Adaptive trial for the treatment of depressive symptoms associated with concussion using accelerated intermittent theta burst stimulation (ADEPT): rationale, design and methods

May combine two claims.

Most clinical rTMS treatments for MDD occur daily and are applied using scalp-based targeting of DLPFC; these standard treatments are only modestly effective, even in the general MDD population.

“Most clinical rTMS treatments for MDD occur daily (one rTMS session per day) and are applied using scalp-based targeting of DLPFC. These standard treatments are only modestly effective, even in the general MDD population (17, 24–31).”

• cites [17] O’Reardon, 2007, Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial, Biol Psychiatry sourceNot checked — no full text of the source
• cites [24] McClintock, 2018, Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression, J Clin Psychiatry sourceNot checked — no full text of the source
• cites [25] Connolly, 2012, Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: results observed with the first 100 consecutive cases of depression at an academic medical center, J Clin Psychiatry sourceNot checked — no full text of the source
• cites [26] Slotema, 2010, Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders, J Clin Psychiatry sourceNot checked — no full text of the source
• cites [27] Gaynes, 2014, Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis, J Clin Psychiatry sourceSupported
• cites [28] Berlim, 2014, Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials, Psychol Med sourceNot checked — no full text of the source
• cites [29] Sale, 2015, Imaging human brain networks to improve the clinical efficacy of non-invasive brain stimulation, Neurosci Biobehav Rev sourceNot checked — no full text of the source
• cites [30] Siddiqi, 2020, Distinct symptom-specific treatment targets for circuit-based neuromodulation, Am J Psychiatry sourcePartly supported

  The paper says clinical TMS targeting is usually based on scalp measurements, and Methods > Subjects and Data Collection describes stimulation of the left DLPFC in two cohorts with treatment-resistant depression (page unavailable). It does not establish that most clinical treatments involve one session per day or that standard treatments are only modestly effective in the general MDD population; searches for daily scheduling and modest efficacy did not resolve those points. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [31] Cash, 2021, Using brain imaging to improve spatial targeting of transcranial magnetic stimulation for depression, Biol Psychiatry sourcePartly supported

  The ‘Targeting TMS Using Scalp Measurements’ section says scalp-based DLPFC targeting was the most common method in randomized trials. The Conclusions table describes a once-daily regimen, and the opening section reports typical response rates of 29–46% and remission rates of 18–31%. However, the paper discusses these outcomes in the context of treatment-resistant depression; it does not establish the same modest effectiveness for the general MDD population. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

The DLPFC plays a critical role in emotion regulation, working memory, and executive functioning; these are impaired in individuals with a history of concussion and shown to improve after rTMS targeted at the DLPFC.

“In addition to its role in depression, the DLPFC plays a critical role in emotion regulation, working memory, and executive functioning. These are all impaired in individuals with a history of concussion and shown to improve after rTMS targeted at the DLPFC (22, 23).”

• cites [22] Guse, 2010, Cognitive effects of high-frequency repetitive transcranial magnetic stimulation: a systematic review, J Neural Transm sourcePartly supported

  The Discussion (Effects on different cognitive domains; page unavailable) links working memory and executive function to the prefrontal cortex. The Results (Cognitive effects of high-frequency rTMS over the prefrontal cortex; page unavailable) report some improvements in working memory and cognitive flexibility after rTMS, but not consistent improvement across executive functions. These passages do not establish impairment or improvement in people with a history of concussion, or improvement in emotion regulation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [23] Sultana, 2023, Neural mechanisms of emotional health in traumatic brain injury patients undergoing rTMS treatment, Mol Psychiatry sourcePartly supported

  The Results (Behavioral analysis; page unavailable) report improved emotional-health scores after rTMS, and the Conclusion says stimulation of the left DLPFC helped emotional health in patients with TBI. But the Conclusion explicitly says it failed to influence executive function. The cited passages do not establish improved working memory or improvement across all three functions in people with a history of concussion. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

May combine two claims.

The severity of depressive symptoms following concussion is strongly correlated with global disability, rate of recovery, and quality of life.

“The severity of depressive symptoms following concussion is strongly correlated with global disability, rate of recovery, and quality of life (4, 10, 11).”

• cites [4] Mac Donald, 2017, Early clinical predictors of 5-year outcome after concussive blast traumatic brain injury, JAMA Neurol sourcePartly supported

  The Results, under “Predictors of Poor Outcome” (page not provided), identify lower depression severity as a predictor of improvement in global outcome in a small subset. The “Global Outcome” and “Psychiatric Evaluation” sections report disability, quality of life, and depression separately; they do not establish a strong correlation between depression severity and all three outcomes, or quantify its relationship with rate of recovery. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [10] Guskiewicz, 2007, Recurrent concussion and risk of depression in retired professional football players, Med Sci Sports Exerc sourceNot checked — no full text of the source
• cites [11] Mooney, 2001, The association between mild traumatic brain injury and psychiatric conditions, Brain Inj sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

rTMS for MDD most commonly targets the left hemisphere DLPFC, a key node in the functional pathophysiology thought to underlie depressive symptoms.

“Consistent with the original FDA label, rTMS for MDD most commonly targets the left hemisphere DLPFC, a key node in the functional pathophysiology thought to underlie depressive symptoms (21).”

• cites [21] Koenigs, 2009, The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex, Behav Brain Res sourcePartly supported

  The Brain stimulation studies section says dozens of studies investigated left dlPFC stimulation for depression, and the Summary and conclusion identifies dlPFC as a key neural substrate underlying depression. The paper does not establish that left dlPFC is the most common rTMS target or discuss the original FDA label. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

It has become possible to construct a resting-state fMRI-based connectome map with high test-retest reliability in an individual subject.

“In recent years, it has become possible to construct a resting-state functional magnetic resonance imaging (rsfMRI)-based connectome map with high test–retest reliability in an individual subject (36, 37).”

• cites [36] Wang, 2015, Parcellating cortical functional networks in individuals, Nat Neurosci sourceSupported
• cites [37] Laumann, 2015, Functional system and areal organization of a highly sampled individual human brain, Neuron sourceSupported

May combine two claims.

Those with a history of concussion may have unique disruptions in functional networks and a complex neurobehavioral clinical presentation, making standard scalp-based DLPFC targeting even less optimal for this population.

“Compounding the variability in functional brain circuitry seen in the general population, those with a history of concussion may have unique disruptions in functional networks and a complex neurobehavioral clinical presentation (16, 33, 34) making standard scalp-based DLPFC targeting even less optimal for this population.”

• cites [16] Siddiqi, 2023, Precision functional MRI mapping reveals distinct connectivity patterns for depression associated with traumatic brain injury, Sci Transl Med sourceNot checked — no full text of the source
• cites [33] Siddiqi, 2019, Repetitive transcranial magnetic stimulation with resting-state network targeting for treatment-resistant depression in traumatic brain injury: a randomized, controlled, double-blinded pilot study, J Neurotrauma sourceSupported
• cites [34] Han, 2014, Disrupted modular organization of resting-state cortical functional connectivity in U.S. military personnel following concussive ‘mild’ blast-related traumatic brain injury, NeuroImage sourcePartly supported

  The Discussion (§4.1; page unavailable) reports disrupted connectivity across multiple regions in patients with concussive blast-related TBI, supporting the functional-network portion of the cited statement. The paper does not establish a complex neurobehavioral clinical presentation, and its findings concern blast-related TBI rather than concussion histories generally. The scalp-based DLPFC targeting conclusion follows the citations and appears to be the citing authors’ inference. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

Recent studies indicate that rTMS affects both local excitability in the stimulated brain region and broader functional connectivity across networks; at least some clinical effects may be due more to changes in functional connectivity than local effects.

“Recent studies indicate that rTMS affects both local excitability in the stimulated brain region and broader functional connectivity across networks. At least some of the clinical effects may be due more to changes in functional connectivity across the brain regions than local effects on the stimulated region itself (35).”

• cites [35] Fox, 2012, Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the Subgenual cingulate, Biol Psychiatry sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Individuals have remarkably variable functional brain circuitry, and most clinics apply a one-size-fits-all scalp-targeted approach, neglecting individual differences.

“Additionally, although individuals have remarkably variable functional brain circuitry (32), most clinics apply a “one size fits all” scalp-targeted approach, neglecting to account for individual differences.”

• cites [32] Gordon, 2017, Individual variability of the system-level Organization of the Human Brain, Cereb Cortex sourceSupported

May combine two claims.

In the trial simulations, if one of the arms had a 5-point improvement over sham, the power was 95% and the expected sample size was 137 patients.

“Alternatively, 95% power and an expected sample size of 137 patients was obtained if one of the arms had a 5-point improvement over sham.”

May combine two claims.

The network mapping and TMS target identification yielded very similar results at each of the sites, with excellent test-retest reliability.

“The network mapping and TMS target identification yielded very similar results at each of the sites, with excellent test–retest reliability.”

May combine two claims.

Evidence suggests that rTMS may promote reorganization of brain networks, which may enhance recovery following injury.

“Of particular relevance to concussion, evidence suggests that rTMS may promote reorganization of brain networks which may enhance recovery following injury (20).”

• cites [20] Villamar, 2012, Noninvasive brain stimulation to modulate neuroplasticity in traumatic brain injury, Neuromodulation Technol Neural Interface sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Primary analyses will be conducted with an intention-to-treat manner with all participants who receive at least one session of aiTBS.

“Primary analyses will be conducted with an intention to treat manner with all participants who receive at least one session of aiTBS.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The current study sample is expected to enroll fewer women than men due to the demographics of the military population.

“Additionally, we expect to enroll fewer women than men in the current study sample due to the demographics of the military population.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Trainers use the Rater Applied Performance Scale (RAPS) to objectively rate administrator performance, and a score of 3 or higher on a 4-point Likert scale indicates good performance and certification.

“Trainers utilize a Rater Applied Performance Scale (RAPS) (52), which has been applied to neuropsychological assessment training, to objectively rate the administrator’s performance; a score of 3 or higher on a 4-point Likert scale indicates a “good” performance and subsequent certification.”

• cites [52] Lipsitz, 2004, The rater applied performance scale: development and reliability, Psychiatry Res sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

A secondary analysis will be done per protocol including participants who complete at least 32 of the 40 sessions (80%).

“A secondary analysis will be done per protocol including participants who complete at least 32 of the 40 sessions (80%).”

May combine two claims.

To maintain the blind and allow for exploratory analyses comparing stimulation target across arms, all participants have a vitamin E capsule placed on their scalp.

“To maintain the blind and allow for exploratory analyses comparing stimulation target across arms, all participants have a vitamin E capsule placed on their scalp.”

Classified as probably not a substantial claim.

Initially, eligible participants are randomized between arms in a 1:1:1 fashion to active rsfMRI-based targeted aiTBS, active Beam F3 scalp-based targeted aiTBS, or sham aiTBS.

“Initially, eligible participants are randomized between arms in a 1:1:1 fashion to either active rsfMRI-based targeted aiTBS, active Beam F3 scalp-based targeted aiTBS, or sham aiTBS.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Most MADRS administrations for each individual participant are performed by the same team member.

“In general, most MADRS administrations for each individual participant are performed by the same team member.”

May combine two claims.

In the SNT trial, active aiTBS led to a 52.5% reduction in depressive symptom severity, with 86% of the active group responding and 79% remitting.

“Cole and colleagues found that active aiTBS leads to a 52.5% reduction in depressive symptom severity with 86% of the active group responding (≥50% reduction in symptom severity) and 79% remitting (a MADRS score ≤ 10).”

• cites [19] Cole, 2022, Stanford neuromodulation therapy (SNT): a double-blind randomized controlled trial, Am J Psychiatry sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

The TMS system used for this trial has designated blinded active and sham coils identical in appearance, weight, noise emission, and tactile sensation.

“The TMS system used for this trial has designated blinded active and sham coils identical in appearance, weight, noise emission, and tactile sensation.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study will use strategies to control the false discovery rate and avoid overinterpreting secondary analyses.

“As the study is not powered to make strong claims about these endpoints, we will be careful to not overinterpret the outcomes of these analyses and utilize strategies to control for the false discovery rate.”

May combine two claims.

In the SNT trial, sham aiTBS led to an 11.1% reduction in symptom severity, with 27% responding and 13% remitting.

“Those randomized to receive sham aiTBS experienced an 11.1% reduction in symptom severity with 27% responding and 13% of participants experiencing remission following sham aiTBS.”

• cites [19] Cole, 2022, Stanford neuromodulation therapy (SNT): a double-blind randomized controlled trial, Am J Psychiatry sourceNot checked — no full text of the source

May combine two claims.

By focusing resources on the better performing arm, the trial obtains equivalent power as a nonadaptive trial with a high probability of sample size savings, as well as treating participants within the trial better than using equal randomization among all three arms.

“By focusing resources on the better performing arm, we obtain equivalent power as a nonadaptive trial with a high probability of sample size savings, as well as treating participants within the trial better than using equal randomization among all three arms (42).”

• cites [42] 2016, Adaptive designs for medical device clinical studies [internet]. U.S. Department of Health and Human Services Food and Drug AdministrationNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

All potential participants undergo a comprehensive MRI safety assessment carried out by trained study personnel.

“All potential participants undergo a comprehensive MRI safety assessment carried out by trained study personnel.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All imaging scans are processed centrally by an unblinded study team member.

“All imaging scans are processed centrally by an unblinded study team member.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Changes in treatment regimen during follow-up are monitored and integrated into the statistical model as covariates for secondary outcome analyses.

“The study team monitor these changes and they are also integrated into the statistical model as co-variates for the secondary outcome analyses related to follow-up time points.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Information about the validity of the blind is collected from both the participant and TMS operator after the first TMS session and at completion of the final TMS session, in two separate self-report measures.

“We collect information about the validity of the blind from both the participant and TMS operator, after the first TMS session and at completion of the final TMS session, in two separate self-report measures.”

Classified as probably not a substantial claim.

If either active arm obtains a 99.75% posterior probability of being superior to sham, the trial will stop for success.

“Success stopping – If either active arm obtains a 99.75% posterior probability of being superior to sham, the trial will stop for success.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Participants will remain double-blinded during the optional Maintenance aiTBS sessions.

“Participants will be able to take part in Maintenance sessions regardless of original group assignment (i.e., the study will remain double-blinded).”

Classified as probably not a substantial claim. May combine two claims.

The trial is a Bayesian adaptive trial with interim analyses allowing for dropping of inferior active arms as well as futility and success stopping.

“We propose a Bayesian adaptive trial with interim analyses allowing for dropping of inferior active arms as well as futility and success stopping.”

Classified as probably not a substantial claim.

The study team developed a comprehensive training plan to standardize MADRS administration across performance sites.

“To ensure robust administration and scoring of the study’s primary outcome measure, the study team has developed a comprehensive training plan to standardize MADRS administration across performance sites.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The Benjamini-Hochberg procedure will be applied to control the false discovery rate when testing multiple secondary outcomes.

“We will apply the Benjamini-Hochberg procedure to control for the false discovery rate when testing multiple secondary outcomes (53).”

• cites [53] Benjamini, 1995, Controlling the false discovery rate: a practical and powerful approach to multiple testing, J R Stat Soc Series B Stat Methodol sourceNot checked — no full text of the source

May combine two claims.

The trial uses a Bayesian adaptive, randomized, double-blind, sham-controlled study design.

“Our ongoing trial uses a Bayesian adaptive, randomized, double-blind, sham-controlled study design (see Figure 1 for Bayesian adaptive trial schema).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Maintenance treatments or other major changes to clinical regimen will be considered as co-variates in secondary analyses of outcomes obtained during the Follow-up Phase.

“Maintenance treatments or other major changes to their clinical regimen will be considered as co-variates in secondary analyses of outcomes obtained during the Follow-up Phase of the study.”

Classified as probably not a substantial claim. May combine two claims.

Brainsight neuronavigation system is used for all participants, independent of randomized arm, to maintain the blind and to maintain consistency of stimulation target across sessions.

“Brainsight neuronavigation system is used for all participants (independent of their randomized arm) to maintain the blind and to maintain consistency of stimulation target across sessions.”

Classified as probably not a substantial claim.

If either active arm has a 60% or greater Bayesian posterior probability of being superior to the other active arm, the inferior active arm will be dropped from the study.

“Arm dropping – If either active arm has a 60% or greater Bayesian posterior probability of being superior to the other active arm, the inferior active arm will be dropped from the study, with the remaining trial maintaining the 2:1 active:sham randomization, but with only one active arm.”