TMS provokes target-dependent intracranial rhythms across human cortical and subcortical sites.

BACKGROUND: Transcranial magnetic stimulation (TMS) is believed to alter ongoing neural activity and cause circuit-level changes in brain function. While the electrophysiological effects of TMS have been extensively studied with scalp electroencephalography (EEG), this approach generally evaluates low-frequency neural activity at the cortical surface. However, TMS can be safely used in patients with intracranial electrodes (iEEG), allowing for direct assessment of deeper and more localized oscillatory responses across the frequency spectrum. OBJECTIVE/HYPOTHESIS: Our study used iEEG to understand the effects of TMS on human neural activity in the spectral domain. We asked (1) which brain regions respond to cortically-targeted TMS, and in what frequency bands, (2) whether deeper brain structures exhibit oscillatory responses, and (3) whether the neural responses to TMS reflect evoked versus induced oscillations. METHODS: We recruited 17 neurosurgical patients with indwelling electrodes and recorded neural activity while patients underwent repeated trials of single-pulse TMS at either the dorsolateral prefrontal cortex (DLPFC) or parietal cortex. iEEG signals were analyzed using spectral methods to understand the oscillatory responses to TMS. RESULTS: Stimulation to DLPFC drove widespread low-frequency increases (3-8Hz) in frontolimbic cortices and high-frequency decreases (30-110Hz) in frontotemporal areas, including the hippocampus. Stimulation to parietal cortex specifically provoked low-frequency responses in the medial temporal lobe. While most low-frequency activity was consistent with phase-locked evoked responses, anterior frontal regions exhibited induced theta oscillations following DLPFC stimulation. CONCLUSIONS: By combining TMS with intracranial EEG recordings, our results suggest that TMS is an effective means to perturb oscillatory neural activity in brain-wide networks, including deeper structures not directly accessed by stimulation itself.

Corrigendum: Early improvement predicts clinical outcomes similarly in 10 Hz rTMS and iTBS therapy for depression.

[This corrects the article DOI: 10.3389/fpsyt.2022.863225.].

Effects of transcranial magnetic stimulation on the human brain recorded with intracranial electrocorticography.

Transcranial magnetic stimulation (TMS) is increasingly used as a noninvasive technique for neuromodulation in research and clinical applications, yet its mechanisms are not well understood. Here, we present the neurophysiological effects of TMS using intracranial electrocorticography (iEEG) in neurosurgical patients. We first evaluated safety in a gel-based phantom. We then performed TMS-iEEG in 22 neurosurgical participants with no adverse events. We next evaluated intracranial responses to single pulses of TMS to the dorsolateral prefrontal cortex (dlPFC) (N = 10, 1414 electrodes). We demonstrate that TMS is capable of inducing evoked potentials both locally within the dlPFC and in downstream regions functionally connected to the dlPFC, including the anterior cingulate and insular cortex. These downstream effects were not observed when stimulating other distant brain regions. Intracranial dlPFC electrical stimulation had similar timing and downstream effects as TMS. These findings support the safety and promise of TMS-iEEG in humans to examine local and network-level effects of TMS with higher spatiotemporal resolution than currently available methods.

Supra-second interval timing in bipolar disorder: examining the role of disorder sub-type, mood, and medication status.

BACKGROUND: Widely reported by bipolar disorder (BD) patients, cognitive symptoms, including deficits in executive function, memory, attention, and timing are under-studied. Work suggests that individuals with BD show impairments in interval timing tasks, including supra-second, sub-second, and implicit motor timing compared to the neuronormative population. However, how time perception differs within individuals with BD based on disorder sub-type (BDI vs II), depressed mood, or antipsychotic medication-use has not been thoroughly investigated. The present work administered a supra-second interval timing task concurrent with electroencephalography (EEG) to patients with BD and a neuronormative comparison group. As this task is known to elicit frontal theta oscillations, signal from the frontal (Fz) lead was analyzed at rest and during the task. RESULTS: Results suggest that individuals with BD show impairments in supra-second interval timing and reduced frontal theta power during the task compared to neuronormative controls. However, within BD sub-groups, neither time perception nor frontal theta differed in accordance with BD sub-type, depressed mood, or antipsychotic medication use. CONCLUSIONS: This work suggests that BD sub-type, depressed mood status or antipsychotic medication use does not alter timing profile or frontal theta activity. Together with previous work, these findings point to timing impairments in BD patients across a wide range of modalities and durations indicating that an altered ability to assess the passage of time may be a fundamental cognitive abnormality in BD.

A randomized trial comparing beam F3 and 5.5 cm targeting in rTMS treatment of depression demonstrates similar effectiveness.

BACKGROUND: The Beam F3 and 5.5 cm methods are the two most common targeting strategies for localizing the left dorsolateral prefrontal cortex (DLPFC) treatment site in repetitive transcranial magnetic stimulation (rTMS) protocols. This prospective, randomized, double-blind comparative effectiveness trial assesses the clinical outcomes for these two methods in a naturalistic sample of patients with major depressive disorder (MDD) undergoing clinical rTMS treatment. METHODS: 105 adult patients with MDD (mean age = 43.2; range = 18-73; 66% female) were randomized to receive rTMS to the Beam F3 (n = 58) or 5.5 cm (n = 47) target. Between group differences from pre-to post-treatment were evaluated with the Patient Health Questionnaire-9 (PHQ-9) [primary outcome measure], Generalized Anxiety Disorder-7 (GAD-7), and clinician-administered Montgomery-Åsberg Depression Scale (MADRS). Primary treatment endpoint was completion of daily treatment series. RESULTS: Per-protocol analyses showed no statistically significant differences on any measure between the 5.5 cm and F3 groups (all p ≥ 0.50), including percent improvement (PHQ-9: 39% vs. 39%; GAD-7: 34% vs. 27%; MADRS: 40% vs. 38%), response rate (PHQ-9: 37% vs. 43%; GAD-7: 27% vs. 30%; MADRS: 43% vs. 43%), and remission rate (PHQ-9: 22% vs. 21%; MADRS: 20% vs. 19%). Post hoc analysis of anxiety symptom change while controlling for depression severity suggested more favorable anxiolytic effects with 5.5 cm targeting (p = 0.03). CONCLUSIONS: Similar antidepressant effects were observed with DLFPC rTMS using either the Beam F3 or 5.5 cm targeting method, supporting clinical equipoise in MDD patients with head circumference ≤ 60 cm. Comparison to MRI-based targeting and differential effects on anxiety symptoms require further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03378570.

TMS provokes target-dependent intracranial rhythms across human cortical and subcortical sites.

Transcranial magnetic stimulation (TMS) is increasingly deployed in the treatment of neuropsychiatric illness, under the presumption that stimulation of specific cortical targets can alter ongoing neural activity and cause circuit-level changes in brain function. While the electrophysiological effects of TMS have been extensively studied with scalp electroencephalography (EEG), this approach is most useful for evaluating low-frequency neural activity at the cortical surface. As such, little is known about how TMS perturbs rhythmic activity among deeper structures - such as the hippocampus and amygdala - and whether stimulation can alter higher-frequency oscillations. Recent work has established that TMS can be safely used in patients with intracranial electrodes (iEEG), allowing for direct neural recordings at sufficient spatiotemporal resolution to examine localized oscillatory responses across the frequency spectrum. To that end, we recruited 17 neurosurgical patients with indwelling electrodes and recorded neural activity while patients underwent repeated trials of single-pulse TMS at several cortical sites. Stimulation to the dorsolateral prefrontal cortex (DLPFC) drove widespread low-frequency increases (3-8Hz) in frontolimbic cortices, as well as high-frequency decreases (30-110Hz) in frontotemporal areas, including the hippocampus. Stimulation to parietal cortex specifically provoked low-frequency responses in the medial temporal lobe. While most low-frequency activity was consistent with brief evoked responses, anterior frontal regions exhibited induced theta oscillations following DLPFC stimulation. Taken together, we established that non-invasive stimulation can (1) provoke a mixture of low-frequency evoked power and induced theta oscillations and (2) suppress high-frequency activity in deeper brain structures not directly accessed by stimulation itself.

Supra-second interval timing in bipolar disorder: examining the role of disorder sub-type, mood, and medication status.

Background : Widely reported by bipolar disorder (BD) patients, cognitive symptoms, including deficits in executive function, memory, attention, and timing are under-studied. Work suggests that individuals with BD show impairments in interval timing tasks, including supra-second, sub-second, and implicit motor timing compared to the neuronormative population. However, how time perception differs within individuals with BD based on BD sub-type (BDI vs II), mood, or antipsychotic medication-use has not been thoroughly investigated. The present work administered a supra-second interval timing task concurrent with electroencephalography (EEG) to patients with BD and a neuronormative comparison group. As this task is known to elicit frontal theta oscillations, signal from the frontal (Fz) lead was analyzed at rest and during the task. Results : Results suggest that individuals with BD show impairments in supra-second interval timing and reduced frontal theta power compared during the task to neuronormative controls. However, within BD sub-groups, neither time perception nor frontal theta differed in accordance with BD sub-type, mood, or antipsychotic medication use. Conclusions : his work suggests that BD sub-type, mood status or antipsychotic medication use does not alter timing profile or frontal theta activity. Together with previous work, these findings point to timing impairments in BD patients across a wide range of modalities and durations indicating that an altered ability to assess the passage of time may be a fundamental cognitive abnormality in BD.

Individualized precision targeting of dorsal attention and default mode networks with rTMS in traumatic brain injury-associated depression.

At the group level, antidepressant efficacy of rTMS targets is inversely related to their normative connectivity with subgenual anterior cingulate cortex (sgACC). Individualized connectivity may yield better targets, particularly in patients with neuropsychiatric disorders who may have aberrant connectivity. However, sgACC connectivity shows poor test-retest reliability at the individual level. Individualized resting-state network mapping (RSNM) can reliably map inter-individual variability in brain network organization. Thus, we sought to identify individualized RSNM-based rTMS targets that reliably target the sgACC connectivity profile. We used RSNM to identify network-based rTMS targets in 10 healthy controls and 13 individuals with traumatic brain injury-associated depression (TBI-D). These "RSNM targets" were compared with consensus structural targets and targets based on individualized anti-correlation with a group-mean-derived sgACC region ("sgACC-derived targets"). The TBI-D cohort was also randomized to receive active (n = 9) or sham (n = 4) rTMS to RSNM targets with 20 daily sessions of sequential high-frequency left-sided stimulation and low-frequency right-sided stimulation. We found that the group-mean sgACC connectivity profile was reliably estimated by individualized correlation with default mode network (DMN) and anti-correlation with dorsal attention network (DAN). Individualized RSNM targets were thus identified based on DAN anti-correlation and DMN correlation. These RSNM targets showed greater test-retest reliability than sgACC-derived targets. Counterintuitively, anti-correlation with the group-mean sgACC connectivity profile was also stronger and more reliable for RSNM-derived targets than for sgACC-derived targets. Improvement in depression after RSNM-targeted rTMS was predicted by target anti-correlation with the portions of sgACC. Active treatment also led to increased connectivity within and between the stimulation sites, the sgACC, and the DMN. Overall, these results suggest that RSNM may enable reliable individualized rTMS targeting, although further research is needed to determine whether this personalized approach can improve clinical outcomes.

Amygdala lesions are associated with improved mood after epilepsy surgery.

Neuroimaging studies in healthy and clinical populations strongly associate the amygdala with emotion, especially negative emotions. The consequences of surgical resection of the amygdala on mood are not well characterized. We tested the hypothesis that amygdala resection would result in mood improvement. In this study, we evaluated a cohort of 52 individuals with medial temporal lobectomy for intractable epilepsy who had resections variably involving the amygdala. All individuals achieved good post-surgical seizure control and had pre- and post-surgery mood assessment with the Beck Depression Inventory (BDI) ratings. We manually segmented the surgical resection cavities and performed multivariate lesion-symptom mapping of change in BDI. Our results showed a significant improvement in average mood ratings from pre- to post-surgery across all patients. In partial support of our hypothesis, resection of the right amygdala was significantly associated with mood improvement (r = 0.5, p = 0.008). The lesion-symptom map also showed that resection of the right hippocampus and para-hippocampal gyrus was associated with worsened post-surgical mood. Future studies could evaluate this finding prospectively in larger samples while including other neuropsychological outcome measures.

Neuroimaging Correlates of Post-Traumatic Stress Disorder in Traumatic Brain Injury: A Systematic Review of the Literature.

Neuroimaging is widely utilized in studying traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). The risk for PTSD is greater after TBI than after non-TBI trauma, and PTSD is associated with worse outcomes after TBI. Studying the neuroimaging correlates of TBI-related PTSD may provide insights into the etiology of both conditions and help identify those TBI patients most at risk of developing persistent symptoms. The objectives of this systematic review were to examine the current literature on neuroimaging in TBI-related PTSD, summarize key findings, and highlight strengths and limitations to guide future research. A Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) compliant literature search was conducted in PubMed (MEDLINE®), PsycINFO, Embase, and Scopus databases prior to January 2022. The database query yielded 4486 articles, which were narrowed based on specified inclusion criteria to a final cohort of 16 studies, composed of 854 participants with TBI. There was no consensus regarding neuroimaging correlates of TBI-related PTSD among the included articles. A small number of studies suggest that TBI-related PTSD is associated with white matter tract changes, particularly in frontotemporal regions, as well as changes in whole-brain networks of resting-state connectivity. Future studies hoping to identify reliable neuroimaging correlates of TBI-related PTSD would benefit from ensuring consistent case definition, preferably with clinician-diagnosed TBI and PTSD, selection of comparable control groups, and attention to imaging timing post-injury. Prospective studies are needed and should aim to further differentiate predisposing factors from sequelae of TBI-related PTSD.

Large-scale lesion symptom mapping of depression identifies brain regions for risk and resilience.

Understanding neural circuits that support mood is a central goal of affective neuroscience, and improved understanding of the anatomy could inform more targeted interventions in mood disorders. Lesion studies provide a method of inferring the anatomical sites causally related to specific functions, including mood. Here, we performed a large-scale study evaluating the location of acquired, focal brain lesions in relation to symptoms of depression. Five hundred and twenty-six individuals participated in the study across two sites (356 male, average age 52.4 ± 14.5 years). Each subject had a focal brain lesion identified on structural imaging and an assessment of depression using the Beck Depression Inventory-II, both obtained in the chronic period post-lesion (>3 months). Multivariate lesion-symptom mapping was performed to identify lesion sites associated with higher or lower depression symptom burden, which we refer to as 'risk' versus 'resilience' regions. The brain networks and white matter tracts associated with peak regional findings were identified using functional and structural lesion network mapping, respectively. Lesion-symptom mapping identified brain regions significantly associated with both higher and lower depression severity (r = 0.11; P = 0.01). Peak 'risk' regions include the bilateral anterior insula, bilateral dorsolateral prefrontal cortex and left dorsomedial prefrontal cortex. Functional lesion network mapping demonstrated that these 'risk' regions localized to nodes of the salience network. Peak 'resilience' regions include the right orbitofrontal cortex, right medial prefrontal cortex and right inferolateral temporal cortex, nodes of the default mode network. Structural lesion network mapping implicated dorsal prefrontal white matter tracts as 'risk' tracts and ventral prefrontal white matter tracts as 'resilience' tracts, although the structural lesion network mapping findings did not survive correction for multiple comparisons. Taken together, these results demonstrate that lesions to specific nodes of the salience network and default mode network are associated with greater risk versus resiliency for depression symptoms in the setting of focal brain lesions.

Depression symptoms in neurological patients: A survey of a large cohort of patients with focal brain lesions.

INTRODUCTION: Examining depression following neurological injury is useful for understanding post-lesion depression and depression more generally. The extant literature shows variability in the incidence and severity of depression post-lesion, likely due to heterogeneity in study methodology, patient samples, measures of depression, and time of assessment. Here, we aim to characterize depression symptoms and their demographic correlates in a large sample of individuals in the chronic epoch following a focal brain lesion. METHOD: We sampled 492 individuals who had focal, stable brain lesions and were in the chronic epoch (≥3 months post-onset). Demographic (gender, years of education), temporal (age at lesion onset, time since lesion onset), and lesion (lesion laterality, lesion etiology, lesion volume) factors were used to predict depression symptoms measured by the Beck Depression Inventory (BDI). RESULTS: We found that on average, neurological patients exhibited elevated levels of depression symptoms (although not clinically significant) relative to a community sample, and the neurological patients showed higher rates of mild and moderate depression symptoms than are typical in a community sample. Gender and lesion etiology were predictive of depression symptoms, whereby women and patients with ischemic stroke had higher levels of depression symptoms. CONCLUSIONS: Our results suggest that depression symptom severity may be elevated following a focal brain lesion. Moreover, some individuals may be more likely to develop depression symptoms post-lesion than others. This may be mediated by individual factors such as gender and lesion etiology. The findings have important implications for the diagnosis, prognosis, and treatment of depression in neurological patients.

National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

Behavioral and Emotional Dyscontrol Following Traumatic Brain Injury: A Systematic Review of Neuroimaging and Electrophysiological Correlates.

BACKGROUND: Behavioral and emotional dyscontrol commonly occur following traumatic brain injury (TBI). Neuroimaging and electrophysiological correlates of dyscontrol have not been systematically summarized in the literature to date. OBJECTIVE: To complete a systematic review of the literature examining neuroimaging and electrophysiological findings related to behavioral and emotional dyscontrol due to TBI. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant literature search was conducted in PubMed (MEDLINE), PsycINFO, EMBASE, and Scopus databases prior to May 2019. The database query yielded 4392 unique articles. These articles were narrowed based on specific inclusion criteria (e.g., clear TBI definition, statistical analysis of the relationship between neuroimaging and dyscontrol). RESULTS: A final cohort of 24 articles resulted, comprising findings from 1552 patients with TBI. Studies included civilian (n = 12), military (n = 10), and sport (n = 2) samples with significant variation in the severity of TBI incorporated. Global and region-based structural imaging was more frequently used to study dyscontrol than functional imaging or diffusion tensor imaging. The prefrontal cortex was the most common neuroanatomical region associated with behavioral and emotional dyscontrol, followed by other frontal and temporal lobe findings. CONCLUSIONS: Frontal and temporal lesions are most strongly implicated in the development of postinjury dyscontrol symptoms although they are also the most frequently investigated regions of the brain for these symptom categories. Future studies can make valuable contributions to the field by (1) emphasizing consistent definitions of behavioral and emotional dyscontrol, (2) assessing premorbid dyscontrol symptoms in subjects, (3) utilizing functional or structural connectivity-based imaging techniques, or (4) restricting analyses to more focused brain regions.

Early Improvement Predicts Clinical Outcomes Similarly in 10 Hz rTMS and iTBS Therapy for Depression.

Background: Prior studies have demonstrated that early treatment response with transcranial magnetic stimulation (TMS) can predict overall response, yet none have directly compared that predictive capacity between intermittent theta-burst stimulation (iTBS) and 10 Hz repetitive transcranial magnetic stimulation (rTMS) for depression. Our study sought to test the hypothesis that early clinical improvement could predict ultimate treatment response in both iTBS and 10 Hz rTMS patient groups and that there would not be significant differences between the modalities. Methods: We retrospectively evaluated response to treatment in 105 participants with depression that received 10 Hz rTMS (n = 68) and iTBS (n = 37) to the dorsolateral prefrontal cortex (DLPFC). Percent changes from baseline to treatment 10 (t10), and to final treatment (tf), were used to calculate confusion matrices including negative predictive value (NPV). Treatment non-response was defined as <50% reduction in PHQ-9 scores according to literature, and population, data-driven non-response was defined as <40% for 10 Hz and <45% for iTBS. Results: For both modalities, the NPV related to degree of improvement at t10. NPV for 10 Hz was 80%, 63% and 46% at t10 in those who failed to improve >20, >10, and >0% respectively; while iTBS NPV rates were 65, 50, and 35%. There were not significant differences between protocols at any t10 cut-off assessed, whether research defined 50% improvement as response or data driven kernel density estimates (p = 0.22-0.44). Conclusion: Patients who fail to achieve >20% improvement by t10 with both 10 Hz rTMS and iTBS therapies have ~70% chance of non-response to treatment. With no significant differences between predictive capacities, identifying patients at-risk for non-response affords psychiatrists greater opportunity to adapt treatment strategies.

The Neuropsychiatric Approach to the Assessment of Patients in Neurology.

Neuropsychiatry is a clinical neuroscience specialty focused on the evaluation and treatment of patients who present with symptoms at the intersection of neurology and psychiatry. Neuropsychiatrists assess and manage the cognitive, affective, behavioral, and perceptual manifestations of disorders of the central nervous system. Although fellowship training in behavioral neurology-neuropsychiatry exists in the United States and several other countries internationally, the need for neuropsychiatric expertise greatly outweighs the number of specialists in practice or training. This article serves as a primer for both neurologists and psychiatrists seeking to improve or refresh their knowledge of the neuropsychiatric assessment, including detailing aspects of the history-taking, physical exam, psychometric testing, and associated diagnostic work-up. In doing so, we urge the next generation of neurologists and psychiatrists to take on both the opportunity and challenge to work at the intersection of both clinical neuroscience specialties using an integrated neuropsychiatric perspective.

Similar Outcomes in Treating Major Depressive Disorder With 10 Hz Repetitive Transcranial Magnetic Stimulation (rTMS) Versus Intermittent Theta Burst Stimulation (iTBS): A Naturalistic Observational Study.

BACKGROUND: Results reported in the existing literature have shown intermittent theta burst stimulation (iTBS) to be noninferior to 10 Hz repetitive transcranial magnetic stimulation (rTMS) in treating major depressive disorder (MDD) when targeted at the left dorsolateral prefrontal cortex. The goal of this naturalistic observational study was to further explore potential differences between these 2 treatment modalities in treating depression in a real-world cohort. METHODS: The participants were 105 patients, 18 years of age or older with a diagnosis of MDD who received standard clinical 10 Hz rTMS or iTBS treatment between 2016 and 2020. Clinical outcomes of depression treatment were assessed on the basis of changes in scores on the Patient Health Questionnaire-9 and on the Montgomery-Asberg Depression Rating Scale. RESULTS: Reduction in depression symptoms was measured with the Patient Health Questionnaire-9 and Montgomery-Asberg Depression Rating Scale from baseline to end of treatment, and no discernible differences in percent change, response, remission, or minimum clinically important difference were found between the 10 Hz rTMS and iTBS treatment groups. CONCLUSIONS: Findings in an observational, real-world clinical sample showed no significant differences in outcomes between 10 Hz rTMS and iTBS targeted at the left dorsolateral prefrontal cortex in the treatment of MDD. Because of the shorter treatment time involved, the choice of iTBS may reduce hospital exposure and increase savings and the treatment capacity of clinics without sacrificing effectiveness.

Neuroimaging Correlates of Syndromal Anxiety Following Traumatic Brain Injury: A Systematic Review of the Literature.

BACKGROUND: Traumatic brain injury (TBI) can precipitate new-onset psychiatric symptoms or worsen existing psychiatric conditions. To elucidate specific mechanisms for this interaction, neuroimaging is often used to study both psychiatric conditions and TBI. This systematic review aims to synthesize the existing literature of neuroimaging findings among patients with anxiety after TBI. METHODS: We conducted a Preferred Reporting Items for Systematic Review and Meta-Analyses-compliant literature search via PubMed (MEDLINE), PsychINFO, EMBASE, and Scopus databases before May, 2019. We included studies that clearly defined TBI, measured syndromal anxiety as a primary outcome, and statistically analyzed the relationship between neuroimaging findings and anxiety symptoms. RESULTS: A total of 5982 articles were retrieved from the systematic search, of which 65 studied anxiety and 13 met eligibility criteria. These studies were published between 2004 and 2017, collectively analyzing 764 participants comprised of 470 patients with TBI and 294 non-TBI controls. Imaging modalities used included magnetic resonance imaging, functional magnetic resonance imaging, diffusion tensor imaging, electroencephalogram, magnetic resonance spectrometry, and magnetoencephalography. Eight of 13 studies presented at least one significant finding and together reflect a complex set of changes that lead to anxiety in the setting of TBI. The left cingulate gyrus in particular was found to be significant in 2 studies using different imaging modalities. Two studies also revealed perturbances in functional connectivity within the default mode network. CONCLUSIONS: This is the first systemic review of neuroimaging changes associated with anxiety after TBI, which implicated multiple brain structures and circuits, such as the default mode network. Future research with consistent, rigorous measurements of TBI and syndromal anxiety, as well as attention to control groups, previous TBIs, and time interval between TBI and neuroimaging, are warranted. By understanding neuroimaging correlates of psychiatric symptoms, this work could inform future post-TBI screening and surveillance, preventative efforts, and early interventions to improve neuropsychiatric outcomes.