Use of Repetitive Transcranial Magnetic Stimulation in the Treatment of Neuropsychiatric and Neurocognitive Symptoms Associated with Concussion in Military Populations

Abstract

Background:

Since the year 2000, over 342,000 military service members have experienced a concussion, often associated with chronic neuropsychiatric and neurocognitive symptoms. Repetitive Transcranial Magnetic Stimulation (rTMS) protocols have been developed for many of these symptoms in the general population.

Objective:

To conduct a scoping review of the literature on rTMS for neuropsychological and neurocognitive symptoms following concussion.

Methods:

PubMed and Google Scholar search engines identified nine articles, written in English, corresponding to the search terms TBI or concussion; and TMS or rTMS; and depression, PTSD, or cognition. Studies that were not therapeutic trials or case reports, did not have neuropsychiatric or neurocognitive primary outcome measures, or described samples where 80% or more of the cohort did not have a TBI were excluded.

Results:

There were no reports of seizures nor difference in the frequency or quality of other adverse events as compared to the broader rTMS literature, supporting the safety of rTMS in this population. Support for the efficacy of rTMS for the treatment of neuropsychiatric and neurocognitive symptoms in this population, is limited.

Conclusions:

Large-scale, innovative, neuroscience-informed protocols are recommended to elucidate the potential utility of rTMS for the complex neuropsychiatric and neurocognitive symptoms associated with military concussions.

Introduction

In the United States Military Health System, traumatic brain injury (TBI) is one of the most prolific medical conditions, affecting over 400,000 service members (SMs) returning from the operations in Iraq and Afghanistan. ^{1, 2} Mild TBI, or concussion, is the most common type of TBI, accounting for over 80% of national TBI rates; however, it frequently remains undiagnosed and untreated. ²

Approximately 23% of SMs with sustained concussions during their service experience subsequent depressive symptoms. ³ Depression severity following concussion is strongly correlated with global disability, rate of recovery, and quality of life. ^4–6 While depression is the strongest correlate of overall disability in the general population, ⁷ and specifically in US military personnel with a history of concussion, ^4–6 PTSD is even more prevalent in this population. A recent study found that 43.9% of SMs who reported loss of consciousness following concussion met PTSD criteria, compared with 16.2% of those with other injuries, and 9.1% of those with no injuries. ³ Furthermore, depression and PTSD are highly comorbid following military concussion. One study found that over 80% of individuals with a concussion and depression also have PTSD, ⁸ while another study found that depression severity was highly correlated with PTSD severity in SMs who had sustained concussions. ⁹

Cognitive concerns following military concussion are also prevalent and often involve difficulties in working memory and executive functioning. ¹⁰ Among combat Veterans with a prior concussion, self-reported “slowed thinking, difficulty organizing and finishing things,” forgetfulness, and concentration problems are common, with 64%-83% of Veterans endorsing these problems at a moderate to very severe level. ¹¹ There is significant disagreement within the clinical and research community, however, about the validity and reliability of measures of cognitive deficits in those who have experienced concussion. ^12–14 The risk for these symptoms may persist with time, and elevated risk of suicide may persist for decades. ^15–17 Neuropsychiatric and neurocognitive symptoms can have broad-reaching, detrimental effects on functional status, quality of life, and military readiness. ^18,19 This has been a major burden on affected SMs, their families, and the Military Health System. Much of this burden may be attributable to the complexities of symptom attribution after TBI. Due to heterogeneous clinical outcomes, it can be difficult to discern whether the TBI is the predominant driver of pathology. ^20,21 Due to these complexities, it has been proposed that the neuropsychiatric symptoms associated with concussion and other TBIs should be managed “one symptom at a time”. ²²

Despite the clear negative impact of chronic neuropsychiatric and neurocognitive symptoms on current and former SMs, there remains a paucity of evidence-based effective treatments for these symptoms in the context of TBI. At present, there are no US Food and Drug Administration (FDA) approved medications for any neuropsychiatric or neurocognitive symptoms associated with TBI. The mechanism underlying neuropsychiatric and neurocognitive symptoms following military concussion is thought to involve multi-factorial biological and psychosocial contributors that may be distinct from each individual symptom in isolation and distinct from the pathophysiology of symptoms associated with civilian TBI. Thus, symptom-targeted, neural circuit-based approaches such as repetitive transcranial magnetic stimulation (rTMS) may be more effective than medications for this population. While clinical practice guidelines offer guidance in support of a symptom-based approach, more work is needed to definitively characterize the effects of different treatments on different symptoms. ²²

10 Hz rTMS to the left dorsolateral prefrontal cortex (DLPFC) was cleared by the FDA for pharmacoresistant MDD in October 2008 ^23–25 and 20 Hz “deep” rTMS for obsessive-compulsive disorder paired with symptom provocation in August 2018. Though rTMS is not cleared for PTSD and cognitive deficits, there is a substantial literature base supporting the efficacy of rTMS in these conditions. ^26–28 Across the current literature, rTMS for MDD, PTSD, and cognitive deficits most commonly targets the DLPFC, however the specific protocol (number of pulses, frequency, laterality, targeting strategy, etc.) varies across studies. Furthermore, it has been suggested that the standard DLPFC target location and/or standard rTMS protocols may not be optimized for those with complex comorbidities such as TBI ²⁹ and/or PTSD. ³⁰

Herein we aim to provide a narrative summary of the evidence base for the use of rTMS to treat chronic neuropsychiatric and neurocognitive symptoms in individuals who have sustained one or more concussions, discuss the limitations in the extant literature, and provide a framework for future investigations.

Methods

A literature search was conducted through PubMed and Google Scholar. The search was limited to English-language peer-reviewed articles. The following search terms were used: “TBI” or “concussion”; and “TMS” or “rTMS”; and “depression”, “PTSD”, or “cognition”. Studies that were not therapeutic trials or case reports, did not have neuropsychiatric/neurocognitive primary outcome measures, or described samples of participants with moderate to severe TBI or where 80% or more of the cohort did not have a prior concussion, were excluded.

Results

rTMS for Depressive Symptoms following Concussion

The literature search produced eight published reports focusing on depressive symptoms; two were case reports ^31,32 and six were randomized trials ^29,33–37 that used various protocols and targeting strategies. Of the six trials, four targeted depression as the primary endpoint, ^29,33,35,37 while in the other two trials, ^34,36 depression was a secondary outcome. Many of these trials were pilot in nature with <15 people in each group. Of the six trials, three ^29,34,35 reported positive outcomes, while the other three ^33,36,37 were negative. Three specifically included SMs or veterans, ^34–36 while the others were of mixed samples ²⁹ or did not indicate the mechanism of injury. ^33,37 Table 1 provides a summary of the study designs, samples, and outcomes of published studies as they relate to depressive symptoms and reported side effects.

Table 1:

Clinical Trials investigating the use of rTMS for depressive symptoms following concussion

Publication	N (Concussion+Depression)	Age in Years (Mean, Standard Deviation)	Gender (Male/Female)	Population	Protocol	Number of Sessions, Frequency of Sessions	Blinding	Depression Outcome Measure	Reported Effects for Depression Outcome Measure	Side-Effects/Adverse Events
Fitzgerald et al., 2011 Journal of ECT	1	41	1 Female	Civilian-Car Accident	R-DLPFC (structural MRI targeting): 900 pulses at 110% MT at 1 Hz Followed by L-DLPFC (structural MRI targeting): 1500 pulses at 110% MT at 10 Hz, 5 second train duration, 25 second intertrain interval	20, 1 session/day	None	MADRS	50% Reduction in MADRS Score	None Reported
George et al., 2014 Brain Stimulation	24 (13 active, 11 sham)	M=42.5, SD=15.5	Approx. 20/4 (subset of the overall sample)	Military/Veteran	L-DLPFC (6 cm anterior to M1 scalp targeting): 6000 pulses at 110% MT at 10 Hz, 5 second train duration, 10 second intertrain interval	9, 3 sessions/day with 1 hour intersession interval.	Double Blind	HAM-D, MADRS	No significant group difference in HAM-D or MADRS	First-degree scalp burn from coil overheating (n=1)
Leung et al., 2018 Neuromodulation	29 (14 active, 15 sham)	M=34.1 SD=7.9	23/6	Veteran	L-DLPFC (structural MRI targeting): 2000 pulses at 80% MT at 10 Hz, 10 second train duration, 1 second intertrain interval	4, 1 session/day	Double Blind	HAM-D	Significant Reduction in HAM-D Score in active group. No significant change in sham group	None Reported
Philip et al., 2019 American Journal of Psychiatry	12 (7 20 sessions of active, 5 10 sessions of sham, 10 sessions of active)	M=52 SD=10	11/1	Veteran	R-DLPFC (F4 scalp targeting): 1,800 pulses at 80%MT iTBS (3 pulse burst of 50 Hz with a 200ms interburst interval for 10 bursts with an 8 second intertrain interval)	10 1 session/day	Double Blind	IDS-SR	Significant Reduction in IDS-SR in active group. No significant change in sham group	Active: drowsiness (n=1), anxiety (n=1), headache (n=1) and dizziness (n=1), Sham: homicidal ideation (n=1), death due to fentanyl/alcohol overdose during the follow up period
Siddiqi et al., 2019 Journal of Neurotrauma	14 (9 active, 5 sham)	M=45.5 SD=14.4	11/3	Mixed Sample (2 military)	L-DLPFC (rsfMRI targeting): 4000 pulses at 120% MT at 10 Hz, 5 second train duration, 20 second intertrain interval Followed by R-DLPFC (rsfMRI targeting): 1000 pulses at 120% MT at 1 Hz	20, 1 session/day	Double Blind	MADRS	56% Reduction in MADRS score in active group, 27.5% Reduction in MADRS score in sham group	Active: transient twitching and discomfort in the facial muscles (n=7), worsening headache (n=1), presyncopal episode (n=1) Sham: worsening headache (n=1)
Hoy et al., 2019 Journal of Neurotrauma	12 (7 active, 5 sham)	M=45.7 SD=11.4	Approx. 6/6 (subset of the overall sample)	Not reported, Academic Medical Center	R-DLPFC (structural MRI targeting): 900 pulses at 110% MT at 1 Hz Followed by L-DLPFC (structural MRI targeting): 1500 pulses at 110% MT at 10 Hz, 5 second train duration, 25 second intertrain interval	20, 1 session/day	Double Blind	MADRS	Significant Reduction in MADRS Score across both groups. No group difference	Active: 72% Sham: 30% one or more of the following: site discomfort, mild headache, severe headache, both headache and site discomfort
Rao et al., 2019 Journal of Neuropsychiatry & Clinical Neurosciences	28 (13 active, 15 sham)	M=40.0 SD=14.4	Approx. 11/17 (subset of the overall sample)	Not Reported, Academic Medical Center and Department of Defense	R-DLPFC (F4 scalp targeting): 1200 pulses at 110% MT at 1 Hz, 300 second train duration, 60 second intertrain interval	20, 1 session/day	Double Blind	HAM-D	Significant Reduction in HAM-D Score across both groups. No group difference	Active: headache (n=Approx. 7), dizziness (n=1), blurred vision (n=1), fatigue (n=1), puffy face (n=1) Sham: headache (n=Approx. 8)

R-DLPFC=Right Dorsolateral Prefrontal Cortex; L-DLPFC=Left Dorsolateral Prefrontal Cortex; cm=centimeters; MADRS=Montgomery Asberg Depression Scale; HAM-D=Hamilton Depression Rating Scale; IDS-SR= Inventory of Depressive Symptoms-Self Report; MRI=Magnetic Resonance Imaging; rsfMRI=Resting State Functional Connectivity Magnetic Resonance Imaging; F4=10-20 scalp-based definition of right dorsolateral prefrontal cortex

rTMS for PTSD Symptoms following Concussion

There are no randomized rTMS trials that have targeted PTSD as a primary outcome in individuals with a history of concussion. However, Philip and colleagues studied a veteran population in one trial, with a subgroup also having a history of concussion. ³⁴ Additionally, given that PTSD has high comorbidity with depression in individuals with a history of concussion, three of the six randomized trials with depression as the primary outcome evaluated PTSD symptoms as secondary outcomes. Of note, all of these trials focused either entirely or partially on military populations.

As with the depression trials in individuals with prior concussion, the limited literature targeting PTSD symptoms is composed of small-scale pilot trials. Thus, although the study by Philip and colleagues ³⁴ demonstrated statistical significance following both the randomized and open-label phases of the study (20 sessions of active stimulation for those randomized to the active group for the first phase compared to 10 sessions of active stimulation for those randomized to the sham group for the first phase), the data presented herein represents a subgroup of the overall study sample (those with a history of concussion) and includes data from fewer than 10 individuals per group. Table 2 provides a summary of the study designs, samples, and outcomes of published studies as they relate to PTSD symptoms and reported side effects.

Table 2:

Clinical Trials investigating the use of rTMS for PTSD symptoms following concussion

Publication	N (Concussion+PTSD)	Age in Years (Mean, Standard Deviation)	Gender (Male/Female)	Population	Protocol	Number of Sessions, Frequency of Sessions	Blinding	PTSD Outcome Measure	Reported Effects for PTSD Outcome Measure	Side-Effects/Adverse Events
George et al., 2014 Brain Stimulation	23 (13 active, 10 sham)	M=42.5, SD=15.5	Approx. 20/3 (subset of the overall sample)	Military/Veteran	L-DLPFC (6 cm anterior to M1 scalp targeting): 6000 pulses at 110% MT at 10 Hz, 5 second train duration, 10 second intertrain interval	9, 3 sessions/day with 1-hour intersession interval.	Double Blind	CAPS	No significant group difference in CAPS	first-degree scalp burn from coil overheating (n=1)
Leung et al., 2018 Neuromodulation	29 (14 active, 15 sham)	M=34.1 SD=7.9	23/6	Veteran	L-DLPFC (structural MRI targeting): 2000 pulses at 80% MT at 10 Hz, 10 second train duration, 1 second intertrain interval	4, 1 session/day	Double Blind	CAPS	No significant group difference in CAPS	None Reported
Philip et al., 2019 American Journal of Psychiatry	12 (7, 20 sessions of active; 5, 10 sessions of sham, 10 sessions of active)	M=52 SD=10	11/1	Veteran	R-DLPFC (F4 scalp targeting): 1,800 pulses at 80%MT iTBS (3 pulse burst of 50 Hz with a 200ms interburst interval for 10 bursts with an 8 second intertrain interval)	10 1 session/day	Double Blind	CAPS, PCL-5	Significant Reduction in CAPS and PCL-5 in both groups. Greater reductions in active as compared to sham	Active: drowsiness (n=1), anxiety (n=1), headache (n=1) and dizziness (n=1), Sham: homicidal ideation (n=1), death due to fentanyl/alcohol overdose during the follow up period
Rao et al., 2019 Journal of Neuropsychiatry & Clinical Neurosciences	28 (13 active, 15 sham)	M=40.0 SD=14.4	Approx. 11/17 (subset of the overall sample)	Not Reported, Academic Medical Center and Department of Defense	R-DLPFC (F4 scalp targeting): 1200 pulses at 110% MT at 1 Hz, 300 second train duration, 60 second intertrain interval	20, 1 session/day	Double Blind	DTS	No significant group difference in DTS	Active: headache (n=Approx. 7), dizziness (n=1), blurred vision (n=1), fatigue (n=1), puffy face (n=1) Sham: headache (n=Approx. 8)

PTSD=post-traumatic stress disorder; R-DLPFC=Right Dorsolateral Prefrontal Cortex; L-DLPFC=Left Dorsolateral Prefrontal Cortex; cm=centimeters; CAPS=Clinically Administered PTSD Scale; PCL-5=PTSD Checklist for DSM-5; DTS=Davidson Trauma Scale; MRI=Magnetic Resonance Imaging; F4=10-20 scalp-based definition of right dorsolateral prefrontal cortex

rTMS for Cognitive Symptoms following Concussion

Many of the aforementioned trials primarily evaluating rTMS for depression and/or PTSD also included secondary cognitive outcome measures. Despite a range of cognitive batteries used, however, none of the reviewed studies reported significant positive effects of rTMS on cognitive assessments. ^29,33,35,37 As these measures are often included for safety monitoring, it is noteworthy that there is no evidence suggesting that rTMS leads to adverse cognitive effects. Table 3 provides a summary of the study designs, samples, and outcomes of published studies as they relate to cognitive symptoms and reported side effects of the published trials in this area.

Table 3:

Clinical Trials investigating the use of rTMS for cognitive symptoms following concussion

Publication	N (Concussion+Cognitive Symptoms)	Age in Years (Mean, Standard Deviation)	Gender (Male/Female)	Population	Protocol	Number of Sessions, Frequency of Sessions	Blinding	Cognitive Outcome Measure	Reported Effects for Cognitive Outcome Measure	Side-Effects/Adverse Events
Koski et al., 2015 Journal of Neurotrauma	15	M=34.3, SD=10.8	9/6	Not reported. Academic Medical Center	L-DLPFC (5 cm anterior to M1 scalp targeting): 1000 pulses at 110% MT at 10 Hz, 5 second train duration, 25 second intertrain interval	20, 1 session/day	Open-Label	Self-report Questionnaire, standardized cognitive tasks	No significant changes in self-report or task performance	headache (n=3), vertigo (n=1), anxiety (n=1), increased sleep/disturbance (n=3)
Leung et al., 2018 Neuromodulation	29 (14 active, 15 sham)	M=34.1 SD=7.9	23/6	Veteran	L-DLPFC (structural MRI targeting): 2000 pulses at 80% MT at 10 Hz, 10 second train duration, 1 second intertrain interval	4, 1 session/day	Double Blind	HVLT, Connors CPT-II, Stroop Test	No significant group difference in any cognitive assessments	None Reported
Siddiqi et al., 2019 Journal of Neurotrauma	14 (9 active, 5 sham)	M=45.5 SD=14.4	11/3	Mixed Sample (2 military)	L-DLPFC (rsfMRI targeting): 4000 pulses at 120% MT at 10 Hz, 5 second train duration, 20 second intertrain interval Followed by R-DLPFC (rsfMRI targeting): 1000 pulses at 120% MT at 1 Hz	20, 1 session/day	Double Blind	NIH Toolbox	No significant group difference in overall performance on NIH Toolbox Cognitive Battery	Active: transient twitching and discomfort in the facial muscles (n=7), worsening headache (n=1), presyncopal episode (n=1) Sham: worsening headache (n=1)
Hoy et al., 2019 Journal of Neurotrauma	12 (7 active, 5 sham)	M=45.7 SD=11.4	Approx. 6/6 (subset of the overall sample)	Not reported, Academic Medical Center	R-DLPFC (structural MRI targeting): 900 pulses at 110% MT at 1 Hz Followed by L-DLPFC (structural MRI targeting): 1500 pulses at 110% MT at 10 Hz, 5 second train duration, 25 second intertrain interval	20, 1 session/day	Double Blind	Digit span forward and backward, arithmetic, Trail Making A and B, RAVLT, BVMT, Verbal Fluency, Stroop	No significant group difference in any cognitive assessments	Active: 72% Sham: 30% one or more of the following: site discomfort, mild headache, severe headache, both headache and site discomfort
Rao et al., 2019 Journal of Neuropsychiatry & Clinical Neurosciences	28 (13 active, 15 sham)	M=40.0 SD=14.4	Approx. 11/17 (subset of the overall sample)	Not Reported, Academic Medical Center and Department of Defense	R-DLPFC (F4 scalp targeting): 1200 pulses at 110% MT at 1 Hz, 300 second train duration, 60 second intertrain interval	20, 1 session/day	Double Blind	MOCA, Trail Making A and B, BVMT, HVLT, WCST, Stroop	Only significant group difference was for the BVMT immediate recall measure. All other cognitive assessments showed no significant group difference.	Active: headache (n=Approx. 7), dizziness (n=1), blurred vision (n=1), fatigue (n=1), puffy face (n=1) Sham: headache (n=Approx. 8)

L-DLPFC=Left Dorsolateral Prefrontal Cortex; cm=centimeters; HVLT=Hopkins Verbal Learning Test; Connors CPT-II=Connors Continuous Performance Test, Second Edition; RVALT=Rey Auditory Verbal Learning Test; BVMT=Brief Visuospatial Memory Test; HVLT=Hopkins Verbal Learning Test; WCST=Wisconsin Card Sorting Test; MRI=Magnetic Resonance Imaging

In addition to the trials included in Table 3, Adamson and colleagues ³⁸ recently completed a double-blind randomized sham-controlled rTMS trial to improve executive functioning in 32 Veterans who sustained a mild or moderate TBI. Twenty sessions of 10 Hz neuronavigated rTMS was administered to the left DLPFC at 120% motor threshold. However, consistent with the rest of the published literature, there was no significant difference between active and sham groups in executive function performance.

Discussion

Historically, a history of concussion (or any traumatic brain injury) has been exclusionary for rTMS studies; hence the paucity of data on the effects of rTMS in this population. Across depression, PTSD, and cognitive symptoms (the most prevalent and debilitating chronic symptoms associated with military concussion), we identified a total of nine unique published studies, only a portion of which explicitly included SMs or Veterans. Given that those with brain injury have been historically excluded due to potential safety concerns, it is notable that the literature reviewed herein does not indicate that a concussion increases one’s risk of any adverse outcome. However, given the small samples and mixed results across trials, there is simply insufficient data to indicate any specific active rTMS protocol is superior to sham (placebo) stimulation. Of note, it does appear that more careful individualized targeting, either through measurements or functional connectivity analyses, may be associated with superior outcomes.

There is currently an unmet need for a Class I study (defined as an adequately data-supported, prospective, randomized, placebo-controlled clinical trial with masked outcome assessment in a representative population (n ≥ 25 patients receiving active treatment)) investigating the use of rTMS for treating postconcussive depression, PTSD, or cognitive symptoms. These larger-scale trials could account for baseline and demographic characteristics such as gender, age, number of concussions, mechanism of injury, time since injury, genetic variability, and co-occurring neurological or psychiatric conditions, which may influence response to treatment. That stated, a multisite, Bayesian adaptive design, randomized, sham-controlled trial of rTMS for postconcussive depressive symptoms with a sample size of over 400 SMs is being developed and scheduled to begin in late 2020 at multiple military treatment facilities (https://www.usuhs.edu/cnrm/clinicaltrials). This would be the first of its kind and would answer some of the outstanding questions regarding safety and efficacy of a variety of targeting strategies, protocols, and targeted hemispheres.

Gaps in the Literature

At this time, there remain several gaps in knowledge regarding the efficacy of rTMS for the treatment of chronic neuropsychiatric and neurocognitive symptoms associated with concussion. To narrow these gaps, we addressed the literature broadly rather than narrowing focus to a specific symptom. This revealed that multiple studies reported varying degrees of improvement in depression, even when this was not a primary outcome or inclusion criterion of the study. By contrast, none of the studies reported substantial improvement in cognition, regardless of the primary outcome. However, several gaps remain, including those discussed below.

1. How to interpret negative trials

When results of a study lead the investigators to fail to reject the null hypothesis, should the interpretation be that rTMS is not effective? In many cases it is not the complete ineffectiveness of the active condition, but rather the impact of generalized effects present across both active and sham groups. In many trials reviewed, both groups significantly improved. It is unclear whether the sham group improved as a result of the placebo effect, symptom resolution due to the natural history of the condition, more general medical attention and monitoring, effects of behavioral activation and social interaction (requiring participants to come into a clinic every day for a therapeutic session), neural entrainment from the sensory aspects of the stimulation, and/or any combination of general factors.

Following one or more concussions, individuals often present with a complex combination of co-occurring neurological, psychiatric, general medical, and cognitive symptoms. The presence of these other conditions undoubtedly creates heterogeneity that can contribute to the negative findings. Furthermore, the studies reviewed herein included individuals whose injuries were incurred under very different contexts ranging from car accidents to sports injuries to injuries obtained in the context of military service. The context of the injury, and thus etiology of the associated symptoms, may contribute to heterogeneity in the efficacy of a treatment. Given the relatively small sample sizes and symptom variability, it is likely that the trials reviewed herein were underpowered. More specific inclusion criteria to try to minimize heterogeneity and/or having large enough trials to allow for participant stratification (e.g. those with and without PTSD) combined with more sensitive measures of symptom change may give investigators sufficient power to observe a significant effect of active rTMS over sham if one exists. As more of these studies come to fruition, future systematic reviews should aim to achieve such stratification, which was not possible in the present scoping review.”

2. What are the optimal stimulus parameters?

Though all of the studies reviewed herein targeted the DLPFC, some have targeted the left hemisphere, others the right, and still others utilized bilateral stimulation. Additionally, some studies have applied lower frequency stimulation while others have applied higher frequency and another a theta burst stimulation protocol. Furthermore, when targeting the DLPFC, some have used a scalp-based targeting method, while others have used anatomical and functional neuroimaging to individualize coil placement. Though the FDA-cleared protocol (unilateral high-frequency stimulation with scalp-based targeting) is sufficient to demonstrate efficacy for pharmacoresistant MDD, ³⁹ many have reasoned that because of general individual variability and heterogeneity due to brain injury, neuronavigated targeting of rTMS may improve efficacy. ⁴⁰ Additionally, concussions may result in unique disruptions in functional brain networks ⁴¹ resulting in unique pathophysiological and clinical manifestations. As the accuracy and reliability of both anatomical and functional neuroimaging protocols and analysis techniques advance, individualized targeting of specific anatomical and/or functional networks to engage the underlying brain target more effectively is now feasible ^30,42.

3. What is an adequate “dose”?

The reviewed literature ranges in number of sessions from 4–20 sessions, 1–3 times per day. However, 20 sessions is still a relatively low “dose” compared to the standard cleared protocol that typically involves up to 36 sessions of rTMS over 6–8 weeks. Furthermore, in a complex syndrome that often presents with multiple comorbid neurological and behavioral symptoms, one may expect that a larger dose may be required. Additionally, the degree of plasticity of the targeted region and network may differ across individuals. Thus, number of sessions may need to be individualized in addition to target location and stimulation frequency.

There is a general consensus that more sessions produce a larger effect, and some patients will continue to show improvements with additional sessions. ⁴³ “Accelerated” protocols are currently being evaluated for pharmacoresistant MDD, in which up to 10 sessions of rTMS (specifically, a 10-minute session of intermittent theta burst stimulation (iTBS)) are applied per day for up to 5 days (for a total of 50 sessions). A recently published small open-label study reported remission rates of over 90% following such an accelerated protocol. ⁴⁴ A randomized controlled trial, following up on this promising open-label data, is ongoing (https://clinicaltrials.gov/ct2/show/NCT03068715). However, feasibility, cost, and both participant and researcher burden should also be considered for such intensive treatment regimens.

4. In the context of a highly comorbid condition, what is the optimal protocol?

Lippa and colleagues found that having co-occurring concussion, depression, and PTSD may increase risk for other clinical issues (e.g., sleep disturbance, substance abuse) and substantial disability. ⁴⁵ Furthermore, concussion (especially in the context of military service) results in not only depression, PTSD, and/or cognitive symptoms in isolation, but rather a complex phenotype involving these symptoms as well as potentially other co-occurring psychiatric, neurological, behavioral, and general medical symptoms (e.g. sleep problems, headache, chronic pain, substance misuse, anxiety, irritability etc.), which complicate treatment. ^3,46,47

In addition to the variety of associated clinical symptoms, the “mild” TBI associated with concussion is also thought to result in pathophysiology at the functional brain network level (the putative target of TMS treatments). It has been proposed that the physiological impact of concussion converges with the psychological trauma in a way that affects stress-vulnerable brain regions including limbic and paralimbic networks. Furthermore, if other injuries are sustained during the concussive event this may increase the overall symptom load, which may also exacerbate the psychological stress affecting the same stress-related networks. ⁴⁸ Concussion may also decrease cognitive reserve, increasing susceptibility to executive functioning challenges and reduced cognitive control. This may in turn make emotion regulation more difficult, potentially contributing to the new onset or exacerbation of psychiatric symptoms (depression, anxiety, PTSD, etc.). ⁴⁹

Treatments effective in MDD in the general population may not necessarily translate to depressive symptoms following concussion or depressive symptoms in combination with PTSD. This was suggested as one of the main contributors to the recently published negative trial in veterans where researchers used a standard FDA cleared protocol for MDD to treat MDD in a veteran population, where a significant proportion had comorbid PTSD. ⁵⁰ Additionally, a standard clinical trial, where the investigator must state a singular primary clinical endpoint (e.g. depression or PTSD or cognitive deficit) and separate secondary clinical endpoints, may be inappropriate for this complex and syndromic condition.

In order to develop an effective treatment for this complex disorder, it may be necessary to completely shift conceptualization of treatment targeting. Rather than evaluating protocols developed for specific disorders, a structural and functional neuroscience-based approach may be more appropriate for individuals who have experienced concussions and related injuries. Under this so-called “experimental therapeutics” approach one can begin to incorporate a basic science understanding of concussion pathophysiology, physiological mechanisms of action of rTMS on the local and network level, and new developments in neuroimaging to develop targeted treatment approaches.

Advanced statistical designs such as Bayesian adaptive trials and statistical tests such as O’Brien, Wei-Lachin, ⁵¹ and other newly developed tests ⁵² that allow for multi-domain outcome measures may be more suitable for this population than the standard clinical trial designs. Although these advanced statistical designs are relatively more complex and require specific expertise planning, execution and interpretation of the results (in particular with one or more interim analyses) and challenges related to data safety and monitoring may arise, there are a number of advantages of these types of designs.

Specifically, Bayesian statistical approaches provide a powerful mathematical framework for determining optimal behavior in the face of uncertainty, allow the efficient and transparent integration of complex clinical trial and external data, and offer the ability to learn from the accruing data what the most therapeutic arms are, therefore allowing the design to focus on the best arms. Bayesian designs also allow for simultaneous evaluation of different parameter combinations (e.g., targeting strategy, laterality (unilateral versus bilateral stimulation), protocol (standard versus accelerated or theta burst), adjunctive versus monotherapies, etc.). Furthermore, under the Bayesian adaptive framework, interim findings are used to dynamically reallocate more participants to treatment arms with higher efficacy. By focusing resources on the better performing arms, statistical power is optimized, there is a higher likelihood of identifying the best treatment, and more participants within the trial receive more effective treatments. ^53–55 The statistical literature supports the efficiency of these Bayesian factorial designs ^56–58 and adaptive trial designs are now well accepted by the FDA. ^59–61

Conclusion

rTMS represents a novel innovative, and possibly transformative approach to the treatment of chronic neuropsychiatric and neurocognitive symptoms associated with military concussion. However, there remains a paucity of conclusive data for which rTMS protocols may be optimal for patients with specific combinations of symptoms. The physiological and psychological impact of concussion (especially in military populations) poses unique challenges that likely require individualized precision at the level of protocol and targeting. It is an undeniably limited evidence-base, but an equally undeniable unmet need. The importance of optimizing feasibility and efficacy of rTMS to treat SMs and veterans with chronic neuropsychiatric and neurocognitive symptoms associated with concussion cannot be overstated. Current treatments are not sufficiently alleviating these symptoms, and there are currently no evidence-based treatments that meet Class-I evidence in this population. ⁶² Decades of research has shown that rTMS is safe and effective and there is no evidence to suggest that a history of concussion significantly changes the risk profile.

If specific rTMS protocols are to be established as safe and efficacious treatment interventions for chronic symptoms associated with concussion, it will require a large, coordinated effort across a number of public (NIH, DoD, VA) and private (e.g., device and navigation companies, statistical consulting firms, etc.) institutions and large number of patients willing to participate in clinical trials. On a positive note, we have the tools, the advanced study designs, the patients willing to participate, and the researchers eager to investigate. We need to begin to design smarter trials that are powered to answer research questions to confidently assess and recommend rTMS as a treatment option for this population. This is an ambitious goal, but if successful, findings from such studies will speed up the widespread implementation of an effective nonpharmacologic treatment for our SMs and Veterans with chronic neuropsychiatric and neurocognitive symptoms associated with concussion.