Brain Stimulation for Working Memory Issues

Overseen By Brian Kavanaugh, PsyD ABPP

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Bradley Hospital

Must not be taking: Seizure threshold reducers

Disqualifiers: Epilepsy, Seizures, Substance abuse, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 session

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Working memory (WM) deficits are a transdiagnostic feature of adolescent psychopathology that substantially contribute to poor clinical and functional outcomes. This proposal will utilize a multimodal neuroscientific approach to investigate whether non-invasive brain stimulation can modulate the neural mechanisms underlying adolescent WM deficits. Directly in line with NIMH priorities, the researchers will identify the contributing roles of prefrontal and parietal regions in WM processes, as well as identify optimal targets and parameters for novel brain-based treatments in adolescent psychopathology. This study is funded by the NIMH-K23

Will I have to stop taking my current medications?

The trial does not require changes to your current medications unless you are taking medications that lower the seizure threshold, which may exclude you from participating. Psychostimulant medications are allowed if deemed safe by the medical review process.

What data supports the effectiveness of the treatment for working memory issues?

Research shows that intermittent theta burst stimulation (iTBS) can improve working memory in healthy individuals by enhancing brain activity patterns, and it has been effective in improving symptoms in conditions like depression and aphasia, suggesting potential benefits for working memory issues. ^{1 2 3 4 5}

Is intermittent theta burst stimulation (iTBS) safe for humans?

Research shows that intermittent theta burst stimulation (iTBS) is generally safe for humans, with most adverse events being mild and occurring in about 5% of subjects. No serious adverse effects were found in studies involving patients with bipolar depression and healthy participants, but caution is advised due to its novelty. ^{6 7 8 9 10}

How is intermittent theta burst stimulation (iTBS) different from other treatments for working memory issues?

Intermittent theta burst stimulation (iTBS) is unique because it mimics the brain's natural firing patterns to enhance working memory by targeting the dorsolateral prefrontal cortex, potentially leading to more effective and longer-lasting improvements compared to standard brain stimulation methods. ^{1 3 11 12 13}

Eligibility Criteria

This trial is for adolescents aged 13-17 with an IQ over 80 and diagnosed ADHD, who struggle with working memory. They must be fluent in English, able to consent (with parental permission), and have a parent-reported BRIEF-2 Working Memory score above the norm. Exclusions include certain neurological conditions, metal implants affecting the brain or spinal cord, active psychosis or mania, current pregnancy, substance abuse within six months, and other specific medical criteria.

Inclusion Criteria

I have been diagnosed with ADHD.

I am between 12-18 years old with ADHD and struggle with working memory.

English fluency of the participant and the legal guardian/parent

Exclusion Criteria

I have a history of seizures or epilepsy, or a close family member does.

I am experiencing symptoms of high pressure inside my skull.

I have had fainting spells that might be seizures.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intermittent theta burst stimulation (iTBS) at the left dorsolateral prefrontal cortex (DLPFC) or inferior parietal lobule (IPL) with both active and sham sessions

1 session

2 visits (in-person)

Follow-up

Participants are monitored for changes in theta-gamma coupling and working memory performance after iTBS sessions

4 weeks

Treatment Details

Interventions

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

Trial Overview The study tests whether non-invasive brain stimulation called Intermittent Theta Burst Stimulation can improve working memory in teens by targeting prefrontal and parietal brain regions. Participants will receive either the active treatment or a sham (placebo) version to compare effects on neural mechanisms underlying memory deficits.

Participant Groups

Group I: Sham intermittent Theta Burst Stimulation Experimental Treatment 1 Intervention

In a 2x2 factorial double-blind design, researchers will randomize a sample of adolescents with WM deficits to intermittent theta burst stimulation (iTBS) at the left dorsolateral prefrontal cortex (DLPFC) or inferior parietal lobule (IPL), based on each participant's structural brain MRI. Participants in both arms will complete an active iTBS session and a sham iTBS session. The primary outcome will be theta-gamma coupling during WM demands, as measured via electroencephalography (EEG) during a Sternberg spatial WM task (SWMT) immediately before and after iTBS.

Group II: Active intermittent Theta Burst Stimulation Experimental Treatment 1 Intervention

In a 2x2 factorial double-blind design, researchers will randomize a sample of adolescents with WM deficits to intermittent theta burst stimulation (iTBS) at the left dorsolateral prefrontal cortex (DLPFC) or inferior parietal lobule (IPL), based on each participant's structural brain MRI. Participants in both arms will complete an active iTBS session and a sham iTBS session. The primary outcome will be theta-gamma coupling during WM demands, as measured via electroencephalography (EEG) during a Sternberg spatial WM task (SWMT) immediately before and after iTBS.

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

Approved in United States as iTBS for:

• Treatment-resistant depression

Approved in European Union as iTBS for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Bradley Hospital

Lead Sponsor

Trials

22

Recruited

1,900+

Findings from Research

A study involving 31 healthy adults tested the effects of intermittent theta burst stimulation (iTBS) on working memory by targeting the left and right dorsolateral prefrontal cortex, but found no significant memory enhancement beyond practice effects.

While participants showed improvements in accuracy and reaction times on working memory tasks after stimulation, these improvements were not attributed to the iTBS itself, indicating that a single session of iTBS may not effectively enhance memory performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does intermittent theta burst stimulation improve working memory capacity? A randomized controlled cross-over experiment. Feng, Y., Zhang, JJ., Zhu, J., et al.[2022]

A 63-year-old male with mild receptive aphasia showed significant improvements in working memory and language skills after receiving 10 sessions of intermittent theta-burst stimulation (iTBS) combined with computerized working memory training.

The combined treatment not only enhanced specific language tasks like naming and reading but also positively impacted the participant's overall quality of life, suggesting that this approach could be beneficial in aphasia rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial Magnetic Stimulation and Working Memory Training to Address Language Impairments in Aphasia: A Case Study. Kranou-Economidou, D., Kambanaros, M.[2023]

In a study involving 19 healthy participants, intermittent theta burst stimulation (iTBS) to the left dorsolateral prefrontal cortex significantly improved working memory performance for up to 40 minutes compared to sham stimulation.

The cognitive improvements were linked to increased synchronization of theta waves and enhanced gamma band power in the brain, suggesting that specialized stimulation techniques may offer more effective neuromodulation for cognitive enhancement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancement of Working Memory and Task-Related Oscillatory Activity Following Intermittent Theta Burst Stimulation in Healthy Controls. Hoy, KE., Bailey, N., Michael, M., et al.[2018]

In a study of 60 patients with treatment-resistant unipolar depression, both intermittent theta burst stimulation (iTBS) and conventional 10 Hz rTMS showed similar efficacy in reducing depression scores and improving quality of life over a 6-month follow-up, with response rates of 36.7% for iTBS and 33.3% for rTMS.

iTBS is highlighted as a more time-efficient and cost-effective option compared to rTMS, suggesting it could be a valuable treatment alternative for patients with severe depression who have not responded to multiple antidepressant trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent theta burst stimulation (iTBS) versus 10 Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP). Bulteau, S., Laurin, A., Pere, M., et al.[2022]

Intermittent theta-burst stimulation (iTBS) significantly improves hand function in stroke patients, particularly in those with higher baseline motor function and the presence of motor-evoked potentials (MEPs).

The study of 72 stroke patients showed that those with MEPs and better grip strength (Group A) had the greatest improvement in motor function, suggesting that iTBS effectiveness can be predicted by these factors, allowing for more tailored neurostimulation strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corticospinal integrity and motor impairment predict outcomes after excitatory repetitive transcranial magnetic stimulation: a preliminary study. Lai, CJ., Wang, CP., Tsai, PY., et al.[2016]

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]

In a study of 26 patients with bipolar depression, active intermittent theta burst stimulation (iTBS) showed a high response rate of 72% and a remission rate of 42%, indicating its potential efficacy in treating this condition.

No adverse events were reported, demonstrating that iTBS is safe and well-tolerated, but further research with larger sample sizes is needed to confirm its superiority over sham treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Twice-daily neuronavigated intermittent theta burst stimulation for bipolar depression: A Randomized Sham-Controlled Pilot Study. Bulteau, S., Beynel, L., Marendaz, C., et al.[2020]

In a study involving 24 healthy participants, intermittent theta-burst stimulation (iTBS) significantly improved working memory response times compared to placebo, while transcranial direct current stimulation (tDCS) did not show similar effects.

No serious adverse effects were reported for any of the stimulation protocols, indicating that these non-invasive brain stimulation techniques are safe for use in enhancing cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation versus intermittent theta-burst stimulation for the improvement of working memory performance. Razza, LB., Luethi, MS., Zanão, T., et al.[2022]

Intermittent theta burst stimulation (iTBS) is as effective as standard high-frequency (10 Hz) rTMS for treating treatment-resistant depression, showing non-inferiority in improving depression scores over 4-6 weeks in a study with 414 participants.

Both iTBS and 10 Hz rTMS had similar safety profiles and dropout rates, with headaches being the most common side effect, indicating that iTBS can be a viable alternative that allows for more patients to be treated in a shorter time without losing effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Blumberger, DM., Vila-Rodriguez, F., Thorpe, KE., et al.[2022]

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]

Intermittent theta-burst stimulation (iTBS) improved working memory performance in healthy subjects, while continuous theta-burst stimulation (cTBS) did not show this effect, indicating that iTBS may be more effective for enhancing cognitive function.

The study involved 51 participants and assessed working memory using various tasks, finding no significant differences in effects based on which hemisphere was stimulated, suggesting that the benefits of TBS on working memory are not lateralized.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuous theta-burst stimulation over the dorsolateral prefrontal cortex inhibits improvement on a working memory task. Vékony, T., Németh, VL., Holczer, A., et al.[2019]

Theta burst stimulation (iTBS and rTMS) significantly improved working memory performance in rats, as evidenced by faster completion times in a T-maze task compared to a control group.

Both iTBS and rTMS enhanced theta and gamma brain wave activity in the medial prefrontal cortex, suggesting that these stimulation techniques improve working memory by modulating neural activity and connectivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of theta burst stimulation on the coherence of local field potential during working memory task in rats. Wang, T., Guo, M., Wang, N., et al.[2023]

Continuous theta-burst stimulation (cTBS) over the left dorsolateral prefrontal cortex (DLPFC) significantly impairs working memory performance for about 15 minutes, particularly affecting tasks with a 2-back load.

The impact of cTBS on working memory performance is load-dependent, as higher memory loads (3-back) and non-memory tasks (0-back) were not significantly affected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuous theta burst stimulation over the left dorsolateral prefrontal cortex decreases medium load working memory performance in healthy humans. Schicktanz, N., Fastenrath, M., Milnik, A., et al.[2018]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Does intermittent theta burst stimulation improve working memory capacity? A randomized controlled cross-over experiment. [2022]

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

Transcranial Magnetic Stimulation and Working Memory Training to Address Language Impairments in Aphasia: A Case Study. [2023]

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

Enhancement of Working Memory and Task-Related Oscillatory Activity Following Intermittent Theta Burst Stimulation in Healthy Controls. [2018]

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

Intermittent theta burst stimulation (iTBS) versus 10 Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP). [2022]

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

Corticospinal integrity and motor impairment predict outcomes after excitatory repetitive transcranial magnetic stimulation: a preliminary study. [2016]

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

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

7. France pubmed.ncbi.nlm.nih.gov

Twice-daily neuronavigated intermittent theta burst stimulation for bipolar depression: A Randomized Sham-Controlled Pilot Study. [2020]

8. Spain pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation versus intermittent theta-burst stimulation for the improvement of working memory performance. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. [2022]

10. 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]

11. England pubmed.ncbi.nlm.nih.gov

Continuous theta-burst stimulation over the dorsolateral prefrontal cortex inhibits improvement on a working memory task. [2019]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Effects of theta burst stimulation on the coherence of local field potential during working memory task in rats. [2023]

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

Continuous theta burst stimulation over the left dorsolateral prefrontal cortex decreases medium load working memory performance in healthy humans. [2018]