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.