White Matter Changes after Neurobehavioral Therapy for Functional Seizures.

OBJECTIVE: We aimed to prospectively quantify changes in white matter morphology after neurobehavioral therapy (NBT) for functional seizures (FS) using neurite orientation dispersion and density imaging (NODDI). We hypothesized that patients with FS would exhibit white matter plasticity in the uncinate fasciculus, fornix/stria terminalis, cingulum, and corticospinal tract following NBT that would correlate with improvements in affective symptoms, postconcussive symptoms, and quality of life (QOL). METHODS: Forty-two patients with traumatic brain injury (TBI) and FS (TBI+FS) underwent NBT and provided pre-/postintervention neuroimaging and behavioral data; 47 controls with TBI without FS (TBI-only) completed the same measures but did not receive NBT. Changes in neurite density, orientation dispersion (orientation dispersion index [ODI]), and extracellular free water (FW) were compared between groups. RESULTS: Significant ODI increases in the left uncinate fasciculus in TBI+FS (mean difference = 0.017, p = 0.039) correlated with improvements in posttraumatic symptoms (r = -0.395, p = 0.013), QOL (r = 0.474, p = 0.002), emotional well-being (r = 0.524, p < 0.001), and energy (r = 0.474, p = 0.002). In TBI-only, ODI decreased (mean difference = -0.008, p = 0.047) and FW increased (mean difference = 0.011, p = 0.003) in the right cingulum. FW increases correlated with increased psychological problems (r = 0.383, p = 0.013). In TBI+FS, NBT resulted in FS decreases of 3.5 seizures per week. None of the imaging changes correlated with FS frequency. INTERPRETATION: We identified white matter changes after NBT in patients with FS that were associated with improved psychosocial functioning. NODDI could be incorporated into future mechanistic assessments of interventions in patients with FS. ANN NEUROL 2023;94:350-365.

Effectiveness of Prefrontal Transcranial Magnetic Stimulation for Depression in Older US Military Veterans.

OBJECTIVE: While typical aging is associated with decreased cortical volume, major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) likely exacerbates this process. Cerebral atrophy leads to increased coil-to-cortex distance and when using transcranial magnetic stimulation (TMS), potentially reducing effectiveness in older adults. METHODS: Data from a large-scale quality improvement project was used. Included veterans eligible for TMS and completed TMS treatment. Age was assessed as a predictive factor of depression outcomes after TMS treatment among veterans. Secondary analyses examined the impact of age on 1) MDD response and remission and 2) MDD change within MDD-only verses comorbid MDD and PTSD groups. RESULTS: The entire sample included 471 veterans. Primary analysis revealed age as a negative predictor of depression outcomes (p = 0.019). Secondary analyses found age to be a significant predictor of remission (p = 0.004), but not clinical response. Age was not a predictive factor in depression outcomes between those with MDD-only compared to MDD+PTSD. CONCLUSIONS: Increased age predicts greater MDD symptom reduction after TMS. Although age did not predict response rates, it did predict increased rates of remission in veterans. Age did not differentially predict depression outcomes between those with or without PTSD. The sample size was sufficient to discern a difference in efficaciousness, and limitations were those inherent to registry studies in veterans. This data indicates that TMS can be an important treatment option for older individuals.

Impulsivity and Psychiatric Diagnoses as Mediators of Suicidal Ideation and Suicide Attempts Among Veterans With Traumatic Brain Injury.

OBJECTIVE: Traumatic brain injury (TBI) is a risk factor for suicide, but questions related to mechanisms remain unanswered. Impulsivity is a risk factor for suicide and is a common sequela of TBI. The authors explored the relationships between TBI and both suicidal ideation and suicide attempts and explored whether impulsivity and comorbid psychiatric diagnoses mediate these relationships. METHODS: This cross-sectional retrospective chart review study included 164 veterans enrolled in a previous study. Sixty-nine veterans had no TBI history, and 95 had a TBI history (mild, N=44; moderate, N=13; severe, N=12; and unclear severity, N=26). To examine the associations between TBI and suicidal ideation or suicide attempts, as well as potential mediators of these relationships, chi-square tests, t tests, and logistic regression models were used. RESULTS: Unadjusted analyses indicated that veterans with TBI were more likely to report suicidal ideation; however, in analyses controlling for mediators, this relationship was no longer significant. Among veterans with TBI, suicidal ideation was related most strongly to high impulsivity (odds ratio=15.35, 95% CI=2.43-96.79), followed by depression (odds ratio=5.73, 95% CI=2.53-12.99) and posttraumatic stress disorder (odds ratio=2.57, 95% CI=1.03-6.42). TBI was not related to suicide attempts, yet suicide attempts were related to high impulsivity (odds ratio=6.95, 95% CI=1.24-38.75) and depression (odds ratio=3.89, 95% CI=1.56-9.40). CONCLUSIONS: These findings suggest that impulsivity, followed by psychiatric diagnoses, most strongly mediate the relationships between TBI and both suicidal ideation and suicide attempts. Impulsivity may be mechanistically related to, and serve as a future treatment target for, suicidality among veterans with TBI.

Altered fronto-limbic-motor response to stress differs between functional and epileptic seizures in a TBI model.

BACKGROUND AND OBJECTIVES: Psychogenic nonepileptic (functional) seizures (FS) clinically resemble epileptic seizures (ES) with both often preceded by traumatic brain injury (TBI). FS and ES emergence and occurrence after TBI may be linked to aberrant neurobehavioral stress responses. We hypothesized that neural activity signatures in response to a psychosocial stress task would differ between TBI + FS and TBI + ES after controlling for TBI status (TBI-only). METHODS: In the current multicenter study, participants were recruited prospectively from Rhode Island Hospital, Providence Rhode Island Veterans Administration Medical Center, and the University of Alabama at Birmingham Medical Center. Previous diagnoses of TBI, ES, and FS were verified based on data collected from participants, medical chart and record review, and, where indicated, results of EEG and/or video-EEG confirmatory diagnosis. TBI + ES (N = 21) and TBI + FS (N = 21) were matched for age and sex and combined into an initial group (TBI + SZ; N = 42). A TBI-only group (N = 42) was age and sex matched to the TBI with seizures (TBI + SZ) group. All participants completed an fMRI control math task (CMT) and stress math task (SMT) based on the Montreal Imaging Stress Task (MIST). RESULTS: The TBI + SZ group (n = 24 female) did not differ in mood or anxiety severity compared to TBI-only group (n = 24 female). However, TBI + FS group (n = 11 female) reported greater severity of these symptoms compared to TBI + ES (n = 13 female). The linear mixed effects analysis identified neural responses that differed between TBI-only and TBI + SZ during math performance within the left premotor cortex and during auditory feedback within bilateral prefrontal cortex and hippocampus/amygdala regions. Additionally, neural responses differed between TBI + ES and TBI + FS during math performance within the right dorsolateral prefrontal cortex and bilateral amygdala during auditory feedback within the supplementary motor area. All tests comparing neural stress responses to psychiatric symptom severity failed to reach significance. DISCUSSION: Controlling for TBI and seizure status, these findings implicate specific nodes within frontal, limbic, and sensorimotor networks that may maintain functional neurological symptoms and possibly distinguish FS from ES. This study provides class II evidence of differences in neural responses to psychosocial stress between ES and FS after TBI.

Relationship between intrinsic network connectivity and psychiatric symptom severity in functional seizures.

BACKGROUND: Traumatic brain injury (TBI) may precipitate the onset of functional seizures (FSs). Many patients with FS report at least one prior TBI, and these patients typically present with more severe psychiatric comorbidities. TBI and psychopathology are linked to changes in neural network connectivity, but their combined effects on these networks and relationship to the effects of FS remain unclear. We hypothesised that resting-state functional connectivity (rsFC) would differ between patients with FS and TBI (FS+TBI) compared with TBI without FS (TBI only), with variability only partially explained by the presence of psychopathology. METHODS: Patients with FS+TBI (n=52) and TBI only (n=54) were matched for age and sex. All participants completed psychiatric assessments prior to resting-state functional MRI at 3 T. Independent component analysis identified five canonical rsFC networks related to emotion and motor functions. RESULTS: Five linear mixed-effects analyses identified clusters of connectivity coefficients that differed between groups within the posterior cingulate of the default mode network, insula and supramarginal gyrus of the executive control network and bilateral anterior cingulate of the salience network (all α=0.05, corrected). Cluster signal extractions revealed decreased contributions to each network for FS+TBI compared to TBI only. Planned secondary analyses demonstrated correlations between signal and severity of mood, anxiety, somatisation and global functioning symptoms. CONCLUSIONS: These findings indicate the presence of aberrant connectivity in FS and extend the biopsychosocial network model by demonstrating that common aetiology is linked to both FS and comorbidities, but the overlap in affected networks varies by comorbid symptoms.

Physical Function Assessment of Older Veterans With Serious Mental Illness.

OBJECTIVE: To characterize the physical function of older veterans with serious mental illness (SMI) across endurance, strength, and mobility domains. DESIGN: Retrospective analysis of clinical performance data. SETTING: Gerofit program, a national outpatient supervised exercise program for older veterans, delivered in Veterans Health Administration sites. PARTICIPANTS: Older veterans aged 60 and older (n = 166 with SMI, n = 1,441 without SMI) enrolled across eight national Gerofit sites between 2010 and 2019. MEASUREMENTS: Performance measures of physical function covering endurance (6-minute walk test), strength (chair stands, arm curls), and mobility (10-m walk, 8-foot-up-and-go), were administered at Gerofit enrollment. Baseline data from these measures were analyzed to characterize the functional profiles of older veterans with SMI. One sample t tests were examined to compare functional performance of older veterans with SMI to age- and sex-based reference scores. Propensity score matching (1:3) and linear mixed effects models were used to evaluate differences in function between veterans with and without SMI. RESULTS: Older veterans with SMI performed worse on all measures of function (chair stands, arm curls, 10-m walk, 6-minute walk test, 8-foot-up-and-go) compared to age- and sex-based reference scores with statistically significant differences present in the male sample. Functional performance of those with SMI was also worse compared to propensity-score matched older veterans without SMI with statistically significant differences on chair stands, 6-minute walk test, and 10-m walk. CONCLUSION: Older veterans with SMI have compromised strength, mobility, and endurance. Physical function should be a core component of screening and treatment for this population.

Repetitive Transcranial Magnetic Stimulation for Depression and Posttraumatic Stress Disorder in Veterans With Mild Traumatic Brain Injury.

OBJECTIVES: Mild traumatic brain injury (mTBI) is a signature injury of military conflicts and is prevalent in veterans with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Although therapeutic transcranial magnetic stimulation (TMS) can reduce symptoms of depression and PTSD, whether traumatic brain injury (TBI) affects TMS responsiveness is not yet known. We hypothesized mTBI would be associated with higher pretreatment symptom burden and poorer TMS response. MATERIALS AND METHODS: We investigated a registry of veterans (N = 770) who received TMS for depression across the US Veterans Affairs system. Of these, 665 (86.4%) had data on TBI and lifetime number of head injuries while 658 had complete data related to depression outcomes. Depression symptoms were assessed using the nine-item Patient Health Questionnaire and PTSD symptoms using the PTSD Checklist for DSM-5. Linear mixed effects models and t-tests evaluated whether head injuries predicted symptom severity before treatment, and how TBI status affected clinical TMS outcomes. RESULTS: Of the 658 veterans included, 337 (50.7%) reported previous mTBI, with a mean of three head injuries (range 1-20). TBI status did not predict depressive symptom severity or TMS-associated changes in depression (all p's > 0.1). TBI status was associated with a modest attenuation of TMS-associated improvement in PTSD (in patients with PTSD Checklist for DSM-5 scores > 33). There was no correlation between the number of head injuries and TMS response (p > 0.1). CONCLUSIONS: Contrary to our hypothesis, presence of mTBI did not meaningfully change TMS outcomes. Veterans with mTBI had greater PTSD symptoms, yet neither TBI status nor cumulative head injuries reduced TMS effectiveness. Limitations include those inherent to retrospective registry studies and self-reporting. Although these findings are contrary to our hypotheses, they support the safety and effectiveness of TMS for MDD and PTSD in patients who have comorbid mTBI.

Regional brain atrophy and aberrant cortical folding relate to anxiety and depression in patients with traumatic brain injury and psychogenic nonepileptic seizures.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) are characterized by multifocal and global abnormalities in brain function and connectivity. Only a few studies have examined neuroanatomic correlates of PNES. Traumatic brain injury (TBI) is reported in 83% of patients with PNES and may be a key component of PNES pathophysiology. In this study, we included patients with TBI preceding the onset of PNES (TBI-PNES) and TBI without PNES (TBI-only) to identify neuromorphometric abnormalities associated with PNES. METHODS: Adults diagnosed with TBI-PNES (n = 62) or TBI-only (n = 59) completed psychological questionnaires and underwent 3-T magnetic resonance imaging. Imaging data were analyzed by voxel- and surface-based morphometry. Voxelwise general linear models computed group differences in gray matter volume, cortical thickness, sulcal depth, fractal dimension (FDf), and gyrification. Statistical models were assessed with permutation-based testing at 5000 iterations with the Threshold-Free Cluster Enhancement toolbox. Logarithmically scaled p-values corrected for multiple comparisons using familywise error were considered significant at p < .05. Post hoc analyses determined the association between structural and psychological measures (p < .05). RESULTS: TBI-PNES participants demonstrated atrophy of the left inferior frontal gyrus and the right cerebellum VIII. Relative to TBI-only, TBI-PNES participants had decreased FDf in the right superior parietal gyrus and decreased sulcal depth in the left insular cortex. Significant clusters were positively correlated with global assessment of functioning scores, and demonstrated varying negative associations with measures of anxiety, depression, somatization, and global severity of symptoms. SIGNIFICANCE: The diagnosis of PNES was associated with brain atrophy and reduced cortical folding in regions implicated in emotion processing, regulation, and response inhibition. Cortical folds primarily develop during the third trimester of pregnancy and remain relatively constant throughout the remainder of one's life. Thus, the observed aberrations in FDf and sulcal depth could originate early in development. The convergence of environmental, developmental, and neurobiological factors may coalesce to reflect the neuropathophysiological substrate of PNES.

Involvement of the brain-heart axis in the link between PTSD and cardiovascular disease.

Posttraumatic stress disorder (PTSD) has long been associated with a heightened risk of cardiovascular disease (CVD). A number of mechanisms have been implicated to underlie this brain-heart axis relationship, such as altered functioning of the autonomic nervous system and increased systemic inflammation. While neural alterations have repeatedly been observed in PTSD, they are rarely considered in the PTSD-CVD link. The brain-heart axis is a pathway connecting frontal and limbic brain regions to the brainstem and periphery via the autonomic nervous system and it may be a promising model for understanding CVD risk in PTSD given its overlap with PTSD neural deficits. We first provide a summary of the primary mechanisms implicated in the association between PTSD and CVD. We then review the brain-heart axis and its relevance to PTSD, as well as findings from PTSD trials demonstrating that a number of PTSD treatments have effects on areas of the brain-heart axis. Finally, we discuss sex considerations in the PTSD-CVD link. A critical next step in this study is to determine if PTSD treatments that affect the brain-heart axis (e.g., brain stimulation that improves autonomic function) also reduce the risk of CVD.

Combined Working Memory Training and Transcranial Magnetic Stimulation Demonstrates Low Feasibility and Potentially Worse Outcomes on Delay to Smoking and Cognitive Tasks: A Randomized 2 × 2 Factorial Design Pilot and Feasibility Study.

INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS) has shown promising results in treating several Substance Use Disorders including Tobacco Use Disorder. However, questions remain regarding how to optimize treatment outcomes. Enhancement of working memory by rTMS is a potential therapeutic mechanism. The current pilot study examined whether rTMS plus a cognitive training program could enhance the effects of rTMS on smoking behaviors using a controlled, factorial design. AIMS AND METHODS: We hypothesized that cognitive training plus stimulation would improve control over smoking behaviors, resulting in enhanced cognitive performance and increased latency to smoke on a delay to smoking analog task. Using a 2 × 2 factorial design, nicotine dependent smokers (n = 43) were randomized to receive 10 sessions of active (10 Hz) or sham rTMS delivered to the left dorsolateral prefrontal cortex, plus active or sham working memory training (WMT) prior to and following stimulation. RESULTS: Contrary to hypotheses, we observed a significant interaction effect, indicating that combining the two active interventions (rTMS+WMT) resulted in worse performance on the smoking analog task (B = -33.0, 95% CI = -64.39, -1.61, p < .05), compared to delivering either intervention alone. Additionally, although active rTMS (compared to sham rTMS) improved letter-sequencing performance (B = 1.23, 95% CI = 0.08-2.38, p < .05), and active WMT (compared to sham WMT) improved back-digit task performance (B = 1.53, 95% CI = 0.02-3.05, p < .05), combining interventions worsened the effect of each on a back-digit task (B = -3.01, 95% CI = -5.96, -0.052, p < .05). CONCLUSIONS: These preliminary findings indicate potential iatrogenic effects of combining rTMS and this working memory training intervention and underscore the need for rigorous evaluation of substance specific conceptual frameworks when selecting future combination interventions. IMPLICATIONS: Counter to hypothesis, this study found no additional benefit of adding a working memory training program to a rTMS protocol in a sample of daily smokers. The combination condition (active rTMS + active training) resulted in worse performance on a delay to smoking analog task and a measure of working memory performance compared to delivering either intervention alone. These preliminary findings inform strategies for optimizing rTMS in smokers and highlight the need for future studies to consider several key components of candidate combination interventions, including effects on regulation of substance use. CLINICAL TRIAL REGISTRATION (IF ANY): The trial was registered at ClinicalTrials.gov (NCT03337113).

Diagnostic delay in functional seizures is associated with abnormal processing of facial emotions.

PURPOSE: In patients with functional seizures (FS), delay in diagnosis (DD) may negatively affect outcomes. Altered brain responses to emotional stimuli have been shown in adults with FS. We hypothesized that DD would be associated with differential fMRI activation in emotion processing circuits. METHODS: Fifty-two adults (38 females) with video-EEG confirmed FS prospectively completed assessments related to symptoms of depression (BDI-II), anxiety (BAI), post-traumatic stress disorder (PCL-S), a measure of how their symptoms affect day-to-day life (GAF), and fMRI at 3T with emotional faces task (EFT). During fMRI, subjects indicated "male" or "female" via button press while implicitly processing happy, sad, fearful, and neutral faces. Functional magnetic resonance imaging (FMRI) response to each emotion was modeled and group analyses were performed in AFNI within pre-specified regions-of-interest involved in emotion processing. A median split (507 days) defined short- (s-DD) and long-delay diagnosis (l-DD) groups. Voxelwise regression analyses were also performed to examine linear relationship between DD and emotion processing. FMRI signal was extracted from clusters showing group differences and Spearman's correlations assessed relationships with symptom scores. RESULTS: Groups did not differ in FS age of onset, sex distribution, years of education, TBI characteristics, EFT in-scanner or post-test performance, or scores on the GAF, BDI-II, BAI, and PCL-S measures. The s-DD group was younger than l-DD (mean age 32.6 vs. 40.1; p = 0.022) at the time of study participation. After correcting for age, compared to s-DD, the l-DD group showed greater fMRI activation to sad faces in the bilateral posterior cingulate cortex (PCC) and to neutral faces in the right anterior insula. Within-group linear regression revealed that with increasing DD, there was increased fMRI activation to sad faces in the PCC and to happy faces in the right anterior insula/inferior frontal gyrus (AI/IFG). There were positive correlations between PCC response to sad faces and BDI-II scores in the l-DD group (rho = 0.48, p = 0.012) and the combined sample (rho = 0.30, p = 0.029). Increased PCC activation to sad faces in those in the l-DD group was associated with worse symptoms of depression (i.e. higher BDI-II score). CONCLUSIONS: Delay in FS diagnosis is associated with fMRI changes in PCC and AI/IFG. As part of the default mode network, PCC is implicated in mood control, self-referencing, and other emotion-relevant processes. In our study, PCC changes are linked to depression. Future studies should assess the effects of interventions on these abnormalities.

Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder and Major Depression: Comparing Commonly Used Clinical Protocols.

Transcranial magnetic stimulation (TMS) is increasingly being used to treat posttraumatic stress disorder (PTSD) comorbid with major depressive disorder (MDD). Yet, identifying the most effective stimulation parameters remains an active area of research. We recently reported on the use of 5 Hz TMS to reduce PTSD and MDD symptoms. A recently developed form of TMS, intermittent theta burst stimulation (iTBS), appears noninferior for treating MDD. Because iTBS can be delivered in a fraction of the time, it provides significant logistical advantages; however, evaluations of whether iTBS provides comparable PTSD and MDD symptom reductions are lacking. We performed a retrospective chart review comparing clinical outcomes in veterans with PTSD and MDD who received iTBS (n = 10) with a matched cohort that received 5-Hz TMS (n = 10). Symptoms were evaluated using self-reported rating scales at baseline and every five treatments for up to 30 sessions. Both protocols were safe and reduced symptoms, ps < .001, but veterans who received iTBS reported poorer outcomes. These results were observed using mixed-model analyses, Group x Time interaction: p = .011, and effect sizes, where 5 Hz TMS demonstrated superior PTSD and MDD symptom improvement, ds = 1.81 and 1.51, respectively, versus iTBS, ds = 0.63 and 0.88, respectively. Data from prior controlled trials of iTBS, with increased stimulation exposure, have appeared to provide comparable clinical outcomes compared with 5 Hz TMS. Prospective and controlled comparisons are required; however, the present findings provide important information for clinicians using TMS to treat these commonly comorbid disorders.

Heart Rate Variability Features as Predictors of Intermittent Theta-Burst Stimulation Response in Posttraumatic Stress Disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with autonomic dysfunction as indicated by deficits in the sympathetic and parasympathetic nervous systems. These abnormalities are expressed as elevated heart rate and reduced heart rate variability (HRV), respectively. Intermittent theta-burst stimulation (iTBS), a form of transcranial magnetic stimulation, has demonstrated effectiveness in PTSD. Nevertheless, it remains unclear whether HRV may be an iTBS biomarker for PTSD and whether iTBS impacts autonomic activity. MATERIALS AND METHODS: Fifty veterans with PTSD participated in a randomized controlled trial, receiving ten daily sessions of sham-controlled iTBS (right dorsolateral prefrontal cortex, 1800 pulses/day, 80% active motor threshold, 9.5 min). With a usable dataset (N = 47), HRV parameters were assessed as predictors of clinical response immediately after stimulation. iTBS effects on autonomic response (mean RR interval, root mean square of successive differences [RMSSD], total power [TP], and low-frequency/high-frequency [LF/HF] ratio) were evaluated using an ultra-short approach. RESULTS: TP and RMSSD were significant predictors of acute clinical response to iTBS. Individuals with higher TP had better response to iTBS with improved symptoms on the Clinician-Administered PTSD Scale (rs = -0.58, p = 0.004), and higher functionality on the Social and Occupational Function Scale (rs = 0.43, p = 0.04). Similarly, higher RMSSD was associated with superior outcomes (rs = -0.44, p = 0.04). No other significant changes in HRV metrics were observed (p ≥ 0.05). CONCLUSIONS: Our findings indicate that autonomic activity is a potential low-cost and technically simple predictive biomarker of iTBS response in PTSD. Less autonomic dysfunction was associated with superior clinical improvements with iTBS. Future studies might consider HRV acquisition during iTBS, as well as prospective testing of these findings in patients with elevated hyperarousal.

Changes in functional connectivity after theta-burst transcranial magnetic stimulation for post-traumatic stress disorder: a machine-learning study.

Intermittent theta burst stimulation (iTBS) is a novel treatment approach for post-traumatic stress disorder (PTSD), and recent neuroimaging work indicates that functional connectivity profiles may be able to identify those most likely to respond. However, prior work has relied on functional magnetic resonance imaging, which is expensive and difficult to scale. Alternatively, electroencephalography (EEG) represents a different approach that may be easier to implement in clinical practice. To this end, we acquired an 8-channel resting-state EEG signal on participants before (n = 47) and after (n = 43) randomized controlled trial of iTBS for PTSD (ten sessions, delivered at 80% of motor threshold, 1,800 pulses, to the right dorsolateral prefrontal cortex). We used a cross-validated support vector machine (SVM) to track changes in EEG functional connectivity after verum iTBS stimulation. We found that an SVM classifier was able to successfully separate patients who received active treatment vs. sham treatment, with statistically significant findings in the Delta band (1-4 Hz, p = 0.002). Using Delta coherence, the classifier was 75.0% accurate in detecting sham vs. active iTBS, and observed changes represented an increase in functional connectivity between midline central/occipital and a decrease between frontal and central regions. The primary limitations of this work are the sparse electrode system and a modest sample size. Our findings raise the possibility that EEG and machine learning may be combined to provide a window into mechanisms of action of TMS, with the potential that these approaches can inform the development of individualized treatment methods.

Identifying response and predictive biomarkers for Transcranial magnetic stimulation outcomes: protocol and rationale for a mechanistic study of functional neuroimaging and behavioral biomarkers in veterans with Pharmacoresistant depression.

BACKGROUND: Although repetitive transcranial magnetic stimulation ('TMS') is becoming a gold standard treatment for pharmacoresistant depression, we lack neural target biomarkers for identifying who is most likely to respond to TMS and why. To address this gap in knowledge we evaluate neural targets defined by activation and functional connectivity of the dorsolateral prefrontal cortex-anchored cognitive control circuit, regions of the default mode network and attention circuit, and interactions with the subgenual anterior cingulate. We evaluate whether these targets and interactions between them change in a dose-dependent manner, whether changes in these neural targets correspond to changes in cognitive behavioral performance, and whether baseline and early change in neural target and cognitive behavioral performance predict subsequent symptom severity, suicidality, and quality of life outcomes. This study is designed as a pragmatic, mechanistic trial partnering with the National Clinical TMS Program of the Veteran's Health Administration. METHODS: Target enrollment consists of 100 veterans with pharmacoresistant Major Depressive Disorder (MDD). All veterans will receive a clinical course of TMS and will be assessed at 'baseline' pre-TMS commencement, 'first week' after initiation of TMS (targeting five sessions) and 'post-treatment' at the completion of TMS (targeting 30 sessions). Veterans will be assessed using functional magnetic resonance imaging (fMRI), a cognitive behavioral performance battery, and established questionnaires. Multivariate linear mixed models will be used to assess whether neural targets change with TMS as a function of dose (Aim 1), whether extent and change of neural target relates to and predicts extent of behavioral performance (Aim 3), and whether extent of neural target change predicts improvement in symptom severity, suicidality, and quality of life (Aim 3). For all three aims, we will also assess the contribution of baseline moderators such as biological sex and age. DISCUSSION: To our knowledge, our study will be the first pragmatic, mechanistic observational trial to use fMRI imaging and cognitive-behavioral performance as biomarkers of TMS treatment response in pharmacoresistant MDD. The results of this trial will allow providers to select suitable candidates for TMS treatment and better predict treatment response by assessing circuit connectivity and cognitive-behavioral performance at baseline and during early treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663481 , December 5th, 2020, retrospectively registered. The first veteran was enrolled October 30th, 2020.

Multimodal Elements of Suicidality Reduction After Transcranial Magnetic Stimulation.

OBJECTIVES: Repetitive transcranial magnetic stimulation (TMS) is a promising treatment for suicidality, but it is underlying neural mechanisms remain poorly understood. Our prior findings indicated that frontostriatal functional connectivity correlates with the severity of suicidal thoughts and behaviors. In this secondary analysis of data from an open label trial, we evaluated whether changes in frontostriatal functional connectivity would accompany suicidality reductions following TMS. We also explored the relationship between frontostriatal connectivity change and underlying white matter (WM) organization. MATERIALS AND METHODS: We conducted seed-based functional connectivity analysis on participants (N = 25) with comorbid post-traumatic stress disorder and depression who received eight weeks of 5 Hz TMS to left dorsolateral prefrontal cortex. We measured clinical symptoms with the Inventory of Depressive Symptomatology-Self Report (IDS-SR) and the PTSD Checklist for DSM-5 (PCL-5). We derived suicidality from IDS-SR item 18. Magnetic resonance imaging data were collected before TMS, and at treatment end point. These data were entered into analyses of covariance, evaluating the effect of suicidality change across treatment on striatal and thalamic functional connectivity. Changes in other PTSD and depression symptoms were included as covariates and results were corrected for multiple comparisons. Diffusion connectometry in a participant subsample (N = 17) explored the relationship between frontal WM integrity at treatment baseline and subsequent functional connectivity changes correlated with differences in suicidality. RESULTS: Suicidal ideation decreased in 65% of participants. Reductions in suicidality and functional connectivity between the dorsal striatum and frontopolar cortex were correlated (p-False Discover Rate-corrected < 0.001), after covariance for clinical symptom change. All other results were nonsignificant. Our connectometry results indicated that the integrity of frontostriatal WM may circumscribe functional connectivity response to TMS for suicide. CONCLUSIONS: Targeted reduction of fronto-striatal connectivity with TMS may be a promising treatment for suicidality. Future research can build on this multimodal approach to advance individualized stimulation approaches in high-risk patients.

A Secondary Analysis on Effects of Theta Burst Transcranial Magnetic Stimulation to Reduce Anger in Veterans With Posttraumatic Stress Disorder.

INTRODUCTION: Anger is an important clinical feature of posttraumatic stress disorder (PTSD) that can hamper recovery. We recently reported that intermittent theta burst stimulation (iTBS) demonstrated preliminary efficacy to reduce symptoms of posttraumatic stress disorder and major depression; here, we performed a secondary analysis testing whether iTBS reduced symptoms of anger over the course of iTBS treatment and compared to sham stimulation. MATERIALS AND METHODS: Fifty veterans with chronic PTSD received ten daily sessions of sham-controlled, double-blind iTBS (1800 pulses/session, once per weekday) targeting the right dorsolateral prefrontal cortex (intent-to-treat = 25 per group). Participants who completed the double-blind phase were offered another ten sessions of unblinded iTBS. Participants completed the Dimensions of Anger Reactions scale at pre-iTBS baseline, treatment midpoints, and endpoints of the blinded and unblinded phases, and at one-month after the last stimulation session. Correlations between anger, PTSD, depression, and sleep were also explored. RESULTS: After the first week, during the double-blind phase, participants randomized to active stimulation reported significantly reduced anger compared to sham stimulation (p = 0.04). Participants initially randomized to sham appeared to catch-up to the point they no longer differed from those initially randomized to active iTBS when they received iTBS during the unblinded phase (p = 0.14). Anger reduction was maintained at one-month after iTBS in participants initially randomized to active stimulation (i.e., total of four weeks of iTBS). CONCLUSIONS: This secondary analysis suggests that iTBS might reduce anger in veterans with PTSD. Future studies focused on more granular level anger outcomes and effects of number of stimulation sessions are needed.

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

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 9 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 with 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.

White matter integrity and functional predictors of response to repetitive transcranial magnetic stimulation for posttraumatic stress disorder and major depression.

BACKGROUND: Recent evidence suggests that therapeutic repetitive transcranial magnetic stimulation (TMS) is an effective treatment for pharmacoresistant posttraumatic stress disorder (PTSD) and comorbid major depressive disorder (MDD). We recently demonstrated that response to 5 Hz TMS administered to the dorsolateral prefrontal cortex was predicted by functional connectivity of the medial prefrontal (MPFC) and subgenual anterior cingulate cortex (sgACC). This functionally-defined circuit is a novel target for treatment optimization research, however, our limited knowledge of the structural pathways that underlie this functional predisposition is a barrier to target engagement research. METHODS: To investigate underlying structural elements of our previous functional connectivity findings, we submitted pre-TMS diffusion-weighted imaging data from 20 patients with PTSD and MDD to anatomically constrained tract-based probabilistic tractography (FreeSurfer's TRActs Constrained by UnderLying Anatomy). Averaged pathway fractional anisotropy (FA) was extracted from four frontal white matter tracts: the forceps minor, cingulum, anterior thalamic radiations (ATRs), and uncinate fasciculi. Tract FA statistics were treated as explanatory variables in backward regressions testing the relationship between tract integrity and functional connectivity coefficients from MPFC and sgACC predictors of symptom improvement after TMS. RESULTS: FA in the ATRs was consistently associated with symptom improvement in PTSD and MDD (Bonferroni-corrected p < .05). CONCLUSION: We found that structural characteristics of the ATR account for significant variance in individual-level functional predictors of post-TMS improvement. TMS optimization studies should target this circuit either in stand-alone or successive TMS stimulation protocols.

Predictors of response to synchronized transcranial magnetic stimulation for major depressive disorder.

BACKGROUND: Synchronized transcranial magnetic stimulation (sTMS) is a new modality to reduce symptoms of major depressive disorder (MDD). sTMS uses rotating neodymium magnets to deliver low-field stimulation matched to the individual alpha frequency (IAF). A previous multisite study showed that sTMS significantly reduced MDD symptoms in the per-protocol sample. To this end, we evaluated clinical features associated with optimal sTMS outcomes. METHODS: Using the per-protocol sample (n = 120) from the parent sham-controlled trial, we performed univariate and stepwise linear regression to identify predictors of response after 6 weeks of sTMS. A subsample (n = 83) that entered a 4-week open/active continuation phase also was examined. Candidate variables included age, sex, comorbid anxiety, number of failed antidepressants in the current depressive episode, MDD severity (17-item Hamilton Depression Rating Scale; HAMD17), anxiety symptom severity (HAMD17 anxiety/somatization factor), and IAF. RESULTS: We found that greater baseline depressive (p < 0.001) and anxiety (p < 0.001) symptom severity were associated with better response to active sTMS, whereas fewer failed antidepressant trials predicted superior response to sham (p < 0.001). MDD severity and antidepressant resistance predicted outcomes in open/active phase sTMS; lower IAF predicted poorer response in participants who received 10 weeks of active sTMS (p = 0.001). CONCLUSIONS: Participants with greater severity of depression and higher anxiety had superior responses to active sTMS, whereas treatment naïve individuals exhibited a greater response to sham. These results lend support to the primary efficacy findings, and support further investigation of sTMS as a therapeutic noninvasive brain stimulation modality.