Multifield extended high-definition transcranial direct current stimulation in mild cognitive impairment: A proof-of-concept study on cognition and brain network connectivity

Abstract

Background

Treatment of mild cognitive impairment (MCI) could delay the progression of cognitive decline. Noninvasive neuromodulation might restore brain plasticity and lead to clinically meaningful cognitive improvements.

Objective

To investigate feasibility and tolerability of a multi-field (four regions) extended (80-min-long) intervention using high-definition transcranial direct current stimulation (HD-tDCS) combined with computerized cognitive training (CCT) in participants with MCI and to explore its effects on cognition and brain functional connectivity.

Methods

Double-blinded, randomized proof-of-concept trial of daily sham HD-tDCS + CCT (n = 4) or anodal HD-tDCS + CCT (n = 4) for 15 sessions over 3 months. Four cortical regions were targeted using neuronavigation, including putative frontal coordinates of cognitive reserve and lateral parietal coordinates hypothesized to have robust hippocampal connectivity. Neurocognitive outcomes were assessed at 3 and 6 months and resting-state functional connectivity changes were evaluated at 3 months. Statistical analysis included independent sample t-tests, Wilcoxon rank-sum tests, and Bonferroni correction for multiple comparisons.

Results

Eleven subjects were eligible and interviewed, and 8 consented (73% consent rate). All 8 completed the trial with only minor adverse events (100% completion rate). Blinding was successful. A large but non-significant increase in Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite scores at 6 months was observed in the anodal group (59.8%) compared with sham (24.5%). Significant declines were seen in left parietal cortex–left caudal hippocampus connectivity (p = 0.004) and right intraparietal sulcus–right frontal eye fields connectivity (p = 0.039) in the anodal group.

Conclusions

The intervention was feasible and well tolerated. Findings suggest possible normalization of aberrant or compensatory hyperconnectivity in MCI. Larger studies are needed.

Clinical Trial Number: NCT04246164

Keywords

Alzheimer's disease cognitive dysfunction cognitive training diagnostic imaging

Introduction

Mild cognitive impairment (MCI) is an important transitional stage between normal aging and dementia in Alzheimer's disease (AD) and is characterized by decline in one or more cognitive domains in the absence of functional impairment. Globally, the yearly rate of progression from MCI to dementia is approximately 10–15%.¹ Approximately 7 million Americans age 65 and older are living with AD dementia today, and approximately 5 to 7 million with MCI caused by the early pathological processes associated with AD.² Preventing or even delaying progression of MCI to AD dementia will provide invaluable improvements in quality of life to affected patients and enormous socioeconomic benefits to society at large. Current pharmaceutical interventions have been unsuccessful in preventing progression to dementia, and recent anti-amyloid therapies are at best, only modestly efficacious at slowing the natural history of the disease.^3,4 There is a need for a broader perspective in clinical trials.

The existing AD literature offers support for pathophysiologic mechanisms of the disease that underlie both resistance and resilience to AD pathology. For example, substantial evidence supports a network dysfunction hypothesis that pathophysiological events may be “upstream” of amyloid-β (Aβ) accumulation: (1) early network dysfunction has been reported before detectable Aβ formation and (2) individuals with AD risk factors, including APOE4 carriers and those with amnestic MCI (aMCI) manifest network dysfunction abnormalities.^5–8 In contrast, a more recently emerged hypothesis postulates that amyloid oligomer synaptotoxicity is an early feature in AD pathophysiology that leads to profound network disconnection and eventually neurodegeneration, making network disconnection in this case an event ‘downstream’ of Aβ accumulation.⁹ Under this general scientific premise, interventions that help normalize network connectivity and function would be promoting both resistance and resilience to AD changes and may have a better chance of slowing cognitive decline and changing the course of the disease.

Noninvasive brain stimulation techniques, in particular transcranial direct current (tDCS) and transcranial magnetic stimulation (TMS), aim to strengthen neuronal networks and improve neuroplasticity. tDCS and high definition tDCS (HD-tDCS) enable noninvasive electrical stimulation of the cortex,^10–12 whereby HD-tDCS allows for superior focality of electrical fields.¹³ Several pilot trials suggest that tDCS may have the potential to slow or even reverse cognitive decline associated with normal aging, MCI and AD.^14,15 tDCS and HD-tDCS have been combined with computerized cognitive training (CCT), which also promotes synaptic plasticity within networks engaged in a training modality, and has been shown to improve cognitive performance in cognitively unimpaired older adults, MCI and AD dementia.^16–19 A recent meta-analysis of clinical trials concluded significant beneficial effects of tDCS on global cognition in MCI and AD.²⁰ However, it remains uncertain whether HD-tDCS with CCT can achieve clinically meaningful and long-lasting cognitive improvements with associated slowing in disease progression in MCI. Important questions related to the optimal dose (intensity and duration of treatment), effective stimulation targets and cognitive/behavioral training with HD-tDCS also remain unresolved.

In the current pilot project, we implemented an extended multifocal HD-tDCS approach: a total of fifteen 80-min daily sessions, administered weekly (Monday-Friday) over 3 months (5 sessions per month) in combination with CCT in 8 participants with MCI. We conducted a double-blinded, randomized trial to explore the feasibility and tolerability of this approach, and to obtain preliminary data from selected cognitive and neuroimaging biomarkers. The multifocal approach targeted frontal and parietal brain regions with anodal HD-tDCS within the same session, targeting specific regions associated with cognitive reserve and those within the parietal-hippocampal network.^21,22 During multifocal HD-tDCS, participants completed CCT training involving executive functions, auditory and associative memory, and visuospatial processing. We hypothesized that excitatory stimulation of frontoparietal regions during a multidomain cognitive training over a period of 3 months would improve cognitive function that is clinically meaningful and long-lasting. The neural markers of improvements would indicate “normalization” of aberrant functional connectivity following treatment, which has been associated with an increased risk of progression from MCI to AD dementia.^23–25

Methods

Study design

The study design (Figure 1) was a double blinded, randomized clinical trial of daily HD-tDCS or sham HD-tDCS administered to participants with aMCI five consecutive days per month over 3 months, in combination with CCT. Our training schedule was informed by the ACTIVE trial. In this pivotal study, ten 60 to 75-min CCT sessions, delivered over the span of 5 to 6 weeks, were sufficient to produce long lasting cognitive benefits that persisted 10 years later.²⁶ Our study was approved by the Institutional Review Board of the Medical College of Wisconsin. All patients provided written informed consent, and the study took place at the Departments of Neurology at the Medical College of Wisconsin (MCW) and the University of Wisconsin Madison under the oversight of the MCW IRB. Clinical trial registration: ClinicalTrials.gov, Number NCT03805659T. All participants provided written informed consent.

Figure 1.

Study design. ADCS-PACC: Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite; CCT: computerized cognitive training; rs-fMRI: resting-state functional magnetic resonance imaging; HD-tDCS: high-definition transcranial direct current stimulation.

Primary outcomes were feasibility and tolerability, measured by the consent rate and the trial completion rate, with expected completion rate greater than 75%. A prior power analysis indicated that a sample of 8 patients would provide enough power to calculate a 90% exact binomial confidence interval of (0.75, 1) if all eight are observed to complete treatment.

The effects of the interventions on cognition, measured by the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC) score at 0 (baseline), 3 and 6 months and resting state functional connectivity, measured at 0 and 3 months were also analyzed.

Participants

Participants were recruited via physician referrals from a Memory Assessment Clinic (UW Hospital and Clinics and the William S. Middleton VA Hospital in Madison, MCW Memory Disorders Clinics and the Geriatric Psychiatry Clinic). The diagnosis of aMCI was reached via consensus between two neurologists (EG and CI) and a neuropsychologist (LMH) based on recent diagnostic criteria.²⁷ Inclusion criteria were: age between 50–90 years, retention of decisional capacity at the first visit and meet criteria for aMCI. Exclusion criteria included significant kidney injury requiring hemodialysis, automatic internal cardiac defibrillator, significant congestive heart failure, modified Hachinski Ischemia Score >4 points, history of seizure disorder requiring medication, history of brain surgery, history of HIV/AIDS, severe untreated obstructive sleep apnea, alcohol abuse or illicit drug use, major neurologic disorders other than dementia, serious mental illness that is not treated or is unstable, lack of study partner, and other significant medical conditions at investigators’ discretion. Randomization occurred by an unblinded member of the team who assigned participants to the anodal or sham tDCS groups. Participants received a modest stipend as compensation for their time and when necessary, were provided with lodging accommodations for the duration of the study.

HD-tDCS stimulation protocol

We targeted four brain regions sequentially during each stimulation session, spanning through left and right frontal and left and right lateral parietal regions. Participants were randomized to begin in any of the four quadrants. After selecting the starting quadrant, stimulation proceeded in a fixed sequence alternating across hemispheric laterality and the anterior–posterior axis (ex: left anterior → right posterior → left posterior → right anterior) to minimize gel accumulation. Excess conductive medium may reduce electrode–skin impedance and promote current shunting along the scalp, potentially altering electric field distribution and reducing the spatial focality of HD-tDCS.²⁸ The stimulation of each target lasted 20 min, and the total duration of stimulation was 80 min. Anodal tDCS was administered at 1.5 mA. For sham, stimulation intensity ramped up to 1.5 mA within the first 30 s, and ramped back down to 0 mA immediately after over the next 30 s. The impedance level to begin stimulation for each electrode was set to be at or below 20 kiloohms. The electrodes were connected to a Soterix Medical 1 × 1 low-intensity DC stimulator with 4 × 1 HD adaptor, or a Soterix MxN-9 High-Definition stimulator (MXN-9, Soterix Medical Inc). See Figure 2.

Figure 2.

(A) EEG cap with 4 electrode montage and Soterix equipment MxN-9 high-definition stimulator; Images used with permission from Soterix Medical, Inc. (B) simulation of generated electrical fields using SimNIBS 2.1. It shows the left lateral parietal and frontal targets (MNI coordinates). Heat map color corresponds to higher field intensity.

The device was programmed by an unblinded team member prior to each session. The exposed scalp was cleaned with alcohol and electrodes were immersed in conductive gel (HD-GEL™, Soterix Medical) and secured with electrode holders. HD-tDCS was administered using a ring configuration (4×1), with a central anode and four surrounding cathodes. The central electrode positioning for 4 participants (2 anodal, 2 sham) was based on the International 10–20 EEG system, targeting FP1, FP2 and CP3, CP4 cortices.

For the remaining four participants (2 anodal, 2 sham), magnetic resonance imaging (MRI)-based neuronavigation was used for central electrode positioning, individualized to target frontal and parietal regions.²⁹ The coordinates for these targets were: left (MNI: −42, 6, 28) and right (MNI: 42, 6, 28) frontal, and left (MNI: −47, −68, 36) and right (47, −68, 36) lateral parietal cortex. We were interested in exploring whether the individualized targeting results in similar feasibility outcomes compared to the one-size-fits-all approach. For the individualized approach, we used participants’ T1-weighted images and spheres indicating stimulation targets in the Brainsight^® neuronavigation software (Rogue Research, Quebec, Canada) together with an infrared positioning system to localize the target (or site for the center electrode) on the participant's scalp. A disposable latex swim cap was fitted to the participant's head and the site was marked in permanent ink directly on the cap. The surrounding return electrodes were also marked on the cap at a radius of 5 cm with 90^o angle from one another. The degree of cortical atrophy was not considered when determining electrode placement, and electric field modeling was not completed for the present study.

To operationalize the incidence of side effects, participants were asked to take post-stimulation tolerability assessments. They were asked to rate 14 different sensations using a 5-point intensity scale ranging from ‘Not at all’ to ‘Strong’. Participants were also asked to judge the timing of the sensation (i.e., beginning, middle and/or end of the session).

Computerized cognitive training

We used Posit Science's brain plasticity-based BrainHQ exercise platform (https://www.brainhq.com). The platform consists of more than two dozen exercises grouped into six broad categories: Attention, Memory, Brain Speed, Intelligence, People Skills, and Navigation. To maximize the synergistic effect of HD-tDCS and CCT we coupled the stimulation of an area with a game that has a preferential effect on cognitive functions subserved by that same area or network (e.g., left lateral parietal stimulation with a verbal memory task, and right lateral parietal stimulation with a navigation task). For this purpose, we selected 12 games and assigned each one of them to one of the four brain regions that were stimulated (3 games/network; see Table 1 for schedule). Participants started at the same level during the first session but the task difficulty was modulated over the course of treatment based on performance history. The same 3 games and regions were targeted but the difficulty of the games was modulated. The active training blocks started 5 min after the onset of each 20-min target stimulation (20 min×4 tDCS targets = 80 min), lasting 15 min/region for a total of 60 min. The laptop with the BrainHQ software was provided by the investigator team.

Table 1.

Computerized cognitive training schedule during each session. Central Executive Network (CEN), Dorsal Attention Network (DAN), Default Mode Network (DMN).

Brain area	Daily schedule	Cognitive function
Left frontal (CEN, DAN, DMN)	1. Divided attention 2. Mixed signals 3. Mind bender	1. Attention, divided attention 2. Attention, response inhibition, conflict resolution 3. Cognitive flexibility and executive control
Left lateral parietal (cortico-hippocampal, DMN)	1. Memory grid 2. Face facts 3. In the know	1. Memory, auditory processing 2. Memory, associative memory 3. Auditory memory
Right frontal (CEN, DAN DMN)	1. Eye for detail 2. Target tracker 3. Double decision	1. Visual processing speed and working memory 2. Divided attention 3. Visual processing speed
Right lateral parietal (cortico-hippocampal, DMN)	1. Hear, hear 2. Right turn 3. Recognition	1. Auditory memory and attention 2. Navigation 3. Face recognition, visual processing speed

Cognitive battery

Participants completed a comprehensive battery of neuropsychological tests administered by trained personnel (many of which are part of the NIH Toolbox and administered using an iPad). The battery was designed to assess performance on the broad set of cognitive domains targeted by plasticity-based CCT³⁰ and by our multifield approach to tDCS,^31,32 including attention, executive functions, processing speed, memory, and visuospatial function. The administered neurocognitive battery included the following tests: Trail Making Test (A) (total seconds to complete trail, maximum 300 s, TMT-A);³³ Trail making test (B) (total seconds to complete trail; maximum of 300 + seconds (penalties past 300 s), TMT-B)³⁴ Clock Drawing Test (total points, maximum score 10, CDT);³⁵ Grooved Pegboard Test, Dominant Hand (total time to place pegs, no maximum score, GPT-D); Grooved Pegboard Test, Non-dominant Hand (total time to place pegs, no maximum score, GPT-ND);³⁶ Judgement of Line Orientation (total correct, maximum score 30, JLO);³⁷ Brief Visuospatial Memory Test-Revised (total correct within 3 tests, maximum score 36, BVMT-R);³⁸ Boston Naming Test-2 (total correct, maximum 60, BNT);³⁹ Wisconsin Card Sorting Test (total errors, maximum score 128, WCST);⁴⁰ Wechsler Memory scale, Logical Memory I (total correct, maximum 50 points, WMS-LM1);⁴¹ Controlled Oral Word Association Test (total score, no maximum score, COWAT);⁴² Geriatric Anxiety Inventory (total score, maximum 20, GAI);⁴³ Geriatric Depression Scale (total score, maximum score of 30, GDS).⁴⁴

The battery also included the ADCS-PACC, a composite of 4 measures with well-established sensitivity for the detection of cognitive decline in prodromal and mild dementia. It is calculated by summing the standardized z-scores of each of its four component change scores.⁴⁵

Magnetic resonance imaging

Site-specific MRI safety screening procedures were followed. MRI was performed on 3T GE (General Electric) SIGNA Premier scanners at both institutions. T1-weighted structural images were acquired using MPRAGE (magnetization prepared gradient echo sequence, TR/TE = 604 ms/2.516 ms, TI = 1060.0 ms, flip angle = 8°, FOV = 25.6 cm, 0.8 mm isotropic). One pair of five-minute resting state functional MRI (rs-fMRI) scans, with opposite phase encoding were acquired using whole-brain SMS (simultaneous multi-slice) imaging⁴⁶ (8 bands, 72 slices, TR/TE = 800 ms/33.5 ms, flip angle = 50°, matrix = 104 × 104, FOV = 20.8 cm, voxel size 2.0 mm isotropic). A phased array 48-channel head coil designed for high SNR brain imaging and high patient population compatibility was used.

Data preprocessing

The reverse phase encoded EPI datasets were mutually aligned to produce a warp ‘that meets in the middle’ to reduce the geometric effects of B0 inhomogeneity.⁴⁷ Data were de-spiked, motion corrected, aligned with the structural MRI, normalized to MNI space, resampled to 2.5 mm³, and spatially smoothed with a 4-mm FWHM Gaussian kernel. Motion censoring (per TR motion > 0.2 mm), nuisance regression, and bandpass filtering (0.01–0.1 Hz) were performed simultaneously in one regression model. Nuisance signals regressed out included six motion estimates and their temporal derivatives, CSF, and the voxel-wise locally averaged white matter signal.

Seed-based connectivity analysis

Sixteen regions of interest (ROIs) were identified from the literature based on their role in memory and executive processing (Supplemental Table 1).^29,48–54 To define these regions for extraction, 5-mm radius spheres were created around the identified coordinates in standard space. To address potential anatomical variability, ROI placement was visually verified against the normalized anatomical images to ensure seed regions fell within cortical gray matter boundaries.

Lateral parietal stimulation coordinates (ROI 1 and 2) were used as seed regions to investigate changes in functional connectivity with the ipsilateral rostral and caudal hippocampus, based on prior literature supporting the modulation of a cortico-hippocampal network when targeting these coordinates.^21,22 We also investigated pair-wise connectivity changes between ROIs, both within and between selected cognitive networks (i.e., dorsal attention network [DAN] and default mode network [DMN]). Frontal stimulation coordinates (ROI 3 and 4) correspond to peak coordinates of meta-analytically detected brain activation associated with cognitive control.^21,55

Pearson r correlation coefficients were computed and transformed to Fisher-z. Independent t-test or Wilcoxon Rank Sum analyses were conducted to investigate changes in connectivity from pre- to post-intervention between groups (Anodal versus Sham).

Statistical analysis

Two feasibility outcomes were included: Consent rate and treatment completion rate. Our a priori power calculations indicated that eight participants would be sufficient to calculate a 90% exact binomial confidence interval of (0.75, 1), if all participants complete the treatment. Thus, this sample size was considered large enough to potentially exclude completion rates of 3/4 or lower.

Statistical analyses of baseline demographic characteristics were performed using chi-square tests for categorical variables, Wilcoxon rank-sum tests for non-normal continuous variables, and independent samples t-tests for normally distributed continuous variables, with equal variances.

Cognitive and functional connectivity outcomes, including the ADCS-PACC, were analyzed using independent t-tests to compare mean score changes between the anodal and sham groups for data meeting the assumption of normality. For non-normally distributed data, the Wilcoxon Rank Sum (Mann-Whitney U) test was used to compare group differences. Normality was assessed using the Shapiro-Wilk test, a commonly preferred method for small sample sizes (n < 50). Homogeneity of variance was confirmed by Levene's test. To evaluate the effect sizes of observed differences, Cohen's d was calculated, where interpretations were based on standard criterion of 0.2, 0.5, and 0.8 as small, medium, and large effect sizes, respectively.

p-values were adjusted for multiple comparisons using family-wise Bonferroni correction, where p-values were multiplied by the number of tests within each family of tests. Significance was determined at α = 0.05.

Multiple comparison correction for the 16 ROIs was implemented using four a priori hypothesis families. Following an ipsilateral-first logic, hemispheric circuits were treated as independent anatomical units to maximize sensitivity to focal stimulation effects. These families included: (A) Ipsilateral Seed connectivity (k = 2), testing parietal seeds (ROIs 1–2) to ipsilateral hippocampal segments (ROIs 5–8); (B) Ipsilateral DAN integrity (k = 3), testing pairwise connections within the ipsilateral Dorsal Attention Network (ROIs 9–14); (C) DMN integrity (n = 1), testing the posterior cingulate cortex-medial prefrontal cortex connection (ROIs 15–16); and (D) Between-Network interactions (k = 12), testing all pairwise DAN-DMN connections. Raw p values were Bonferroni-corrected by multiplying by the family-specific n, with significance set at alpha corrected < 0.05.

All statistical analyses were performed using SPSS version 27.0 (IBM, Armonk NY).

Results

Of the 11 eligible participants interviewed, 8 consented to participate, yielding a consent rate of 73%. All 8 consented participants completed all the study sessions of the trial (100% completion rate).

The demographics and baseline neuropsychological data of the cohort are shown in Table 2. There were no significant differences between demographical and neuropsychological variables between the tDCS groups (anodal versus sham). Sex distribution was uneven with 75% females in the anodal and 75% males in sham group, but not statistically significant.

Table 2.

Baseline characteristics.

Characteristic	Anodal (n = 4)	Sham (n = 4)	s-statistic (t, z, or χ²)	p
Age [years, mean SD]	69 (12.463)	67.5 (7.550)	t = −0.206	0.844
Sex [total M, total F]	1,3	3,1	Χ² = 2.000	0.157
Education [mean years, SD]	14.25 (3.304)	17.13 (2.394)	t = 1.409	0.208
RAVLT total learning trials [mean, SD]	31.33 (6.505)	33.50 (10.116)	z = 0.321	0.762
RAVLT retention % [mean, SD]	−44.45 (26.78)	−8.20 (67.50)	z = 0.976	0.427
WMS-LMI total score [mean, SD]	12 (5.598)	16.25 (12.148)	z = 0.635	0.549
WMS-LMII total score [mean, SD]	5 (4.320)	7.75 (7.847)	t = 0.614	0.568
DSST raw score [mean, SD]	37.75 (20.435)	39.50 (8.347)	z = 0.159	0.882
MMSE total score [mean, SD]	22.00 (4.243)	26.750 (2.872)	z = 1.854	0.113
TMT-A raw score, Secs [ mean, SD]	42.99 (24.282)	38.58 (7.526)	z = −0.347	0.748
TMT-B raw score, Secs [mean, SD]	109.47 (52.748)	118.405 (34.536)	t = 0.273	0.795
CDT total score [mean, SD]	7.00 (3.162)	8.25 (2.061)	z = 0.662	0.532
Grooved Pegboard raw score- Dominant Hand, Secs [mean, SD]	102.00 (51.987)	98.000 (29.246)	t = 0.134	0.898
Grooved Pegboard raw score- Non-dominant Hand, sec [mean, SD]	141.25 (99.14)	108.50 (33.451)	z = −0.626	0.554
JLO raw score [mean, SD]	15.00 (10.863)	19.75 (5.852)	z = 0.770	0.471
BVMT-R learning total score [mean, SD]	3.75 (4.991)	9.75 (6.397)	z = 1.479	0.190
BVMT-R delayed recall [mean, SD]	−40.47 (79.64)	16.79 (85.05)	z = 0.904	0.407
BNT-2 total score [mean, SD]	52.50 (5.196)	52.50 (6.403)	z = 0.000	1.000
WRAT-4 standard score [mean, SD]	61.50 (1.915)	58.50 (5.508)	z = −1.029	0.366
WCST total errors [mean, SD]	56.00 (27.568)	35.00 (26.627)	z = −1.011	0.358
COWAT total score [mean, SD]	38.67 (9.019)	41.000 (11.547)	z = 0.288	0.785
GAI raw score [mean, SD]	2.25 (2.630)	1.00 (0.816)	t = −0.908	0.421
GDS raw score [mean, SD]	7.00 (2.160)	3.00 (1.826)	z = −2.828	0.059

t-tests (t), or Wilcoxon rank-sum test (z) and Chi-square (Χ²) for sex, a categorical variable.

Statistically significant, p < 0.05. No significant differences found.

Age = participant age in years at the time of participation; Sex = male (M) or female (F); Education = number of years of formal schooling. Rey Auditory Verbal Learning Test, total learning trials (RAVLT); Rey Auditory Verbal Learning Test, retention (RAVLT- retention); Wechsler Memory Scale, Logical Memory I total score (WMS-LMI); Wechsler Memory Scale, Logical Memory II total score (WMS-LMII); Digit Symbol Substitution Test raw score (DSST); Mini Mental State Exam total score (MMSE); Trail Making Test (A) raw score in seconds (TMT-A). Trail Making Test (B) raw score in seconds (TMT-B) ; Clock Drawing Test total score (CDT); Grooved Pegboard Test-Dominant raw score in seconds (GPT-D); Grooved Pegboard Test- Non-Dominant raw score in seconds (GPT-ND); Judgement of Line Orientation raw score (JLO); Brief Visuospatial Memory Test-Revised, total score (BVMT-R total score); Brief Visuospatial Memory Test-Revised, delayed recall (BVMT-R Delayed recall); Boston Naming Test - Second edition, total score (BNT-2); Standard Scoring of Wide Range Achievement Test-Fourth Edition, Word Reading subtest Standard Score (WRAT-4 Standard Score); Wisconsin Card Sorting Test; total errors (WCST total errors); Controlled Oral Word Association Test total score (COWAT); Geriatric Anxiety Inventory raw score (GAI); Geriatric Depression Scale raw score (GDS).

The blinding was successful. Following the stimulation sessions, both participants and researchers completed a blinding assessment where they were asked to respond to the question, “Do you believe that you received a real or placebo stimulation?” The answer choices included “Real, Placebo, or I don’t know”. Throughout the study, results showed 7 out of the 8 participants were unable to correctly identify their group assignment (88% of all post-stimulation sessions; 100% sham; 75% anodal). Only one participant correctly identified their anodal group assignment. In comparison, researchers identified the correct treatment condition with 49% accuracy.

Due to a technical error four participants completed the tolerability questionnaire in all 15 sessions, while four others answered the questionnaire during their last session. At least one side effect was reported in 59 of the 64 recorded sessions. The severity of these observed side effects mostly ranged from mild-to-moderate. All 4 participants receiving sham stimulation reported a side effect with ratings in the mild to moderate range (100% sham; 91% anodal). In total, 55% of all side effects reported were mild (81% sham and 40% anodal), 23% mild-moderate (9% sham and 31% anodal), and 16% moderate (9% sham and 5% anodal). Tingling was the most common sensation reported (75% sham; 36% anodal), followed by burning (15% sham; 35% anodal) and itching, a symptom only mentioned from the anodal treatment cohort (13% anodal). Participants were also asked to describe when they experienced side effects during the sessions (beginning, middle, or end). From their answers, 76% of all adverse effects reported occurred only at the beginning of sessions (72% sham; 78% anodal). Additionally, no new neurological/physical deficits or side effects were observed at the 4-week and 3-month checkpoints post-stimulation. For these and other symptoms as a proportion of the total number of participants see Table 3. All recruited participants were able to fully complete their treatment schedules.

Table 3.

Adverse events experienced by participants in the sham and anodal group. As proportion of participants.

Adverse event	Sham	Anodal	Caused by intervention (per PI discretion)
Tingling	4/4	4/4	Yes
Local Irritation	0/4	4/4	Yes
Burning	1/4	2/4	Yes
Itching	0/4	1/4	Yes
Nausea	1/4	0/4	No

The ADCS-PACC scores and their components are shown for the 3 assessment time points in Supplemental Table 2. The summed or averaged z scores at baseline did not significantly differ between the two groups. No significant effect of the intervention on ADCS-PACC summed scores was observed in either group, although the anodal group demonstrated a trend towards higher scores at the 6-month assessment (59.8% increase anodal, 24.5% increase sham; T2-T0 p = 0.067). These results are illustrated in Figure 3.

Figure 3.

Results of ADCS-PACC. Red bars = represent participants in the Sham group; Blue bars = represent participants in the Anodal group; Green bars = mean change in the indicated group; Whiskers = Standard deviation of the mean change in each group; Percentage Change (T1-T0): Percentage change = ((T1-T0)/T0)×100, T0 = baseline value, T1 = value at 3 months; Percentage Change (T2-T0): Percentage change = ((T2-T0)/T0)×100, T0 = baseline value, T2 = value at 6 months.

Scores from other cognitive assessments at baseline, 3 and 6 months, are provided in Supplemental Table 3. No significant changes in any of the tests were found with the exception of the GDS. Both groups experienced a decline in depression scores at 3 and 6 months; after correcting for multiple comparisons, the sham group demonstrated a significantly larger percent decline in depression scores at the 3-month timepoint compared to the Anodal group. At the 3-month mark, the percent decline for the sham group was greater than that of the Anodal group (45% decrease for sham versus 31% decline for anodal), with the difference remaining significant after correction for multiple comparisons (K = 2, corrected p = 0.036, Wilcoxon rank-sum Z = 0.175) (Figure 4).

Resting state functional connectivity

Motion was addressed using framewise displacement (FD)-based censoring at the TR level. Across participants, motion was generally low in both arms (mean FD ∼0.05–0.10 mm). There were no significant differences in motion metrics between sham and anodal groups for either session (ses-1: p = 0.89 [censored TRs], 0.65 [mean FD], 0.71 [max FD]; ses-2: p = 0.12, 0.17, and 0.09, respectively), indicating comparable data quality across conditions. At the 3-month timepoint, significant between-group differences were found in resting state connectivity between the anodal and sham stimulation groups. Only the results reaching statistical significance (p < 0.05) after family-wise Bonferroni correction for multiple comparisons are reported. Cohen's d was computed for effect size estimates of the observed differences.

Between-group connectivity differences reached significance for the left caudal hippocampus and the left lateral parietal stimulation site (MNI: −47, −68, 36; t(6) = 7.585, corrected p = 0.004 (K = 2), d = 1.878; Figure 5A, and the right intraparietal sulcus and the right frontal eye fields (t(6) = 3.863, corrected p = 0.039 (K = 3), d = 1.450; Figure 5B) connections. Specifically, the anodal stimulation group exhibited decreased connectivity relative to the sham group in the aforementioned connections. Additional analyses of resting-state functional connectivity revealed several non-significant associations across other ROI pairs; detailed statistics for these null findings are provided in Supplemental Table 4.

Figure 4.

Results of GDS. Red bars = represent participants in the Sham group; Blue bars = represent participants in the Anodal group; Green bars = mean change in the indicated group; Whiskers = Standard deviation of the mean change in each group; Percentage Change (T1-T0): Percentage change = ((T1-T0)/T0)×100, T0 = baseline value, T1 = value at 3 months; Percentage Change (T2-T0): Percentage change = ((T2-T0)/T0)×100, T0 = baseline value, T2 = value at 6 months. * = statistical significance, with Wilcoxon Rank-sum test and survived Bonferroni correction for multiple comparisons (p = 0.018). Corrected p = 0.036.

Discussion

This prospective, randomized and double-blinded pilot trial was designed to evaluate the feasibility and tolerability of multifocal and extended HD-tDCS combined with CCT in participants with aMCI. The secondary objectives were to evaluate the effects of this intervention on measures of global cognition, using the ADCS-PACC over 0- (baseline), 3- and 6-month time points. We also examined neural changes using fMRI resting-state functional connectivity with respect to the stimulation targets, measured at 0 and 3 months after the intervention.

Figure 5.

Resting state functional connectivity results. (A) Resting state functional connectivity change at 3 months compared to baseline for left caudal hippocampus and stimulation coordinates (−47,−68,36) in the left lateral parietal cortex. (X = axis): tDCS assignment = anodal or sham treatment; (Y-axis): Post-pre change in Resting State Functional connectivity (T1-T0) = Fisher-z transformed correlation coefficient from baseline (T0) to three months (T1) of stimulation. (B) Same for Right intraparietal sulcus-Right frontal Eye fields functional connectivity, * = statistical significance, surviving family-wise correction for multiple comparisons. Individual black bars represent participant-level data; green bars with error bars represent group averages ± SD.

The anodal HD-tDCS + CCT and sham stimulation groups did not differ statistically in age, sex, education or baseline performance on neuropsychological measures. However, baseline ADCS-PACC scores tended to be lower in the anodal group, indicating more severe disease stage among participants receiving the anodal stimulation compared to sham. Sex distribution was unbalanced, with 75% females in the anodal group and 25% females in the sham group. A primary limitation of this pilot trial was the use of simple randomization without stratification, which resulted in unmatched groups at baseline. Specifically, variations in baseline disease severity may have influenced treatment response—a confounding variable we were unable to control for. Furthermore, with a small sample size (n = 8), change-score comparisons are inherently unstable and highly sensitive to baseline imbalances and individual outliers. To verify these preliminary findings, future larger studies should employ a more rigorous design, utilizing stratified randomization to ensure balance across demographic variables, disease severity, and cognitive impairment measures.

Data showed that the multifocal and extended HD-tDCS approach combined with CCT is feasible, well tolerated and safe in participants with MCI, adding to the growing body of evidence indicating feasibility of a multifocal approach to noninvasive brain stimulation.^56,57 Based on our completion rate of 100%, our sample size of eight participants is large enough to potentially exclude completion rates of 75% or lower in future trials. While prior studies have proved the feasibility of a similar approach in healthy adults, this trial extends it to the MCI population. Other features of the study design, relevant to planning a larger clinical trial are blinding, which was successful, as neither the participants nor the researchers could define the type of intervention they received beyond chance. Reported adverse events (tingling, local irritation) attributable to the intervention were classified as mild. Importantly, the use of neuronavigation in our cohort did not influence completion rates; while increasingly adopted to enhance targeting precision, neuronavigation does not appear to affect participant adherence, which is more strongly influenced by study design and participant-related factors.^58,59

A limitation of this study was the inconsistent collection of tolerability data. While final session data suggest the protocol was well-tolerated, future trials should prioritize consistent per-session monitoring to capture longitudinal effects more accurately.

Beyond basic feasibility, a critical consideration for future large-scale trials is the standardization of dosing precision. While our preliminary results show that both coordinate targeting methods are feasible and well-tolerated, standard practice is shifting toward MRI-based neuronavigation to minimize the risk of substantive alterations in dosing across larger cohorts.⁶⁰ Furthermore, the lack of electric-field modeling and atrophy compensation may limit biological interpretability, as cortical atrophy significantly alters the magnitude and focality of the induced field.⁶¹

The effects of HD-tDCS combined with CCT or CCT alone on ADCS-PACC scores and other neurocognitive measures at 3 and 6 months were not significant, potentially because this pilot study is underpowered to detect these changes. Overall, there was a trend toward improvement based on ADCS-PACC scores over time in the entire cohort and within each of the two treatment arms, with a slightly improved performance in the anodal group at 6 months. Although not significant, the improvements observed in the anodal group will inform effect size calculations and data-guided power analyses for future clinical trials to determine the group sizes, powered to detect differences compared to the sham + CCT group.

Geriatric depression scores declined in both groups, though baseline levels were low, which may reflect placebo effects or nonspecific motivational changes related to daily protocol engagement. While the sham group exhibited a higher relative decline in GDS, these changes likely reflect minor fluctuations within an already asymptomatic baseline. In contrast, anodal stimulation was associated with a categorical shift, as participants moved from a symptomatic baseline into the sub-clinical range. These observations suggest that while sham improvements might represent floor-effect artifacts, anodal tDCS could potentially offer a signal for symptom reduction.

While these trends remain tentative due to the limited sample size and require validation in larger cohorts, tDCS has been shown to have antidepressant effects and our findings appear consistent with this established literature.

Multifocal anodal HD-tDCS seemed to have significantly impacted fMRI resting state connectivity. All participants assigned to anodal HD-tDCS + CCT demonstrated a reduction in connectivity at 3 months of a left-sided cortico-hippocampal network, while all participants in the sham + CCT group demonstrated a trend towards increased connectivity. These findings are consistent with prior results in young^22,62 and elderly⁶³ populations in which TMS to the same left lateral parietal regions served as a cortical window to modulate parieto-hippocampal connectivity, with associated improvements in a memory task. These previous studies showcase a remarkable example of targeted brain engagement, where physiological effects directly correlate with behavioral enhancements, setting a new standard in noninvasive neuromodulation research.

To our knowledge, this is the first time similar findings of cortico-hippocampal network engagement after lateral parietal stimulation have been reproduced in the MCI population using HD-tDCS, albeit with opposite directionality.

Our study also found that the anodal group experienced a decline within-DAN connectivity compared to sham, specifically between the Intraparietal Sulcus and Frontal Eye Field. Although counterintuitive, the findings are consistent with previous research indicating association between cognitive decline and hyperactivation over the course of aging.^8,55,64 In fact, studies have shown that interventions like tDCS and repetitive TMS can improve cognitive function in MCI patients by reducing abnormal hyperactivity and promoting more normalized network configurations. For example, anodal tDCS has been found to improve performance, reduce task-related prefrontal hyperactivity, and normalize resting-state network configuration in MCI patients.⁶⁵ Similarly, inducing hypoconnectivity within the DMN has been linked to cognitive improvements in patients with aMCI.⁶⁶ These findings suggest that our results, although in the opposite direction of what might be expected, are consistent with the existing literature and highlight the complex relationship between brain connectivity and cognitive function in MCI.

While suggesting significant trends, these findings should be interpreted with caution pending further mechanistic validation. Although we observed post-intervention divergence in cortico-hippocampal network activity, analyses were limited to group differences in the absence of a cognitively unimpaired benchmark, rather than a formal Group × Time interaction. In addition, the absence of electric field (EF) modeling constrains the biological interpretability of the stimulation “dose” and limits mechanistic inferences. Although heterogeneity could not be formally addressed due to the small sample size, future studies should incorporate analytical approaches to account for inter-individual variability. Future work should also incorporate change-score or longitudinal interaction models to better characterize individual plastic trajectories across the disease spectrum. Consequently, these findings remain exploratory and warrant confirmation in larger, more rigorously designed studies.

Consistent with these limitations, data on secondary outcomes are inconclusive, potentially due to the small group sizes and a larger Phase IIa clinical trial is needed to prove our hypotheses. For a future phase II clinical trial, a randomized, double-blinded, 2 × 2 factorial trial design, including a sham and HD-tDCS groups without CCT would be desirable. Such a design would be appropriate for estimating the respective treatment effects of HD-tDCS and CCT, their interaction, and the modulatory effect of combining the two interventions.

Lengthening the duration of the treatment may also increase efficacy of our approach. Modulation of synaptic networks using neuromodulation may require longitudinal protocols, over 6 to 12 months to induce any significant cognitive benefits.^67–69 Finally, in future trials, perfusion and other anatomical neuroimaging and fluid biomarkers of AD pathology that are cost-effective (e.g., AD serum biomarkers) could help explain individual variability in response to HD-tDCS and/or CCT, help track disease progression, and assist in assessing outcomes.

Conclusion

A multifocal approach to HD-tDCS using longer-lasting sessions appears feasible and safe in elderly participants with MCI, expanding the array of potentially efficacious stimulation protocols to be explored in future trials. Novel aspects of this trial are the multifocality of HD-tDCS, targeting four brain regions as opposed to one or two areas, and the use of the ADCS-PACC score as a neurocognitive outcome.^70,71 Targeting selective posterior parietal and frontal coordinates reduced connectivity within cortico-hippocampal and dorsal attention networks. The clinical significance of these findings should be the subject of further investigation.

Supplemental Material

sj-docx-1-alr-10.1177_25424823261449802 - Supplemental material for Multifield extended high-definition transcranial direct current stimulation in mild cognitive impairment: A proof-of-concept study on cognition and brain network connectivity

Supplemental material, sj-docx-1-alr-10.1177_25424823261449802 for Multifield extended high-definition transcranial direct current stimulation in mild cognitive impairment: A proof-of-concept study on cognition and brain network connectivity by Elias Granadillo, Abigail Peterson, Emilie Bloyer, Laura M Hancock, Priyanka Shah-Basak, Peter Kraegel, Shelby Schold, Ozioma Okonkwo, Veena A Nair, Vivek Prabhakaran and Chrysanthy Ikonomidou in Journal of Alzheimer's Disease Reports

Footnotes

Acknowledgements

The authors would like to thank the participants and their families for their time and commitment to this study. We also acknowledge the staff of the Memory Disorders Clinics at the Medical College of Wisconsin, University of Wisconsin Hospital and Clinics, and the William S. Middleton VA Hospital for their assistance with participant recruitment and study coordination. We thank the neuropsychology, MRI, and research support teams for their contributions to data collection and study implementation.

ORCID iDs

Elias Granadillo

Abigail Peterson

Emilie Bloyer

Laura M Hancock

Priyanka Shah-Basak

Vivek Prabhakaran

Ethical considerations

This study was approved by the Institutional Review Board of the Medical College of Wisconsin. The study was conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The trial was registered at ClinicalTrials.gov (NCT03805659).

Consent to participate

Written informed consent was obtained from all individual participants included in the study prior to enrollment.

Consent for publication

All participants provided written informed consent for the use of de-identified clinical, neurocognitive, and imaging data for research and publication purposes.

Author contribution(s)

Elias Granadillo: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Visualization; Writing – original draft; Writing – review & editing.

Abigail Peterson: Formal analysis; Investigation; Validation; Visualization; Writing – review & editing.

Emilie Bloyer: Formal analysis; Investigation; Validation; Visualization; Writing – review & editing.

Laura M Hancock: Conceptualization; Investigation; Writing – original draft; Writing – review & editing.

Priyanka Shah-Basak: Validation; Writing – review & editing.

Peter Kraegel: Investigation; Methodology; Project administration; Validation; Writing – review & editing.

Shelby Schold: Supervision; Validation; Writing – review & editing.

Ozioma Okonkwo: Validation; Writing – review & editing.

Veena A Nair: Data curation; Formal analysis; Validation; Writing – review & editing.

Vivek Prabhakaran: Investigation; Validation; Writing – review & editing.

Chrysanthy Ikonomidou: Formal analysis; Supervision; Validation; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: CTSI Mentored Clinical and Translational Research Training Program (KL2) & Pilot Collaborative Clinical and Translational Research Grants Program (PCCTRP)., National Institute of Health Sciences, (grant number PRO00035757, 5T35AG 076419-02, R01NS123378 ).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The datasets generated and/or analyzed during the current study are not publicly available due to participant privacy considerations and institutional restrictions but are available from the corresponding author on reasonable request and with appropriate institutional approvals.

Supplemental material

Supplemental material for this article is available online.

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