Brain Stimulation for Stress

(NUMBER Trial)

Overseen By Thomas E Kraynak, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of Pittsburgh

Must not be taking: Antihypertensives, Anticonvulsants, Antipsychotics, others

Disqualifiers: Epilepsy, Heart disease, Cancer, others

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

Compensation: Varies

Number of Visits: 3

Duration: 2 visits

55 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications to participate in this trial. The study excludes participants who have used specific medications, like heart or brain-related drugs, in the past 14 days. If you've stopped a disallowed medication for at least a month, you may still be eligible.

What data supports the effectiveness of the treatment Active continuous theta burst stimulation for stress?

The research suggests that theta burst stimulation can influence brain plasticity, which is how the brain adapts and changes. Although stress can impair certain brain functions, theta burst stimulation still affects brain circuits, indicating it might help manage stress-related changes in the brain. ^{1 2 3 4 5}

Is brain stimulation for stress generally safe in humans?

The research articles provided do not contain specific safety data for brain stimulation treatments like continuous theta burst stimulation in humans. They focus on the effects of stress on brain plasticity in animal models, which does not directly address human safety concerns. ^{1 2 3 5 6}

How does continuous theta burst stimulation differ from other treatments for stress?

Continuous theta burst stimulation (cTBS) is unique because it uses magnetic pulses to target specific brain areas, potentially reducing stress by altering brain activity. Unlike traditional stress treatments, cTBS is non-invasive and focuses on modulating brain connectivity, which may offer a novel approach for those who do not respond well to other therapies. ^{7 8 9 10 11}

What is the purpose of this trial?

Investigators are conducting this study to test if temporarily and non-invasively stimulating the brain will affect the emotional response to stress in healthy participants. Participants will perform a series of tasks while completing an MRI scan. After this, participants will be randomized to undergo transcranial magnetic stimulation (TMS) at two visits, undergoing active stimulation at one visit and undergoing 'sham' stimulation at another visit. Immediately following both stimulation sessions, participants will repeat the tasks during MRI scanning.

Research Team

Thomas E Kraynak, PhD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for healthy individuals interested in how brain stimulation might affect their emotional response to stress. Participants should be willing to undergo MRI scans and two sessions of transcranial magnetic stimulation (TMS), one active and one sham.

Inclusion Criteria

I am between 30 and 50 years old.

English language proficiency (English as the primary language used in the home for the past 10 years)

Report that they will reside in the Pittsburgh area for at least 6 weeks, to maintain scheduling availability

Exclusion Criteria

Substance use: excessive alcohol consumption and illicit drug use

I regularly take more than 2 non-insulin diabetes medications.

I have been taking certain medications regularly for the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Baseline Assessment

Participants perform a series of tasks while completing an MRI scan

1 day

1 visit (in-person)

Treatment

Participants undergo transcranial magnetic stimulation (TMS) with active and sham stimulation at two visits

2 visits

2 visits (in-person)

Follow-up

Participants are monitored for changes in arousal, valence, perceived control, and physiological responses post-stimulation

30-60 minutes post-stimulation

Treatment Details

Interventions

• Active continuous theta burst stimulation
• Sham continuous theta burst stimulation

Trial Overview The study tests the effects of a non-invasive brain stimulation technique called continuous theta burst stimulation on managing stress and anxiety. It involves comparing active TMS with a placebo-like 'sham' version while participants complete tasks during an MRI scan.

Participant Groups

Group I: Sham then Active Experimental Treatment 2 Interventions

In this arm, participants will first undergo sham theta burst stimulation (cTBS) at the first visit and then undergo active cTBS in the second visit.

Group II: Active then Sham Experimental Treatment 2 Interventions

In this arm, participants will first undergo active theta burst stimulation (cTBS) at the first visit and then undergo sham cTBS in the second visit.

Who Is Running the Clinical Trial?

University of Pittsburgh

Lead Sponsor

Trials

1,820

Recruited

16,360,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

In a study involving 20 healthy participants over five days, daily intermittent theta burst stimulation (iTBS) did not show any significant cumulative increase in cortical excitability compared to sham stimulation, suggesting that repeated sessions may not enhance therapeutic effects as previously believed.

The results indicate high variability in individual responses to both active and sham iTBS, with no consistent pattern of improvement, which raises questions about the effectiveness of iTBS in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5-day repeated sessions study. Perellón-Alfonso, R., Kralik, M., Pileckyte, I., et al.[2022]

Continuous theta burst stimulation (cTBS) effectively inhibits synaptic transmission in the primary motor cortex for up to 1 hour, demonstrating its potential as a novel neuromodulation technique.

cTBS applied to the left motor cortex increases local GABA levels, indicating enhanced GABAergic activity, while not significantly affecting glutamate/glutamine levels, suggesting a specific mechanism of action for this stimulation technique.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy. Stagg, CJ., Wylezinska, M., Matthews, PM., et al.[2022]

In a randomized, double-blind trial involving 56 patients, intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex showed a significant reduction in negative symptoms for patients with depression, but not for those with schizophrenia.

The treatment was generally safe and well-tolerated, with serious adverse events occurring only in the sham group, indicating that iTBS may be a promising intervention for depressive symptoms in certain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dorsomedial prefrontal theta burst stimulation to treat anhedonia, avolition, and blunted affect in schizophrenia or depression - a randomized controlled trial. Bodén, R., Bengtsson, J., Thörnblom, E., et al.[2021]

In a study involving 34 healthy female participants, the effectiveness of intermittent theta burst stimulation (iTBS) on reducing stress was linked to the resting-state functional connectivity (rsFC) between the left dorsolateral prefrontal cortex (DLPFC) and the caudal anterior cingulate cortex (ACC).

Participants with a stronger negative correlation in rsFC experienced a greater reduction in stress sensitivity after active iTBS, suggesting that individual brain connectivity patterns could help tailor and improve the treatment's effectiveness for stress-related disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Individual resting-state frontocingular functional connectivity predicts the intermittent theta burst stimulation response to stress in healthy female volunteers. de Wandel, L., Pulopulos, MM., Labanauskas, V., et al.[2021]

In a study of 60 treatment-refractory patients with major depressive disorder, both intermittent and combined theta-burst stimulation showed significantly better antidepressant responses compared to continuous theta-burst stimulation and sham treatment after 2 weeks.

Theta-burst stimulation is well-tolerated and effective, especially in patients with lower levels of treatment refractoriness, indicating that the severity of refractoriness can influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Li, CT., Chen, MH., Juan, CH., et al.[2022]

References

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

Exposure to forced swim stress alters local circuit activity and plasticity in the dentate gyrus of the hippocampus. [2021]

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

Effect of stress and long-term potentiation (LTP) on subsequent LTP and the theta burst response in the dentate gyrus. [2019]

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

Acute stress impairs (or induces) synaptic long-term potentiation (LTP) but does not affect paired-pulse facilitation in the stratum radiatum of rat hippocampus. [2003]

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

Glucocorticoid receptor activation selectively hampers N-methyl-D-aspartate receptor dependent hippocampal synaptic plasticity in vitro. [2014]

5. Ireland pubmed.ncbi.nlm.nih.gov

Time-dependent blockade of STP and LTP in hippocampal slices following acute stress in mice. [2019]

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

Transient and persistent consequences of acute stress on long-term potentiation (LTP), synaptic efficacy, theta rhythms and bursts in area CA1 of the hippocampus. [2006]

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

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5-day repeated sessions study. [2022]

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

Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Dorsomedial prefrontal theta burst stimulation to treat anhedonia, avolition, and blunted affect in schizophrenia or depression - a randomized controlled trial. [2021]

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

Individual resting-state frontocingular functional connectivity predicts the intermittent theta burst stimulation response to stress in healthy female volunteers. [2021]

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

Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. [2022]