High Definition Transcranial Direct Current Stimulation (HD-tDCS) for Early Alzheimer's Disease (HD-tDCS)

This completed randomized trial evaluated the clinical and neural effects of high-definition transcranial direct current stimulation (HD-tDCS) combined with computerized cognitive training in patients with Alzheimer's disease. Participants were assigned to active HD-tDCS plus computerized cognitive training, computerized cognitive training control, or active HD-tDCS control. The study assessed whether combined neuromodulation and cognitive training produced greater cognitive and clinical benefit than either component condition, and whether treatment-related benefit was associated with changes in brain network organization.

Study Overview

• Status: Completed
• Conditions: Early Alzheimer's Disease; Functional Magnetic Resonance Imaging; Transcranial Direct Current Stimulation
• Intervention / Treatment: Other: computer-based cognitive training; Other: Sham tDCS; Other: HD-tDCS; Behavioral: Control cognitive training

Detailed Description

Upon meeting the inclusion criteria and providing informed consent, each participant completed a series of cognitive, neuropsychological, and neuroimaging assessments at the hospital outpatient clinics or inpatient department before receiving the assigned intervention.

Participants were randomly allocated to one of three parallel intervention arms: active anodal high-definition transcranial direct current stimulation (HD-tDCS) combined with computerized cognitive training, active anodal HD-tDCS combined with control cognitive training, or sham HD-tDCS combined with computerized cognitive training. Approximately 20 participants were assigned to each group.

Participants were studied using a masked randomized design. Study participants and personnel responsible for clinical and neuropsychological outcome assessments remained masked to the assigned stimulation condition and allocation parameters. Only trained tDCS administrators had access to the randomization list; they had minimal contact with participants and had no role in cognitive or clinical assessments.

Each participant received the assigned intervention for 10 sessions over 2 weeks. Active HD-tDCS was delivered using an anodal stimulation protocol. In the combined intervention arm, active HD-tDCS was paired with computerized cognitive training. In the active HD-tDCS control arm, active stimulation was paired with control cognitive training. Control cognitive training consisted of structured computer-based cognitive activities matched for session duration, computer exposure, task instructions, and participant contact, but used fixed or minimally adaptive task difficulty and did not include individualized performance-based progression. In the sham stimulation arm, computerized cognitive training was paired with sham HD-tDCS.

Before intervention, trained investigators obtained baseline cognitive and neuropsychological assessments. The assessment battery included the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Montreal Cognitive Assessment (MoCA), associative memory measures, and additional tasks and questionnaires assessing general cognition, attention, executive function, language, memory, mood, and daily functioning. These measures included Digit Span, Stroop test, verbal fluency test, Symbol Digit Modalities Test, Auditory Verbal Learning Test, associative memory tasks, working memory tasks, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and other executive-function tasks. Stimulation tolerability and adverse events were also assessed. The baseline assessment was completed over approximately 2 days.

Participants also underwent multimodal magnetic resonance imaging and electroencephalography recording to assess neural mechanisms related to the intervention. Follow-up evaluations were conducted after the intervention course, including clinical and neuropsychological assessments, stimulation tolerability assessment, and adverse-event monitoring. Post-intervention assessments, neuropsychological testing, multimodal MRI, and EEG recording were completed within 24 hours after the last stimulation session whenever feasible. Additional follow-up assessments were conducted approximately 1 month and 3 months after the last stimulation session using the same or comparable clinical and cognitive assessment battery. Participants were instructed to answer symptom and function questionnaires based on the relevant recent assessment period.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China, 230032
      • Anhui Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject diagnosed with early Alzheimer's disease or related diseases according to NINCDS-ACDRADA criteria.
• Subjects must have a MMSE score between 10 and 27,indicating mild cognitive impairment or dementia
• CDR score ≤ 2
• Subject under treatment by IAChE for at least 3 months.
• psychotropic treatments are tolerated if they were administered and unchanged for at least 3 months

Exclusion Criteria:

• CDR > 2
• Any history or clinical signs of other severe psychiatric illnesses (like major depression,psychosis or obsessive compulsive disorder).
• History of head injury,stroke,or other neurologic disease.
• Organic brain defects on T1 or T2 images.
• History of seizures or unexplained loss of consciousness.
• Implanted pacemaker,medication pump,vagal stimulator,deep brain stimulator.
• Family history of medication refractory epilepsy.
• History of substance abuse within the last 6 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham-Anode tDCS & Computerized cognitive training; Participants will receive Computerized cognitive training+Sham tDCS daily for two weeks	Other: computer-based cognitive training; Computer-based cognitive training (CCT) is a potentially important tool for individuals at risk of dementia. This trial will employ a computerized multi-domain adaptive training program. This program and training model have been demonstrated to be effective and beneficial in patients with vascular cognitive impairment. In the CCT intervention group, participants will undergo 2 weeks of computerized, multi-domain, adaptive training. The training domains include processing speed, attention, perception, long-term memory, working memory, calculation, executive control, reasoning, and problem-solving. Task rigor varies across domains and determines task grouping. Participants are required to complete 30 minutes of daily training(one session each of six 5-minute tasks).; Other: Sham tDCS; Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool that alters cortical excitability and activity via application of weak direct currents.HD-tDCS was administered using the Soterix 1×1 tDCS Low-Intensity Stimulator and the Soterix 4×1 Adapter. The selection of the electrode montage was based on computational models generating simulated current topography using HD Explore, which demonstrated good current distribution in the left dorsolateral prefrontal cortex (DLPFC). For left DLPFC stimulation, the anodal electrode was placed at the F3 position (using the International 10-20 EEG system), and the 4 return electrodes (cathodes) were placed at positions AFz, FCz, F7, and C5 (4-6 cm from the anode). The center position CZ was aligned with the vertex of the head. For sham stimulation, participants received only the initial 30-second ramp-up to 2 mA, after which stimulation was immediately terminated.
Active Comparator: Anodal tDCS with Computerized cognitive training; Participants will receive anoale tDCS daily and Computerized cognitive training for two weeks	Other: computer-based cognitive training; Computer-based cognitive training (CCT) is a potentially important tool for individuals at risk of dementia. This trial will employ a computerized multi-domain adaptive training program. This program and training model have been demonstrated to be effective and beneficial in patients with vascular cognitive impairment. In the CCT intervention group, participants will undergo 2 weeks of computerized, multi-domain, adaptive training. The training domains include processing speed, attention, perception, long-term memory, working memory, calculation, executive control, reasoning, and problem-solving. Task rigor varies across domains and determines task grouping. Participants are required to complete 30 minutes of daily training(one session each of six 5-minute tasks).; Other: HD-tDCS; Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool that alters cortical excitability and activity via application of weak direct currents.HD-tDCS was administered using the Soterix 1×1 tDCS Low-Intensity Stimulator and the Soterix 4×1 Adapter. The selection of the electrode montage was based on computational models generating simulated current topography using HD Explore, which demonstrated good current distribution in the left dorsolateral prefrontal cortex (DLPFC). For left DLPFC stimulation, the anodal electrode was placed at the F3 position (using the International 10-20 EEG system), and the 4 return electrodes (cathodes) were placed at positions AFz, FCz, F7, and C5 (4-6 cm from the anode). The center position CZ was aligned with the vertex of the head. During anodal DLPFC stimulation, participants received stimulation at 2 mA for 30 minutes, including a 30-second ramp-up period at the start and a 30-second ramp-down period at the end.
Active Comparator: Anodal tDCS with Control Cognitive training; Participants will receive anoale tDCS daily with control cognitive training for two weeks	Other: HD-tDCS; Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool that alters cortical excitability and activity via application of weak direct currents.HD-tDCS was administered using the Soterix 1×1 tDCS Low-Intensity Stimulator and the Soterix 4×1 Adapter. The selection of the electrode montage was based on computational models generating simulated current topography using HD Explore, which demonstrated good current distribution in the left dorsolateral prefrontal cortex (DLPFC). For left DLPFC stimulation, the anodal electrode was placed at the F3 position (using the International 10-20 EEG system), and the 4 return electrodes (cathodes) were placed at positions AFz, FCz, F7, and C5 (4-6 cm from the anode). The center position CZ was aligned with the vertex of the head. During anodal DLPFC stimulation, participants received stimulation at 2 mA for 30 minutes, including a 30-second ramp-up period at the start and a 30-second ramp-down period at the end.; Behavioral: Control cognitive training; Control cognitive training consisted of a structured, computer-based cognitive activity matched to the adaptive computerized cognitive training program for session duration, screen exposure, task instructions, and participant contact. The control tasks used fixed or minimally adaptive task difficulty and did not provide individualized, performance-based progression. This condition was designed to control for nonspecific effects of computer use, task engagement, therapist contact, and repeated cognitive activity, while minimizing the adaptive cognitive-training component.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes assessed by Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)	This is an very common clinical motor estimating scale. including orientation, language, structure, application of concepts, immediate recall of words and recognition of words, with a full score of 70. Higher scores indicate worse symptoms.	changes from baseline at 14 days and 12 weeks post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LMT (Logic Memory Test)	The changes in LMT will constitute the secondary research outcome	changes from baseline at 7,14 days and 4,12 weeks post-treatment
special-version working memory	the accuracy and reaction time in working memory task	changes from baseline at 14 days and 4,12 weeks post-treatment
Associative Memory	The changes in Associative Memory will constitute the major research outcome measure used to assess response to HD-tDCS.	changes from baseline at 14 days and 4,12 weeks post-treatment
MMSE(Mini Mental State Examination)	The full name of MMSE is mini-mental state examination, and the scale consists of 30 subject, include the following seven aspects: time orientation, place orientation,immediate memory,attention and calculation,delay memory,language, visual space.One point is awarded for each question correctly answered during MMSE evaluation. If subject give the wrong answer or don't know answe he/she awarded 0 score, scope of scale score of 0 to 30 points. The higher the score, the better.	changes from baseline at 14 days and 4,12 weeks post-treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
DST (Digital Span Test; Forward and Backward)	The changes in DST will constitute the other research outcome.	changes from baseline at 14 days and 4,12 weeks post-treatment
TMT (Trail Making Test)	The Trail Making Test (TMT) is divided into two parts, part A and part B. Part A requires the subject to connect 25 Numbers on the paper in sequence, and part B requires the subject to connect 25 Numbers of different colors alternately in sequence. The time it takes for the subject to complete all the Numbers is the subject's final score.	changes from baseline at 14 days and 4,12 weeks post-treatment
HAMD (Hamilton Depression Scale)	The changes in HAMD will constitute the other research outcome. The examination content consists of 17 questions (about 10 minutes), with a full score of 52. The higher the score, the more severe the depressive symptoms are.	changes from baseline at 14 days and 4,12 weeks post-treatment
HAMA (Hamilton Anxiety Scale)	The changes in HAMD will constitute the other research outcome. The examination content consists of 14 questions (about 10 minutes), with a full score of 56. The higher the score, the more severe the anxiety symptoms are.	changes from baseline at 14 days and 4,12 weeks post-treatment
NPI (Neuropsychiatric Inventory)	The changes in HAMD will constitute the other research outcome.	changes from baseline at 14 days and 4,12 weeks post-treatment
MRI measures	Multimodal magnetic resonance data were acquired, including structural phase magnetic resonance and rest state magnetic resonance.	changes from baseline at 14 days and 4,12 weeks post-treatment
changes in Montreal Cognitive Assessment (MoCA)	MoCA was developed by Nasreddine et al. based on clinical experience and reference to the MMSE cognitive items and scores, and the final version was finalized in November 2004. We adopted a localized version (Mandarin version，includes 2 alternative versions) in line with the Chinese cultural background.It includes 11 inspection items in 8 cognitive fields, including visual structure skills, executive function, naming, attention and calculation, language, abstract thinking, memory, and orientation. With a total score of 30 or more than 26, it is normal. Anyone who has been education for less than 12 years will need to add one point to his final score.	changes from baseline at 14 days and 4,12 weeks post-treatment
GDS(Geriatric depression scale)	The Geriatric Depression Scale (GDS) was created in 1982 by Brank et al. and is dedicated to screening for depression in the elderly. The most suitable feelings for the elderly in the past week were evaluated.There are 30 items in the scale, the total score is 30 points. The higher the score, the more obvious the depressive symptoms. It is generally considered that less than 10 points is normal.	changes from baseline at 14 days and 4,12 weeks post-treatment
JLOT(Judgment of line Judgment of line orientation test orientation test)	The JLOT test was determined by Benton et al. in 1994. There are two versions of H and V. The difference is that the order in which the pictures are presented is different. Each version contains 35 images, of which the official test consists of 30 images, and the other 5 images are for the participants to learn. The final score is the correct number of subjects to answer, the full score is 30 points, the higher the score, the better the space perception ability of the subject.	changes from baseline at 14 days and 4,12 weeks post-treatment
HVOT(Hooper visual organization test Hooper visual organization test)	The changes in HVOT(Hooper visual organization test Hooper visual organization test) will constitute assess response to rTMS the secondary research outcome measure.HVOT is a cognitive test used to evaluate the perceived structure of the subject. It consists of 30 items，and each question is 1 point and the total score is 30 points. The final score is the correct number of subjects to answer, the full score is 30 points, the higher the score, the better the space perception ability of the subject.	changes from baseline at 14 days and 4,12 weeks post-treatment
The Stroop color test	The Stroop color word test was developed by Stroop in 1935 and is used to evaluate the attention function of the subject. The subject is required to correctly read the target color on the stimulus card and record the completion time. The final completion time is the score of the participant. The shorter the time used, the better the performance of the subjects.	changes from baseline at 14 days and 4,12 weeks post-treatment

Collaborators and Investigators

• Sponsor: Anhui Medical University

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Actual): December 1, 2025
• Study Completion (Actual): December 1, 2025

Study Registration Dates

• First Submitted: October 18, 2020
• First Submitted That Met QC Criteria: October 18, 2020
• First Posted (Actual): October 23, 2020

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Functional Magnetic Resonance Imaging; Neuropsychology; Working Memory; Early Alzheimer's Disease; High Definition Transcranial Direct Current Stimulation; Alzheimer's Disease Assessment Scale-Cognitive Subscale
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: AH med university2018913

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Contact us by email with intent to use and decide whether to share data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No