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Mild Cognitive ImpairmentPUSH2NCT05992831

Transcranial Magnetic Stimulation for MCI

A study testing Accelerated iTBS in people with Mild Cognitive Impairment and Depression, run by Medical University of South Carolina at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

The goal of this phase II study is to establish the dose-response curves of a safe and clinically feasible non-invasive brain stimulation technique (accelerated Transcranial Magnetic Stimulation (TMS)) to improve both depression and cognitive function in Mild Cognitive Impairment (MCI) patients with comorbid… Read more about this study

Who is it for?
Ages 60 to 85 years
Conditions the study is for
Mild Cognitive Impairment, Depression
What is being tested?
Accelerated iTBS
Type of treatment
Medical device
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
60 participants
Where
1 siteUnited States
Study dates
18 Jun 2024to 30 Apr 2028
Phase
Interventional
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 60 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age 60-85 (inclusive). ii. English as a first/primary language. iii. Adequate sensorimotor function and verbal expressive abilities to complete all assessments.
  • Must have a Co-Participant (e.g. spouse, adult child or relative, sibling, cohabitator, friend, caregiver) who has at least weekly in-person contact with the participant and is willing to participate in the study as a collateral informant.
  • Is on fixed pharmacotherapy (i.e. a stable dose of medication/s) for at least 4 weeks prior to enrollment. Cholinesterase inhibitors, NMDA receptor antagonists, and antidepressants are allowed if on a stable regimen for at least 4 weeks prior to enrollment. Prior treatment with anti-amyloid monoclonal antibody therapy is acceptable if last infusion was at least 8 weeks prior to enrollment. Prior TMS treatment is acceptable if last stimulation session was at least 24 weeks prior to enrollment.
  • A documented diagnosis of MCI per NIA-AA criteria or Mild Neurocognitive Disorder per DSM-5 criteria by a healthcare provider within the past 2 years, with a presumed etiology of either (or both): vi.a Possible or probable AD vi.b Chronic cerebrovascular disease (CVD), specifically small vessel disease as defined in STRIVE-2 which includes small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, cerebral micro bleeds, cortical superficial siderosis, or cortical cerebral microinfarcts. .
  • Met actuarial neuropsychological criteria for MCI within the past 2 years (i.e. ≥2 impaired scores within one cognitive domain, or ≥1 impaired scores in ≥3 domains, where an impaired score is defined as ≤16th percentile using appropriate demographically-corrected norms).
  • Any lifetime depression, as defined by current or past Major Depressive Disorder per DSM-5.

Who cannot join

  • A TICS score of ≤ 19 suggestive of dementia. ii. Prior diagnosis of Dementia (NIA-AA) or Major Neurocognitive Disorder (DSM-5).
  • Daily/weekly anticholinergic or sedative use. Stimulants may be allowed pending investigator review.
  • History of significant or unstable condition/s or treatments for these condition/s that may impact cognition (as determined by the study investigators) such as significant cardiac (e.g. heart failure), infectious (e.g. HIV, urinary tract infection), or metabolic disease (e.g. labile diabetes), cancer (e.g. brain cancer, chemotherapy-induced cognitive impairment), developmental disorder (e.g. autism spectrum disorder, intellectual disability), or other neurologic disease (e.g. movement disorder, multiple sclerosis, moderate to severe brain injury, seizures).
  • Current treatment for AD/MCI with monoclonal antibody therapy or plan to initiate treatment within three months of enrollment.
  • Current use of any implanted brain stimulation device. vii. Enrolled in a clinical trial or has received an investigational medication or device in the last 30 days.
  • MRI contraindications (e.g., ferromagnetic implants, claustrophobia) ix. TMS contraindications (e.g., ferromagnetic implants, conditions or treatments that lower seizure threshold, taking medications that have short half-lives, no identifiable motor threshold).
  • Current alcohol or substance use disorder, bipolar disorder, schizophrenia spectrum or other psychotic disorder, suicidal/homicidal intent within the past month, or any suicide attempts within the past year.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Andreana Benitez, PhD contact

843-876-2479

benitez@musc.edu

Katrina Madden, MBA contact

843-792-9186

maddenka@musc.edu

United States1 site, 1 recruiting

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

    Katrina Madden, 843-792-9186, PUSHstudy@musc.edu

    Recruiting

Other trials in United States

About this study

Official title: Transcranial Magnetic Stimulation for MCI: A Phase II Dose-Response Study

The goal of this phase II study is to establish the dose-response curves of a safe and clinically feasible non-invasive brain stimulation technique (accelerated Transcranial Magnetic Stimulation (TMS)) to improve both depression and cognitive function in Mild Cognitive Impairment (MCI) patients with comorbid depression. It is known that TMS can effectively treat depression. Identifying the right dose of accelerated TMS in MCI patients is necessary prior to designing subsequent trials to determine efficacy. These results will inform future clinical trials of accelerated TMS for MCI, with the long-term goal of developing an efficacious treatment to prevent dementia.

Read the detailed description

Mild Cognitive Impairment (MCI) is a heterogenous syndrome of cognitive and neuropsychiatric symptoms, with as much as 40% of patients being diagnosed with comorbid depression. The goal of this phase II trial is to establish the functional form of the dose-response curves for accelerated intermittent theta burst stimulation (iTBS) to ameliorate depression and cognitive function in MCI. Identifying the right dose is necessary prior to designing subsequent trials to ascertain the efficacy of accelerated iTBS for MCI. In our two phase I trials, we chose treatment parameters based on robust prior literature on accelerated, high-dose rTMS delivery (i.e. accelerated iTBS, 600 pulses at 50 Hz per session), intensity (at 120% resting motor threshold [rMT]), stimulation site left dorsolateral prefrontal cortex (l-dlPFC), and site targeting (Beam F3). The course of treatment was guided by our clinical experience with mild cognitive impairment and vascular cognitive impairment patients as to what we hypothesized they would comfortably tolerate, which was confirmed by the acceptability ratings. In this phase II trial, we focus on manipulating one dosing parameter - total number of active pulses - to rigorously model the dose-response curves such that future phase II/III trials can be more efficient, decrease treatment burden, and accelerate response time.

Aim 1: Establish the dose-response curves for reduced depression following accelerated iTBS in MCI.

Aim 2: Establish the dose-response curves for improved cognition following accelerated iTBS in MCI.

Exploratory Aim 1: Examine alterations in functional connectivity following accelerated iTBS-rTMS in MCI.

Exploratory Aim 2: Examine blood-based biomarkers of neurodegeneration as effect modifiers.

Being tested
Accelerated iTBS, Sham Comparator
Keywords
"mild cognitive impairment", Depression
Medical subject headings
Cognitive Dysfunction, Depression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Accelerated iTBSDevice

    The investigators will treat participants with accelerated intermittent theta burst stimulation. iTBS will be delivered via a MagVenture MagPro TMS System with a Cool-B65 coil, targeting to direct the stimulation to the left dorsolateral prefrontal cortex (l-dlPFC). The investigators will use a standard resting motor threshold (rMT) determination to determine the TMS dose. Treatment will be delivered at 120% of the motor threshold. Total treatment time will be controlled; all participants will perceive receiving active treatment for 10 3-min sessions with 10-15 min inter-session intervals, resulting in a 3-hour treatment day. At pre-treatment, a focal electrical sham will be individually titrated to participant tolerability. Participants then receive an individualized level of sham stimulation throughout treatment, to bolster the blind. Participants will be told that they will be receiving different doses throughout the treatment day, again to maintain the integrity of the blind.

  • Sham ComparatorDevice

    To achieve adequate blinding, participants will go through the same number of sessions per day irrespective of the active and/or sham dose-step combination to which they are assigned. Sham sessions will be assigned in random order over the 10 sessions. The sequence of active and/or sham sessions for each treatment day is assigned a random code that is entered into the TMS system by the coordinator to maintain the integrity of the blind.

Study groups in NCT05992831
Study groupRoleWhat they receive
Dose Step 1 - 0 Active Accelerated iTBS SessionsSham comparatorParticipant will receive 10 sessions of accelerated iTBS on each of 6 treatment days, including 0/10 active sessions and 10/10 sham sessions per day for a total of 0 active sessions
Receives: Device: Sham Comparator
Dose Step 2 - 12 Active Accelerated iTBS SessionsExperimentalParticipant will receive 10 sessions of accelerated iTBS on each of 6 treatment days, including 2/10 active sessions and 8/10 sham sessions per day for a total of 12 active sessions (7,200 active pulses).
Receives: Device: Accelerated iTBS; Device: Sham Comparator
Dose Step 3 - 24 Active Accelerated iTBS SessionsExperimentalParticipant will receive 4/10 active sessions and 6/10 sham sessions per day for a total of 24 active sessions (14,400 active pulses).
Receives: Device: Accelerated iTBS; Device: Sham Comparator
Dose Step 4 - 36 Active Accelerated iTBS SessionsExperimentalParticipant will receive 6/10 active sessions and 4/10 sham sessions per day for a total of 36 active sessions (21,600 active pulses).
Receives: Device: Accelerated iTBS; Device: Sham Comparator
Dose Step 5 - 48 Active Accelerated iTBS SessionsExperimentalParticipant will receive 8/10 active sessions and 2/10 sham sessions per day for a total of 48 active sessions (28,800 active pulses).
Receives: Device: Accelerated iTBS; Device: Sham Comparator
Dose Step 6 - 60 Active Accelerated iTBS SessionsExperimentalParticipant will receive 10/10 active sessions and 0/10 sham sessions per day for a total of 60 active sessions (36,000 active pulses).
Receives: Device: Accelerated iTBS

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Geriatric Depression Scale (GDS) raw score

    The GDS is a ~3 minute self-report questionnaire of depression symptoms to which respondents answer yes/no (range=0-30, where higher scores indicate greater depression severity). Co-Participants will complete an informant-reported short form.

    Measured: Week 0 (1 week pre-treatment), Week 3 (1 week post-treatment), Week 10 (8 weeks post-treatment), and Week 26 (6 months post-treatment)

  2. Change in NIH Toolbox-Cognition Battery (NIHTB-CB) Fluid Composite

    The NIHTB-CB is a performance-based, iPad-administered ~30-minute suite of 7 tests that ascertain abilities in different cognitive domains (i.e. executive function, episodic memory, working memory, processing speed, language). It was developed using advanced psychometric techniques to minimize measurement error and produces normed subtest and composite scores. We will use the fully-corrected T-score (range T=0-100; Mean T=50, SD=10; higher scores indicating better cognition) of the Fluid Cognition Composite (normed for age, sex, years of education, and race/ethnicity) to more accurately reflect global, dynamic thinking abilities that reflect the presence of disease or the impact of interventions, and not premorbid influences on test scores.

    Measured: Week 0 (1 week pre-treatment), Week 3 (1 week post-treatment), Week 10 (8 weeks post-treatment), and Week 26 (6 months post-treatment)

Secondary outcomes (3)

  1. Change in PROMIS Depression T-score

    The PROMIS Depression scale is a self-report questionnaire of affective and cognitive symptoms to which respondents rate the frequency with which they experience the symptom on a 5-point scale (from 1-"Never" to 5-"Always") in the past 7 days. It is a computer adaptive test given as a REDCap survey, takes 1-2 minutes to complete, and yields a normed T-score (range T=0-100; Mean T=50, SD=10; higher scores indicate greater depression severity).

    Measured: Week 0 (1 week pre-treatment), Week 3 (1 week post-treatment), Week 10 (8 weeks post-treatment), and Week 26 (6 months post-treatment)

  2. Change in Alzheimer's Disease Cooperative Study scale for Activities of Daily Living in MCI (ADCS-ADL-MCI)

    This 18-item clinician-administered structured interview is given to co-participant informants and assesses the participant's ability to accomplish activities of daily living (independently, with supervision, or with help) within the past 4 weeks, with high scores indicating greater ability (raw score range=0-57).

    Measured: Week 0 (1 week pre-treatment) Week 10 (8 weeks post-treatment), and Week 26 (6 months post-treatment)

  3. Change in Clinical Dementia Rating (CDR) scale Sum of Boxes

    This clinician-administered structured interview is given to both participants and their co-participant informants to assesses the participant's abilities in six domains (i.e. Memory, Orientation, Judgment \& Problem Solving, Community Affairs, Home \& Hobbies, and Personal Care), rating each domain on a 5-point scale, with the sum of these 6 "box scores" indicating greater symptom severity (raw score range=0-18)

    Measured: Week 0 (1 week pre-treatment) Week 10 (8 weeks post-treatment), and Week 26 (6 months post-treatment)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Aug 2023
  2. Study start18 Jun 2024
  3. Primary completion30 Apr 2028 (estimated)
  4. Study completion30 Apr 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Each participant will be randomized to one of six possible dose-steps for the duration of the 6 treatment days (of their choosing) within a span of 2 weeks. We will use the FDA-approved MagVenture MagPro TMS System. Total treatment time will be controlled; all participants will perceive receiving treatment for 10 3-min stimulation sessions with 10-15 min inter-session intervals, resulting in a 2-3 hour treatment day. In addition to block randomization to dose step (which determines how many total active sessions they receive), the order of daily active and/or sham sessions will also be randomized. For example, if a participant is assigned to receive 4 active sessions in a day, 6 sham sessions will be given at random. The sequence of active and/or sham sessions for each treatment day is assigned a random code that is entered into the TMS system by the coordinator to maintain the integrity of the blind.
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
60 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05992831
Sponsor's protocol ID
Pro00127160
Other IDs
R01AG081237
Acronym
PUSH2
Status last verified
Mar 2026
First submitted
31 Jul 2023
Last updated
2 Apr 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
Yes
Individual data sharing
Yes: De-identified images will be shared with OpenNeuro, an NIH-funded platform for sharing de-identified neuroimaging data, which will be linked using study IDs to uploaded de-identified clinical data and data dictionaries, also in OpenNeuro. Data will be shared with Clinical Research Operations \& Management System (CROMS) in accordance with National Institute on Aging (NIA) requirements.

Questions about this trial

What is this clinical trial studying?

A study testing Accelerated iTBS in people with Mild Cognitive Impairment and Depression, run by Medical University of South Carolina at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 2 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Andreana Benitez, PhD (843-876-2479, benitez@musc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Geriatric Depression Scale (GDS) raw score (time frame: Week 0 (1 week pre-treatment), Week 3 (1 week post-treatment), Week 10 (8 weeks post-treatment), and Week 26 (6 months post-treatment)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05992831.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Apr 2026.

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