Accelerated iTBS for Mild Cognitive Impairment

(PUSH2 Trial)

Overseen By Katrina Madden, MBA

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Medical University of South Carolina

Must not be taking: Anticholinergics, Sedatives

Disqualifiers: Dementia, Bipolar, Schizophrenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 6 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a non-invasive brain stimulation technique called accelerated TMS (Transcranial Magnetic Stimulation) to improve depression and cognitive function in people with Mild Cognitive Impairment (MCI). The main aim is to determine the right dose to potentially prevent future dementia. Participants will receive either different doses of active TMS sessions or a sham (inactive) treatment. Suitable candidates for the trial include those diagnosed with MCI who also experience depression. As an unphased trial, this study offers participants the chance to contribute to groundbreaking research that could lead to new preventive treatments for dementia.

Will I have to stop taking my current medications?

The trial requires that you stay on a stable dose of your current medications for at least 4 weeks before joining. Some medications like anticholinergics or sedatives are not allowed, but others like antidepressants are okay if stable.

What prior data suggests that this non-invasive brain stimulation technique is safe for improving cognitive function in MCI patients?

Research has shown that accelerated intermittent theta burst stimulation (iTBS) is generally safe and well-tolerated. One study found that using iTBS in people with mild cognitive impairment (MCI) did not cause major side effects and was practical and acceptable for participants. Another study supported the safety of iTBS for older adults, even after multiple sessions. While more research is needed, early results are promising, and the treatment appears to have a good safety record. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about accelerated iTBS (intermittent Theta Burst Stimulation) for mild cognitive impairment because it offers a novel, non-invasive approach potentially different from traditional treatments like medications and cognitive therapies. Unlike standard options that often take weeks to see results, accelerated iTBS aims to deliver benefits more quickly, with the possibility of seeing improvements in just a few days. This method uses magnetic pulses to target specific brain areas, promoting brain plasticity and potentially enhancing cognitive function. By varying the dose and intensity of sessions, researchers hope to optimize the treatment's effectiveness and determine the best protocol for improving cognitive symptoms.

What evidence suggests that accelerated iTBS could be an effective treatment for mild cognitive impairment with comorbid depression?

Research shows that accelerated intermittent theta-burst stimulation (iTBS) can improve thinking and memory in people with mild cognitive impairment (MCI). Early results suggest that iTBS may enhance brain function by altering how different brain regions connect and work together. Studies have also found iTBS effective in treating depression, which is common in people with MCI. Additionally, accelerated iTBS has proven safe and well-tolerated in older adults. In this trial, some participants will receive varying doses of active accelerated iTBS sessions, while others will receive sham sessions. This approach offers a promising option for improving both depression and cognitive function in people with MCI. ^{1 3 4 6 7}

Who Is on the Research Team?

Lisa McTeague, PhD

Principal Investigator

Medical University of South Carolina

Andreana Benitez, PhD

Principal Investigator

Medical University of South Carolina

Are You a Good Fit for This Trial?

This trial is for people aged 60-85 with mild cognitive impairment (MCI) and moderate to severe depression. Participants must have a stable medication regimen, adequate mental and motor functions, an informant who knows them well, and meet specific neuropsychological criteria for MCI.

Inclusion Criteria

English as a first/primary language

Must have a Co-Participant who has at least weekly in-person contact with the participant and is willing to participate in the study as a collateral informant

Met actuarial neuropsychological criteria for MCI within the past 2 years

Exclusion Criteria

I have been diagnosed with dementia or a major thinking (cognitive) disorder.

A TICS score of ≤ 22 suggestive of dementia and a PHQ-9 score of 0-9

I've been on a stable dose of certain medications like antidepressants for over 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive accelerated Transcranial Magnetic Stimulation (TMS) sessions to establish dose-response curves for depression and cognitive function improvement in MCI patients.

6 weeks

Daily sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of cognitive and depression scales.

26 weeks

Assessments at Week 3, Week 10, and Week 26

What Are the Treatments Tested in This Trial?

Interventions

• Accelerated iTBS
• Sham Comparator

Trial Overview The study tests accelerated Transcranial Magnetic Stimulation (TMS), comparing it to a sham procedure to see if it can improve depression and cognitive function in MCI patients. The right TMS dose needs identification before larger trials on its effectiveness.

How Is the Trial Designed?

Group I: Dose Step 6 - 60 Active Accelerated iTBS Sessions Experimental Treatment 1 Intervention

Participant will receive 10/10 active sessions and 0/10 sham sessions per day for a total of 60 active sessions (36,000 active pulses).

Group II: Dose Step 5 - 48 Active Accelerated iTBS Sessions Experimental Treatment 2 Interventions

Participant will receive 8/10 active sessions and 2/10 sham sessions per day for a total of 48 active sessions (28,800 active pulses).

Group III: Dose Step 4 - 36 Active Accelerated iTBS Sessions Experimental Treatment 2 Interventions

Participant will receive 6/10 active sessions and 4/10 sham sessions per day for a total of 36 active sessions (21,600 active pulses).

Group IV: Dose Step 3 - 24 Active Accelerated iTBS Sessions Experimental Treatment 2 Interventions

Participant will receive 4/10 active sessions and 6/10 sham sessions per day for a total of 24 active sessions (14,400 active pulses).

Group V: Dose Step 2 - 12 Active Accelerated iTBS Sessions Experimental Treatment 2 Interventions

Participant 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).

Group VI: Dose Step 1 - 0 Active Accelerated iTBS Sessions Placebo Group 1 Intervention

Participant 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

Accelerated iTBS is already approved in United States, European Union for the following indications:

Approved in United States as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)
• Migraines
• Smoking cessation

Approved in European Union as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

In a study of 40 patients with amnestic mild cognitive impairment (aMCI), it was found that they exhibited lower cortical excitability and altered synaptic plasticity compared to healthy controls, as measured by 5 Hz repetitive transcranial magnetic stimulation (5 Hz-rTMS).

The study revealed that specific TMS parameters, such as the resting motor threshold and the ratio of the first to the tenth motor-evoked potential, correlated with the time it took for patients to convert to Alzheimer's disease, suggesting these measures could serve as early neurophysiological markers for disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered Cortical Synaptic Plasticity in Response to 5-Hz Repetitive Transcranial Magnetic Stimulation as a New Electrophysiological Finding in Amnestic Mild Cognitive Impairment Converting to Alzheimer's Disease: Results from a 4-year Prospective Cohort Study. Trebbastoni, A., Pichiorri, F., D'Antonio, F., et al.[2023]

In a study involving 12 Alzheimer's disease patients, four sessions of high-frequency repetitive transcranial magnetic stimulation (rTMS) over two weeks led to significant improvements in language skills, which were sustained for at least four weeks after treatment.

Functional MRI results indicated increased brain activation during cognitive tasks following rTMS, supporting the idea that rTMS may enhance cognitive function in Alzheimer's patients, consistent with findings from other studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, short-term, repetitive transcranial magnetic stimulation in patients with Alzheimer's disease with functional imaging correlates and literature review. Devi, G., Voss, HU., Levine, D., et al.[2014]

In a study involving 40 patients with mild cognitive impairment (MCI), 10 sessions of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex significantly improved memory performance compared to a sham treatment.

The improvement in memory was linked to changes in brain activity and connectivity, specifically increased activity in certain brain regions and altered functional connectivity, suggesting that rTMS may enhance memory by modulating neuronal networks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Frequency rTMS Could Improve Impaired Memory in Mild Cognitive Impairment Patients in China: A Randomized Controlled Study. Wang, T., Guo, Z., Wu, H., et al.[2023]

In a study involving 22 patients (16 with amnesic mild cognitive impairment and 6 with Alzheimer's disease), repetitive transcranial magnetic stimulation (rTMS) targeting the left angular gyrus significantly improved episodic memory and cognitive assessment scores, particularly in aMCI patients.

The cognitive improvements were linked to changes in neuroplasticity within the thalamic system, suggesting that rTMS could be a promising strategy for enhancing cognitive function in the early stages of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive Improvement via Left Angular Gyrus-Navigated Repetitive Transcranial Magnetic Stimulation Inducing the Neuroplasticity of Thalamic System in Amnesic Mild Cognitive Impairment Patients. Yang, Z., Sheng, X., Qin, R., et al.[2022]

In a study of 21 patients with amnestic mild cognitive impairment (aMCI), repetitive transcranial magnetic stimulation (rTMS) significantly improved cognitive performance and altered functional connectivity within the default mode network (DMN) compared to a sham treatment.

The changes in DMN connectivity, particularly a decrease in connectivity, were linked to cognitive improvements, suggesting that baseline DMN activity could predict how well patients respond to rTMS therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation Induced Hypoconnectivity Within the Default Mode Network Yields Cognitive Improvements in Amnestic Mild Cognitive Impairment: A Randomized Controlled Study. Cui, H., Ren, R., Lin, G., et al.[2020]

In a study involving 11 patients with mild-to-moderate Alzheimer's disease, chronic treatment with rivastigmine increased the amplitude of motor evoked potentials (MEP) after a single stimulus, indicating some improvement in cortical excitability.

However, rivastigmine did not affect short-term synaptic plasticity or the normal facilitation of MEP during repetitive transcranial magnetic stimulation (rTMS), suggesting that the limited clinical benefits of cholinesterase inhibitors in Alzheimer's may not be due to enhanced cortical plasticity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic treatment with rivastigmine in patients with Alzheimer's disease: a study on primary motor cortex excitability tested by 5 Hz-repetitive transcranial magnetic stimulation. Trebbastoni, A., Gilio, F., D'Antonio, F., et al.[2015]

In a double-blind, sham-controlled trial involving 24 patients with amnestic mild cognitive impairment (aMCI), high-frequency repetitive transcranial magnetic stimulation (rTMS) significantly improved cognitive function as measured by the Montreal Cognitive Assessment after 4 weeks of treatment.

The rTMS treatment also led to notable changes in brain activity, specifically increasing the amplitude of low-frequency fluctuations in key cognitive areas, suggesting that rTMS may enhance cognitive function by altering brain activity patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroimaging mechanisms of high-frequency repetitive transcranial magnetic stimulation for treatment of amnestic mild cognitive impairment: a double-blind randomized sham-controlled trial. Yuan, LQ., Zeng, Q., Wang, D., et al.[2021]

High-frequency repetitive transcranial magnetic stimulation (HFrTMS) showed significant short-term improvements in general cognition for patients with Alzheimer's disease (AD), while anodal transcranial direct current stimulation (atDCS) also had positive effects, but to a lesser extent.

Cognitive training during rTMS or tDCS may negatively impact general cognition, and the best responses to these treatments were observed in patients with AD rather than those with mild cognitive impairment (MCI).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive effects and acceptability of non-invasive brain stimulation on Alzheimer's disease and mild cognitive impairment: a component network meta-analysis. Chu, CS., Li, CT., Brunoni, AR., et al.[2021]

In a study involving 22 patients with mild cognitive impairment (MCI), repetitive Transcranial Magnetic Stimulation (rTMS) was found to significantly enhance the effects of Cognitive Stimulation (CS) as measured by the Montreal Cognitive Assessment (MoCA).

The study consisted of 30 sessions over 10 weeks, and while the active group showed significant improvements, the sham group did not, indicating that rTMS may be a beneficial tool for cognitive enhancement in MCI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of transcranial magnetic stimulation as an enhancer of cognitive stimulation sessions on mild cognitive impairment: Preliminary results. Gy, RR., Jv, RL., J, RG., et al.[2021]

Citations

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A phase I trial of accelerated intermittent theta burst rTMS ... Background: Emerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) enhances cognition in mild cognitive impairment (MCI).

2. jnnp.bmj.com jnnp.bmj.com/content/95/11/1036

A phase I trial of accelerated intermittent theta burst rTMS for ... This phase I clinical trial demonstrates that 3 days of accelerated iTBS (14,400 total pulses) is safe, feasible, tolerable, and acceptable in older adults with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12465570/

Effects of intermittent theta-burst stimulation on cognition ... These findings suggest that iTBS can produce delayed cognitive enhancement in individuals with amnestic MCI and very mild AD, while the impact ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X25000932

Accelerated iTBS-Induced changes in resting-state ... Cognitive improvement following a-iTBS in MCI may be attributable to local and network-level reconfigurations in functional connectivity.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT07188753?term=NA

Study Details | NCT07188753 | Randomized Controlled ... Several meta-analyses have demonstrated its efficacy as an antidepressant treatment and its potential for treating mild cognitive impairment.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11306417/

Efficacy and Safety of Transcranial Magnetic Stimulation on ... We aim to analyze the efficacy and safety of TMS on cognition in mild cognitive impairment (MCI), Alzheimer disease (AD), AD-related dementias, and nondementia ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06445894

Accelerated Intermittent Theta-burst Stimulation to Modify ... aiTBS has been shown to be a tolerable and safe form of non-invasive brain stimulation with rapid antidepressant efficacy and anti-suicidal effects in patients ...