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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new brain stimulation treatment called accelerated intermittent theta burst stimulation (iTBS) to determine its effectiveness in alleviating symptoms such as brain fog, depression, and anxiety in individuals with Long COVID. The study compares real iTBS with a placebo version to assess whether the real treatment leads to better symptom improvement. Participants will undergo various tests, including brain scans, to identify changes linked to brain inflammation. Individuals experiencing ongoing cognitive difficulties, like brain fog, due to Long COVID, and who meet other criteria, might find this trial suitable. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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 prior data suggests that this brain stimulation technique is safe for treating Long COVID symptoms?

Research has shown that accelerated intermittent theta burst stimulation (iTBS) is generally safe. In a small study with Long COVID patients, iTBS improved symptoms like tiredness and brain fog. Participants handled the sessions easily without major problems.

Other studies have examined iTBS for various health issues and also found it safe. For instance, older adults using iTBS for depression found it safe and manageable.

Overall, iTBS appears safe based on current evidence. However, since this trial focuses on Long COVID, more information from this study will help confirm its safety for these symptoms. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Long COVID?

Unlike the standard treatments for Long COVID, which often involve medications targeting symptoms like fatigue and brain fog, Accelerated Intermittent Theta Burst Stimulation (iTBS) offers a non-invasive brain stimulation approach. This technique is unique because it directly targets the brain's left dorsolateral prefrontal cortex with bursts of magnetic stimulation, potentially enhancing brain function and alleviating cognitive symptoms. Researchers are excited because iTBS could provide faster relief compared to medications, with sessions showing potential benefits in just a few days. Additionally, the use of fMRI guidance allows for precise targeting of brain areas, potentially increasing the effectiveness of the treatment.

What evidence suggests that accelerated intermittent theta burst stimulation is effective for Long COVID?

Research has shown that accelerated intermittent theta burst stimulation (iTBS) might reduce symptoms like brain fog, depression, and anxiety in people with Long COVID. The trial includes an active treatment arm where participants receive fMRI-guided iTBS, and a sham comparator arm where participants receive sham stimulation. This non-invasive method uses magnetic fields to stimulate the brain and has improved symptoms in those with post-viral conditions. Early results suggest that multiple iTBS sessions can relieve symptoms in conditions similar to Long COVID, such as depression. Some studies also indicate changes in brain chemicals related to inflammation after iTBS treatment, which could benefit Long COVID. Overall, while more research is needed, iTBS shows promise for improving mental health symptoms associated with Long COVID. ^{1 2 3 6 7}

Who Is on the Research Team?

Davin Quinn, MD

Principal Investigator

University of New Mexico

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7362844/

A Possible Option for Older Depressed Adults in Need of ECT ... The effects of treatment can be accelerated into a shorter course by repeated application of stimulation with a sufficient time interval to ...

2. amjmed.com amjmed.com/article/S0002-9343(24)00468-6/fulltext

Non-Invasive Brain Stimulation for Post-COVID-19 ... We aim to summarize the current evidence for the effectiveness of non-invasive or minimally invasive brain stimulation techniques in reducing symptoms of post- ...

3. sciencedirect.com sciencedirect.com/science/article/am/pii/S1876201822004361

Real world research on transcranial magnetic stimulation ... Post-acute sequelae of SARS-CoV-2 infection: relationship of central nervous system manifestations with physical disability and systemic inflammation.

4. researchgate.net researchgate.net/publication/342967975_Accelerated_Intermittent_Theta_Burst_Stimulation_in_Late-Life_Depression_A_Possible_Option_for_Older_Depressed_Adults_in_Need_of_ECT_During_the_COVID-19_Pandemic

Accelerated Intermittent Theta Burst Stimulation in Late-Life ... ... Chatterjee and colleagues (2020) have reported remission with well-tolerated 12 daily sessions of intermittent theta-burst stimulation given ...

5. trialstoday.org trialstoday.org/search/results?status=recruiting&gender=&age=&zip=&radius=25&condition=covid-19&healthy=&type=&interventionalpurpose=&observationalmodel=&page=eJyLVspLrShR0lHycw4xMDU1MTYzNFPS0bWEARxMIzM9E0sjIxMdQ3MDM3MTUzMDENBRyksuMTC1NDExNzBVigUA114Umw--

Save Selected 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 ...

6. trialstoday.org trialstoday.org/search/results?status=recruiting&gender=&age=&zip=&radius=25&condition=covid-19&healthy=&type=&interventionalpurpose=&observationalmodel=&page=eJyLVspLrShR0lHycw4xMDU1MTYzNFPS0bWEARxMI0s9QxNLAwsTHUNzEzMDU3MzAxDQUcpLLjEwNbQ0NzMyVIoFAOwLFNA-

Save Selected This is a pilot randomized trial of rTMS for symptoms of fatigue and brain fog, and other neuropsychiatric symptoms of Long-COVID (Post-COVID, post-acute ...

7. researchgate.net researchgate.net/publication/377994198_rTMS_for_post-covid-19_condition_A_sham-controlled_case_series_involving_iTBS-300_and_iTBS-600

rTMS for post-covid-19 condition: A sham-controlled case ... In summary, in this case series iTBS was well tolerated among 4 individuals with PCC; active stimulation was associated with positive trends in ...