Theta Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder

Abstract

OBJECTIVE:

Posttraumatic Stress Disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. To this end, transcranial magnetic stimulation (TMS) represents a novel approach to PTSD. Intermittent theta-burst stimulation (iTBS) is a new, more rapid administration protocol with data supporting efficacy in depression.

METHODS:

Fifty veterans with PTSD received ten days of sham-controlled iTBS (1800 pulses/day), followed by ten unblinded sessions. Primary outcome measures included acceptability (retention rates), changes in PTSD (clinician- and self-rated symptoms), quality of life, social and occupational function, and depression, obtained at the end of two weeks using analysis of variance to compare active versus sham stimulation. Secondary outcomes, using mixed model analyses, were evaluated at one-month post-treatment. Resting state fMRI was acquired at pretreatment baseline on an eligible subset (n=26) to identify response predictors.

RESULTS:

Retention was high, side effects consistent with standard TMS, and blinding was successful. At two weeks, active iTBS significantly improved social and occupational function (Cohen’s d = .39; p = .04), and produced a trend towards depression improvement (d = −.45; p = .07), and moderate (nonsignificant) effect sizes on self-reported PTSD (d=−.34). One-month outcomes, which incorporated data from the unblinded phase of the study, indicated superiority of active iTBS on clinician- and self-rated PTSD (d = −.74 and −.63, respectively), depression (d = −.47), and social and occupational function (d = .93)(all p<.001).

Neuroimaging indicated clinical improvement was predicted by stronger (greater positive) connectivity within the default mode network (DMN), and by anticorrelated (greater negative) cross-network connectivity (FDR-corrected p<.05).

CONCLUSIONS:

iTBS appears to be a promising new treatment for PTSD. Most clinical improvements from stimulation occurred early, necessitating further investigation of optimal iTBS time course and duration. Consistent with prior neuroimaging studies of TMS, DMN connectivity played an important role in response prediction.

Trial Registration:

ClinicalTrials.gov Identifier:

INTRODUCTION

Posttraumatic Stress Disorder (PTSD) is a prevalent psychiatric disorder associated with marked occupational and social dysfunction (1), characterized by pervasive intrusive thoughts/recollections, avoidance of trauma-related stimuli, hyperarousal, and mood/cognitive impairment (1–3). PTSD also has substantial psychiatric and medical comorbidity (4). Evidence-based PTSD treatments, including psychotherapy and pharmacology, might be less effective at reducing symptoms and improving function in veterans compared to the general population (5). There is thus a pressing need to develop novel interventions for veterans with PTSD.

Theta Burst Stimulation

Non-invasive neuromodulation is developing rapidly across psychiatry, setting the stage for innovative new interventions. A body of literature now supports the efficacy of repetitive TMS (rTMS, hereafter simply TMS) for pharmacoresistant major depression (e.g., 6,7), although this may be less effective in veterans and particularly for those with comorbid PTSD (8). While existing data suggests effectiveness of TMS for PTSD (9–11; reviewed in 12,13), in our opinion (and others, e.g., see (14)), lengthy administration times impede broader implementation. Moreover, whether stimulation yields functional improvement remains unknown.

Theta-burst stimulation (TBS) is a novel TMS protocol that rapidly induces synaptic plasticity (15). During TBS, short bursts of high frequency (50Hz) stimulation are repeated at 5 Hz (200ms interval). TBS can be intermittent (iTBS) or continuous (cTBS), and is associated with long-term potentiation (LTP)-like and long-term depression (LTD)-like activity, respectively (15). Several factors suggest TBS may be useful in PTSD. First, its brevity allows for easy clinic operation, and potential combination with psychotherapy. Second, TBS’ patterned nature resembles theta oscillations of hippocampal memory systems (16). PTSD is defined, at its core, by the impact of intrusive traumatic memories, and in translational models TBS can induce hippocampal synaptic connections and activity (17). Taken together, the data provide a theoretical justification for use of TBS for PTSD.

Neural Networks in PTSD

PTSD is associated with pathological function in three large-scale functional networks: the default mode network (DMN), executive control network (ECN), and salience network (SN) (18). The DMN is involved in self-referential processing and episodic memory; core regions include the medial prefrontal cortex (MPFC), posterior cingulate, medial parietal, and temporal cortex (18). The ECN, with hubs in the dorsolateral PFC (DLPFC) and lateral posterior parietal regions, is involved in executive functioning including emotion regulation and working memory (20). Finally, the SN, with hubs in the dorsal anterior cingulate cortex, anterior insula, and amygdala, is implicated in detection of, and attention to, salient environmental stimuli (21). Prior PTSD neuroimaging studies reported increased SN connectivity reflecting increased threat-detection (22) and disrupted ECN connectivity. Reduced DMN connectivity is generally identified in PTSD (23–25, but see also 26), likely related to fear learning and memory dysfunction (reviewed in 27,28). Network relationships appear important to treatment response, and we previously identified connectivity patterns that predicted PTSD improvement with TMS (29).

To this end, we conducted the first sham-controlled study of iTBS for PTSD. We hypothesized stimulation would be acceptable and efficacious, reduce symptoms of PTSD, and improve social and occupational function and quality of life. Furthermore, we hypothesized efficacy could be predicted using neural networks; specifically, greater negative (i.e., anticorrelated) connectivity between the SN/ECN and DMN would be associated with PTSD improvement.

METHODS

Under IRB approval, participants were recruited from the Providence VA Medical Center from May 2016 to December 2017. Fifty-six participants signed informed consent, and 50 were randomized (Figure 1). The principle inclusion criterion was chronic PTSD by DSM-5 criteria assessed by the SCID-5 (2; also used for comorbidity assessment), trauma exposure assessed using the Life Events Checklist (30), between the ages 18–70, and, if applicable, symptomatic despite stable treatment (medications and/or psychotherapy) for at least 6 weeks prior to study procedures. Ongoing treatment was allowed to continue unchanged during the entirety of participation.

Figure 1. CONSORT Diagram.

Definitions: PTSD, posttraumatic stress disorder; SAE, serious adverse event; TBS, theta burst stimulation

Participants were excluded if they had (unless MRI-safe) implanted devices or metal above the upper thoracic spinal cord, pregnancy risk, lifetime history of moderate or severe traumatic brain injury (using VA/DoD Clinical Practice Guidelines), current unstable medical conditions, or history of a) seizure or other significant neurological disorders b) CNS tumors c) stroke or d) cerebral aneurysm. Other exclusions were primary psychotic disorders, bipolar I, current moderate or severe substance use disorders, or active suicidality.

Randomization and blinding

Participants were randomized in a 1:1 design, stratified by PTSD symptom severity and sex. A study member uninvolved with TBS delivery performed randomization. Because the TMS system used separate coils for active and sham stimulation, a staff member uninvolved in treatment delivery or rating scale administration selected the coil for each participant. Blinding was assessed by asking participants to guess group assignment after the double-blind phase.

Intervention

Using a modified parallel group, double blind, sham-controlled design, we delivered iTBS to the right DLPFC (80% active motor threshold, 1800 pulses; 9.5 minutes; based on prior TBS studies (31)). The right DLPFC was chosen because meta-analyses indicated that right-sided higher frequency stimulation might yield larger PTSD symptom reduction (12,13), and high frequency TMS administered to this location can reduce amygdala activation to threatening stimuli (32).

Following randomization, active motor threshold was determined (i.e., stimulator output sufficient to induce movement in the contralateral hand >50% of the time), and participants received sham-controlled iTBS daily for 10 business days (intent-to-treat=25 per group) using a Magstim Rapid 2+1 system (Magstim, UK). All participants could receive another 10 sessions of unblinded iTBS, to explore effects of greater number of iTBS sessions on outcomes. Right DLPFC was found using scalp measurements to place the coil over F4 (modified from (33)); measurements were checked and monitored at every session to ensure placement.

Statistical Analyses: Clinical Outcomes

Our primary outcome measures were acceptability (measured using retention rates and participant reports), followed by changes in PTSD symptoms (using the Clinician Administered PTSD Scale for DSM-5 (CAPS)(34). Social and occupational function was measured using the Social and Occupational Function Scale (SOFAS)(35) and quality of life using the Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ)(36). Blinded raters obtained all clinician-administered scales. Self-reported PTSD and depressive symptoms were measured using the PTSD Checklist for DSM-5 (PCL)(37) and Inventory of Depressive Symptomatology Self-Report (IDSSR)(38), respectively. Primary clinical outcomes were measured using analysis of variance (39) to compare groups at the end of the 2-week double blind phase. Missing data was addressed using multiple imputations (n=20 imputations, or maximum likelihood parameter estimation in mixed models)(40). Follow-up analyses used a general linear mixed effect model (41) with piecewise time effects (42) to capture the effect of active treatment on outcomes, testing whether active stimulation had superior outcomes compared to sham up to a one-month follow-up visit. Linear parameter constraints were used to capture comparable time on active treatment among those in the group initially randomized to active treatment and those initially randomized to sham that converted to active stimulation during the unblinded period. This approach permitted inference regarding the effect of cumulative “dose” of iTBS on clinical outcomes observed at 1-month. Statistical analyses were performed in Stata (v15.1, StataCorp LLC, Texas, USA). Estimated sample size was informed by prior sham-controlled TMS PTSD studies and meta-analyses (12).

Results are summarized using effect size statistics capturing mean differences standardized to a pooled baseline standard deviation (Cohen’s d)(43) to reflect estimated change due to treatment (at a particular time point). Data was analyzed in an intent-to-treat fashion, defined as participants that were randomized and received at least one iTBS session.

Safety

Safety was assessed at every treatment visit by spontaneous adverse event reports coded using the Medical Dictionary for Regulatory Activities, plus a Treatment Satisfaction Form (44) administered at endpoint. Adverse events were analyzed following prior TMS research, i.e., any side effect that occurred in the active treatment group at a rate of 5% or more and at least twice the rate for sham (7).

Neuroimaging

Resting state fMRI was acquired on a convenience subset of participants (n=26) to identify predictors of improvement. All imaging was obtained less than five days before baseline. Neuroimaging data were acquired using a 3T MRI (Siemens, Erlangen, Germany) and a 32-channel head coil. Imaging acquisition included high-resolution (1 mm3) anatomical images and eight minutes of standard resting-state echo-planar imaging. See supplemental information of acquisition, preprocessing, quality control, and motion (used in first- and second-level analyses) details. MRI data processing used the CONN Functional Toolbox (45) unless indicated.

Neuroimaging analyses examined predictors of response to active stimulation. This was based on our mixed model analysis for clinical outcomes, using clinical change observed during the first two weeks in participants randomized to active stimulation (n=15), and clinical changes observed when patients randomized to sham received active iTBS (n=11). Because prior research indicated that within- and between-network connectivity predicted clinical improvement in PTSD (29) and depressive symptoms (46–49), we took a focused, region-of-interest approach to neuroimaging data analyses. This included a 38-region matrix inclusive of the DMN, ECN, SN and prefrontal areas implicated in PTSD (described in the supplemental information) to examine connectivity patterns predictive of clinical improvement. Only results surviving false-discovery rate (p-FDR)(50) correction are reported; results were robust to post-hoc sensitivity tests for data quality and sex unless stated.

RESULTS

Randomization resulted in groups balanced on demographic variables and symptom severity (Table 1) that reflected the veteran population. Baseline PTSD scores were in the moderate range, nearly all (90%) participants met criteria for comorbid depression, and over half had substance use disorders. Baseline ratings also indicated low social/occupational function and poor quality of life. Trauma exposure was multifactorial (Supplemental Table 1).

Table 1.

Demographic and clinical features

	Active iTBS (n=25)		Sham iTBS (n=25)
Demographic Variables	Mean	SD	Mean	SD
Age(years)	48	13	53	12
	n	%	n	%
Sex (female)	5	20	3	12
Race a
White	22	88	20	80
African American	0	0	2	8
American Indian/Alaska Native	1	4	0	0
Multiracial	2	8	1	4
Ethnicity a
Hispanic origin	0	0	2	8
Not of Hispanic origin	23	92	23	92
Education
Less than high school	1	4	1	4
High school or equivalent	2	8	5	20
Some college	11	4	7	28
Trade or vocational degree	3	12	0	0
Bachelor’s degree	2	8	8	32
Advanced degree and/or education beyond college	2	8	3	12
Employment status a
Full time	6	24	4	16
Part time	1	4	2	8
Unemployed	10	40	9	36
Retired	6	24	9	36
Service connected disability (mental health)	14	56	17	68
Military History
Branch a
Army	8	32	8	32
Navy	8	32	6	24
Marines	2	8	1	4
Air Force	0	0	3	12
Clinical Variables	Mean	SD	Mean	SD
PTSD Symptom Severity
CAPS-5 Score	47.9	10.0	47.4	10.6
PCL-5 Score	49.4	9.4	50.0	11.4
Social/Occupational Function & Quality of Life
SOFAS Score	44.3	13.1	44.6	14.9
QLESQ (General Quality of Life Index)	2.5	0.8	2.6	0.7
Depressive Symptom Severity
IDSSR Score	42.8	11.9	39.2	11.5
	n	%	n	%
Psychiatric Comorbidity
MDD	23	92	22	88
Bipolar II, most recent episode depressed	2	8	3	12
Substance Use Disorder, mild severity	16	64	11	44
Opioid use disorder	6	24	5	20
Prior brain stimulation
Transcranial Magnetic Stimulation	0	0	2	8
Electroconvulsive Therapy	2	8	1	4
Mild traumatic brain injury	7	28	5	20
Psychiatric History
Suicide attempt(s)	6	24	6	24
Inpatient hospitalization(s)	13	52	15	64

Abbreviations: SD, Standard deviation; PTSD, posttraumatic stress disorder; CAPS-5, Clinician Administered PTSD Scale for DSM5; PCL-5, PTSD Checklist for DSM-5; SOFAS, Social and Occupational Function Scale; QLESQ, Quality of Life Enjoyment and Satisfaction Questionnaire; IDSSR, Inventory of Depressive Symptomatology, Self-Report; MDD, Major Depressive Disorder

^aTotals do not equal 100% due to participant non-response

Clinical Outcomes

High retention rates indicated acceptability; only three participants (2 sham, 1 active) withdrew during the double-blind phase (see Figure 1/CONSORT diagram and accompanying Patient Perspectives). Participants were unable to accurately guess group assignment (ChiSq=1.43, p=.49). At the end of the two-week double-blind phase, active stimulation (versus sham) produced statistically significant improvement on the SOFAS (p=.04, d=0.39). Although active stimulation was not statistically superior on CAPS (p=.61, d=−0.12) and PCL, the effect size on the PCL was clinically meaningful (p =.31, d =−0.34). We also observed superiority on depressive symptom improvement that approached a medium effect size, but was not significant (p=.07, d =−0.45)(Table 2a).

Table 2a.

Clinical outcomes at two weeks, comparing active iTBS vs. sham using ANOVA

	Sham				Active
	Baseline		Two Weeks		Baseline		Two Weeks
Rating Scale	Mean	SD	Mean	SD	Mean	SD	Mean	SD	p value	Effect Size (d)
CAPS	47.4	10.6	39.4	13.8	47.9	10.0	38.6	11.4	0.61	−0.12
PCL-5	50.0	11.4	39.4	16.8	49.4	9.4	35.5	13.9	.31	−0.34
SOFAS	44.6	14.9	48.1	17.7	44.3	13.1	53.4	17.0	0.04	0.39
QLESQ	2.6	0.7	2.7	0.8	2.5	0.8	2.8	0.8	0.46	0.16
IDSSR	39.2	11.5	33.5	14.3	42.8	11.9	31.3	14.8	0.07	−0.45

Mixed model analyses, which included data from the unblinded phase, found clinically meaningful superiority of active over sham iTBS on most outcome measures (Table 2b). Active stimulation was associated with statistically significant reduction in PTSD on the CAPS (d=−0.74; p<.001) and PCL (d=−0.63, p<.001). Superiority was also found on depression (d =−0.47; p<.001), and social and occupational function (d=0.93; p<.001). Improvements occurred within the first week of active stimulation and were sustained with minimal additional change (i.e., |d| loss/gain <.2 through follow up), except on the SOFAS that improved over time (Table 2b). We observed statistically significant, but likely clinically irrelevant, improvement on the QLESQ (all changes d<.1). When exploring outcomes across the two groups, participants initially randomized to active (i.e., received a total of 4 weeks of stimulation) demonstrated superior results. For example, using clinically meaningful reduction of at least 12 points on the CAPS (51), 67% of those originally randomized to sham achieved this outcome at 1-month, compared to 81% in those randomized to active iTBS (p<.001, NNT=7).

Table 2b.

Clinical outcomes up to one-month follow-up, comparing active iTBS versus sham, using mixed models ^a

	1st week of active iTBS		2nd week of active iTBS, (and/or effects of additional active iTBS)		Loss or gain through 1-month		Net change up to 1-montth
Rating Scale	Effect size (d)	p-value	Effect size (d)	p-value	Effect size (d)	p-value	Effect size (d)	p-value
CAPS	-	-	−0.59	<0.001	−0.16	0.12	−0.74	<0.001
PCL-5	−0.41	<0.001	−0.16	0.20	−0.06	0.58	−0.63	<0.001
SOFAS	-	-	0.60	<0.001	0.33	<0.001	0.93	<0.001
QLESQ	-	-	0.02	0.005	0.00	0.94	0.02	0.01
IDSSR	−0.36	<0.001	−0.08	0.47	0.04	0.70	−0.47	<0.001

^aResults from linear mixed effect model to capture the common effect of active treatment in those initially randomized to active treatment and those converted to active treatment in the unblinded phase.

Note that the CAPS, SOFAS and QLESQ were obtained at the end of every two weeks, whereas the PCL-5 and IDSSR were obtained at the end of every week; negative Cohen’s d represents reduction in scale value, whereas positive value of Cohen’s d represents increase (i.e., reduction in CAPS score, and increase in SOFAS score).

Abbreviations: iTBS, intermittent theta burst stimulation; ANOVA, analysis of variance; SD, Standard deviation; PTSD, posttraumatic stress disorder; CAPS-5, Clinician Administered PTSD Scale for DSM5; PCL-5, PTSD Checklist for DSM-5; SOFAS, Social and Occupational Function Scale; QLESQ, Quality of Life Enjoyment and Satisfaction Questionnaire; IDSSR, Inventory of Depressive Symptomatology, Self-Report

Safety

Side effects were consistent with previous TMS studies; most commonly reported adverse events were treatment site discomfort and headache. There were no group differences in reporting (all p’s >.1), although treatment site discomfort occurred more frequently in the active group (n=6 (24%) versus none in sham). Three serious adverse events occurred. One participant (never randomized) could not tolerate MRI procedures, and one in the sham group exhibited emergent homicidal ideation. A third participant, originally randomized to sham, required hospitalization for suicidality during the follow up period. There were no seizures.

Neuroimaging Results

Neuroimaging analyses indicated that baseline resting state functional connectivity predicted clinical changes with active iTBS. Superior PTSD improvement was associated with stronger within-DMN functional connectivity (Figure 2a), and stronger anticorrelated (greater negative) connectivity between the DMN and externally oriented networks (Figure 2b).

Figure 2: Neuroimaging Predictors of PTSD Improvement.

Baseline resting state functional connectivity predicted clinical changes with active stimulation; superior improvement was associated with stronger within-default mode network functional connectivity (Figure 2A), and stronger anticorrelated (greater negative) connectivity between the default mode and externally oriented networks (Figure 2B). Images are shown in brain location (top left), followed by connectome-style representation (right). Box plots show examples of the direction of effects, e.g., greater pretreatment connectivity between the left anterior temporal cortex to medial prefrontal cortex predicted superior improvement, compared less connectivity between these two regions (top pane). Conversely, greater anticorrelated connectivity between the temporoparietal junction and dorsolateral prefrontal cortex observed at baseline predicted superior improvement (bottom pane).

Abbreviations: L, left; R, Right; DMPFC, dorsomedial prefrontal cortex; MPFC, medial prefrontal cortex; LTC, lateral temporal cortex; TPJ, temporoparietal junction; RS, retrosplenial; DLPFC, dorsolateral prefrontal cortex; Ant DLPFC, Anterior DLFPC.

Significant within-DMN findings included connectivity between the dorsomedial PFC (DMPFC) and right temporoparietal junction (TPJ), and between the MPFC and left anterior temporal cortex (all p-FDR<.05). When using CAPS scores the same pattern held but became marginally significant after controlling for data quality (p-FDR=0.06).

Significant cross-network relationships included greater negative connectivity between the left DLPFC (ECN) and DMN elements of the TPJ and anterior temporal cortex, and between the right lateral temporal cortex (DMN) and left ventrolateral prefrontal cortex/opercularis (all p-FDR<.05). These relationships were no longer significant when covarying for sex (p-FDR>.1).

Improvement in depression was also associated with stronger connectivity within the DMN-DMPFC network. Connectivity between the right TPJ and right anterior temporal cortex was associated with improvement (p-FDR<.01). Depressive symptom improvement was also associated with greater anticorrelated connectivity between the DMN and DLPFC, and between the ECN and insula (all p-FDR<.05). Subgenual ACC-to-DLPFC connectivity was not predictive of improvement (PTSD or depression), even with lenient statistical thresholds.

DISCUSSION

To our knowledge, this is the first study indicating utility of iTBS for PTSD, with neuroimaging biomarkers predicting clinical improvement. While our results require replication, they are promising. At two weeks, active stimulation improved social and occupational function, and had indications of efficacy on depressive and self-reported PTSD symptoms; at one month (inclusive of data from the unblinded phase), active stimulation was superior across all outcome measures, including self- and clinician-reported PTSD, social and occupational function, and depressive symptoms. Treatment was well tolerated and side effects were consistent with prior reports. Even though participants that received active iTBS more often reported treatment site discomfort, headaches were evenly distributed. Of note, both SAEs in the intent-to-treat sample occurred in participants randomized to sham.

The majority of clinical benefit occurred in the first week of active stimulation. This was unexpected, as prior TMS and iTBS studies in depression indicated that efficacy increased over time with more treatment sessions (e.g., 7,52). This suggests that the ideal duration or “dose” of stimulation is an important area of future TBS research; for example, our data suggests that while improvements may occur early, durable clinical effects require greater accumulated exposure to stimulation. We also observed different time courses between depressive and PTSD symptom reduction; depression improved earlier whereas PTSD improvements were of a larger magnitude by study endpoint. This suggests future research should evaluate whether change in one domain predicts subsequent reductions in another, and how these trajectories relate to quality of life or functional outcomes.

Neuroimaging analyses demonstrated a role of within- and between-network connectivity in treatment prediction; positive response was associated with increased connectivity within the DMN, and increased negative connectivity between networks. For quality control, we evaluated those participants who received active stimulation only and found comparable results. Within-DMN connectivity consistently involved memory-related subsystems in the medial temporal lobe. Memory dysfunction is a clinical hallmark of PTSD, and recent research indicates TMS can modulate memory formation (53), thus demonstrating the need for further investigation into the interaction between stimulation and memory systems in PTSD.

These results are consistent with a recent report associating greater DMN functional segregation and reduced PTSD severity (54), and are broadly consistent with idea that patients who have network architecture that more resembles healthy individuals have superior responses to TMS for depression (48,55). Our findings, among others, suggest that neural markers of network integrity may be a near-term biomarker of stimulation response, regardless of the technology used or treated diagnosis. Future studies comparing TMS and iTBS (ideally compared to medications and psychotherapy) are needed to identify intervention-specific biomarkers of improvement.

Of note, we did not find sgACC-to-DLPFC connectivity predicted clinical improvement. This was unexpected given the comorbid depression in our sample; prior imaging studies of TMS for depression have often, but not always, found sgACC/DLPFC connectivity to predict TMS response (e.g., 56; reviewed in 55). Yet, we observed conceptually similar results, such that increased negative connectivity between the DMN and ECN (i.e., networks inclusive of the sgACC and DLPFC) predicted superior outcomes.

Parameter selection was guided by the available literature at the time of trial design and intentionally conservative first use of iTBS in PTSD. Recently, a study of iTBS for depression used higher motor thresholds (52), suggesting greater energy might improve efficacy. That study also used a smaller number of pulses per session, reasoning that more stimulation yields an inhibitory effect (at least in motor cortex) (57). Whether fewer pulses per session, delivered to non-motor cortex, impacts efficacy remains an important question for future TMS research; the current report should be placed in the context of a wider need for systematic study of stimulation parameters.

Limitations of this study include its modest sample size, and those inherent to a demographically homogenous patient population. Although PTSD in veterans is often associated with combat, our participants reported a wide range of trauma, and all demonstrated comorbid depressive symptoms. While this study demonstrates iTBS use in a “real-world” patient sample, we cannot conclude whether observed effects are uniquely attributable to stimulation or augmentation of ongoing treatments (e.g., similar to (11)), or if specific medications or trauma exposure definitively impacted outcomes (see Supplemental information). Direct comparisons of acceptability of iTBS versus standard TMS were beyond the scope of this initial iTBS PTSD study. We used scalp-based measurements to place the TMS coil, and neuronavigation might have improved results. Nonspecific clinical effects were likely unequally distributed across blinded and unblinded phases, favoring unblinded outcomes in mixed model analyses; longer prospective blinded studies of iTBS are clearly needed. Neuroimaging was obtained in a convenience subset and evaluated only regions or networks identified in prior studies, an approach that could have influenced findings.

In summary, this first study of iTBS for PTSD demonstrated feasibility and preliminary efficacy on clinical symptoms and social and occupational function. Neuroimaging revealed predictors of clinical improvement, and underscored the role of DMN connectivity. This study reflects an important step forward in the use of TMS outside of major depression, and demonstrates the broader potential of brain stimulation for patients suffering from psychiatric diseases.