Search results

Mild traumatic brain injuries (mTBI) are common injuries across civilian and military populations. Although most individuals recover after mTBI, some individuals continue to show long-term symptoms as well as increased risk for neurodegenerative and neuropsychiatric disorders. Currently, diagnosing TBI severity relies primarily on self-report and subjective symptoms, with limited tools for diagnosis or prognosis. Brain-derived exosomes, a form of extracellular vesicle, may offer a solution for interpreting injury states by aiding in diagnosis as well as outcome prediction with relatively low patient burden. Exosomes, which are released into circulation, contain both protein and RNA cargo that can be isolated and quantified, providing a molecular window into molecular status of the exosome source. Here we examined the current literature studying the utility of exosomes, in particular neuronal- and astrocyte-derived exosomes, to identify protein and miRNA biomarkers of injury severity, trajectory, and functional outcome. Current evidence supports the potential for these emerging new tools to capture an accessible molecular window into the brain as it responds to a traumatic injury, however a number of limitations must be addressed in future studies. Most current studies are relatively small and cross sectional; prospective, longitudinal studies across injury severity, and populations are needed to track exosome cargo changes after injury. Standardized exosome isolation as well as advancement in identifying/isolating exosomes from CNS-specific tissue sources will improve mechanistic understanding of cargo changes as well as reliability of findings. Exosomes are also just beginning to be used in model systems to understand functional effects of TBI-associated cargo such as toxicity. Finally linking exosome cargo changes to objective markers of neuronal pathology and cognitive changes will be critical in validating these tools to provide insights into injury and recovery states after TBI.

Background:Posttraumatic Stress Disorder (PTSD) is associated with a number of negative physical and mental health consequences. Fear conditioning plays an important mechanistic role in PTSD, and PTSD patients also show deficits in safety signal learning. Sleep, particularly REM sleep, is linked to improved safety learning and extinction processes in animal models and healthy humans. No studies have examined the link between REM sleep and safety signal learning or extinction memory in clinical populations. Methods:This study examined the relationship between REM sleep, safety signal learning, and extinction processes in veterans with PTSD (n = 13). Patients' overnight sleep was characterized in the laboratory via polysomnography (PSG). The next day, participants underwent a fear conditioning paradigm during which they acquired fear toward a visual cue. This testing session also included a visual cue that became a safety signal (CS-). Following conditioning, the veterans' sleep was monitored overnight again, after which they underwent extinction training. Following a third night of sleep, extinction recall and safety recall were tested. Bivariate correlations examined the relationship between the slope of safety signal learning and subsequent REM sleep, as well as the relationship between REM sleep and subsequent extinction recall and safety recall on the last day of testing. Results:Veterans learned to differentiate the CS+ and the CS- on the first day of testing. Veterans who underwent safety learning more quickly on the first day of testing showed more efficient REM sleep that night (r = .607, p = .028). On the second day of testing, the patients successfully underwent extinction learning. Patients with a higher percentage of REM sleep on the last night of the study showed more safety recall early on the last day of testing (r = .688, p = .009). Conclusion:To our knowledge, this was the first study to examine the relationship between objective sleep and fear-potentiated startle performance in veterans with PTSD. Study methods were well tolerated by participants, supporting feasibility of the experimental design. Results indicated REM sleep was associated with both initial safety learning and subsequent safety recall. Taken together with previous studies in healthy controls, these preliminary results provide additional evidence suggesting REM sleep could play a mechanistic role in the maintenance of PTSD and thus identify a modifiable biological process to target in treatment of PTSD. These findings should be replicated in larger samples.

BackgroundPosttraumatic Stress Disorder (PTSD) is associated with a number of negative physical and mental health consequences. Fear conditioning plays an important mechanistic role in PTSD, and PTSD patients also show deficits in safety signal learning. Sleep, particularly REM sleep, is linked to improved safety learning and extinction processes in animal models and healthy humans. No studies have examined the link between REM sleep and safety signal learning or extinction memory in clinical populations.MethodsThis study examined the relationship between REM sleep, safety signal learning, and extinction processes in veterans with PTSD (n = 13). Patients' overnight sleep was characterized in the laboratory via polysomnography (PSG). The next day, participants underwent a fear conditioning paradigm during which they acquired fear toward a visual cue. This testing session also included a visual cue that became a safety signal (CS-). Following conditioning, the veterans' sleep was monitored overnight again, after which they underwent extinction training. Following a third night of sleep, extinction recall and safety recall were tested. Bivariate correlations examined the relationship between the slope of safety signal learning and subsequent REM sleep, as well as the relationship between REM sleep and subsequent extinction recall and safety recall on the last day of testing.ResultsVeterans learned to differentiate the CS+ and the CS- on the first day of testing. Veterans who underwent safety learning more quickly on the first day of testing showed more efficient REM sleep that night (r = .607, p = .028). On the second day of testing, the patients successfully underwent extinction learning. Patients with a higher percentage of REM sleep on the last night of the study showed more safety recall early on the last day of testing (r = .688, p = .009).ConclusionTo our knowledge, this was the first study to examine the relationship between objective sleep and fear-potentiated startle performance in veterans with PTSD. Study methods were well tolerated by participants, supporting feasibility of the experimental design. Results indicated REM sleep was associated with both initial safety learning and subsequent safety recall. Taken together with previous studies in healthy controls, these preliminary results provide additional evidence suggesting REM sleep could play a mechanistic role in the maintenance of PTSD and thus identify a modifiable biological process to target in treatment of PTSD. These findings should be replicated in larger samples.

Background: Posttraumatic Stress Disorder (PTSD) is associated with a number of negative physical and mental health consequences. Fear conditioning plays an important mechanistic role in PTSD, and PTSD patients also show deficits in safety signal learning. Sleep, particularly REM sleep, is linked to improved safety learning and extinction processes in animal models and healthy humans. No studies have examined the link between REM sleep and safety signal learning or extinction memory in clinical populations. Methods: This study examined the relationship between REM sleep, safety signal learning, and extinction processes in veterans with PTSD (n = 13). Patients' overnight sleep was characterized in the laboratory via polysomnography (PSG). The next day, participants underwent a fear conditioning paradigm during which they acquired fear toward a visual cue. This testing session also included a visual cue that became a safety signal (CS-). Following conditioning, the veterans' sleep was monitored overnight again, after which they underwent extinction training. Following a third night of sleep, extinction recall and safety recall were tested. Bivariate correlations examined the relationship between the slope of safety signal learning and subsequent REM sleep, as well as the relationship between REM sleep and subsequent extinction recall and safety recall on the last day of testing. Results: Veterans learned to differentiate the CS+ and the CS- on the first day of testing. Veterans who underwent safety learning more quickly on the first day of testing showed more efficient REM sleep that night (r =.607, p =.028). On the second day of testing, the patients successfully underwent extinction learning. Patients with a higher percentage of REM sleep on the last night of the study showed more safety recall early on the last day of testing (r =.688, p =.009). Conclusion: To our knowledge, this was the first study to examine the relationship between objective sleep and fear-potentiated startle performance in veterans with ...

BackgroundHeightened startle response is a symptom of PTSD, but evidence for exaggerated startle in PTSD is inconsistent. This prospective study aimed to clarify whether altered startle reactivity represents a trait risk-factor for developing PTSD or a marker of current PTSD symptoms.MethodsMarines and Navy Corpsmen were assessed before (n = 2,571) and after (n = 1,632) deployments to Iraq or Afghanistan with the Clinician-Administered PTSD Scale (CAPS). A predeployment startle-threshold task was completed with startle probes presented over 80-114 dB[A] levels. Latent class mixture modeling identified three growth classes of startle performance: "high," "low," and "moderate" threshold classes. Zero-inflated negative binomial regression was used to assess relationships between predeployment startle threshold and pre- and postdeployment psychiatric symptoms.ResultsAt predeployment, the low-threshold class had higher PTSD symptom scores. Relative to the moderate-threshold class, low-threshold class membership was associated with decreased likelihood of being symptom-free at predeployment, based on CAPS, with particular associations with numbing and hyperarousal subscales, whereas high-threshold class membership was associated with more severe predeployment PTSD symptoms, in particular avoidance. Associations between low-threshold membership and CAPS symptoms were independent from measures of trauma burden, whereas associations between high-threshold membership and CAPS were not. Predeployment startle threshold did not predict postdeployment symptoms.ConclusionsThis study found that both low startle threshold (heightened reactivity) and high startle threshold (blunted reactivity) were associated with greater current PTSD symptomatology, suggesting that startle reactivity is associated with current PTSD rather than a risk marker for developing PTSD.

BackgroundIt is unknown how traumatic brain injury (TBI) increases risk for posttraumatic stress disorder (PTSD). One potential mechanism is via alteration of fear-learning processes that could affect responses to trauma memories and cues. We utilized a prospective, longitudinal design to determine if TBI is associated with altered fear learning and extinction, and if fear processing mediates effects of TBI on PTSD symptom change.MethodsEight hundred fifty two active-duty Marines and Navy Corpsmen were assessed before and after deployment. Assessments included TBI history, PTSD symptoms, combat trauma and deployment stress, and a fear-potentiated startle task of fear acquisition and extinction. Startle response and self-reported expectancy and anxiety served as measures of fear conditioning, and PTSD symptoms were measured with the Clinician-Administered PTSD Scale.ResultsIndividuals endorsing "multiple hit" exposure (both deployment TBI and a prior TBI) showed the strongest fear acquisition and highest fear expression compared to groups without multiple hits. Extinction did not differ across groups. Endorsing a deployment TBI was associated with higher anxiety to the fear cue compared to those without deployment TBI. The association of deployment TBI with increased postdeployment PTSD symptoms was mediated by postdeployment fear expression when recent prior-TBI exposure was included as a moderator. TBI associations with increased response to threat cues and PTSD symptoms remained when controlling for deployment trauma and postdeployment PTSD diagnosis.ConclusionsDeployment TBI, and multiple-hit TBI in particular, are associated with increases in conditioned fear learning and expression that may contribute to risk for developing PTSD symptoms.

ImportanceDisrupted autonomic nervous system functioning as measured by heart rate variability (HRV) has been associated with posttraumatic stress disorder (PTSD). It is not clear, however, whether reduced HRV before trauma exposure contributes to the risk for development of PTSD.ObjectiveTo examine whether HRV before combat deployment is associated with increased risk of a PTSD diagnosis after deployment when accounting for deployment-related combat exposure.Design, setting, and participantsBetween July 14, 2008, and May 24, 2012, active-duty Marines were assessed 1 to 2 months before a combat deployment and again 4 to 6 months after their return. The first phase of the Marine Resiliency Study (MRS-I) included 1415 male Marines, 59 of whom developed PTSD after deployment. Participants in the second phase of the Marine Resiliency Study (MRS-II) included 745 male Marines, 25 of whom developed PTSD after deployment. Analysis was conducted from November 25, 2013, to April 16, 2015.Main outcomes and measuresPredeployment HRV was measured via finger photoplethysmography during a 5-minute period of rest. Frequency-domain measures of HRV were generated. Diagnosis of PTSD was determined using the Clinician-Administered PTSD Scale.ResultsAfter accounting for deployment-related combat exposure, lower HRV before deployment as measured by an increased low-frequency (LF) to high-frequency (HF) ratio of HRV was associated with risk of PTSD diagnosis after deployment (combined MRS-I and MRS-II cohort meta-analysis odds ratio, 1.47; 95% CI, 1.10-1.98; P = .01). The prevalence of postdeployment PTSD was higher in participants with high predeployment LF:HF ratios (15.8% [6 of 38 participants]) compared with participants who did not have high LF:HF ratios (3.7% [78 of 2122 participants]).Conclusions and relevanceThis prospective longitudinal study provides initial and modest evidence that an altered state of autonomic nervous system functioning contributes to PTSD vulnerability, taking into account other key risk factors. If these findings are replicated, interventions that change autonomic nervous system function may open novel opportunities for prevention and treatment of PTSD.

ObjectiveHeart rate variability (HRV), thought to reflect autonomic nervous system function, is lowered under conditions such as posttraumatic stress disorder (PTSD). The potential confounding effects of traumatic brain injury (TBI) and depression in the relationship between HRV and PTSD have not been elucidated in a large cohort of military service members. Here we describe HRV associations with stress disorder symptoms in a large study of Marines while accounting for well-known covariates of HRV and PTSD including TBI and depression.MethodsFour battalions of male active-duty Marines (n = 2430) were assessed 1 to 2 months before a combat deployment. HRV was measured during a 5-minute rest. Depression and PTSD were assessed using the Beck Depression Inventory and Clinician-Administered PTSD Scale, respectively.ResultsWhen adjusting for covariates, including TBI, regression analyses showed that lower levels of high-frequency HRV were associated with a diagnosis of PTSD (β = -0.20, p = .035). Depression and PTSD severity were correlated (r = 0.49, p < .001); however, participants with PTSD but relatively low depression scores exhibited reduced high frequency compared with controls (p = .012). Marines with deployment experience (n = 1254) had lower HRV than did those with no experience (p = .033).ConclusionsThis cross-sectional analysis of a large cohort supports associations between PTSD and reduced HRV when accounting for TBI and depression symptoms. Future postdeployment assessments will be used to determine whether predeployment HRV can predict vulnerability and resilience to the serious psychological and physiological consequences of combat exposure.

ObjectiveHeart rate variability (HRV), thought to reflect autonomic nervous system function, is lowered under conditions such as posttraumatic stress disorder (PTSD). The potential confounding effects of traumatic brain injury (TBI) and depression in the relationship between HRV and PTSD have not been elucidated in a large cohort of military service members. Here we describe HRV associations with stress disorder symptoms in a large study of Marines while accounting for well-known covariates of HRV and PTSD including TBI and depression.MethodsFour battalions of male active-duty Marines (n = 2430) were assessed 1 to 2 months before a combat deployment. HRV was measured during a 5-minute rest. Depression and PTSD were assessed using the Beck Depression Inventory and Clinician-Administered PTSD Scale, respectively.ResultsWhen adjusting for covariates, including TBI, regression analyses showed that lower levels of high-frequency HRV were associated with a diagnosis of PTSD (β = -0.20, p = .035). Depression and PTSD severity were correlated (r = 0.49, p < .001); however, participants with PTSD but relatively low depression scores exhibited reduced high frequency compared with controls (p = .012). Marines with deployment experience (n = 1254) had lower HRV than did those with no experience (p = .033).ConclusionsThis cross-sectional analysis of a large cohort supports associations between PTSD and reduced HRV when accounting for TBI and depression symptoms. Future postdeployment assessments will be used to determine whether predeployment HRV can predict vulnerability and resilience to the serious psychological and physiological consequences of combat exposure.

To examine whether cause, severity, and frequency of traumatic brain injury (TBI) increase risk of postdeployment tinnitus when accounting for comorbid posttraumatic stress disorder.Self-report and clinical assessments were done before and after an "index" deployment to Iraq or Afghanistan.Assessments took place on Marine Corps bases in southern California and the VA San Diego Medical Center. Participants were 1647 active-duty enlisted Marine and Navy servicemen who completed pre- and postdeployment assessments of the Marine Resiliency Study. The main outcome was the presence of tinnitus at 3 months postdeployment.Predeployment TBI increased the likelihood of new-onset postdeployment tinnitus (odds ratio [OR] = 1.86; 95% confidence interval [CI], 1.28-2.70). Deployment-related TBIs increased the likelihood of postdeployment tinnitus (OR = 2.65; 95% CI, 1.19-5.89). Likelihood of new-onset postdeployment tinnitus was highest for those who were blast-exposed (OR = 2.93; 95% CI, 1.82-6.17), who reported moderate-severe TBI symptoms (OR = 2.22; 95% CI, 1.22-3.40), and who sustained multiple TBIs across study visits (OR = 2.27; 95% CI, 1.44-4.24). Posttraumatic stress disorder had no effect on tinnitus outcome.Participants who were blast-exposed, sustained multiple TBIs, and reported moderate-severe TBI symptoms were most at risk for new-onset tinnitus.

BackgroundResearch on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort.MethodsParticipants (N=3494) were assessed using the Clinician-Administered PTSD Scale and diagnosed using the DSM-IV diagnostic criterion. Subjects with partial and/or full PTSD diagnosis were called cases, all other subjects were designated controls, and study-wide maximum CAPS scores were used for longitudinal assessments. Genomic DNA was genotyped on the Illumina HumanOmniExpressExome array. Individual genetic ancestry was determined by supervised cluster analysis for subjects of European, African, Hispanic/Native American, and other descent. To test for association of SNPs with PTSD, logistic regressions were performed within each ancestry group and results were combined in meta-analyses. Measures of childhood and adult trauma were included to test for gene-by-environment (GxE) interactions. Polygenic risk scores from the Psychiatric Genomic Consortium were used for major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ).ResultsThe array produced >800K directly genotyped and >21M imputed markers in 3494 unrelated, trauma-exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR=1.47, SE=0.06, p=2.04×10(-9)), with a similar effect across ancestry groups. Association of PRTFDC1 with PTSD in an independent military cohort showed some evidence for replication. Loci with suggestive evidence of association (n=25 genes, p<5×10(-6)) further implicated genes related to immune response and the ubiquitin system, but these findings remain to be replicated in larger GWASs. A replication analysis of 25 putative PTSD genes from the literature found nominally significant SNPs for the majority of these genes, but associations did not remain significant after correction for multiple comparison. A cross-disorder analysis of polygenic risk scores from GWASs of BPD, MDD, and SCZ found that PTSD diagnosis was associated with risk sores of BPD, but not with MDD or SCZ.ConclusionsThis first multi-ethnic/racial GWAS of PTSD highlights the potential to increase power through meta-analyses across ancestry groups. We found evidence for PRTFDC1 as a potential novel PTSD gene, a finding that awaits further replication. Our findings indicate that the genetic architecture of PTSD may be determined by many SNPs with small effects, and overlap with other neuropsychiatric disorders, consistent with current findings from large GWAS of other psychiatric disorders.

BackgroundResearch on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort.MethodsParticipants (N=3494) were assessed using the Clinician-Administered PTSD Scale and diagnosed using the DSM-IV diagnostic criterion. Subjects with partial and/or full PTSD diagnosis were called cases, all other subjects were designated controls, and study-wide maximum CAPS scores were used for longitudinal assessments. Genomic DNA was genotyped on the Illumina HumanOmniExpressExome array. Individual genetic ancestry was determined by supervised cluster analysis for subjects of European, African, Hispanic/Native American, and other descent. To test for association of SNPs with PTSD, logistic regressions were performed within each ancestry group and results were combined in meta-analyses. Measures of childhood and adult trauma were included to test for gene-by-environment (GxE) interactions. Polygenic risk scores from the Psychiatric Genomic Consortium were used for major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ).ResultsThe array produced >800K directly genotyped and >21M imputed markers in 3494 unrelated, trauma-exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR=1.47, SE=0.06, ...

Mild traumatic brain injury (mTBI) disproportionately affects military service members and is very difficult to diagnose. To-date, there is currently no blood-based, diagnostic biomarker for mTBI cases with persistent post concussive symptoms. To examine the potential of neuronally-derived (NDE) and astrocytic-derived (ADE) exosome cargo proteins as biomarkers of chronic mTBI in younger adults, we examined plasma exosomes from a prospective longitudinal study of combat-related risk and resilience, marine resiliency study II (MRSII). After return from a combat-deployment participants were interviewed to assess TBI exposure while on deployment. Plasma exosomes from military service members with mTBI (mean age, 21.7 years, n = 19, avg. days since injury 151), and age-matched, controls (deployed service members who did not endorse a deployment-related TBI or a pre-deployment history of TBI; mean age, 21.95 years, n = 20) were precipitated and enriched against a neuronal adhesion protein, L1-CAM, and an astrocyte marker, glutamine aspartate transporter (GLAST) using magnetic beads to immunocapture the proteins and subsequently selected by fluorescent activated cell sorting (FACS). Extracted protein cargo from NDE and ADE preparations were quantified for protein levels implicated in TBI neuropathology by standard ELISAs and on the ultra-sensitive single molecule assay (Simoa) platform. Plasma NDE and ADE levels of Aβ42 were significantly higher while plasma NDE and ADE levels of the postsynaptic protein, neurogranin (NRGN) were significantly lower in participants endorsing mTBI exposure compared to controls with no TBI history. Plasma NDE and ADE levels of Aβ40, total tau, and neurofilament light (NFL), P-T181-tau, P-S396-tau were either undetectable or not significantly different between the two groups. In an effort to understand the pathogenetic potential of NDE and ADE cargo proteins, neuron-like cultures were treated with NDE and ADE preparations from TBI and non-TBI groups. Lastly, we determined that plasma NDE but not ADE cargo proteins from mTBI samples were found to be toxic to neuron-like recipient cells in vitro. These data support the presence of markers of neurodegeneration in NDEs of mTBI and suggest that these NDEs can be used as tools to identify pathogenic mechanisms of TBI.

Mild traumatic brain injury (mTBI) disproportionately affects military service members and is very difficult to diagnose. To-date, there is currently no blood-based, diagnostic biomarker for mTBI cases with persistent post concussive symptoms. To examine the potential of neuronally-derived (NDE) and astrocytic-derived (ADE) exosome cargo proteins as biomarkers of chronic mTBI in younger adults, we examined plasma exosomes from a prospective longitudinal study of combat-related risk and resilience, marine resiliency study II (MRSII). After return from a combat-deployment participants were interviewed to assess TBI exposure while on deployment. Plasma exosomes from military service members with mTBI (mean age, 21.7 years, n = 19, avg. days since injury 151), and age-matched, controls (deployed service members who did not endorse a deployment-related TBI or a pre-deployment history of TBI; mean age, 21.95 years, n = 20) were precipitated and enriched against a neuronal adhesion protein, L1-CAM, and an astrocyte marker, glutamine aspartate transporter (GLAST) using magnetic beads to immunocapture the proteins and subsequently selected by fluorescent activated cell sorting (FACS). Extracted protein cargo from NDE and ADE preparations were quantified for protein levels implicated in TBI neuropathology by standard ELISAs and on the ultra-sensitive single molecule assay (Simoa) platform. Plasma NDE and ADE levels of Aβ42 were significantly higher while plasma NDE and ADE levels of the postsynaptic protein, neurogranin (NRGN) were significantly lower in participants endorsing mTBI exposure compared to controls with no TBI history. Plasma NDE and ADE levels of Aβ40, total tau, and neurofilament light (NFL), P-T181-tau, P-S396-tau were either undetectable or not significantly different between the two groups. In an effort to understand the pathogenetic potential of NDE and ADE cargo proteins, neuron-like cultures were treated with NDE and ADE preparations from TBI and non-TBI groups. Lastly, we determined that plasma NDE but not ADE cargo proteins from mTBI samples were found to be toxic to neuron-like recipient cells in vitro. These data support the presence of markers of neurodegeneration in NDEs of mTBI and suggest that these NDEs can be used as tools to identify pathogenic mechanisms of TBI.

Post-traumatic stress disorder (PTSD) is a leading cause of sustained impairment, distress, and poor quality of life in military personnel, veterans, and civilians. Indirect functional neuroimaging studies using PET or fMRI with fear-related stimuli support a PTSD neurocircuitry model that includes amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC). However, it is not clear if this model can fully account for PTSD abnormalities detected directly by electromagnetic-based source imaging techniques in resting-state. The present study examined resting-state magnetoencephalography (MEG) signals in 25 active-duty service members and veterans with PTSD and 30 healthy volunteers. In contrast to the healthy volunteers, individuals with PTSD showed: 1) hyperactivity from amygdala, hippocampus, posterolateral orbitofrontal cortex (OFC), dorsomedial prefrontal cortex (dmPFC), and insular cortex in high-frequency (i.e., beta, gamma, and high-gamma) bands; 2) hypoactivity from vmPFC, Frontal Pole (FP), and dorsolateral prefrontal cortex (dlPFC) in high-frequency bands; 3) extensive hypoactivity from dlPFC, FP, anterior temporal lobes, precuneous cortex, and sensorimotor cortex in alpha and low-frequency bands; and 4) in individuals with PTSD, MEG activity in the left amygdala and posterolateral OFC correlated positively with PTSD symptom scores, whereas MEG activity in vmPFC and precuneous correlated negatively with symptom score. The present study showed that MEG source imaging technique revealed new abnormalities in the resting-state electromagnetic signals from the PTSD neurocircuitry. Particularly, posterolateral OFC and precuneous may play important roles in the PTSD neurocircuitry model.