Resting-state magnetoencephalography source magnitude imaging with deep-learning neural network for classification of symptomatic combat-related mild traumatic brain injury.

Combat-related mild traumatic brain injury (cmTBI) is a leading cause of sustained physical, cognitive, emotional, and behavioral disabilities in Veterans and active-duty military personnel. Accurate diagnosis of cmTBI is challenging since the symptom spectrum is broad and conventional neuroimaging techniques are insensitive to the underlying neuropathology. The present study developed a novel deep-learning neural network method, 3D-MEGNET, and applied it to resting-state magnetoencephalography (rs-MEG) source-magnitude imaging data from 59 symptomatic cmTBI individuals and 42 combat-deployed healthy controls (HCs). Analytic models of individual frequency bands and all bands together were tested. The All-frequency model, which combined delta-theta (1-7 Hz), alpha (8-12 Hz), beta (15-30 Hz), and gamma (30-80 Hz) frequency bands, outperformed models based on individual bands. The optimized 3D-MEGNET method distinguished cmTBI individuals from HCs with excellent sensitivity (99.9 ± 0.38%) and specificity (98.9 ± 1.54%). Receiver-operator-characteristic curve analysis showed that diagnostic accuracy was 0.99. The gamma and delta-theta band models outperformed alpha and beta band models. Among cmTBI individuals, but not controls, hyper delta-theta and gamma-band activity correlated with lower performance on neuropsychological tests, whereas hypo alpha and beta-band activity also correlated with lower neuropsychological test performance. This study provides an integrated framework for condensing large source-imaging variable sets into optimal combinations of regions and frequencies with high diagnostic accuracy and cognitive relevance in cmTBI. The all-frequency model offered more discriminative power than each frequency-band model alone. This approach offers an effective path for optimal characterization of behaviorally relevant neuroimaging features in neurological and psychiatric disorders.

Changes in physiological reactivity in response to the trauma memory during prolonged exposure and virtual reality exposure therapy for posttraumatic stress disorder.

OBJECTIVE: A key symptom of posttraumatic stress disorder (PTSD) is hyperreactivity to trauma-relevant stimuli. Though physiological arousal is reliably elevated in PTSD, the question remains whether this arousal responds to treatment. Virtual reality (VR) has been posited to increase emotional engagement during prolonged exposure therapy (PE) for PTSD by augmenting imaginal exposures with trauma-relevant sensory information. However, the comparative effects of VR exposure therapy (VRE) have received limited empirical inquiry. METHOD: Ninety active-duty soldiers with combat-related PTSD participating in a randomized-controlled trial to receive PE, VRE, or a waitlist-control (WL) condition had their physiological reactivity, indexed by galvanic skin response (GSR), to their trauma memories assessed at pre-, mid-, and posttreatment. RESULTS: Although both VRE and PE conditions showed reduced GSR reactivity to trauma memories from pre- to posttreatment, only the VRE group differed significantly from WL. Across the sample, reductions in GSR were significantly correlated with reductions in self-reported PTSD and anxiety symptoms. CONCLUSIONS: This was the first study comparing effects of VRE and PE on psychophysiological variables. Given previous research finding limited differences between VRE and PE in PTSD symptom reduction, these findings lend support to the rationale for including VR in exposure therapy protocols while raising important questions about the potential benefits of VRE. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Novel Pharmacological Targets for Combat PTSD-Metabolism, Inflammation, The Gut Microbiome, and Mitochondrial Dysfunction.

INTRODUCTION: Current pharmacological treatments of post-traumatic stress disorder (PTSD) have limited efficacy. Although the diagnosis is based on psychopathological criteria, it is frequently accompanied by somatic comorbidities and perhaps "accelerated biological aging," suggesting widespread physical concomitants. Such physiological comorbidities may affect core PTSD symptoms but are rarely the focus of therapeutic trials. METHODS: To elucidate the potential involvement of metabolism, inflammation, and mitochondrial function in PTSD, we integrate findings and mechanistic models from the DOD-sponsored "Systems Biology of PTSD Study" with previous data on these topics. RESULTS: Data implicate inter-linked dysregulations in metabolism, inflammation, mitochondrial function, and perhaps the gut microbiome in PTSD. Several inadequately tested targets of pharmacological intervention are proposed, including insulin sensitizers, lipid regulators, anti-inflammatories, and mitochondrial biogenesis modulators. CONCLUSIONS: Systemic pathologies that are intricately involved in brain functioning and behavior may not only contribute to somatic comorbidities in PTSD, but may represent novel targets for treating core psychiatric symptoms.

A common neural substrate for elevated PTSD symptoms and reduced pulse rate variability in combat-exposed veterans.

Previous studies have identified reduced heart rate variability (HRV) in post-traumatic stress disorder (PTSD), which may temporally precede the onset of the disorder. A separate line of functional neuroimaging research in PTSD has consistently demonstrated hypoactivation of the ventromedial prefrontal cortex (vmPFC), a key aspect of a descending neuromodulatory system that exerts inhibitory control over heart rate. No research to date, however, has simultaneously investigated whether altered vmPFC activation is associated with reduced HRV and elevated PTSD symptoms in the same individuals. Here, we collected fMRI data during alternating conditions of threat of shock and safety from shock in 51 male combat-exposed veterans with either high or low levels of PTSD symptoms. Pulse rate variability (PRV)-a HRV surrogate calculated from pulse oximetry-was assessed during a subsequent resting scan. Correlational analyses tested for hypothesized relationships between reduced vmPFC activation, lower PRV, and elevated PTSD symptomatology. We found that PTSD re-experiencing symptoms were inversely associated with high-frequency (HF)-PRV, thought to primarily reflect parasympathetic control of heart rate, in veterans with elevated PTSD symptoms. Reduced vmPFC activation for the contrast of safety-threat was associated both with lower HF-PRV and elevated PTSD re-experiencing symptoms. These results tie together previous observations of reduced HRV/PRV and impaired vmPFC function in PTSD and call for further research on reciprocal brain-body relationships in understanding PTSD pathophysiology.

Nonlinear relations between post-traumatic stress symptoms and electrocortical reactivity during emotional face processing in combat-exposed veterans.

Combat-related post-traumatic stress symptoms (PTSS) are prevalent among recently deployed veterans, making identification of biomarkers of PTSS in this population a public health priority. Given the link between threat processing neurobiology and PTSS, the threat-related late positive potential (LPP), an ERP reflective of attentional processing sensitive to emotion and its regulation, may have utility as a cost-effective biomarker. Existing PTSS/threat-related LPP findings are mixed, possibly due to variability in PTSS across samples, but this has never been explicitly tested. To address this gap, LPP amplitudes to angry, fearful, and happy emotional face stimuli were recorded among 81 combat-exposed veterans at a VA hospital. A quadratic relationship between self-reported PTSS and LPP amplitude modulation by angry faces emerged such that greater PTSS was related to a decreased LPP response to angry faces among veterans with subthreshold PTSD and an enhanced LPP response to angry faces among veterans with probable PTSD. These results suggest that prior mixed findings may be due to variability in PTSS severity. In addition, exploratory moderation analysis revealed that PTSS was positively associated with late LPP modulation for veterans reporting low cognitive reappraisal use and negatively associated with late LPP modulation for veterans reporting high cognitive reappraisal use. All results were specific to the 1,000-3,000 ms LPP time window. Thus, the functional nature of LPP modulation by direct threat cues may depend upon PTSS severity and/or related variables (e.g., cognitive reappraisal utilization).

Neurophysiology of threat processing bias in combat-related post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a debilitating condition that may develop after experiencing a traumatic event. Combat exposure increases an individual's chance of developing PTSD, making veterans especially susceptible to the disorder. PTSD is characterized by dysregulated emotional networks, memory deficits, and a hyperattentive response to perceived threatening stimuli. Recently, there have been a number of imaging studies that show structural and functional abnormalities associated with PTSD; however, there have been few studies utilizing electroencephalography (EEG). The goal of this study was to characterize **EEG brain dynamics in individuals with PTSD, in order to better understand the neurophysiological underpinnings of some of the salient features of PTSD, such as threat-processing bias. Veterans of Operation Enduring Freedom/Iraqi Freedom completed an implicit visual threat semantic memory recognition task with stimuli that varied on both category (animals, items, nature, and people) and feature (threatening and nonthreatening) membership, including trauma-related stimuli. Combat veterans with PTSD had slower reaction times for the threatening stimuli relative to the combat veterans without PTSD (VETC). There were trauma-specific effects in frontal regions, with theta band EEG power reductions for the threatening combat scenes in the PTSD patients compared to the VETC group. Additionally, a moderate negative correlation was observed between trauma-specific frontal theta power and hyperarousal symptoms as measured by clinically administered PTSD scale. These findings complement and extend current models of cortico-limbic dysfunction in PTSD. The moderate negative correlation between frontal theta power and hyperarousal endorsements suggests the utility of these measures as therapeutic markers of symptomatology in PTSD patients.

Post-exertional malaise in veterans with gulf war illness.

Post-exertional malaise (PEM) is a potentially debilitating aspect of Gulf War Illness (GWI) that has received limited research attention. The purpose of the present investigation was to determine symptom severity changes following exercise in Veterans with GWI compared to control Veterans without GWI (CO). Sixty-seven Veterans (n = 39 GWI; n = 28 CO) underwent a 30-minute submaximal exercise challenge at 70% of heart rate reserve. Symptom measurements (e.g. fatigue, pain) occurred pre-, immediately post-, and 24-hour post-exercise. Self-reported physical and mental health, and physiological and perceptual responses to exercise were compared between groups using descriptive statistics, independent samples t-tests and repeated measures Analysis of Variance (RM-ANOVA). Post-exertional malaise was modeled using Group by Time (2 × 3) doubly-multivariate, RM-MANOVAs for (1) mood, (2) pain and (3) GWI-related symptoms, respectively (α = 0.05). Data were analyzed for the full sample of Veterans with GWI (n = 39) compared to CO (n = 28) and a subsample of Veterans (n = 18) who endorsed "feeling unwell after physical exercise or exertion" ("PEM endorsers") during screening. Veterans with GWI reported significantly lower physical and mental health. Groups exercised at similar relative exercise intensities, but GWI perceived exercise as more painful and fatiguing. Group-by-Time interactions were not significant for the entire sample for the three PEM models, however limiting the GWI sample to "PEM endorsers" resulted in significant interactions for Pain- and GWI-related PEM models. These results indicate that not all GVs with GWI experience PEM 24 h after exercise, and that more research is needed to determine the extent that exercise worsens symptoms in GWI.

A resting-state network comparison of combat-related PTSD with combat-exposed and civilian controls.

Resting-state functional connectivity (rsFC) is an emerging means of understanding the neurobiology of combat-related post-traumatic stress disorder (PTSD). However, most rsFC studies to date have limited focus to cognitively related intrinsic connectivity networks (ICNs), have not applied data-driven methodologies or have disregarded the effect of combat exposure. In this study, we predicted that group independent component analysis (GICA) would reveal group-wise differences in rsFC across 50 active duty service members with PTSD, 28 combat-exposed controls (CEC), and 25 civilian controls without trauma exposure (CC). Intranetwork connectivity differences were identified across 11 ICNs, yet combat-exposed groups were indistinguishable in PTSD vs CEC contrasts. Both PTSD and CEC demonstrated anatomically diffuse differences in the Auditory Vigilance and Sensorimotor networks compared to CC. However, intranetwork connectivity in a subset of three regions was associated with PTSD symptom severity among executive (left insula; ventral anterior cingulate) and right Fronto-Parietal (perigenual cingulate) networks. Furthermore, we found that increased temporal synchronization among visuospatial and sensorimotor networks was associated with worse avoidance symptoms in PTSD. Longitudinal neuroimaging studies in combat-exposed cohorts can further parse PTSD-related, combat stress-related or adaptive rsFC changes ensuing from combat.

Post-traumatic stress disorder is associated with altered modulation of prefrontal alpha band oscillations during working memory.

OBJECTIVE: To investigate the relationship between the severity of PTSD symptoms, modulation of alpha band oscillations, and behavioral performance in a working memory task. METHODS: Magnetoencephalography data were recorded in 35 participants with combat exposure and various degrees of PTSD symptom severity while they performed a modified Sternberg working memory task: briefly presented sets of two or six letters had to be held in memory and participants indicated whether subsequent probe letters were present or absent from these sets. RESULTS: PTSD scores were positively correlated with the false positive rate in the high memory load condition. Higher rates of false recognition were associated with negative probes that were seen in recent previous trials (negative probe recency effect) or were physically similar with the list letters. The relative alpha band power in the left middle frontal gyrus was negatively correlated with both PTSD scores and false positive rates. CONCLUSIONS: Reduced task specific modulation of alpha band oscillations in left middle frontal cortex may reflect alterations in the functions of pattern separation and suppression of memory traces for irrelevant or no longer relevant information in PTSD. SIGNIFICANCE: The lower amplitude of prefrontal alpha band oscillations may represent an important physiological basis for core PTSD symptoms and can provide a target for interventions to augment response to treatment.

Evaluation of objective and subjective clinical outcomes in combat veterans with and without mild TBI and PTSD: A four-group design.

Introduction: Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are highly prevalent comorbid conditions in military Veterans. However, lack of appropriate comparison groups has clouded interpretation of the chronic effects of these conditions. The present study evaluated the neuropsychological, psychiatric/neurobehavioral, and functional outcomes associated with mTBI and PTSD in a well-characterized sample of combat-exposed Veterans. Method: Participants included 73 Iraq/Afghanistan Veterans (91.8% male; age: M = 34.00, SD = 6.39) divided into four groups: mTBI-only (n = 23), PTSD-only (n = 14), comorbid mTBI + PTSD (n = 19), and combat-control (CC; n = 17). Participants were administered a neuropsychological assessment and completed questionnaires assessing psychiatric/neurobehavioral symptoms and functional outcomes. Results: Kruskal-Wallis H-tests showed no group differences across measures of neuropsychological functioning; however, there were significant differences across groups on all psychiatric/neurobehavioral variables examined. In general, the comorbid and PTSD-only groups endorsed the most severe symptoms, followed by the mTBI-only and CC groups, respectively. As for functional outcomes, the comorbid and PTSD-only groups had higher rates of service-connection disability and greater perceived decline in work and education-related abilities, relative to the mTBI-only and CC groups, despite similar proportions of Veterans employed or in school in each group. Conclusions: Findings suggest that Veterans with comorbid mTBI + PTSD and PTSD alone are at greatest risk for experiencing long-lasting subjective distress, including negative perceptions of their ability to work or pursue an education, despite being comparable to mTBI-only and CC Veterans on objective measures of functioning. Our results highlight the importance of emphasizing mental health treatment in this population.

Trauma-related psychiatric and behavioral conditions are uniquely associated with sustained attention dysfunction.

OBJECTIVE: It is increasingly recognized that trauma victims, particularly Veterans, have co-occurring psychological and physical conditions that impact cognition, especially the domains of sustained attention and executive functioning. Although previous work has generally attempted to isolate the unique cognitive effects of common combat-related comorbidities, less work has been done to examine how these conditions co-occur, and whether unique cognitive signatures accompany certain clinical combinations. METHOD: To address this gap, we examined how several deployment-related conditions were associated with performance on a well-validated measure of sustained attention (i.e., gradual onset continuous performance task [gradCPT]) and a battery of standard neuropsychological measures in 123 Veterans from the Translational Research Center for TBI and Stress Disorders. Initially, a Principal component analysis was conducted to investigate how comorbid conditions grouped together. RESULTS: Several sustained attention measures from the gradCPT were differentially associated with four unique combinations of trauma-related pathology. Specifically, a somatic component representing the combination of current pain, sleep disturbance, and mild traumatic brain injury was associated with a higher rate of failures of attentional engagement. On the other hand, a comorbid posttraumatic stress disorder (PTSD) and mood disorder component (moodPTSD), as well as a substance use disorder component, were associated with higher rates of inhibitory control failures. Increased attentional instability was associated with moodPTSD as well as an anxiety disorder component. In contrast, the cognitive effects of deployment-related trauma were not observed on standard neuropsychological measures. CONCLUSION: These findings suggest that unique combinations of trauma-related pathology have dissociable effects on sustained attentional control. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effect of Experience and Psychophysiological Modification by Combat Stress in Soldier's Memory.

The present research aimed to analyze the effect of experience and psychophysiological modification by combat stress in soldier's memory in a simulated combat situation. Variables of rate of perceived exertion, blood glucose, blood lactate, lower body muscular strength manifestation, cortical arousal, specific fine motor skills, autonomic modulation, state anxiety, and memory and attention through a postmission questionnaire were analyzed before and after a combat simulation in 15 experienced soldiers of a special operation unit and 20 non-experienced soldiers of light infantry unit from the Spanish Army. The stress of combat simulation produces a significant increase (p < 0.05) in rated perceived exertion, blood glucose, blood lactate, somatic anxiety and a low frequency domain of the heart rate, and a significant decrease of rifle magazine reload time, high frequency domain of the heart rate and somatic anxiety in both groups. The variables of RPE, glucose, CFFT, RMRT, RMSSD, LF/HF, CA, SA and STAI were significantly different in experienced soldiers shown the activation of fight-flight system. The anticipatory anxiety in experienced soldiers shows a cognitive behavioral association by past experiences. The analysis of correct response in the postmission questionnaire show elements more related with the sight and that endanger the physical integrity of soldiers are more remembered, and some significant differences (p < 0.05) in the memory performance of experienced soldiers and non experienced soldiers where experienced soldiers shown a better performance. As conclusion, combat stress produce an increase in the psichophysiological response of soldiers independently of experience, but experienced ones presented a lower negative effect on memory than non experienced.

Predictors of Consent to Treatment and Premature Termination of Treatment in a Sample of Veterans With Military-Related PTSD.

This study examined different variables as predictors of treatment entry and treatment dropout among veterans with military-related posttraumatic stress disorder (PTSD). First, we examined predictors of treatment entry versus refusal of treatment. Among the veterans who started therapy, we examined predictors of treatment completion. Symptom severity of PTSD, depression, and anxiety at baseline were measured. Daily functioning at baseline was also measured. Results indicate that the younger the veterans were, the more likely they were to refuse treatment. Dropout from treatment was also predicted by younger age at referral, as well as by past treatment, higher number of years of education, and higher depression levels at baseline. Two conclusions can be drawn from the results. First, it may be beneficial to increase awareness of treatment options for PTSD among younger veterans as this may increase treatment consent rates. Second, to reduce treatment dropout in veteran patients with PTSD, therapists should take into consideration both past treatment and baseline depression levels as risk factors for dropout.

Exercise challenge alters Default Mode Network dynamics in Gulf War Illness.

BACKGROUND: Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War and has no known cause. Everyday symptoms include pain, fatigue, migraines, and dyscognition. A striking syndromic feature is post-exertional malaise (PEM). This is recognized as an exacerbation of everyday symptoms following a physically stressful or cognitively demanding activity. The underlying mechanism of PEM is unknown. We previously reported a novel paradigm that possibly captured evidence of PEM by utilizing fMRI scans taken before and after sub-maximal exercises. We hypothesized that A) exercise would be a sufficient physically stressful activity to induce PEM and B) Comparison of brain activity before and after exercise would provide evidence of PEM's effect on cognition. We reported two-exercise induced GWI phenotypes with distinct changes in brain activation patterns during the completion of a 2-back working memory task (also known as two-back > zero-back). RESULTS: Here we report unanticipated findings from the reverse contrast (zero-back > two-back), which allowed for the identification of task-related deactivation patterns. Following exercise, patients developed a significant increase in deactivation patterns within the Default Mode Network (DMN) that was not seen in controls. The DMN is comprised of regions that are consistently down regulated during external goal-directed activities and is often altered within many neurological disease states. CONCLUSIONS: Exercise-induced alterations within the DMN provides novel evidence of GWI pathophysiology. More broadly, results suggest that task-related deactivation patterns may have biomarker potential in Gulf War Illness.

A systematic review of the psychosocial impact of emotional numbing in US combat veterans.

CONTEXT: Previous studies have linked posttraumatic emotional numbing symptoms in US combat veterans with an adverse impact in multiple important life domains. OBJECTIVES: We updated and evaluated the evidence examining the psychosocial impact of combat-related emotional numbing, including ethnoracial and gender differences. METHOD: We reviewed 1,209 articles published betwen January 2012 and 2018 and selected 24 studies for inclusion. We assessed the overall study quality as fair using a national quality assessment tool. RESULTS: Studies found emotional numbing to wield adverse effects in the areas of symptom nonimprovement, mental health difficulties, increased service utilization, poor relationship functioning, reduced quality of life, substance use disorders, suicidality, and aggression/violence. We also found evidence of ethnoracial and gender differences in veterans' posttraumatic stress disorder-related emotional numbing symptoms. CONCLUSION: Clinicians should incorporate findings on emotional numbing into assessment, treatment planning, and monitoring, to improve treatment retention and psychosocial outcomes. Implications for ethnoracial and gender differences require further exploration.

Pain perception and modulation in ex-POWs who underwent torture: The role of subjective and objective suffering.

OBJECTIVE: Previous findings have demonstrated that torture survivors exhibit chronic pain and alterations in pain perception. However, not much is known regarding the characteristics of the torture experience and its contribution to these long-term ramifications. The current study examined the unique role of objective severity and subjective suffering in torture in predicting chronic pain and acute pain perception and pain modulation. METHOD: Eighteen years after war, 59 former prisoners of war who were subjected to severe torture in captivity were assessed for subjective suffering in torture and estimated weight loss during captivity (an indication of torture severity) using self-administered questionnaires. Thirty-five years after captivity, systemic quantitative somatosensory testing was conducted, which included the measurement of pain threshold, pain tolerance, conditioned pain modulation, and perceived suprathreshold stimuli. Self-administered questionnaires were also used to evaluate chronic pain and posttraumatic stress disorder. RESULTS: The findings indicated that subjective suffering was associated with pain threshold, conditioned pain modulation, perceived suprathreshold stimuli, and chronic pain while controlling for posttraumatic stress symptoms. Estimated weight loss was associated only with pain threshold. CONCLUSION: The findings demonstrate that the experience of chronic and acute pain is rooted in the subjective perception of traumatic experiences. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Neural computations of threat in the aftermath of combat trauma.

By combining computational, morphological, and functional analyses, this study relates latent markers of associative threat learning to overt post-traumatic stress disorder (PTSD) symptoms in combat veterans. Using reversal learning, we found that symptomatic veterans showed greater physiological adjustment to cues that did not predict what they had expected, indicating greater sensitivity to prediction errors for negative outcomes. This exaggerated weighting of prediction errors shapes the dynamic learning rate (associability) and value of threat predictive cues. The degree to which the striatum tracked the associability partially mediated the positive correlation between prediction-error weights and PTSD symptoms, suggesting that both increased prediction-error weights and decreased striatal tracking of associability independently contribute to PTSD symptoms. Furthermore, decreased neural tracking of value in the amygdala, in addition to smaller amygdala volume, independently corresponded to higher PTSD symptom severity. These results provide evidence for distinct neurocomputational contributions to PTSD symptoms.

Latent profile analysis exploring potential moral injury and posttraumatic stress disorder among military veterans.

OBJECTIVES: Theoretical support for the moral injury (MI) construct is mounting, yet empirical support has lagged behind. A conceptual model has been proposed, but studies have not yet explored the constellation of symptoms within treatment-seeking Veterans. METHODS: Veterans (N = 212) seeking trauma recovery services completed measures of potential MI symptoms that functioned as indicators in person-centered Latent Profile Analysis. Differences in exposure to potentially morally injurious experiences (pMIEs) were compared across profiles using logistic regression. RESULTS: Three profiles emerged that varied by symptom severity, levels of trauma-related guilt, and levels of dispositional forgiveness. Exposure to pMIEs predicted membership in a class consistent with proposed MI symptomatology. CONCLUSIONS: Person-centered approaches are useful for identifying a distinct group of veterans whose trauma recovery may benefit from specifically targeting moral emotions, consistent with the emerging construct of MI .

MEG Working Memory N-Back Task Reveals Functional Deficits in Combat-Related Mild Traumatic Brain Injury.

Combat-related mild traumatic brain injury (mTBI) is a leading cause of sustained cognitive impairment in military service members and Veterans. However, the mechanism of persistent cognitive deficits including working memory (WM) dysfunction is not fully understood in mTBI. Few studies of WM deficits in mTBI have taken advantage of the temporal and frequency resolution afforded by electromagnetic measurements. Using magnetoencephalography (MEG) and an N-back WM task, we investigated functional abnormalities in combat-related mTBI. Study participants included 25 symptomatic active-duty service members or Veterans with combat-related mTBI and 20 healthy controls with similar combat experiences. MEG source-magnitude images were obtained for alpha (8-12 Hz), beta (15-30 Hz), gamma (30-90 Hz), and low-frequency (1-7 Hz) bands. Compared with healthy combat controls, mTBI participants showed increased MEG signals across frequency bands in frontal pole (FP), ventromedial prefrontal cortex, orbitofrontal cortex (OFC), and anterior dorsolateral prefrontal cortex (dlPFC), but decreased MEG signals in anterior cingulate cortex. Hyperactivations in FP, OFC, and anterior dlPFC were associated with slower reaction times. MEG activations in lateral FP also negatively correlated with performance on tests of letter sequencing, verbal fluency, and digit symbol coding. The profound hyperactivations from FP suggest that FP is particularly vulnerable to combat-related mTBI.