Theta-burst Stimulation for Memory Improvement in Mild Cognitive Impairment

Overseen By Sonja Hiller

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of California, Los Angeles

Must not be taking: Anticholinergics, Antihistamines, Benzodiazepines

Disqualifiers: Dementia, Stroke, Substance abuse, others

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

Compensation: Varies

Number of Visits: 9

Duration: 3 weeks

70 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to see if stimulation of the brain can improve memory. The investigators will use a device called transcranial magnetic stimulation that can stimulate and activate a specific part of the brain that is important for memory. The study will enroll MCI subjects and subjects with subjective memory complaints who will be randomly assigned to receive active or sham brain stimulation. 'Blinded' or 'sham-controlled' means that the subject will not know whether the treatment they receive is the active treatment or the non-active stimulation. In the 'sham' condition, the stimulator will turn on but will not actually be stimulating the target brain region.

Will I have to stop taking my current medications?

The trial requires that you do not change your use of medications for depression, anxiety, ADHD, or psychosis for one month before and during the study. If you are taking certain medications like anticholinergics, sedating antihistamines, or benzodiazepines, you may need to stop or adjust them, but this will be decided on a case-by-case basis.

What data supports the effectiveness of this treatment for memory improvement in mild cognitive impairment?

Research suggests that theta burst stimulation (TBS) can improve memory and brain connectivity in people with mild cognitive impairment (MCI). Additionally, similar treatments have shown promise in reducing Alzheimer's disease symptoms in animal studies, indicating potential benefits for memory-related conditions. ^{1 2 3 4 5}

Is theta-burst stimulation (TBS) safe for humans?

Theta-burst stimulation (TBS) is generally considered safe, with most side effects being mild and occurring in about 5% of people. However, there is a small risk of seizures, so it should be used carefully, especially since it is a newer technique. ^{1 6 7 8 9}

How does theta-burst stimulation differ from other treatments for mild cognitive impairment?

Theta-burst stimulation (TBS) is unique because it uses magnetic pulses to target specific brain areas, like the hippocampus, to improve memory and brain connectivity, which is different from traditional drug treatments that often focus on chemical changes in the brain. ^{1 2 3 4 10}

Research Team

Nanthia Suthana

Principal Investigator

University of California, Los Angeles

Eligibility Criteria

This trial is for individuals aged 55-90 with mild cognitive impairment, who are in good health, right-handed, and speak English fluently. They should have memory complaints verified by specific tests and be able to consent to a long-term study. Excluded are those with dementia, major psychiatric or neurological disorders, substance abuse issues, certain medication use, or contraindications to MRI.

Inclusion Criteria

MMSE score > 24

Hamilton Depression score < 7

I can perform most daily activities without help.

Exclusion Criteria

I have been diagnosed with dementia.

Unwilling or unable to provide informed consent

Not right handed based on self-report or evaluation based on a standard report

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either active or sham transcranial magnetic stimulation to improve memory

3 weeks

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

3 visits (in-person)

Long-term follow-up

Participants undergo additional assessments to evaluate long-term effects of the treatment

2 months

1 visit (in-person)

Treatment Details

Interventions

• Active Theta Burst Stimulation
• Sham Theta Burst Stimulation
• Theta Burst Stimulation

Trial Overview The trial examines whether brain stimulation using transcranial magnetic stimulation (TMS) can improve memory in people with mild cognitive impairment. Participants will be randomly assigned to receive either active TMS or sham (fake) treatment without knowing which one they're getting.

Participant Groups

Group I: Active TBS Experimental Treatment 1 Intervention

Theta burst stimulation (TBS) will be delivered at 100% of motor threshold (MT).

Group II: Sham TBS Placebo Group 1 Intervention

Sham stimulation will be delivered at 0% of motor threshold (MT), with all other parameters matching the active TBS condition.

Active Theta Burst Stimulation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder
• Obsessive-Compulsive Disorder
• Migraines

Approved in European Union as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder
• Obsessive-Compulsive Disorder

Approved in Canada as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder
• Obsessive-Compulsive Disorder

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

Theta burst stimulation (TBS) shows promise in improving associative memory and enhancing functional connectivity in the hippocampus and other brain regions in individuals with mild cognitive impairment (MCI).

This study suggests that TBS can effectively target the hippocampus using functional MRI and diffusion-weighted MRI, although the findings are preliminary and based on a small sample size.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diffusion MRI-guided theta burst stimulation enhances memory and functional connectivity along the inferior longitudinal fasciculus in mild cognitive impairment. Chen, YC., Ton That, V., Ugonna, C., et al.[2022]

In a study involving 36 participants, it was found that the intensity of transcranial magnetic stimulation (TMS) significantly affects the plasticity response in the primary motor cortex, with higher intensities (150% of resting motor threshold) yielding greater depression effects from continuous theta burst stimulation (cTBS).

For intermittent theta burst stimulation (iTBS), the most effective probing intensity was at 110% of resting motor threshold, indicating that different intensities are crucial for accurately assessing neuroplasticity responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Probing changes in corticospinal excitability following theta burst stimulation of the human primary motor cortex. Goldsworthy, MR., Vallence, AM., Hodyl, NA., et al.[2017]

In a study involving 17 amyloid-positive participants with mild cognitive impairment (MCI) and 10 cognitively unimpaired controls, researchers found that LTP-like neuroplasticity was significantly impaired in those with MCI compared to controls, indicating early neuroplasticity issues in prodromal Alzheimer's disease.

Interestingly, a greater LTP-like response was associated with worse memory function in the MCI group, suggesting that neuroplasticity may play a complex role in the early stages of Alzheimer's disease and highlighting the potential of TMS as a tool for early diagnosis or treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LTP-like plasticity is impaired in amyloid-positive amnestic MCI but independent of PET-amyloid burden. Buss, SS., Press, DZ., McDonald, K., et al.[2021]

Repeated applications of Theta Burst stimulation (TBS) in rats showed complex effects on neuronal activity markers, with some markers increasing while others decreased, indicating that the response to TBS is not simply accumulative.

Specifically, while the expression of the vesicular glutamate transporter (VGLUT1) increased with stimulation, markers for inhibitory activity like GAD67 and calcium-binding proteins decreased, suggesting a nuanced interaction between excitatory and inhibitory neuronal responses to repeated TBS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-dependence of changes in cortical protein expression induced with repeated transcranial magnetic theta-burst stimulation in the rat. Volz, LJ., Benali, A., Mix, A., et al.[2016]

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 (TBS) is a promising technique for altering brain excitability, with a review of studies showing that adverse events were mostly mild and occurred in only 5% of subjects, indicating a generally safe profile.

Despite its safety, TBS carries a theoretical higher risk of seizures compared to other stimulation methods, necessitating cautious application and further research into its dosing parameters to better understand seizure risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. Oberman, L., Edwards, D., Eldaief, M., et al.[2022]

Theta-burst stimulation (TBS) was found to be safe for children, with no serious adverse events reported among 40 participants aged under 18, including those with Tourette syndrome and typically developing children.

Only 11.6% of participants experienced mild, self-limited side effects, such as finger twitching and headaches, indicating that TBS is well tolerated in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta-burst transcranial magnetic stimulation in children. Wu, SW., Shahana, N., Huddleston, DA., et al.[2012]

In a study involving 17 healthy older participants, there was a significant correlation between changes in motor evoked potentials (MEPs) and early TMS-evoked EEG potentials (TEPs) after intermittent Theta Burst Stimulation (iTBS) to the left primary motor cortex, indicating a relationship between corticospinal and cortical excitability.

While MEP amplitudes increased significantly after iTBS, TEP responses did not show significant changes, suggesting that the effects of iTBS on cortical activity (as measured by TEPs) are more complex and may not directly reflect changes in motor output.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent theta-burst stimulation induces correlated changes in cortical and corticospinal excitability in healthy older subjects. Gedankien, T., Fried, PJ., Pascual-Leone, A., et al.[2019]

In a study of 165 pediatric participants aged 6 to 18, theta-burst TMS (TBS) demonstrated a similar safety profile to single- and paired-pulse TMS (sp/ppTMS), with no severe adverse effects reported.

The overall rate of adverse effects was 10.5% for TBS and 12.4% for sp/ppTMS, with most effects rated as minimal or mild, indicating that TBS is a safe option for further investigation in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects. Hong, YH., Wu, SW., Pedapati, EV., et al.[2020]

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]

References

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

Diffusion MRI-guided theta burst stimulation enhances memory and functional connectivity along the inferior longitudinal fasciculus in mild cognitive impairment. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Probing changes in corticospinal excitability following theta burst stimulation of the human primary motor cortex. [2017]

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

LTP-like plasticity is impaired in amyloid-positive amnestic MCI but independent of PET-amyloid burden. [2021]

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

Dose-dependence of changes in cortical protein expression induced with repeated transcranial magnetic theta-burst stimulation in the rat. [2016]

5. 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]

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

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta-burst transcranial magnetic stimulation in children. [2012]

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

Intermittent theta-burst stimulation induces correlated changes in cortical and corticospinal excitability in healthy older subjects. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects. [2020]

10. 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]