Brain Stimulation for Long COVID

(MANIFEST Trial)

Overseen By Crystal Garcia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of New Mexico

Disqualifiers: Neurological disease, Seizures, Psychotic disorder, Substance dependence, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 25

Duration: 2 weeks

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on psychotropic medications (drugs that affect your mood or mind), you must have been on a stable dose for the past month to participate.

What data supports the effectiveness of the treatment Accelerated Intermittent Theta Burst Stimulation for Long COVID?

A case report showed that a 30-year-old woman with anxiety, depression, insomnia, and mild cognitive impairment after COVID-19 improved significantly after receiving accelerated theta-burst stimulation over the prefrontal cortex. This suggests the treatment might help with similar symptoms in Long COVID. ^{1 2 3 4 5}

Is theta burst stimulation safe for humans?

Theta burst stimulation (TBS), including intermittent theta burst stimulation (iTBS), has been studied for various conditions and is generally considered safe in humans. Some studies report minor tolerability issues, but serious side effects are rare. ^{1 4 6 7 8}

How does the treatment Accelerated Intermittent Theta Burst Stimulation differ from other treatments for Long COVID?

Accelerated Intermittent Theta Burst Stimulation (iTBS) is unique because it uses magnetic pulses to stimulate specific areas of the brain, potentially improving neuropsychiatric symptoms like anxiety and depression associated with Long COVID. Unlike traditional treatments, it is non-invasive and focuses on altering brain activity directly, which may offer benefits for symptoms that are not well-managed by standard medications. ^{1 2 3 6 9}

What is the purpose of this trial?

The goal of this clinical trial is to test whether a type of rapid outpatient brain stimulation that uses magnetic fields, called accelerated intermittent theta burst stimulation (iTBS), can treat symptoms such as brain fog, depression, and anxiety in patients with Long COVID. The main questions it aims to answer are: * Is iTBS effective and feasible for reducing Long COVID symptoms? We will measure these symptoms using the Symptom Burden Questionnaire. * Are there changes in inflammatory brain chemicals associated with treatment with iTBS? We will be looking at levels of choline in the brain, which is thought to be related to inflammation. Researchers will compare sham versus active forms of iTBS to see if the active group has greater improvement in symptoms. Participants will complete symptom surveys, cognitive tests, and magnetic resonance imaging scans at the beginning, middle, and end of treatment.

Research Team

Davin Quinn, MD

Principal Investigator

University of New Mexico

Eligibility Criteria

This trial is for individuals experiencing Long COVID symptoms like brain fog, depression, and anxiety. Participants should be able to complete surveys, cognitive tests, and MRI scans. Specific inclusion or exclusion criteria are not provided.

Inclusion Criteria

Fluency in English

I experience 'brain fog' or have trouble thinking clearly.

My doses of psychiatric medication have been stable for the last month.

Exclusion Criteria

Ongoing litigation related to medical diagnosis or disability

Membership in an identified vulnerable population, including minors, pregnant women, and prisoners

History of a psychotic disorder, such as schizophrenia or bipolar disorder

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive accelerated iTBS or sham stimulation for 10 days, with 5 sessions per day

2 weeks

25 blinded sessions followed by 25 open-label sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Accelerated Intermittent Theta Burst Stimulation

Trial Overview The study is testing accelerated intermittent theta burst stimulation (iTBS), a rapid outpatient brain stimulation technique using magnetic fields. It compares active iTBS with sham treatment to see if it reduces Long COVID symptoms and affects brain inflammation markers.

Participant Groups

Group I: Active accelerated iTBS Experimental Treatment 1 Intervention

Participants will be assigned to receive fMRI-guided iTBS (5 days, 5 sessions/day) to the left dorsolateral prefrontal cortex (dlPFC) during the sham-controlled phase. Each participant is invited to undergo 25 more sessions (5 more days) of open label, unblinded active accelerated fMRI-guided iTBS to the left dlPFC.

Group II: Sham accelerated iTBS Placebo Group 1 Intervention

Sham stimulation is delivered using the same coil as active stimulation, producing an equivalent sound, however it is shielded so that no effective magnetic field reaches the participant's brain. To blind participants to active versus sham condition, a mild electrical skin stimulation that has no brain effects is delivered simultaneously with iTBS at the scalp to both active and sham groups, creating the same sense of skin sensation in both groups.

Who Is Running the Clinical Trial?

University of New Mexico

Lead Sponsor

Trials

393

Recruited

3,526,000+

The Mind Research Network

Collaborator

Trials

27

Recruited

2,300+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

In a study involving 12 subacute stroke patients, prolonged transcranial magnetic stimulation (iTBS1200) was found to be safe and well-tolerated, with no significant adverse effects reported.

Patients receiving iTBS1200 showed measurable improvements in stroke severity and upper extremity function shortly after treatment and at 60 days post-stroke, suggesting potential benefits that warrant further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent theta burst stimulation over ipsilesional primary motor cortex of subacute ischemic stroke patients: a pilot study. Hsu, YF., Huang, YZ., Lin, YY., 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]

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]

Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex significantly decreased the N100 amplitude in participants with treatment-resistant depression, indicating a neurophysiological response to the treatment.

Responders to iTBS showed a notable decrease in N100 amplitude and higher N45 amplitude post-treatment compared to nonresponders, suggesting that these TMS-EEG markers could help predict treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying Neurophysiological Markers of Intermittent Theta Burst Stimulation in Treatment-Resistant Depression Using Transcranial Magnetic Stimulation-Electroencephalography. Strafella, R., Momi, D., Zomorrodi, R., et al.[2023]

Theta burst stimulation (TBS) has been shown to affect brain connectivity, with continuous TBS (cTBS) generally decreasing functional connectivity and intermittent TBS (iTBS) increasing it, aligning with the expected neuroplasticity effects of long-term depression (LTD) and long-term potentiation (LTP).

Task-related outcomes from TBS are more inconsistent, particularly when applied to the prefrontal cortex, suggesting that individual differences and methodological factors significantly influence the effectiveness and variability of TBS responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of the neurobiological effects of theta-burst stimulation (TBS) as measured using functional magnetic resonance imaging (fMRI). Kirkovski, M., Donaldson, PH., Do, M., et al.[2023]

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]

References

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

A 30-Year-Old Woman with an 8-Week History of Anxiety, Depression, Insomnia, and Mild Cognitive Impairment Following COVID-19 Who Responded to Accelerated Bilateral Theta-Burst Transcranial Magnetic Stimulation Over the Prefrontal Cortex. [2023]

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

Intermittent theta burst stimulation over ipsilesional primary motor cortex of subacute ischemic stroke patients: a pilot study. [2022]

3. 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]

4. Ireland pubmed.ncbi.nlm.nih.gov

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

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

Identifying Neurophysiological Markers of Intermittent Theta Burst Stimulation in Treatment-Resistant Depression Using Transcranial Magnetic Stimulation-Electroencephalography. [2023]

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

Effect of regional intrinsic activity following two kinds of theta burst stimulation on precuneus. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

A systematic review of the neurobiological effects of theta-burst stimulation (TBS) as measured using functional magnetic resonance imaging (fMRI). [2023]

8. England pubmed.ncbi.nlm.nih.gov

Effects of intermittent theta burst stimulation on cerebral blood flow and cerebral vasomotor reactivity. [2019]

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]