Rebecca K. Sripada

Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder

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 PTSD showed greater positive connectivity between the amygdala and insula, reduced positive connectivity between the amygdala and hippocampus, and reduced anticorrelation between the amygdala and dorsal ACC and rostral ACC. LIMITATIONS Only male veterans with combat exposure were tested, thus our findings cannot be generalized to women or to individuals with non-combat related PTSD. CONCLUSION These results demonstrate that studies of functional connectivity during resting state can discern aberrant patterns of coupling within emotion circuits and suggest a possible brain basis for emotion-processing and emotion-regulation deficits in individuals with PTSD.

Neural Dysregulation in Posttraumatic Stress Disorder: Evidence for Disrupted Equilibrium between Salience and Default Mode Brain Networks

Objective Convergent research demonstrates disrupted attention and heightened threat sensitivity in posttraumatic stress disorder (PTSD). This might be linked to aberrations in large-scale networks subserving the 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 with and without PTSD (n = 15 in each group) and in healthy community controls (n = 15). Correlation coefficients were calculated between the time course of seed regions in key SN and DMN regions and all other voxels of the brain. Results Compared with control groups, participants with PTSD showed reduced functional connectivity within the DMN (between DMN seeds and other DMN regions) including the rostral anterior cingulate cortex/ventromedial prefrontal cortex (z = 3.31; p = .005, corrected) and increased connectivity within the SN (between insula seeds and other SN regions) including the amygdala (z = 3.03; p = .01, corrected). Participants with PTSD also demonstrated increased cross-network connectivity. DMN seeds exhibited elevated connectivity with SN regions including the insula (z = 3.06; p = .03, corrected), and SN seeds exhibited elevated connectivity with DMN regions including the hippocampus (z = 3.10; p = .048, corrected). Conclusions During resting-state scanning, participants with PTSD showed reduced coupling within the DMN, greater coupling within the SN, and increased coupling between the DMN and the 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.

Impaired Contextual Modulation of Memories in PTSD: An fMRI and Psychophysiological Study of Extinction Retention and Fear Renewal

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 (CS+E) 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 CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E 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.

Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits.

BACKGROUND The neurosteroid allopregnanolone is a potent allosteric modulator of the gamma-aminobutyric acid type 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 allopregnanolones impact on emotion regulation, participants were administered 400 mg of pregnenolone (n=16) or placebo (n=15) and underwent 3T functional magnetic resonance imaging while performing the shifted-attention emotion appraisal task, which probes emotional processing and regulation. RESULTS Compared with 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 pharmacologic intervention in the treatment of anxiety disorders and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.

Childhood Poverty and Stress Reactivity Are Associated with Aberrant Functional Connectivity in Default Mode Network

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=26) and matched controls from middle-income families (n=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.

DHEA Enhances Emotion Regulation Neurocircuits and Modulates Memory for Emotional Stimuli

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.

Mild Traumatic Brain Injury and Treatment Response in Prolonged Exposure for PTSD

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.

The neurosteroids allopregnanolone and dehydroepiandrosterone modulate resting-state amygdala connectivity.

The neurosteroids allopregnanolone and dehydroepiandrosterone (DHEA) are integral components of the stress response and exert positive modulatory effects on emotion in both human and animal studies. Although these antidepressant and anxiolytic effects have been well established, to date, little research has examined their neural correlates, and no research has been conducted into the effects of neurosteroids on large‐scale networks at rest. To investigate the neurosteroid impact on intrinsic connectivity networks, participants were administered 400 mg of pregnenolone (N = 16), 400 mg of DHEA (N = 14), or placebo (N = 15) and underwent 3T fMRI. Resting‐state brain connectivity was measured using amygdala as a seed region. When compared with placebo, pregnenolone administration reduced connectivity between amygdala and dorsal medial prefrontal cortex, between amygdala and precuneus, and between amygdala and hippocampus. DHEA reduced connectivity between amygdala and periamygdala and between amygdala and insula. Reductions in amygdala to precuneus connectivity were associated with less self‐reported negative affect. These results demonstrate that neurosteroids modulate amygdala functional connectivity during resting state and may be a target for pharmacological intervention. Additionally, allopregnanolone and DHEA may shift the balance between salience network and default network, a finding that could provide insight into the neurocircuitry of anxiety psychopathology. Hum Brain Mapp 35:3249–3261, 2014.

Avoidant symptoms in PTSD predict fear circuit activation during multimodal fear extinction

Convergent evidence suggests that individuals with posttraumatic stress disorder (PTSD) exhibit exaggerated avoidance behaviors as well as abnormalities in Pavlonian fear conditioning. However, the link between the two features of this disorder is not well understood. In order to probe the brain basis of aberrant extinction learning in PTSD, we administered a multimodal classical fear conditioning/extinction paradigm that incorporated affectively relevant information from two sensory channels (visual and tactile) while participants underwent fMRI scanning. The sample consisted of fifteen OEF/OIF veterans with PTSD. In response to conditioned cues and contextual information, greater avoidance symptomatology was associated with greater activation in amygdala, hippocampus, vmPFC, dmPFC, and insula, during both fear acquisition and fear extinction. Heightened responses to previously conditioned stimuli in individuals with more severe PTSD could indicate a deficiency in safety learning, consistent with PTSD symptomatology. The close link between avoidance symptoms and fear circuit activation suggests that this symptom cluster may be a key component of fear extinction deficits in PTSD and/or may be particularly amenable to change through extinction-based therapies.

Between-session and within-session habituation in Prolonged Exposure Therapy for posttraumatic stress disorder: A hierarchical linear modeling approach

Prolonged Exposure Therapy is a frontline intervention for posttraumatic stress disorder, but the mechanisms underlying its efficacy are not fully understood. Previous research demonstrates that between- and within-session habituation of fear during exposure is associated with treatment outcome, but these calculations are historically performed with summary statistics such as mean subjective units of distress (SUDS). This question could be better assessed with an analytic technique that uses all SUDS measurements available within sessions. Hierarchical linear modeling was used to investigate the impact of treatment response on SUDS nested within therapy sessions nested within 14 patients. Symptom change (t=-2.43, p=.03) and responder status (t=-2.68, p=.02) predicted slope of SUDS across sessions, but did not reliably predict slope of SUDS within-session, indicating that high responders demonstrated differential between- but not within-session habituation. Thus, individuals who show greater habituation between treatment sessions may be more likely to respond to treatment.