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

Trial Summary

What is the purpose of this trial?

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.

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 data supports the effectiveness of the treatment Accelerated iTBS for Mild Cognitive Impairment?

Research suggests that repetitive transcranial magnetic stimulation (rTMS), which is similar to Accelerated iTBS, may help improve memory and cognitive function in patients with Alzheimer's disease and mild cognitive impairment by stimulating brain areas linked to memory. ^{1 2 3 4 5}

Is accelerated iTBS safe for humans?

Repetitive transcranial magnetic stimulation (rTMS), which is similar to accelerated iTBS, has been studied in people with Alzheimer's disease and mild cognitive impairment. These studies suggest that rTMS is generally safe, as no major safety concerns were reported. ^{1 2 6 7 8}

How is the Accelerated iTBS treatment different from other treatments for mild cognitive impairment?

Accelerated iTBS (intermittent Theta Burst Stimulation) is a form of transcranial magnetic stimulation (TMS) that uses magnetic fields to stimulate nerve cells in the brain, potentially improving memory and cognitive function. Unlike traditional treatments, it is non-invasive and focuses on enhancing brain plasticity (the brain's ability to change and adapt) by targeting specific brain regions associated with memory. ^{1 4 5 7 9}

Research Team

Lisa McTeague, PhD

Principal Investigator

Medical University of South Carolina

Andreana Benitez, PhD

Principal Investigator

Medical University of South Carolina

Eligibility Criteria

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

Met actuarial neuropsychological criteria for MCI within the past 2 years

I can move, feel, and speak well enough to complete tests.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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 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 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]

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 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]

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]

References

1. United States 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. [2014]

2. England 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. [2021]

3. Netherlands 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. [2015]

4. Netherlands 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. [2022]

5. Switzerland 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. [2023]

6. Ireland pubmed.ncbi.nlm.nih.gov

Effect of transcranial magnetic stimulation as an enhancer of cognitive stimulation sessions on mild cognitive impairment: Preliminary results. [2021]

7. Netherlands 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. [2020]

8. India 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. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

High-Frequency rTMS Could Improve Impaired Memory in Mild Cognitive Impairment Patients in China: A Randomized Controlled Study. [2023]