TMS for Apathy in Alzheimer's Disease

Overseen By Mark Eldaief, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Massachusetts General Hospital

Must not be taking: Antidepressants, Neuroleptics, Tobacco, others

Disqualifiers: Seizures, Pacemakers, Metal implants, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a non-invasive treatment called Transcranial Magnetic Stimulation (TMS) can reduce apathy in people with Alzheimer's disease. Apathy, a lack of interest or motivation, poses a significant challenge for those with Alzheimer's. The trial will compare the effects of stimulating different brain circuits to determine which one might be most effective. Individuals with Alzheimer's who exhibit noticeable apathy symptoms and are accompanied by a caregiver may be suitable candidates. As an unphased trial, this study provides a unique opportunity to contribute to groundbreaking research that could enhance the quality of life for Alzheimer's patients.

Will I have to stop taking my current medications?

If you are dependent on certain medications that affect dopamine, like some antidepressants or neuroleptics, you may need to stop taking them before joining the trial. You can participate if you can safely stop these medications and they are fully out of your system.

What prior data suggests that Transcranial Magnetic Stimulation is safe for Alzheimer's patients with apathy?

Research has shown that transcranial magnetic stimulation (TMS) is generally safe for people with Alzheimer's disease. TMS uses magnets to stimulate the brain without surgery.

For TMS targeting the ventral circuit, studies have not identified any serious side effects. Most people experience only mild issues like headaches or scalp discomfort, which resolve quickly.

For TMS targeting the dorsal circuit, one study focused on repetitive TMS over the left front part of the brain in Alzheimer's patients. It found the treatment safe, with no major concerns. Again, minor side effects like headaches may occur but do not last long.

In summary, TMS treatments for both ventral and dorsal circuits are considered safe, with only minor and short-lived side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about TMS (Transcranial Magnetic Stimulation) for apathy in Alzheimer's disease because it offers a non-invasive way to target specific brain circuits associated with motivation and emotional engagement. Unlike current treatments, which often rely on medications with systemic effects, TMS directly stimulates particular brain areas like the ventral and dorsal circuits, potentially improving apathy with fewer side effects. By focusing on individual brain connectivity patterns, TMS can be tailored to each person, aiming for more precise and effective results.

What evidence suggests that TMS could be an effective treatment for apathy in Alzheimer's disease?

Research has shown that transcranial magnetic stimulation (TMS) can help reduce lack of interest or motivation in people with Alzheimer's disease. In this trial, participants will receive TMS targeting different brain circuits. One arm involves stimulation of the ventral circuit (vmPFC), focusing on brain areas linked to motivation and emotions. Another arm targets the dorsal circuit (DLPFC), aiming to strengthen brain connections that may help with mental focus and motivation. Additionally, a sham stimulation arm serves as a comparison. Although evidence remains limited, these findings suggest TMS could be a promising treatment for apathy in Alzheimer's patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Mark Eldaief, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for individuals aged 50-80 with Alzheimer's disease, including atypical variants. They must have mild cognitive impairment (MMSE ≥22) and significant apathy symptoms as reported by a caregiver who will accompany them to visits.

Inclusion Criteria

Clinical Dementia Rating of 0.5 or mild 1.0 (MMSE equal to or greater than 22)

I have been diagnosed with Alzheimer's disease, including any unusual forms.

My caregiver reports I show strong signs of apathy, confirmed by a high AES-I score.

Exclusion Criteria

Involvement in any PET studies within 12 months

I do not have a history of seizures or any implants that would interfere with TMS.

I rely on medication that affects my brain's dopamine levels.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive repetitive transcranial magnetic stimulation (rTMS) targeting apathy-relevant circuits in Alzheimer's Disease patients

6 weeks

Multiple sessions per week

Follow-up

Participants are monitored for changes in apathy-related task performance, dopamine availability, mood scores, and resting-state connectivity

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• TMS

Trial Overview The study tests Intermittent Theta Burst Stimulation (iTBS), a non-invasive brain stimulation technique, to see if it can improve behavior related to apathy in Alzheimer's patients by affecting specific brain circuits.

How Is the Trial Designed?

Group I: Ventral circuit (vmPFC) stimulation Experimental Treatment 1 Intervention

This arm will involve stimulation of the ventral apathy-relevant circuit. Specifically, a target will be individually selected based on resting-state functional connectivity with a given subject's ventral striatum.

Group II: Dorsal circuit (DLPFC) stimulation Experimental Treatment 1 Intervention

This arm will involve stimulation of the dorsal apathy-relevant circuit. Specifically, a target will be individually selected based on resting-state functional connectivity with a given subject's dorsal striatum.

Group III: Sham stimulation Placebo Group 1 Intervention

This arm will involve sham stimulation to a prefrontal target.

TMS is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Transcranial Magnetic Stimulation for:

• Depression
• Anxiety disorders
• Post-traumatic stress disorder (PTSD)
• Obsessive-compulsive disorder (OCD)

Approved in European Union as Transcranial Magnetic Stimulation for:

• Depression
• Anxiety disorders
• Post-traumatic stress disorder (PTSD)
• Obsessive-compulsive disorder (OCD)

Approved in Canada as Transcranial Magnetic Stimulation for:

• Depression
• Anxiety disorders
• Post-traumatic stress disorder (PTSD)
• Obsessive-compulsive disorder (OCD)

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Published Research Related to This Trial

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]

The NeuroAD procedure, which combines repetitive transcranial magnetic stimulation with cognitive training, showed long-term improvements in apathy among Alzheimer's disease patients, with significant benefits observed even 28 months after treatment initiation.

While cognitive scores improved initially, they deteriorated over time, indicating that the NeuroAD procedure may be particularly effective for patients who respond well to the initial treatment, highlighting the need for further research to identify predictors of success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-site rTMS with cognitive training improves apathy in the long term in Alzheimer's disease: A 4-year chart review. Suarez Moreno, A., Nguyen, JP., Calmelet, A., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) has shown a positive impact on apathy in patients with Alzheimer's disease and some potential benefits in chronic stroke, suggesting it may be a feasible treatment option for these conditions.

The safety of rTMS was confirmed across various studies, but its efficacy varied significantly among different neurodegenerative conditions, with limited evidence of effectiveness in Parkinson's disease and mild traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation for apathy in patients with neurodegenerative conditions, cognitive impairment, stroke, and traumatic brain injury: a systematic review. Espiritu, AI., Hara, T., Tolledo, JK., et al.[2023]

In a study involving 15 Alzheimer's disease patients, those receiving repetitive transcranial magnetic stimulation combined with cognitive training (rTMS-COG) showed significant improvements in cognitive scores after 6 weeks and 4.5 months compared to a placebo group.

The treatment was found to be safe and effective, with notable enhancements in cognitive function and overall clinical impression, while the placebo group experienced mild worsening in their scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation combined with cognitive training is a safe and effective modality for the treatment of Alzheimer's disease: a randomized, double-blind study. Rabey, JM., Dobronevsky, E., Aichenbaum, S., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) significantly improved apathy in older adults with Mild Cognitive Impairment (MCI) after 2 weeks of treatment, as measured by the Apathy Evaluation Scale-Clinical version (AES-C).

In addition to reducing apathy, rTMS also led to notable improvements in cognitive function and executive tasks, indicating its potential as a therapeutic intervention for MCI-related symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study. Padala, PR., Padala, KP., Lensing, SY., et al.[2022]

Transcranial magnetic stimulation (TMS) is shown to be safe for patients with major depressive disorder, with no significant increase in dropout rates or serious adverse events compared to sham treatment, based on a meta-analysis of 53 trials involving 3,273 participants.

While TMS may lead to some mild and transient non-serious adverse events like headaches and discomfort, these side effects are manageable, suggesting that TMS can be a viable treatment option either alone or alongside other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcranial magnetic stimulation in unipolar depression: A systematic review and meta-analysis of randomized-controlled trials. Wang, WL., Wang, SY., Hung, HY., et al.[2022]

In a study involving 13 chronic stroke patients, high-frequency repetitive transcranial magnetic stimulation (rTMS) significantly improved apathy and depression scores compared to a sham stimulation group, indicating its potential efficacy for treating apathy post-stroke.

The rTMS was applied over the dorsal anterior cingulate cortex and medial prefrontal cortex, suggesting that targeting these brain regions may be beneficial for addressing apathy in stroke patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of High-Frequency Repetitive Transcranial Magnetic Stimulation for Improving Apathy in Chronic Stroke Patients. Sasaki, N., Hara, T., Yamada, N., et al.[2018]

This study will evaluate the effectiveness of combining transcranial direct current stimulation (tDCS) with cognitive training to treat apathy in 24 patients with mild-to-moderate Alzheimer's Disease, aiming to improve motivation and cognitive function.

The trial is designed as a randomized, double-blind study, comparing the combined treatment to cognitive training alone, with primary and secondary endpoints focused on measuring changes in apathy and cognitive scores over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Transcranial Direct Current Stimulation Combined with Cognitive Training in the Treatment of Apathy in Patients with Alzheimer's Disease: Study Protocol for a Randomized Trial. Nguyen, JP., Boutoleau-Bretonniere, C., Lefaucheur, JP., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10684725/

Repetitive transcranial magnetic stimulation for apathy in ... Limited evidence suggests that rTMS intervention may have the potential to modify apathy among patients with AD, PPA, MCI and chronic stroke, but less so in PD ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9138229/

Repetitive Transcranial Magnetic Stimulation (rTMS) of ... Our preliminary findings suggest that targeting DLPFC by rTMS application may lead to a significant long-term increase in FC in MCI patients in a RS network ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05389644

TMS as a Treatment for Apathy in Alzheimer's Disease This proposal will demonstrate that non-invasive brain stimulation is able to modulate cortico-striatal circuits in neurodegenerative patients with apathy, ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165178117312544

Repetitive transcranial magnetic stimulation for apathy in ... This study establishes that rTMS is efficacious in improving apathy in subjects with MCI. Introduction. Over five million Americans have Alzheimer's disease (AD) ...

5. eurjmedres.biomedcentral.com eurjmedres.biomedcentral.com/articles/10.1186/s40001-025-02493-8

Therapeutic potential and mechanisms of repetitive ... This review synthesizes current evidence supporting rTMS as an effective intervention for alleviating clinical symptoms of Alzheimer's disease.

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. sciencedirect.com sciencedirect.com/science/article/pii/S1878747924000175

Repetitive transcranial magnetic stimulation as a treatment ... We report results of a large multisite double-blind randomized trial investigating the short and long-term efficacy of repetitive transcranial magnetic ...

8. frontiersin.org frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.679585/full

Repetitive Transcranial Magnetic Stimulation of the ... Methods: We conducted a 2-week treatment course of 10-Hz rTMS over the left dorsolateral prefrontal cortex in 23 patients with AD who were split ...

9. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.70043

Broad repetitive transcranial magnetic stimulation (rTMS) of ... Induction-to-maintenance repetitive transcranial magnetic stimulation (rTMS) of the precuneus is a promising treatment for Alzheimer's disease ( ...

10. thejcn.com thejcn.com/DOIx.php?id=10.3988/jcn.2016.12.1.57

Treatment of Alzheimer's Disease with Repetitive ... Repetitive transcranial magnetic stimulation (rTMS) has been examined as a potential treatment for many neurological disorders. High-frequency ...