will be measured as a biomarker of astroglial injury, where higher levels may indicate greater glial damage.

Serum S100β concentration will be measured as a biomarker of blood-brain barrier disruption and glial injury, where higher levels may indicate worse neurological injury.

Serum α-synuclein concentration will be measured as a biomarker related to neuronal degeneration, where higher levels may indicate greater neuronal pathology.

Feasibility will be evaluated by enrollment rate, recruitment rate, adherence rate (proportion of completed scheduled stimulation hours), and retention rate (completion of all outcome assessments).

Adverse events related to the intervention (e.g., skin pain, uncomfortable cutaneous sensations, dizziness, abnormal blood pressure, or heart rhythm disturbances) will be recorded. Side effects will be monitored using a 10-item Likert-scale questionnaire (score range: 1 = absent to 5 = severe).