IntroductionPosttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder characterized by symptoms of re-experiencing, hyperarousal, emotional numbing and avoidance; 1 however, exact brain mechanisms involved in the generation of PTSD symptoms or in PTSD pathophysiology have yet to be elucidated. Converging neuroimaging research points to a potentially critical role for disrupted emotion neurocircuitry in individuals with PTSD, and whereas many studies have delineated patterns of activations during face viewing or symptom provocation (for a review, see Shin and Liberzon 2 ), relatively few have examined patterns of connectivity in the brains of patients with PTSD at rest, a potentially powerful method for illuminating brain network structure. 3,4 Most PTSD neuroimaging studies to date have described abnormalities in emotion-generation regions, such as the amygdala or insula, and emotion-regulation regions, including the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC). This is consistent with the known role of the amygdala as a key region in threat detection, 5 fear conditioning 6 and emotional salience, 7 and of the mPFC as a modulatory region interconnected with limbic structures 8 and involved in emotion regulation.9 Taken together, functional magnetic resonance imaging (fMRI) studies of individuals with PTSD suggest patterns of hyperactivation of the amygdala and insula to emotion-related stimuli and corresponding hypoactivation of ventromedial prefrontal and rostral anterior cingulate cortices.2 This pattern of amygdala hyperactivity and mPFC hypoactivity was recently confirmed by a meta-analysis of 15 PTSD neuroimaging studies 10 and is generally understood to reflect a lack of regulatory control over emotion in individuals with PTSD.Studies of functional connectivity, however, can provide additional and potentially more direct information about regu latory relationships between the mPFC and amygdala. The amygdala has tight structural connections and reciprocal feedback loops with the mPFC and orbitofrontal cortex 11 as well as with the dorsolateral PFC 12 and ACC. 13 As amygdala Background: Converging neuroimaging research suggests altered emotion neurocircuitry in individuals with posttraumatic stress disorder (PTSD). Emotion activation studies in these individuals have shown hyperactivation in emotion-related regions, including the amygdala and insula, and hypoactivation in emotion-regulation regions, including the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). However, few studies have examined patterns of connectivity at rest in individuals with PTSD, a potentially powerful method for illuminating brain network structure. Methods: Using the amygdala as a seed region, we measured resting-state brain connectivity using 3 T functional magnetic resonance imaging in returning male veterans with PTSD and combat controls without PTSD. Results: Fifteen veterans with PTSD and 14 combat controls enrolled in our study. Compared with controls, veterans with ...

Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CSϩE) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CSϩ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CSϩE and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression.

Objective Convergent neuroimaging and neuropsychological research demonstrates disrupted attention and heightened threat sensitivity in PTSD. This might be linked to aberrations in large-scale networks subserving detection of salient stimuli, i.e. the salience network (SN), and stimulus-independent, internally-focused thought, i.e. the default mode network (DMN). Methods Resting state brain activity was measured in returning veterans who served in Iraq or Afghanistan with (n=15) and without PTSD (n=15) and in healthy community controls (n=15). Correlation coefficients were calculated between the time course of seed regions in key SN and DMN regions (posterior cingulate, ventromedial prefrontal cortex, and bilateral anterior insula) and all other voxels of the brain. Results Compared to control groups, PTSD participants showed reduced functional connectivity within DMN (between DMN seeds and other DMN regions), including rostral ACC/vmPFC (Z=3.31; p=.005, corrected) and hippocampus (Z=2.58; p=.005), and increased connectivity within SN (between insula seeds and other SN regions), including amygdala (Z=3.03; p=.01, corrected). PTSD participants also demonstrated increased cross-network connectivity. DMN seeds exhibited elevated connectivity with SN regions, including insula (Z=3.06; p=.03, corrected), putamen, and supplementary motor area (Z=4.14; Z=4.08; p<.001), and SN seeds exhibited elevated connectivity with DMN regions, including hippocampus (Z=3.10; p=.048, corrected). Conclusions During resting state scanning, PTSD participants showed reduced coupling within DMN, greater coupling within SN, and increased coupling between DMN and SN. Our findings suggest a relative dominance of threat-sensitive circuitry in PTSD, even in task-free conditions. Disequilibrium between large-scale networks subserving salience detection versus internally focused thought may be associated with PTSD pathophysiology.

Increased connectivity between DMN and executive control regions following mindfulness training could underlie increased capacity for volitional shifting of attention. The increased PCC-DLPFC rsFC following MBET was related to PTSD symptom improvement, pointing to a potential therapeutic mechanism of mindfulness-based therapies.

Convergent research suggests that childhood poverty is associated with perturbation in the stress response system. This might extend to aberrations in the connectivity of large-scale brain networks, which subserve key cognitive and emotional functions. Resting-state brain activity was measured in adults with a documented history of childhood poverty (n ¼ 26) and matched controls from middle-income families (n ¼ 26). Participants also underwent a standard laboratory social stress test and provided saliva samples for cortisol assay. Childhood poverty was associated with reduced default mode network (DMN) connectivity. This, in turn, was associated with higher cortisol levels in anticipation of social stress. These results suggest a possible brain basis for exaggerated stress sensitivity in low-income individuals. Alterations in DMN may be associated with less efficient cognitive processing or greater risk for development of stress-related psychopathology among individuals who experienced the adversity of chronic childhood poverty.

Background The neurosteroid allopregnanolone is a potent allosteric modulator of the GABA(A) receptor with anxiolytic properties. Exogenous administration of allopregnanolone reduces anxiety, and allopregnanolone blockade impairs social and affective functioning. However, the neural mechanism whereby allopregnanolone improves mood and reduces anxiety is unknown. In particular, brain imaging has not been used to link neurosteroid effects to emotion regulation neurocircuitry. Methods To investigate the brain basis of allopregnanolone’s impact on emotion regulation, participants were administered 400mg of pregnenolone (N=16) or placebo (N=15) and underwent 3T fMRI while performing the Shifted-Attention Emotion Appraisal Task (SEAT), which probes emotional processing and regulation. Results Compared to placebo, allopregnanolone was associated with reduced activity in the amygdala and insula across all conditions. During the appraisal condition, allopregnanolone increased activity in the dorsal medial prefrontal cortex and enhanced connectivity between the amygdala and dorsal medial prefrontal cortex, an effect that was associated with reduced self-reported anxiety. Conclusions These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacological intervention in the treatment of anxiety disorders, and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.

Dehydroepiandrosterone (DHEA) is a neurosteroid with anxiolytic, antidepressant, and antiglucocorticoid properties. It is endogenously released in response to stress, and may reduce negative affect when administered exogenously. Although there have been multiple reports of DHEA's antidepressant and anxiolytic effects, no research to date has examined the neural pathways involved. In particular, brain imaging has not been used to link neurosteroid effects to emotion neurocircuitry. To investigate the brain basis of DHEA's impact on emotion modulation, patients were administered 400 mg of DHEA (N=14) or placebo (N=15) and underwent 3T fMRI while performing the shifted-attention emotion appraisal task (SEAT), a test of emotional processing and regulation. Compared with placebo, DHEA reduced activity in the amygdala and hippocampus, enhanced connectivity between the amygdala and hippocampus, and enhanced activity in the rACC. These activation changes were associated with reduced negative affect. DHEA reduced memory accuracy for emotional stimuli, and also reduced activity in regions associated with conjunctive memory encoding. These results demonstrate that DHEA reduces activity in regions associated with generation of negative emotion and enhances activity in regions linked to regulatory processes. Considering that activity in these regions is altered in mood and anxiety disorders, our results provide initial neuroimaging evidence that DHEA may be useful as a pharmacological intervention for these conditions and invite further investigation into the brain basis of neurosteroid emotion regulatory effects.

A proportion of U.S. veterans returning from Iraq and Afghanistan have experienced mild traumatic brain injury (mTBI), which is associated with increased risk for developing posttraumatic stress disorder (PTSD). Prolonged Exposure (PE) has proven effectiveness in the treatment of PTSD; however, some clinicians have reservations about using PE with individuals with a history of mTBI. We examined the impact of PE for veterans with PTSD and with or without a history of mTBI in a naturalistic sample of 51 veterans who received PE at a Veterans Health Administration PTSD clinic. We also analyzed previously collected data from a controlled trial of 22 veterans randomly assigned to PE or present centered therapy. For both sets of data, we found that PE reduced symptom levels and we also did not detect an effect for mTBI, suggesting that PE may be helpful for individuals with PTSD and a history of mTBI.