Neuromodulation + Cognitive Training for Post-Concussion Depression

Overseen By Janae Wyckoff

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of California, San Diego

Must not be taking: Benzodiazepines, Anticonvulsants

Disqualifiers: Moderate TBI, Neurological conditions, others

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

Compensation: Varies

Number of Visits: 22

Duration: 4 weeks

72 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of cognitive training and brain stimulation to treat depression in individuals who have experienced a mild traumatic brain injury (TBI). The researchers aim to determine if adding a specific type of brain stimulation, called intermittent theta burst stimulation (iTBS), to cognitive exercises can improve depression symptoms more effectively than cognitive exercises alone. The trial seeks military service members and civilians who had a mild TBI over three months ago and currently experience moderate to severe depression. Participants should be stable on their psychiatric medications and able to adhere to the treatment schedule. As an unphased trial, this study provides a unique opportunity to explore innovative treatments for depression following a mild TBI.

Will I have to stop taking my current medications?

The trial requires that participants have been stable on their psychiatric medications for at least 6 weeks and do not change these medications during the study. However, if you are taking lorazepam 2 mg or greater daily, any anticonvulsant, or medication that lowers the seizure threshold, you may not be eligible to participate.

What prior data suggests that this neuromodulation and cognitive training protocol is safe for treating post-concussion depression?

Research has shown that intermittent theta burst stimulation (iTBS) is a safe treatment, particularly for depression. In 2018, the FDA approved iTBS for treating major depressive disorder, indicating it is generally well-tolerated.

A review found that iTBS is safe and affects brain activity similarly to other treatments like rTMS, but with shorter sessions. These studies have reported no major safety concerns.

For Personalized Augmented Cognitive Training (PACT), research indicates it effectively improves thinking skills in military members with brain injuries. However, specific safety data for PACT alone isn't highlighted, suggesting more research might be needed to fully understand its safety. So far, no significant safety issues have been noted.

Overall, both iTBS and PACT are considered safe based on current evidence, but always discuss any concerns with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the combination of iTBS and Personalized Augmented Cognitive Training (PACT) for post-concussion depression because it offers a new approach that could enhance brain recovery and improve mood. Unlike traditional treatments like medication and psychotherapy, iTBS uses non-invasive brain stimulation to rapidly target and modulate brain activity associated with depression. PACT further complements this by providing tailored cognitive exercises designed to improve mental functions affected by concussion. Together, these treatments aim to provide faster and potentially more effective relief from depressive symptoms compared to standard options.

What evidence suggests that this trial's treatments could be effective for post-concussion depression?

In this trial, participants will receive either intermittent theta burst stimulation (iTBS) combined with Personalized Augmented Cognitive Training (PACT) or PACT combined with sham iTBS. Research has shown that iTBS can improve depression symptoms, even in individuals who have experienced a concussion. This type of brain stimulation can match the effectiveness of traditional treatments but often works faster.

Personalized Augmented Cognitive Training (PACT) has shown promise in boosting brain function and improving symptoms in various groups, including military service members. PACT employs specific exercises to enhance brain function, leading to better mood and thinking skills.

Combining iTBS and PACT might provide a more effective treatment for depression in those who have experienced a mild traumatic brain injury (TBI). ^{1 3 6 7 8}

Who Is on the Research Team?

Elizabeth Twamley, PhD

Principal Investigator

UC San Diego

Are You a Good Fit for This Trial?

This trial is for Service Members, Veterans, and civilians aged 18-65 with post-mTBI depression who can commit to the treatment schedule. They must have moderate to severe depressive symptoms, no MRI or TMS contraindications, stable psychiatric medications for 6 weeks, and meet criteria for a current Major Depressive Episode.

Inclusion Criteria

Able to commit to the treatment schedule

Able to complete assessment procedures in English

I am either male or female.

Exclusion Criteria

Active manic or psychotic illness per MINI

Pregnant or intending to become pregnant within the study period; breastfeeding

History of moderate, severe, or penetrating TBI

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Personalized Augmented Cognitive Training (PACT) plus 20 sessions of intermittent theta burst stimulation (iTBS) or sham iTBS over 4 weeks

4 weeks

20 sessions (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Assessments at 2 weeks, 4 weeks, and 8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• iTBS
• Personalized Augmented Cognitive Training (PACT)
• sham iTBS

Trial Overview The study tests if Personalized Augmented Cognitive Training (PACT) combined with intermittent theta burst stimulation (iTBS) improves depression in those with mild TBI more than PACT with sham iTBS. Participants will undergo 20 sessions over four weeks and be assessed up to eight weeks.

How Is the Trial Designed?

Group I: PACT+iTBS Experimental Treatment 2 Interventions

Personalized, Augmented Cognitive Training (PACT; 6 sessions over 4 weeks) + intermittent theta burst stimulation (iTBS; 20 sessions over 4 weeks)

Group II: PACT+sham iTBS Placebo Group 2 Interventions

Personalized, Augmented Cognitive Training (PACT; 6 sessions over 4 weeks) + sham intermittent theta burst stimulation (sham iTBS; 20 sessions over 4 weeks)

iTBS is already approved in United States for the following indications:

Approved in United States as iTBS for:

• Treatment-resistant depression
• Major depressive disorder

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

San Diego Veterans Healthcare System

Collaborator

Trials

38

Recruited

5,500+

Published Research Related to This Trial

A clinical trial involving 96 outpatients with moderate depression will investigate the effectiveness of intermittent theta burst stimulation (iTBS) on reducing depressive symptoms, comparing it to a sham treatment over ten sessions.

The study will also explore various factors, including genetic and neuropsychological measures, that may influence the response to iTBS, ensuring a thorough safety screening and adherence to ethical guidelines throughout the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial. Ørbo, MC., Grønli, OK., Larsen, C., et al.[2023]

Intermittent Theta Burst Stimulation (iTBS) was well-tolerated by eight Australian veterans with PTSD, with only mild to moderate side effects reported, such as cranial pain and headaches, which were manageable with analgesics.

Participants showed significant reductions in PTSD and depression symptoms after 20 sessions of iTBS, along with improvements in cognitive functions like working memory and processing speed, suggesting that iTBS could be a promising new treatment for veterans with PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring Theta Burst Stimulation for Post-traumatic Stress Disorder in Australian Veterans-A Pilot Study. Nursey, J., Sbisa, A., Knight, H., et al.[2021]

Intermittent theta-burst stimulation (iTBS) shows promise as a targeted treatment for cognitive and psychosocial deficits following traumatic brain injury (TBI), potentially enhancing recovery when combined with behavioral interventions like cognitive rehabilitation and psychotherapy.

This review suggests that iTBS could lead to consistent functional gains in TBI patients, and future research may explore its application in other complex neuropsychiatric conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

rTMS/iTBS and Cognitive Rehabilitation for Deficits Associated With TBI and PTSD: A Theoretical Framework and Review. Lindsey, A., Ellison, RL., Herrold, AA., et al.[2023]

Accelerated intermittent Theta Burst Stimulation (iTBS) was found to be safe and well tolerated in a study of 50 treatment-resistant depressed patients, with no worsening of suicidal ideation observed during the treatment.

The study showed a significant decrease in suicide risk, as measured by the Beck Scale of Suicide Ideation, lasting up to one month after treatment, regardless of whether patients received active or sham stimulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated Intermittent Theta Burst Stimulation for Suicide Risk in Therapy-Resistant Depressed Patients: A Randomized, Sham-Controlled Trial. Desmyter, S., Duprat, R., Baeken, C., et al.[2020]

In a study involving 72 patients with major depressive disorder, two daily sessions of prolonged intermittent theta-burst stimulation (piTBS) over two weeks showed significantly more responders compared to a sham treatment, indicating its efficacy as an antidepressant option.

However, the study found no evidence that longer piTBS sessions led to greater improvements in depression scores compared to other treatments, suggesting that while piTBS is effective, increasing treatment duration does not enhance its antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder: A randomized sham-controlled study. Li, CT., Cheng, CM., Lin, HC., et al.[2023]

Theta burst stimulation (TBS) shows significant efficacy in reducing depression symptoms, with a large effect size (Hedges' g = 1.0) based on a meta-analysis of 5 randomized controlled trials involving 221 subjects.

Active TBS resulted in higher response rates compared to sham TBS (35.6% vs. 17.5%), although there was no significant difference in remission rates, indicating that while TBS is promising, further research is needed to optimize treatment parameters.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of theta burst stimulation (TBS) for major depression: An exploratory meta-analysis of randomized and sham-controlled trials. Berlim, MT., McGirr, A., Rodrigues Dos Santos, N., et al.[2018]

A study involving 30 patients recovering from mild traumatic brain injury (mTBI) and 26 matched controls found that one session of intermittent theta burst stimulation (iTBS) did not significantly change neurophysiological activity or cognitive performance, as measured by EEG and working memory tests.

The results indicate that iTBS may not be an effective intervention for enhancing brain recovery after mTBI, suggesting that further research is needed to explore its potential effects before considering it for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of neurobiological responses to theta burst stimulation during recovery from mild traumatic brain injury (mTBI). Coyle, HL., Bailey, NW., Ponsford, J., 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]

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 involving 81 participants with major depressive disorder, accelerated intermittent theta burst stimulation (iTBS) significantly reduced suicidality and depressive symptoms over a 6-week period, indicating its potential as an effective treatment.

The intervention was found to be safe, with no serious adverse events reported, and showed particularly pronounced anti-suicidal effects in individuals with higher risk profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suicidality and relief of depressive symptoms with intermittent theta burst stimulation in a sham-controlled randomized clinical trial. Wilkening, J., Witteler, F., Goya-Maldonado, R.[2023]

Accelerated, high-dose intermittent theta burst stimulation (iTBS) showed promising results in treating highly treatment-resistant depression, with most patients achieving remission after treatment.

However, the effects were short-lived, as all patients experienced relapse within two weeks, indicating a need for improved treatment strategies that enhance the durability of the therapeutic response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is accelerated, high-dose theta burst stimulation a panacea for treatment-resistant depression? Caulfield, KA.[2021]

Citations

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Concussion clinical trials at University of California Health The primary goal of this clinical trial is to evaluate whether Personalized Augmented Cognitive Training (PACT) plus intermittent theta ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04560946?tab=table

Personalized, Augmented Cognitive Training (PACT) for ... The primary goal of this study is to evaluate whether PACT is effective at improving cognition, symptoms, and functional outcomes among military service members ...

3. adaa.trialstoday.org adaa.trialstoday.org/trial/NCT05682677

Anxiety & Depression Association of America The primary goal of this clinical trial is to evaluate whether Personalized Augmented Cognitive Training (PACT) plus intermittent theta ...

4. clinicaltrial.be clinicaltrial.be/en/details/246312?per_page=20&only_recruiting=0&only_eligible=0

Personalized, Augmented Cognitive Training (PACT) for ... The primary goal of this study is to evaluate whether PACT is effective at improving cognition, symptoms, and functional outcomes among military ...

5. clinicaltrials.ucsd.edu clinicaltrials.ucsd.edu/trial/NCT05682677

Combined Neuromodulation and Cognitive Training for Post ... This clinical trial is to evaluate whether Personalized Augmented Cognitive Training (PACT) plus intermittent theta burst stimulation (iTBS) is effective for ...

6. fitbir.nih.gov fitbir.nih.gov/content/submitted-data

Submitted Data | FITBIR - NIH The FITBIR Informatics System includes a full range of data from TBI patients and controls enrolled in studies funded by the DoD and NIH.

7. cognitivefxusa.com cognitivefxusa.com/blog/post-concussion-syndrome-treatment-independent-study

Post-Concussion Syndrome Study: 77% See Improvement A peer-reviewed study published by Dutch researchers found that ~77% of participants who received our treatment experienced substantial ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04568369

Treatment of Post-concussion Syndrome With TMS: Using ... The primary objective of this study is to determine whether rTMS treatment can significantly improve persistent post-concussion symptoms.