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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This proposal will demonstrate that non-invasive brain stimulation is able to modulate cortico-striatal circuits in neurodegenerative patients with apathy, and that doing so results in circuit-specific increases in FC and DA availability. These circuit changes will be accompanied by changes in specific behavioral dimensions of apathy. This work will lead to larger studies which develop personalized, circuit-specific neuromodulation strategies for AD patients suffering from this intractable neuropsychiatric symptom.

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 data supports the effectiveness of the treatment TMS for apathy in Alzheimer's Disease?

Research shows that repetitive transcranial magnetic stimulation (rTMS) can improve apathy in people with mild cognitive impairment, which is often a precursor to Alzheimer's disease. Additionally, rTMS has been shown to improve apathy in patients with chronic stroke, suggesting it may have potential benefits for similar symptoms in Alzheimer's patients. ^{1 2 3 4 5}

Is transcranial magnetic stimulation (TMS) safe for humans?

Research shows that repetitive transcranial magnetic stimulation (rTMS) is generally safe for humans, including those with Alzheimer's disease and other conditions like depression. Studies have found it to be well-tolerated, with no major safety concerns reported. ^{1 2 6 7 8}

How is the treatment TMS for apathy in Alzheimer's disease different from other treatments?

Transcranial Magnetic Stimulation (TMS) is unique because it uses magnetic fields to stimulate nerve cells in the brain, which is different from traditional drug treatments. It is non-invasive and has shown promise in improving apathy in conditions like mild cognitive impairment and stroke, where other treatments have limited effectiveness. ^{1 2 3 4 5}

Research Team

Mark Eldaief, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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

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

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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]

References

1. Switzerland 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. [2023]

2. Ireland 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. [2022]

3. Netherlands 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. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The Efficacy of High-Frequency Repetitive Transcranial Magnetic Stimulation for Improving Apathy in Chronic Stroke Patients. [2018]

5. United Arab Emirates 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. [2019]

6. 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]

7. Austria 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. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Safety of transcranial magnetic stimulation in unipolar depression: A systematic review and meta-analysis of randomized-controlled trials. [2022]