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.

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.

Trauma, treatment and Tetris: video gaming increases hippocampal volume in male patients with combat-related posttraumatic stress disorder.

Background: Tetris has been proposed as a preventative intervention to reduce intrusive memories of a traumatic event. However, no neuroimaging study has assessed Tetris in patients with existing posttraumatic stress disorder (PTSD) or explored how playing Tetris may affect brain structure. Methods: We recruited patients with combat-related PTSD before psychotherapy and randomly assigned them to an experimental Tetris and therapy group (n = 20) or to a therapy-only control group (n = 20). In the control group, participants completed therapy as usual: eye movement desensitization and reprocessing (EMDR) psychotherapy. In the Tetris group, in addition to EMDR, participants also played 60 minutes of Tetris every day from onset to completion of therapy, approximately 6 weeks later. Participants completed structural MRI and psychological questionnaires before and after therapy, and we collected psychological questionnaire data at follow-up, approximately 6 months later. We hypothesized that the Tetris group would show increases in hippocampal volume and reductions in symptoms, both directly after completion of therapy and at follow-up. Results: Following therapy, hippocampal volume increased in the Tetris group, but not the control group. As well, hippocampal increases were correlated with reductions in symptoms of PTSD, depression and anxiety between completion of therapy and follow-up in the Tetris group, but not the control group. Limitations: Playing Tetris may act as a cognitive interference task and as a brain-training intervention, but it was not possible to distinguish between these 2 potential mechanisms. Conclusion: Tetris may be useful as an adjunct therapeutic intervention for PTSD. Tetris-related increases in hippocampal volume may ensure that therapeutic gains are maintained after completion of therapy.

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.

Neural indicators of interpersonal anger as cause and consequence of combat training stress symptoms.

BACKGROUND: Angry outbursts are an important feature of various stress-related disorders, and commonly lead to aggression towards other people. Findings regarding interpersonal anger have linked the ventromedial prefrontal cortex (vmPFC) to anger regulation and the locus coeruleus (LC) to aggression. Both regions were previously associated with traumatic and chronic stress symptoms, yet it is unclear if their functionality represents a consequence of, or possibly also a cause for, stress symptoms. Here we investigated the relationship between the neural trajectory of these indicators of anger and the development and manifestation of stress symptoms. METHOD: A total of 46 males (29 soldiers, 17 civilians) participated in a prospective functional magnetic resonance imaging experiment in which they played a modified interpersonal anger-provoking Ultimatum Game (UG) at two-points. Soldiers were tested at the beginning and end of combat training, while civilians were tested at the beginning and end of civil service. We assumed that combat training would induce chronic stress and result in increased stress symptoms. RESULTS: Soldiers showed an increase in stress symptoms following combat training while civilians showed no such change following civil service. All participants were angered by the modified UG irrespective of time point. Higher post-combat training stress symptoms were associated with lower pre-combat training vmPFC activation and with higher activation increase in the LC between pre- and post-combat training. CONCLUSIONS: Results suggest that during anger-provoking social interactions, flawed vmPFC functionality may serve as a causal risk factor for the development of stress symptoms, and heightened reactivity of the LC possibly reflects a consequence of stress-inducing combat training. These findings provide potential neural targets for therapeutic intervention and inoculation for stress-related psychopathological manifestations of anger.

Individual differences in cognitive reappraisal use and emotion regulatory brain function in combat-exposed veterans with and without PTSD.

BACKGROUND: Veterans with posttraumatic stress disorder (PTSD) exhibit marked deficits in emotion regulation. Past research has demonstrated underengagement of the prefrontal cortex during regulation of negative affect in those with PTSD, but has been unable to find evidence of impaired downregulation of the amygdala. One possibility is that there exists variability in amygdala reactivity that cuts across diagnostic status and which can be characterized using a continuous measure of individual differences. In healthy/nontraumatized volunteers, individual variability in amygdala engagement during emotion processing and regulation has been shown to relate to habitual use of regulation strategies. METHODS: The current study examined whether self-reported use of cognitive reappraisal and expressive suppression regulation strategies correlated with brain activation during cognitive reappraisal in combat-exposed veterans with (n = 28) and without PTSD (combat-exposed controls, CEC; n = 20). RESULTS: Results showed that greater self-reported use of cognitive reappraisal was associated with less activation in the right amygdala during volitional attempts to attenuate negative affect using reappraisal, irrespective of PTSD diagnosis. CONCLUSIONS: This finding is in line with prior work and extends evidence of an association between habitual use of regulation strategies and amygdala engagement during emotion regulation to a trauma-exposed sample of individuals both with and without PTSD. Furthermore, by providing evidence of individual differences in regulation-related amygdala response in a traumatized sample, this result may increase understanding of the neural mechanisms that support variability in symptom manifestation observed across individuals with PTSD.

Combat-related blast exposure and traumatic brain injury influence brain glucose metabolism during REM sleep in military veterans.

Traumatic brain injury (TBI), a signature wound of Operations Enduring and Iraqi Freedom, can result from blunt head trauma or exposure to a blast/explosion. While TBI affects sleep, the neurobiological underpinnings between TBI and sleep are largely unknown. To examine the neurobiological underpinnings of this relationship in military veterans, [(18)F]-fluorodeoxyglucose positron emission tomography (FDG PET) was used to compare mTBI-related changes in relative cerebral metabolic rate of glucose (rCMRglc) during wakefulness, Rapid Eye Movement (REM) sleep, and non-REM (NREM) sleep, after adjusting for the effects of posttraumatic stress (PTS). Fourteen veterans with a history of blast exposure and/or mTBI (B/mTBI) (age 27.5±3.9) and eleven veterans with no history (No B/mTBI) (age 28.1±4.3) completed FDG PET studies during wakefulness, REM sleep, and NREM sleep. Whole-brain analyses were conducted using Statistical Parametric Mapping (SPM8). Between group comparisons revealed that B/mTBI was associated with significantly lower rCMRglc during wakefulness and REM sleep in the amygdala, hippocampus, parahippocampal gyrus, thalamus, insula, uncus, culmen, visual association cortices, and midline medial frontal cortices. These results suggest that alterations in neurobiological networks during wakefulness and REM sleep subsequent to B/mTBI exposure may contribute to chronic sleep disturbances and differ in individuals with acute symptoms.

Deep brain stimulation of the amygdala for treatment-resistant combat post-traumatic stress disorder: Long-term results.

Deep brain stimulation (DBS) holds promise for neuropsychiatric conditions where imbalance in network activity contributes to symptoms. Treatment-resistant Combat post-traumatic stress disorder (TR-PTSD) is a highly morbid condition and 50% of PTSD sufferers fail to recover despite psychotherapy or pharmacotherapy. Reminder-triggered symptoms may arise from inadequate top-down ventromedial prefrontal cortex (vmPFC) control of amygdala reactivity. Here, we report long-term data on two TR-PTSD participants from an investigation utilizing high-frequency amygdala DBS. The two combat veterans were implanted bilaterally with quadripolar electrodes targeting the basolateral amygdala. Following a randomized staggered onset, patients received stimulation with adjustments based on PTSD symptom severity for four years while psychiatric and neuropsychiatric symptoms, neuropsychological performance, and electroencephalography were systematically monitored. Evaluation of vmPFC-Amygdala network engagement was assessed with 18FDG positron emission tomography (PET). CAPS-IV scores varied over time, but improved 55% from 119 at baseline to 53 at 4-year study endpoint in participant 1; and 44%, from 68 to 38 in participant 2. Thereafter, during 5 and 1.5 years of subsequent clinical care respectively, long-term bilateral amygdala DBS was associated with additional, clinically significant symptomatic and functional improvement. There were no serious stimulation-related adverse psychiatric, neuropsychiatric, neuropsychological, neurological, or neurosurgical effects. In one subject, symptomatic improvement was associated with an intensity-dependent reduction in amygdala theta frequency power. In our two participants, FDG-PET findings were inconclusive regarding the hypothesized mechanism of suppression of amygdala hyperactivity. Our findings encourage further research to confirm and extend our preliminary observations.

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.

Initial Validation of the Mid-Atlantic Mental Illness Research, Education, and Clinical Center Assessment of Traumatic Brain Injury.

With the increasing prevalence of traumatic brain injury (TBI), the need for reliable and valid methods to evaluate TBI has also increased. The purpose of this study was to establish the validity and reliability of a new comprehensive assessment of TBI, the Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) Assessment of TBI (MMA-TBI). The participants in this study were post-deployment, combat exposed veterans. First, MMA-TBI outcomes were compared with those of independently conducted clinical TBI assessments. Next, MMA-TBI outcomes were compared with those of a different validated TBI measure (the Ohio State University TBI Identification method [OSU-TBI-ID]). Next, four TBI subject matter experts independently evaluated 64 potential TBI events based on both clinical judgment and Veterans Administration/Department of Defense (VA/DoD) Clinical Practice Guidelines. Results of the MMA-TBI algorithm (based on VA/DoD clinical guideline) were compared with those of the subject matter experts. Diagnostic correspondence with independently conducted expert clinical evaluation was 96% for lifetime TBI and 92% for deployment-acquired TBI. Consistency between the MMA-TBI and the OSU-TBI-ID was high (κ = 0.90; Kendall Tau = 0.94). Comparison of MMA-TBI algorithm results with those of subject matter experts was high (κ = 0.97-1.00). The MMA-TBI is the first TBI interview to be validated against an independently conducted clinical TBI assessment. Overall, results demonstrate the MMA-TBI is a highly valid and reliable instrument for determining TBI based on VA/DoD clinical guidelines. These results support the need for application of standardized TBI criteria across all diagnostic contexts.

Combat exposure, posttraumatic stress disorder, and head injuries differentially relate to alterations in cortical thickness in military Veterans.

Combat-exposed Veterans are at increased risk for developing psychological distress, mood disorders, and trauma and stressor-related disorders. Trauma and mood disorders have been linked to alterations in brain volume, function, and connectivity. However, far less is known about the effects of combat exposure on brain health. The present study examined the relationship between severity of combat exposure and cortical thickness. Post-9/11 Veterans (N = 337; 80% male) were assessed with structural neuroimaging and clinically for combat exposure, depressive symptoms, prior head injury, and posttraumatic stress disorder (PTSD). Vertex-wide cortical thickness was estimated using FreeSurfer autosegmentation. FreeSurfer's Qdec was used to examine relationship between combat exposure, PTSD, and prior head injuries on cortical thickness (Monte Carlo corrected for multiple comparisons, vertex-wise cluster threshold of 1.3, p < 0.01). Covariates included age, sex, education, depressive symptoms, nonmilitary trauma, alcohol use, and prior head injury. Higher combat exposure uniquely related to lower cortical thickness in the left prefrontal lobe and increased cortical thickness in the left middle and inferior temporal lobe; whereas PTSD negatively related to cortical thickness in the right fusiform. Head injuries related to increased cortical thickness in the bilateral medial prefrontal cortex. Combat exposure uniquely contributes to lower cortical thickness in regions implicated in executive functioning, attention, and memory after accounting for the effects of PTSD and prior head injury. Our results highlight the importance of examining effects of stress and trauma exposure on neural health in addition to the circumscribed effects of specific syndromal pathology.

Changes in relative glucose metabolic rate following cortisol administration in aging veterans with posttraumatic stress disorder: an FDG-PET neuroimaging study.

The authors aimed to examine central glucocorticoids effects by measuring relative glucose metabolic rate (rGMR) in the hippocampus, amygdala, and anterior cingulate cortex (ACC) and the relationship between amygdala and ACC activity. The participants were male combat veterans with and without PTSD, 52 to 81 years old. The authors utilized randomized, double-blind, placebo-controlled examinations of the rGMR response to 17.5 mg hydrocortisone (HCORT) using 2-Deoxy-2-[(18)F]fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) neuroimaging. Group differences in hemispheric laterality of rGMR were observed following placebo administration, reflecting lower rGMR in the right hippocampus and ventral amygdala, and higher rGMR in the left ventral amygdala in the PTSD+ group compared to the PTSD- group. HCORT reduced these group differences in laterality. The net effect of HCORT was to restore a normal inverse association between the ACC and amygdala in the PTSD+ group, but disrupt this neural network in the PTSD- group. The magnitude of improvement in working memory correlated with greater hemispheric laterality in the dorsal amygdala following HCORT in both groups. The restorative effects of HCORT on metabolism and working memory provide a rationale for examining the therapeutic benefits of glucocorticoid manipulation in aging PTSD patients.

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.

Elevated perceived threat is associated with reduced hippocampal volume in combat veterans.

Reduced hippocampal volume is frequently observed in posttraumatic stress disorder (PTSD), but the psychological processes associated with these alterations remain unclear. Given hippocampal involvement in memory and contextual representations of threat, we investigated relationships between retrospectively reported combat exposure, perceived threat, and hippocampal volume in trauma-exposed veterans. T1-weighted anatomical MRI scans were obtained from 56 veterans (4 women, 52 men; 39 with elevated PTSD symptoms, "PTSS" group) and hippocampal volume was estimated using automatic segmentation tools in FreeSurfer. Hippocampal volume was regressed on self-reported perceived threat from the Deployment Risk and Resilience Inventory, and combat exposure from the Combat Exposure Scale. As a secondary analysis, hippocampal volume was regressed on Clinician-Administered PTSD Scale (CAPS) symptoms. In veterans with elevated PTSD symptoms, hippocampal volume was inversely related to perceived threat while deployed while controlling for self-reported combat exposure. Hippocampal volume was also inversely correlated with avoidance/numbing CAPS symptoms. Future research should clarify the temporal milieu of these effects and investigate whether individual differences in hippocampal structure and function contribute to heightened threat appraisal at the time of trauma vs. subsequently elevated appraisals of traumatic events.

Attention training modulates resting-state neurophysiological abnormalities in posttraumatic stress disorder.

Recent research indicates the relative benefits of computerized attention control treatment (ACT) and attention bias modification treatment (ABMT) for posttraumatic stress disorder (PTSD); however, neural changes underlying these therapeutic effects remain unknown. This study examines how these two types of attention training modulate neurological dysfunction in veterans with PTSD. A community sample of 46 combat veterans with PTSD participated in a randomized double-blinded clinical trial of ACT versus ABMT and 32 of those veterans also agreed to undergo resting-state magnetoencephalography (MEG) recordings. Twenty-four veterans completed psychological and MEG assessments at pre- and post-training to evaluate treatment effects. MEG data were imaged using an advanced Bayesian reconstruction method and examined using statistical parametric mapping. In this report, we focus on the neural correlates and the differential treatment effects observed using MEG; the results of the full clinical trial have been described elsewhere. Our results indicated that ACT modulated occipital and ABMT modulated medial temporal activity more strongly than the comparative treatment. PTSD symptoms decreased significantly from pre- to post-test. These initial neurophysiological outcome data suggest that ACT modulates visual pathways, while ABMT modulates threat-processing regions, but that both are associated with normalizing aberrant neural activity in veterans with PTSD.

Neural correlates of response bias: Larger hippocampal volume correlates with symptom aggravation in combat-related posttraumatic stress disorder.

The diagnosis of posttraumatic stress disorder (PTSD) is vulnerable to the simulation or exaggeration of symptoms as it depends on the individual's self-report of symptoms. The use of symptom validity tests is recommended to detect malingering in PTSD. However, in neuroimaging research, PTSD diagnosis is often taken at face validity. To date, no neuroimaging study has compared credible PTSD patients with those identified as malingering, and the potential impacts of including malingerers along with credible patients on results is unclear. We classified male patients with combat-related PTSD as either credible (n = 37) or malingerers (n = 9) based on the Morel Emotional Numbing Test and compared structural neuroimaging and psychological questionnaire data. Patients identified as malingerers had larger gray matter volumes in the hippocampus, right inferior frontal gyrus and thalamus, and reported higher PTSD symptoms than credible PTSD patients. This is the first structural neuroimaging study to compare credible PTSD patients and malingerers. We find evidence of structural differences between these groups, in regions implicated in PTSD, inhibition and deception. These results emphasize the need for the inclusion of SVTs in neuroimaging studies of PTSD to ensure future findings are not confounded by an unknown mix of valid PTSD patients and malingerers.

Real-time fMRI amygdala neurofeedback positive emotional training normalized resting-state functional connectivity in combat veterans with and without PTSD: a connectome-wide investigation.

Self-regulation of brain activation using real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) is an emerging approach for treating mood and anxiety disorders. The effect of neurofeedback training on resting-state functional connectivity warrants investigation as changes in spontaneous brain activation could reflect the association between sustained symptom relief and brain alteration. We investigated the effect of amygdala-focused rtfMRI-nf training on resting-state functional connectivity in combat veterans with and without posttraumatic stress disorder (PTSD) who were trained to increase a feedback signal reflecting left amygdala activity while recalling positive autobiographical memories (Zotev et al., 2018). The analysis was performed in three stages: i) first, we investigated the connectivity in the left amygdala region; ii) next, we focused on the abnormal resting-state functional connectivity identified in our previous analysis of this data (Misaki et al., 2018); and iii) finally, we performed a novel data-driven longitudinal connectome-wide analysis. We introduced a longitudinal multivariate distance matrix regression (MDMR) analysis to comprehensively examine neurofeedback training effects beyond those associated with abnormal baseline connectivity. These comprehensive exploratory analyses suggested that abnormal resting-state connectivity for combat veterans with PTSD was partly normalized after the training. This included hypoconnectivities between the left amygdala and the left ventrolateral prefrontal cortex (vlPFC) and between the supplementary motor area (SMA) and the dorsal anterior cingulate cortex (dACC). The increase of SMA-dACC connectivity was associated with PTSD symptom reduction. Longitudinal MDMR analysis found a connectivity change between the precuneus and the left superior frontal cortex. The connectivity increase was associated with a decrease in hyperarousal symptoms. The abnormal connectivity for combat veterans without PTSD - such as hypoconnectivity in the precuneus with a superior frontal region and hyperconnectivity in the posterior insula with several regions - could also be normalized after the training. These results suggested that the rtfMRI-nf training effect was not limited to a feedback target region and symptom relief could be mediated by brain modulation in several regions other than in a feedback target area. While further confirmatory research is needed, the results may provide valuable insight into treatment effects on the whole brain resting-state connectivity.

Paralimbic and medial prefrontal cortical involvement in neuroendocrine responses to traumatic stimuli.

OBJECTIVE: Hypothalamic-pituitary-adrenal axis activity and cortisol release are consequences of central stress system activation, but they may also influence cognitive and emotional processes within the brain. Despite the importance of central stress response systems, little is known about the specific brain circuits through which psychosocial stimuli activate the hypothalamic-pituitary-adrenal axis and through which cortisol feedback modulates central processing. The authors used [(15)O]H(2)O positron emission tomography (PET) on subjects with posttraumatic stress disorder (PTSD) to study these circuits. METHOD: Participants were combat-PTSD patients, combat-exposed healthy comparison subjects, and noncombat-exposed healthy comparison subjects. Participants were scanned using [(15)O]H(2)O PET while they experienced a series of emotional-induction conditions, which included aversive pictures and autobiographic narratives. Blood samples were obtained 2 minutes before and 5 minutes after each activation scan in order to measure the subjects' plasma adrenocorticotropic hormone and cortisol levels. RESULTS: In voxel-wise analyses, the authors found that adrenocorticotropic hormone responses were covaried with regional cerebral blood flow (rCBF) in the dorsal medial prefrontal cortex, rostral anterior cingulate cortex, and right insula, with some differences between PTSD patients and comparison subjects. Prestimulus cortisol levels covaried with rCBF responses in the rostral anterior cingulate cortex. In combat-PTSD patients only, prestimulus cortisol levels covaried with rCBF in the subgenual anterior cingulate cortex. CONCLUSIONS: These findings provide evidence of cortical involvement in hypothalamic-pituitary-adrenal responses to psychological stimuli, specifically implicating the insula, dorsal medial prefrontal cortex, and rostral anterior cingulate cortex. These findings also show, for the first time, that cortisol may modulate activity in specific brain areas such as the rostral and subgenual anterior cingulate cortices. Differential patterns of covariation between combat veterans with and without PTSD potentially implicate the dorsal medial prefrontal cortex and subgenual anterior cingulate cortex as areas of dysregulation in PTSD.

Corticolimbic blood flow during nontraumatic emotional processing in posttraumatic stress disorder.

CONTEXT: Recent brain imaging studies implicate dysfunction of limbic and paralimbic circuitry, including the amygdala and medial prefrontal cortex (MPFC), in the pathogenesis of posttraumatic stress disorder (PTSD) during traumatic recollection and imagery. However, the relationship between activity in these regions and general emotional processing unrelated to traumatic experience has not been fully examined. OBJECTIVE: To investigate activity in the limbic and paralimbic brain regions in PTSD in response to a challenge with emotionally salient generic visual images. DESIGN: Cross-sectional, case-control study. SETTING: Academic medical center. PARTICIPANTS: Sixteen Vietnam veterans with combat-related PTSD (PTSD group), 15 combat-exposed Vietnam veterans without PTSD (combat control group), and 15 age- and sex-matched healthy controls (normal control group). MAIN OUTCOME MEASURES: We used positron emission tomography to study regional cerebral blood flow while participants viewed complex visual pictures with negatively valenced/aversive, nonaversive ("neutral"), and blank pictures. Psychophysiologic and emotional self-report data were also recorded. RESULTS: All 3 groups activated the dorsal MPFC to general salient content. Controls without PTSD activated the left amygdala in response to aversive stimuli. Normal controls activated the ventral MPFC and combat-exposed non-PTSD and PTSD participants exhibited either no response or deactivation in these regions, respectively, during negative emotional experience. CONCLUSIONS: Consistent with current functional neuroanatomic models, patients with PTSD exhibited altered neural responses in the amygdala and ventral MPFC during the processing of emotionally salient but trauma-unrelated stimuli, potentially reflecting disorder-specific changes. Activation of the amygdala and lack of ventral MPFC deactivation to negatively valenced images in combat controls may reflect compensatory changes after trauma exposure that are not associated with PTSD.

Automated measurement of hippocampal subfields in PTSD: Evidence for smaller dentate gyrus volume.

Smaller hippocampal volume has been consistently observed as a biomarker of posttraumatic stress disorder (PTSD). However, less is known about individual volumes of the subfields composing the hippocampus such as the dentate gyrus and cornu ammonis (CA) fields 1-4 in PTSD. The aim of the present study was to examine the hypothesis that volume of the dentate gyrus, a region putatively involved in distinctive encoding of similar events, is smaller in individuals with PTSD versus trauma-exposed controls. Ninety-seven recent war veterans underwent structural imaging on a 3T scanner and were assessed for PTSD using the Clinician-Administered PTSD Scale. The hippocampal subfield automated segmentation program available through FreeSurfer was used to segment the CA4/dentate gyrus, CA1, CA2/3, presubiculum, and subiculum of the hippocampus. Results showed that CA4/dentate gyrus subfield volume was significantly smaller in veterans with PTSD and scaled inversely with PTSD symptom severity. These results support the view that dentate gyrus abnormalities are associated with symptoms of PTSD, although additional evidence is necessary to determine whether these abnormalities underlie fear generalization and other memory alterations in PTSD.