Transcranial Magnetic Stimulation for Alzheimer's Disease

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: HealthPartners Institute

Must be taking: Cholinesterase inhibitors, Memantine

Disqualifiers: Non-AD dementia, Seizure disorder, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

6 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that participants have been on a stable dose of cholinesterase inhibitors and memantine for at least one month, so you will not need to stop these medications.

What data supports the effectiveness of the treatment Intermittent Theta Burst Stimulation for Alzheimer's Disease?

Research shows that Intermittent Theta Burst Stimulation (iTBS) can improve memory and brain connectivity in people with mild to moderate Alzheimer's disease. In studies with mice, iTBS also reduced harmful brain proteins and inflammation, suggesting it might help with Alzheimer's symptoms. ^{1 2 3 4 5}

Is transcranial magnetic stimulation safe for humans?

Research shows that transcranial magnetic stimulation, including intermittent theta burst stimulation, is generally safe and well-tolerated in humans, with studies in conditions like major depression reporting few side effects. ^{1 2 6 7 8}

How does intermittent theta burst stimulation differ from other treatments for Alzheimer's disease?

Intermittent theta burst stimulation (iTBS) is unique because it uses magnetic pulses to stimulate specific brain areas, potentially reducing harmful proteins and inflammation in Alzheimer's disease. Unlike other treatments, iTBS may improve brain connectivity and cognitive function, with effects lasting several weeks after treatment. ^{1 2 3 8 9}

What is the purpose of this trial?

Alzheimer's disease (AD) is a progressive neurodegenerative condition affecting 6.2 million individuals in the United States, resulting in an annual cost of care of $305 billion. AD is functionally characterized by progressive degeneration of large-scale brain networks (LSBNs), including the default mode network (DMN) presumably from the deposition of amyloid plaques and neurofibrillary tangles. Available FDA-approved medications for AD such as donepezil and memantine offer limited benefit and modest impact on quality of life. Transcranial magnetic stimulation (TMS) with intermittent theta burst stimulation (iTBS) offers a non-invasive alternative to pharmacotherapy in persons with AD. We propose a case series study to compare sham with iTBS.

Research Team

Bhavani Kashyap, MBBS, PhD

Principal Investigator

HealthPartners Institute

Eligibility Criteria

This trial is for people aged 40-90 with Mild Cognitive Impairment or mild Alzheimer's Disease, scoring over 24 on the MMSE and having a CDR of 0.5-1. Participants must show evidence of amyloidosis in the brain and have been on a stable dose of Alzheimer's medications for at least one month.

Inclusion Criteria

I have been diagnosed with mild cognitive impairment or mild Alzheimer's disease.

Mini Mental Status Examination (MMSE) >24

Clinical Dementia Rating (CDR) 0.5-1

Exclusion Criteria

My condition is a type of dementia, but not Alzheimer's disease.

I have a seizure disorder.

Inability to tolerate resting state-function magnetic resonance imaging (rs-fMRI)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 5 treatments of intermittent theta burst stimulation (iTBS) or sham over a 2-week period

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-7 weeks

Open-label extension (optional)

Participants who received the sham treatment may opt into continuation of treatment with iTBS without further data collection

Long-term

Treatment Details

Interventions

• Intermittent Theta Burst Stimulation

Trial Overview The study tests if transcranial magnetic stimulation (TMS) using intermittent theta burst stimulation (iTBS) can be an effective non-invasive treatment compared to a sham (placebo-like) procedure in individuals with early-stage Alzheimer's Disease.

Participant Groups

Group I: Intermittent theta burst stimulation Experimental Treatment 1 Intervention

Subjects will receive treatment with intermittent theta burst stimulation (iTBS) with the active coil. There will be a total of 5 treatments over a 2-week period. All subjects will receive iTBS to the 8Av region. TBS treatment will also be provided for two additional sites within the large-scale brain networks (LSBNs) that is found to contain the greatest number of connectivity anomalies. Total participation will be 6-9 weeks.

Group II: Sham device Placebo Group 1 Intervention

Subjects will receive treatment with sham coil. There will be a total of 5 treatments over a 2-week period. Coil will be placed over the same region as the experimental group. Total participation will be 6-9 weeks. An open-label extension will be offered to participants that received the sham (control) treatment without further data collection.

Who Is Running the Clinical Trial?

HealthPartners Institute

Lead Sponsor

Trials

196

Recruited

3,721,000+

Findings from Research

In a study involving 58 participants with mild to moderate Alzheimer's disease, intermittent theta burst stimulation (iTBS) was found to enhance gamma connectivity in the brain, which is linked to cognitive function.

Active iTBS treatment led to significant improvements in delayed recall on memory tasks, suggesting that this non-invasive stimulation technique could be a promising therapeutic approach for cognitive impairment in Alzheimer's.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gamma connectivity predicts response to intermittent theta burst stimulation in Alzheimer's disease: a randomized controlled trial. Hoy, KE., Emonson, MRL., Bailey, NW., et al.[2023]

Intermittent theta burst stimulation (iTBS) significantly reduces amyloid-beta (Aβ) accumulation in the brains of APP/PS1 mice, indicating its potential to mitigate Alzheimer's disease-related pathologies.

The treatment not only lowers Aβ levels by inhibiting its production and enhancing its degradation but also reduces neuroinflammation, neuronal cell death, and synaptic loss, suggesting long-lasting protective effects on brain health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The long-term effects of intermittent theta burst stimulation on Alzheimer's disease-type pathologies in APP/PS1 mice. Huang, H., Zhu, Y., Liao, L., et al.[2023]

Theta-burst stimulation appears to significantly reduce the severity of unilateral spatial neglect in stroke patients, based on a systematic review of nine studies involving 148 participants.

Despite the promising results, the evidence is limited and inconsistent due to variations in study protocols and terminology, making it difficult to draw definitive conclusions about its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of theta-burst stimulation on unilateral spatial neglect following stroke: a systematic review. Cotoi, A., Mirkowski, M., Iruthayarajah, J., et al.[2019]

Theta-burst Stimulation (TBS) is a promising form of repetitive transcranial magnetic stimulation that can induce significant and lasting changes in brain activity with lower intensity and shorter duration than traditional methods, making it a potentially more efficient treatment option.

TBS may have therapeutic implications for neuropsychiatric disorders due to its ability to promote synaptic plasticity, although the exact neurobiological mechanisms, including processes like long-term potentiation and GABAergic modulation, are still being researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms and applications of theta-burst rTMS on the human motor cortex. Cárdenas-Morales, L., Nowak, DA., Kammer, T., et al.[2009]

Theta-burst transcranial magnetic stimulation (TBS) is safe and well tolerated in patients with major depression, based on a study involving 33 participants over 10 consecutive days.

The study suggests that TBS may have antidepressant effects, and increasing stimulation parameters does not lead to more side effects, potentially enhancing its therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. Chistyakov, AV., Rubicsek, O., Kaplan, B., et al.[2019]

In a study of 27 participants, a prolonged intermittent theta burst stimulation (piTBS) protocol using 1,800 pulses showed limited effectiveness for major depressive disorder, with only 18.2% of participants achieving a response and 9.1% reaching remission.

Safety and tolerability were concerns, as 18.5% of participants experienced issues, suggesting that while piTBS is a promising approach, further research is needed to optimize its parameters and improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. Richard, M., Noiseux, C., Desbeaumes Jodoin, V., et al.[2022]

Transcranial magnetic intermittent theta burst stimulation (iTBS) with a prolonged protocol (1200 pulses) significantly increased corticospinal excitability in the targeted primary motor cortex (M1) while inhibiting excitability in the opposite M1 for up to 30 minutes, indicating its potential for modulating motor function.

iTBS1200 also enhanced post-movement beta synchronisation in the stimulated M1, suggesting a link between this brain activity and improved motor output, while not affecting alpha and low gamma rhythms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent θ burst stimulation over primary motor cortex enhances movement-related β synchronisation. Hsu, YF., Liao, KK., Lee, PL., et al.[2011]

In a study involving 36 multiple sclerosis patients, intermittent theta burst stimulation (iTBS) significantly improved manual dexterity, as shown by faster completion times in the nine-hole peg test and increased performance in the Box and Block Test.

However, iTBS did not have a significant impact on hand motor imagery abilities, indicating that while it can enhance physical tasks, it may not affect cognitive aspects of motor function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Intermittent Theta Burst Stimulation on Manual Dexterity and Motor Imagery in Patients with Multiple Sclerosis: A Quasi-Experimental Controlled Study. Azin, M., Zangiabadi, N., Iranmanesh, F., et al.[2020]

References

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

Gamma connectivity predicts response to intermittent theta burst stimulation in Alzheimer's disease: a randomized controlled trial. [2023]

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

The long-term effects of intermittent theta burst stimulation on Alzheimer's disease-type pathologies in APP/PS1 mice. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Impaired LTP- but not LTD-like cortical plasticity in Alzheimer's disease patients. [2012]

4. England pubmed.ncbi.nlm.nih.gov

The effect of theta-burst stimulation on unilateral spatial neglect following stroke: a systematic review. [2019]

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

Mechanisms and applications of theta-burst rTMS on the human motor cortex. [2009]

6. England pubmed.ncbi.nlm.nih.gov

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. [2019]

7. Ireland pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. [2022]

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

Intermittent θ burst stimulation over primary motor cortex enhances movement-related β synchronisation. [2011]

9. Estonia pubmed.ncbi.nlm.nih.gov

Effects of Intermittent Theta Burst Stimulation on Manual Dexterity and Motor Imagery in Patients with Multiple Sclerosis: A Quasi-Experimental Controlled Study. [2020]