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The aging US population threatens to overwhelm our healthcare infrastructure, especially since the rate of Alzheimer's disease (AD) alone is expected to triple in the coming decades. Memory cause functional impairment, reduced quality of life, increased caregiver burnout, and eventual institutionalization. The diagnosis of mild cognitive impairment (MCI) identifies those with memory deficits but who remain relatively independent in everyday life. MCI provides a window for interventions that target memory functioning. The proposed study focuses specifically on a groundbreaking combination of mnemonic rehabilitation and non-invasive brain stimulation. The main idea is that brain stimulation can enhance functioning in the specific brain regions/networks, thereby increasing the patients' ability to benefit from different types of memory rehabilitation. This will be a randomized, double-blind study (active vs. fake brain stimulation), that provides multiple treatment session. Outcome will be examined using both laboratory-based and real-world memory testing as well as brain imaging. This first-of-its-kind study has the potential to meaningfully translate more "basic" science findings into neuroanatomically targeted and functionally meaningful treatments for our aging population.
Enrollment and interactions/interventions are temporarily paused due to COVID-19 and are expected to resume in the future. This is not a suspension of IRB approval.
The proposed study focuses specifically on a groundbreaking combination of mnemonic rehabilitation and non-invasive brain stimulation. The main idea is that brain stimulation can enhance functioning in the specific brain regions/networks, thereby increasing the patients' ability to benefit from memory rehabilitation. This will be a randomized, double-blind study (active vs. fake brain stimulation), that provides multiple treatment session. Outcome will be examined using both laboratory-based and real-world memory testing as well as brain imaging. This first-of-its-kind study has the potential to meaningfully translate more "basic" science findings into neuroanatomically targeted and functionally meaningful treatments for our aging population.
The general purpose of this study is to examine the effects of two types of treatments for memory impairment in those with mild cognitive impairment (MCI). One form of treatment is cognitive rehabilitation, which involves teaching new ways to learn and remember information. The second form of treatment uses a type of electrical brain stimulation called transcranial direct current stimulation (tDCS) to increase activity in certain brain areas that may be involved with memory. We will use brain imaging to see whether these treatments changed how individuals learn and remember information. We will also use cognitive tests and questionnaires to examine whether memory (and related abilities) changed because of treatment.
Values were updated in February 2023 after discovering coding errors in the original database. An exploratory outcome variable (effect of brain volumes) was removed at that time since the electrical field analyses are fundamentally dependent on brain volumes - the EF outcome measure remained but was modified to remove the two sham conditions since, by design, they did not receive any electric field (i.e., sham) and the statistical corrections could not be performed.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| active tDCS + mnemonic strategy training | Experimental | Group receives active brain stimulation plus memory rehabilitation |
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| sham tDCS + mnemonic strategy training | Active Comparator | Group receives sham brain stimulation plus memory rehabilitation |
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| active tDCS + autobiographical memory recall | Active Comparator | Group receives active brain stimulation plus reminiscence training |
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| sham tDCS + autobiographical memory recall | Active Comparator | Group receives sham brain stimulation plus reminiscence training |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit | Device | Active brain stimulation |
|
| Measure | Description | Time Frame |
|---|---|---|
| Face-name Memory Test Performance | Raw number of face-name pairs correctly recalled with a maximum of 15 points; higher values are better at each time point. Change at post-session 5 (day 5 after baseline)) calculated relative to baseline performance (positive differences indicate improvement; negative values indicate decline). Data coding errors were identified and accurate values were reported 2/6/2023. | change from baseline to post session 5 (day 5 after baseline) |
| Object Location Association Memory Test Performance - Recognition Condition | Performance measured using number of correctly identified locations (3 locations per stimulus; 15 total stimuli). Higher values indicate better performance. Change at post-session 5 (day 5 after baseline) calculated relative to baseline performance (positive differences indicate improvement; negative values indicate decline). Data coding errors were identified and accurate data were updated 2/6/2023. | change from baseline to post session 5 (day 5 after baseline) |
| fMRI Betaweight Change | Changes in task related blood oxygen dependent signal (BOLD) activation for the face-name (novel post > novel pre) contrast in the left inferior frontal gyrus (pars triangularis, pars orbitalis, pars opercularis). Data are preliminary betaweights for the above noted contrast. Positive values reflect increased BOLD signal while negative values represent reduced BOLD signal. Not all participants were able to complete fMRI, which explains sample size discrepancies with other outcome measures. Data coding errors were discovered and accurate, updated data reported on 2/6/2023 | change from baseline to post session 5 (day 5 after baseline) |
| Measure | Description | Time Frame |
|---|---|---|
| Prose Memory | Performance on the Ecological Memory Simulations- Medical Instructions subtest. Raw points where higher values reflect better performance at each time point (0-15 possible points at each time point). Reported values reflect change from baseline (i.e., post-session day 5 vs. baseline) where positive values represent improvement and negative values represent decline. Corrected values are now included (2/23) that account for age, sex, and baseline neuropsychological abilities. |
| Measure | Description | Time Frame |
|---|---|---|
| Planned (Tertiary) Analyses of Patient-specific Characteristics That Affect Treatment Outcome | Planned analyses to examine patient specific characteristics that affect treatment efficacy and would be vital for clinical translation at the individual patient level. Data analyzed using a composite "recognition" score that combined the face-name and object-location task recognition scores (total on a 0-30 point scale; values below are change from baseline; higher values are "better" and reflect improved memory test performance). Patient-level factors of age, sex, race, RBANS Delayed Memory Index, MoCA, Emory version of the Wisconsin Card Sorting Test (total sorts) were included as covariates. |
Inclusion Criteria:
General inclusion criteria (all patients):
MCI Inclusion Criteria:
- Diagnosis of amnestic MCI based on criteria set forth by Petersen (2004). Additionally, other potential causes of cognitive deficit ruled out by the referring physician
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Benjamin M. Hampstead, PhD | VA Ann Arbor Healthcare System, Ann Arbor, MI | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VA Ann Arbor Healthcare System, Ann Arbor, MI | Ann Arbor | Michigan | 48105 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm 1 | Group receives active brain stimulation plus mnemonic strategy training Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Active brain stimulation |
| FG001 | Arm 2 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 1, 2022 | Jul 1, 2022 |
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| Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit | Device | Sham (placebo) |
|
| change from baseline to post Session 5 (day 5 after baseline) |
| MMQ - Strategy Subscale | Changes on the Multifactorial Memory Questionnaire - strategy subscale. Raw points where higher values reflect better performance at each time point (0-76 possible points at each time point). Reported values reflect change from baseline (i.e., post-session day 5 vs. baseline) where positive values represent improvement and negative values represent decline. | change from baseline to post session 5 (day 5 after baseline) |
| Spatial Navigation | Performance on Ecological Memory Simulations routes subtest (serial order). Higher values indicate better performance at each time point (0-9 possible points at each time point). Change from baseline is reported (post-session day 5 vs. baseline) so higher values indicate better recall while negative values indicate decline. Corrected data are now reported (2/23) accounting for age, sex, and baseline neuropsychological abilities. | change from baseline to post session 5 (day 5 after baseline) |
| change from baseline post treatment (within ~ 96 hours of session 5) |
| Change in Beta-weights Controlling for Electric Field (EF) | Outcome measure is the change in betaweight (as a percent signal change: post session 5 minus baseline) during the face-name and object-location tasks (same metric as Primary Outcome measure 3) while controlling for the electric field (EF). Finite element model based measurement of electric field in the targeted brain regions (Values range from 0 to no theoretical upper limit with higher values reflecting more electrical current; most values will be under 0.5 V/m). The EF was calculated using the baseline MRI T1 scan for each individual. EF values were then included in the linear mixed model analysis of fMRI Beta-weight change (post training vs. baseline) since EF values at the targeted brain region varied across participants. Note, EF values only apply to active HD-tDCS groups, so sham groups have no data to report and were removed accordingly (updated 2/23). | Betaweight change: Post session 5 (day 5) minus baseline |
Group receives sham brain stimulation plus mnemonic strategy training
Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo)
| FG002 | Arm 3 | Group receives active brain stimulation plus autobiographical recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Active brain stimulation |
| FG003 | Arm 4 | Group receives sham brain stimulation plus autobiographical recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Arm 1 | Group receives active brain stimulation plus mnemonic strategy training Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Active brain stimulation |
| BG001 | Arm 2 | Group receives sham brain stimulation plus mnemonic strategy training Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
| BG002 | Arm 3 | Group receives active brain stimulation plus autobiographical memory recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Active brain stimulation |
| BG003 | Arm 4 | Group receives sham brain stimulation plus autobiographical memory recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | Years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Face-name Memory Test Performance | Raw number of face-name pairs correctly recalled with a maximum of 15 points; higher values are better at each time point. Change at post-session 5 (day 5 after baseline)) calculated relative to baseline performance (positive differences indicate improvement; negative values indicate decline). Data coding errors were identified and accurate values were reported 2/6/2023. | Patient-level factors of age, sex, race, RBANS Delayed Memory Index, MoCA, Emory version of the Wisconsin Card Sorting Test were included as covariates. | Posted | Mean | 95% Confidence Interval | pairs correctly recalled/recognized | change from baseline to post session 5 (day 5 after baseline) |
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| Primary | Object Location Association Memory Test Performance - Recognition Condition | Performance measured using number of correctly identified locations (3 locations per stimulus; 15 total stimuli). Higher values indicate better performance. Change at post-session 5 (day 5 after baseline) calculated relative to baseline performance (positive differences indicate improvement; negative values indicate decline). Data coding errors were identified and accurate data were updated 2/6/2023. | Patient-level factors of age, sex, race, RBANS Delayed Memory Index, MoCA, Emory version of the Wisconsin Card Sorting Test were included as covariates. | Posted | Mean | 95% Confidence Interval | Number correct relative to baseline | change from baseline to post session 5 (day 5 after baseline) |
| ||||||||||||||||||||||||||||||||||||
| Primary | fMRI Betaweight Change | Changes in task related blood oxygen dependent signal (BOLD) activation for the face-name (novel post > novel pre) contrast in the left inferior frontal gyrus (pars triangularis, pars orbitalis, pars opercularis). Data are preliminary betaweights for the above noted contrast. Positive values reflect increased BOLD signal while negative values represent reduced BOLD signal. Not all participants were able to complete fMRI, which explains sample size discrepancies with other outcome measures. Data coding errors were discovered and accurate, updated data reported on 2/6/2023 | Posted | Mean | 95% Confidence Interval | Percent BOLD signal change | change from baseline to post session 5 (day 5 after baseline) |
| |||||||||||||||||||||||||||||||||||||
| Secondary | Prose Memory | Performance on the Ecological Memory Simulations- Medical Instructions subtest. Raw points where higher values reflect better performance at each time point (0-15 possible points at each time point). Reported values reflect change from baseline (i.e., post-session day 5 vs. baseline) where positive values represent improvement and negative values represent decline. Corrected values are now included (2/23) that account for age, sex, and baseline neuropsychological abilities. | Posted | Mean | 95% Confidence Interval | units on a scale | change from baseline to post Session 5 (day 5 after baseline) |
| |||||||||||||||||||||||||||||||||||||
| Secondary | MMQ - Strategy Subscale | Changes on the Multifactorial Memory Questionnaire - strategy subscale. Raw points where higher values reflect better performance at each time point (0-76 possible points at each time point). Reported values reflect change from baseline (i.e., post-session day 5 vs. baseline) where positive values represent improvement and negative values represent decline. | Posted | Mean | 95% Confidence Interval | units on a scale | change from baseline to post session 5 (day 5 after baseline) |
| |||||||||||||||||||||||||||||||||||||
| Secondary | Spatial Navigation | Performance on Ecological Memory Simulations routes subtest (serial order). Higher values indicate better performance at each time point (0-9 possible points at each time point). Change from baseline is reported (post-session day 5 vs. baseline) so higher values indicate better recall while negative values indicate decline. Corrected data are now reported (2/23) accounting for age, sex, and baseline neuropsychological abilities. | Posted | Mean | 95% Confidence Interval | units on a scale | change from baseline to post session 5 (day 5 after baseline) |
| |||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Planned (Tertiary) Analyses of Patient-specific Characteristics That Affect Treatment Outcome | Planned analyses to examine patient specific characteristics that affect treatment efficacy and would be vital for clinical translation at the individual patient level. Data analyzed using a composite "recognition" score that combined the face-name and object-location task recognition scores (total on a 0-30 point scale; values below are change from baseline; higher values are "better" and reflect improved memory test performance). Patient-level factors of age, sex, race, RBANS Delayed Memory Index, MoCA, Emory version of the Wisconsin Card Sorting Test (total sorts) were included as covariates. | linear mixed model Data analyzed using a composite "recognition" total score that combined the face-name and object-location task (change on 0-30 point scale relative to baseline) higher scores are better). Patient-level factors of age, sex, race, RBANS Delayed Memory Index, MoCA, Emory version of the Wisconsin Card Sorting Test (total sorts) were included as covariates. | Posted | Mean | 95% Confidence Interval | change in total score on 30 point scale | change from baseline post treatment (within ~ 96 hours of session 5) |
| ||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Change in Beta-weights Controlling for Electric Field (EF) | Outcome measure is the change in betaweight (as a percent signal change: post session 5 minus baseline) during the face-name and object-location tasks (same metric as Primary Outcome measure 3) while controlling for the electric field (EF). Finite element model based measurement of electric field in the targeted brain regions (Values range from 0 to no theoretical upper limit with higher values reflecting more electrical current; most values will be under 0.5 V/m). The EF was calculated using the baseline MRI T1 scan for each individual. EF values were then included in the linear mixed model analysis of fMRI Beta-weight change (post training vs. baseline) since EF values at the targeted brain region varied across participants. Note, EF values only apply to active HD-tDCS groups, so sham groups have no data to report and were removed accordingly (updated 2/23). | linear mixed model that includes EF as a predictor variable as well as covariates of age, sex, education, and race. | Posted | Mean | 95% Confidence Interval | % signal change (session 5 vs baseline) | Betaweight change: Post session 5 (day 5) minus baseline |
|
Primary study intervention period (5 days)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Arm 1 | Group receives active brain stimulation plus mnemonic strategy training Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Active brain stimulation | 0 | 29 | 0 | 29 | 0 | 29 |
| EG001 | Arm 2 | Group receives sham brain stimulation plus mnemonic strategy training Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) | 0 | 23 | 0 | 23 | 0 | 23 |
| EG002 | Arm 3 | Group receives active brain stimulation plus autobiographical recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Active brain stimulation | 0 | 29 | 0 | 29 | 0 | 29 |
| EG003 | Arm 4 | Group receives sham brain stimulation plus autobiographical recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) | 0 | 24 | 0 | 24 | 0 | 24 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Benjamin Hampstead | VA Ann Arbor | 734-763-9259 | bhampste@med.umich.edu |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 1, 2022 | Jul 1, 2022 | SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Nov 14, 2019 | Jul 1, 2022 | ICF_002.pdf |
| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| D000544 | Alzheimer Disease |
| D003704 | Dementia |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
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| ID | Term |
|---|---|
| D065908 | Transcranial Direct Current Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D003295 | Convulsive Therapy |
| D013000 | Psychiatric Somatic Therapies |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| OG003 | Arm 4 | Group receives sham brain stimulation plus autobiographical recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
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| OG003 | Arm 4 | Group receives sham brain stimulation plus autobiographical recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
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| OG003 |
| Arm 4 |
Group receives sham brain stimulation plus autobiographical recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
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Group receives sham brain stimulation plus autobiographical recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
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| Arm 4 |
Group receives sham brain stimulation plus autobiographical recall Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
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Group receives sham brain stimulation plus memory rehabilitation Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
| OG002 | Active tDCS + Autobiographical Memory Recall | Group receives active brain stimulation plus ABR Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Active brain stimulation |
| OG003 | Sham tDCS + Autobiographical Memory Recall | Group receives sham brain stimulation plus ABR Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Sham (placebo) |
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Group receives active brain stimulation plus ABR
Transcranial direct current stimulation (tDCS) Soterix Medical Inc. tDCS unit: Active brain stimulation
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