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Currently, the treatment of cognitive dysfunction after acute TBI remains a challenge, and novel therapeutic methods are urgently needed. Median nerve stimulation (MNS) is a non-invasive neuromodulation technique and recently has shown positive effects in awaking coma of acute brain injury. It has been shown to improve cognition in healthy volunteers and may be a potential therapeutic approach for cognitive dysfunction in patients with acute TBI. Therefore, the main purpose of the study is to evaluate the feasibility, safety, and preliminary efficacy of MNS for cognitive dysfunction in patients with acute TBI.
Traumatic brain injury (TBI), a major cause of death and disability, is a significant public health problem in the worldwide. It can cause cognitive dysfunctions including executive function, memory, attention, language and visuospatial function, which seriously affects the patient's quality of life and places a heavy burden on the country and family. Currently, the main therapeutic methods for cognitive impairment include cognitive training, drug therapy, hyperbaric oxygen therapy, and aerobic exercise therapy. They all have been shown to have potentially positive effects on cognitive impairment. However, the improvement in overall cognitive function is inconsistent. Moreover, all the interventions are usually performed during chronic stage of TBI, leading to often delayed and suboptimal therapeutic outcomes. Thus, treatment options for cognitive impairment during the acute stage of TBI remain limited.
Recently, noninvasive neuromodulation techniques, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, transcutaneous auricular vagus nerve stimulation, and median nerve stimulation, were recognized to have promising potentials in improving cognitive function in patients with cognitive impairment caused by stroke, intracerebral hemorrhage, and TBI. Within them, MNS is a simple, inexpensive, and noninvasive neuromodulation technique that has been found to improve recovery from TBI, hasten awakening from coma in our previous study. Furthermore, clinical studies have shown that it can effectively improve cognitive function in healthy individuals and enhance cognitive recovery following stroke. However, whether MNS has the same beneficial effects in those with cognitive dysfunction after TBI is unclear. The investigators designed the present study to assess the feasibility and safety of MNS and the preliminary effects on cognitive dysfunction in patients with acute TBI. The present study details a pilot trial that will be conducted before a large-scale randomized controlled trial.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Median nerve stimulation group | Experimental | Participants will receive right median nerve stimulation therapy (right median nerve electrical stimulator, XCH-B1, Jiangxi Nuocheng Electrical Equipment Co., Ltd.). Both frequency of 40 Hz and pulse width of 300 µs are fixed and applied within a 20-s on/40-s off protocol. Stimulation will be administered for 8 hours per day over a 2-week period. |
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| Sham group | Sham Comparator | The participants in the sham stimulation group will receive no electrical stimulation (0 mA) via an activated stimulator, with all other device settings and procedures identical to those used in the active stimulation group. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Median nerve stimulation | Device | Participants will receive right median nerve stimulation therapy (right median nerve electrical stimulator, XCH-B1, Jiangxi Nuocheng Electrical Equipment Co., Ltd.). Both frequency of 40 Hz and pulse width of 300 µs are fixed and applied within a 20-s on/40-s off protocol. Stimulation will be administered for 8 hours per day over a 2-week period. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in global cognitive function assessed by the Mini-Mental State Examination(MMSE) | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Measure | Description | Time Frame |
|---|---|---|
| Global cognitive function (MoCA) | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Measure | Description | Time Frame |
|---|---|---|
| Feasibility outcomes | 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). | From baseline (Day 7 after injury) to 3 months after injury. |
| Safety outcomes |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Liang Wu, MD | Contact | 18301674233 | +86 | wuliang@bjtth.org |
| Yu Deng, MD | Contact | 15611308032 | +86 | drdy1998@126.com |
| Name | Affiliation | Role |
|---|---|---|
| Guoyi Gao, MD | Beijing Tiantan Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beijing Tiantan Hospital, Capital Medical University | Recruiting | Beijing | Beijing Municipality | 100070 | China |
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Investigators in charge of the recruitment and follow-up evaluation, outcome assessors, and data analysts will be blinded to group allocation. Participants and independent researchers who apply the MNS will not be blinded. Researchers who monitor patients' safety and perform risk management can access group allocation if necessary. Before the outcome assessment begins at every follow-up evaluation, the participants will be reminded not to reveal any information about their group allocation to decrease the risk of unblinding. If the investigator can detect details of group allocation during follow-up, another blinded researcher will evaluate the outcome.
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| Sham | Drug | The participants in the sham stimulation group will receive no electrical stimulation (0 mA) via an activated stimulator, with all other device settings and procedures identical to those used in the active stimulation group. |
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| Verbal fluency | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Language function | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Visuospatial 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Verbal learning and memory | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Executive function | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Attention and working memory | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Neuropsychiatric symptoms | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Sleep quality | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Anxiety symptoms | Anxiety symptoms will be assessed using the Hamilton Anxiety Scale (HAMA), a clinician-rated scale where higher scores indicate more severe anxiety symptoms. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Depressive symptoms | Depressive symptoms will be assessed using the Hamilton Depression Scale (HAMD), where higher scores indicate more severe depressive symptoms. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Apathy | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Agitation | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Level of consciousness | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Functional neurological outcome | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Activities of daily living | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Health-related quality of life | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Functional activities | 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. | Baseline (Day 7 after injury), 1 month after injury, and 3 months after injury. |
| Neuroimaging outcomes | Functional connectivity of brain networks will be assessed using magnetoencephalography (MEG), with quantification of connectivity within the default mode network and executive control network. | Baseline (Day 7 after injury) and 1 month after injury. |
| Serum tau level | Serum tau concentration will be measured as a biomarker of neuronal injury, where higher levels may indicate greater neuronal damage. | Baseline (Day 7 after injury) and 1 month after injury. |
| Serum amyloid-β (Aβ) level | Serum amyloid-β (Aβ) concentration will be measured as a biomarker related to cognitive impairment, where higher levels may indicate increased pathological burden. | Baseline (Day 7 after injury) and 1 month after injury. |
| Serum glial fibrillary acidic protein (GFAP) level | Serum GFAP concentration will be measured as a biomarker of astroglial injury, where higher levels may indicate greater glial damage. | Baseline (Day 7 after injury) and 1 month after injury. |
| Serum S100β level | 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. | Baseline (Day 7 after injury) and 1 month after injury. |
| Serum α-synuclein level | Serum α-synuclein concentration will be measured as a biomarker related to neuronal degeneration, where higher levels may indicate greater neuronal pathology. | Baseline (Day 7 after injury) and 1 month after injury. |
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). |
| From baseline (Day 7 after injury) to 3 months after injury. |
| ID | Term |
|---|---|
| D000070642 | Brain Injuries, Traumatic |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D001930 | Brain Injuries |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D006259 | Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C005703 | salicylhydroxamic acid |
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