Trauma exposure relates to heightened stress, altered amygdala morphology and deficient extinction learning: Implications for psychopathology.

Stress exposure causes a structural reorganization in neurons of the amygdala. In particular, animal models have repeatedly shown that both acute and chronic stress induce neuronal hypertrophy and volumetric increase in the lateral and basolateral nuclei of amygdala. These effects are visible on the behavioral level, where stress enhances anxiety behaviors and provokes greater fear learning. We assessed stress and anxiety levels in a group of 18 healthy human trauma-exposed individuals (TR group) compared to 18 non-exposed matched controls (HC group), and related these measurements to amygdala volume. Traumas included unexpected adverse experiences such as vehicle accidents or sudden loss of a loved one. As a measure of aversive learning, we implemented a cued fear conditioning paradigm. Additionally, to provide a biological marker of chronic stress, we measured the sensitivity of the hypothalamus-pituitary-adrenal (HPA) axis using a dexamethasone suppression test. Compared to the HC, the TR group showed significantly higher levels of chronic stress, current stress and trait anxiety, as well as increased volume of the left amygdala. Specifically, we observed a focal enlargement in its lateral portion, in line with previous animal data. Compared to HC, the TR group also showed enhanced late acquisition of conditioned fear and deficient extinction learning, as well as salivary cortisol hypo-suppression to dexamethasone. Left amygdala volumes positively correlated with suppressed morning salivary cortisol. Our results indicate differences in trauma-exposed individuals which resemble those previously reported in animals exposed to stress and in patients with post-traumatic stress disorder and depression. These data provide new insights into the mechanisms through which traumatic stress might prompt vulnerability for psychopathology.

Deficient fear extinction memory in posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) might be maintained by deficient extinction memory. We used a cued fear conditioning design with extinction and a post-extinction phase to provoke the return of fear and examined the role of the interplay of amygdala, hippocampus and prefrontal regions. METHODS: We compared 18 PTSD patients with two healthy control groups: 18 trauma-exposed subjects without PTSD (nonPTSD) and 18 healthy controls (HC) without trauma experience. They underwent a three-day ABC-conditioning procedure in a functional magnetic resonance imaging scanner. Two geometric shapes that served as conditioned stimuli (CS) were presented in the context of virtual reality scenes. Electric painful stimuli were delivered after one of the two shapes (CS+) during acquisition (in context A), while the other (CS-) was never paired with pain. Extinction was performed in context B and extinction memory was tested in a novel context C. RESULTS: The PTSD patients showed significantly higher differential skin conductance responses than the non-PTSD and HC and higher differential amygdala and hippocampus activity than the HC in context C. In addition, elevated arousal to the CS+ during extinction and to the CS- throughout the experiment was present in the PTSD patients but self-reported differential valence or contingency were not different. During extinction recall, differential amygdala activity correlated positively with the intensity of numbing and ventromedial prefrontal cortex activity correlated positively with behavioral avoidance. CONCLUSIONS: PTSD patients show heightened return of fear in neural and peripheral measures. In addition, self-reported arousal was high to both danger (CS+) and safety (CS-) cues. These results suggest that a deficient maintenance of extinction and a failure to identify safety signals might contribute to PTSD symptoms, whereas non-PTSD subjects seem to show normal responses.

Reduced amygdala responsivity during conditioning to trauma-related stimuli in posttraumatic stress disorder.

Exaggerated conditioned fear responses and impaired extinction along with amygdala overactivation have been observed in posttraumatic stress disorder (PTSD). These fear responses might be triggered by cues related to the trauma through higher-order conditioning, where reminders of the trauma may serve as unconditioned stimuli (US) and could maintain the fear response. We compared arousal, valence, and US expectancy ratings and BOLD brain responses using fMRI in 14 traumatized persons with PTSD and 14 without PTSD (NPTSD) and 13 matched healthy controls (HC) in a differential aversive conditioning paradigm. The US were trauma-specific pictures for the PTSD and NPTSD group and equally aversive and arousing for the HC; the conditioned stimuli (CS) were graphic displays. During conditioning, the PTSD patients compared to the NPTSD and HC indicated higher arousal to the conditioned stimulus that was paired with the trauma picture (CS+) compared to the unpaired (CS-), increased dissociation during acquisition and extinction, and failure to extinguish the CS/US-association compared to NPTSD. During early and late acquisition, the PTSD patients showed a significantly lower amygdala activation to CS+ versus CS- and a negative interaction between activation in the amygdala and dorsolateral prefrontal cortex (PFC), while NPTSD and HC displayed a negative interaction between amygdala and medial PFC. These findings suggest maladaptive anticipatory coping with trauma-related stimuli in patients with PTSD, indicated by enhanced conditioning, with related abnormal amygdala reactivity and connectivity, and delayed extinction.

Hippocampal but not amygdalar volume affects contextual fear conditioning in humans.

Both animal and human studies have identified a critical role of the hippocampus in contextual fear conditioning. In humans mainly functional magnetic resonance imaging has been used. To extend these findings to volumetric properties, 58 healthy participants underwent structural magnetic resonance imaging and participated in a differential fear conditioning paradigm with contextual stimuli. Ratings of emotional valence, arousal, and contingency as well as skin conductance responses (SCRs) were used as indicators of conditioning. Twenty-nine participants with the smallest hippocampal volumes were compared with 29 persons with the largest hippocampal volumes. Persons with larger hippocampal volume (especially on the right side) learned to discriminate between two conditioned contexts, whereas those with small hippocampal volumes did not, as indicated by SCRs. Further analyses showed that these results could not be explained by amygdalar volumes. In contrast, the participant answers on the self-report measures were not significantly influenced by hippocampal or amygdalar, but by total brain volume, suggesting a role of cortical structures in these more cognitive evaluation processes. Reanalysis of the self-report data using partial hippocampal volumes revealed a significant influence of the posterior but not anterior subvolumes, which is in accordance with theories and empirical findings on hippocampal functioning. This study shows the relevance of hippocampal volume for contextual fear conditioning in healthy volunteers and may have important implications for anxiety disorders.

Enhanced stress analgesia to a cognitively demanding task in patients with posttraumatic stress disorder.

BACKGROUND: Uncontrollable stress is frequently accompanied by a primarily opioid-mediated stress analgesia. In posttraumatic stress disorder (PTSD) exaggerated stress-induced analgesia to trauma reminders was proposed. The present study investigated whether enhanced analgesia occurs in response to a trauma-unrelated cognitive stressor in PTSD. METHODS: Functional magnetic resonance imaging data were obtained from fourteen outpatients with PTSD and 14 trauma-exposed subjects without PTSD (NPTSD) during mechanical painful stimulation before and after stress. Blood oxygenation level-dependent (BOLD) responses were assessed during painful stimulation. Pain ratings, pain thresholds and pain tolerance were assessed pre- and post-stress. Heart rate and blood pressure were recorded before, during and after stress. RESULTS: In comparison to NPTSD, PTSD-patients showed significantly more analgesia in terms of an increase of pain threshold and tolerance and a decrease in pain ratings after the stressor. Post-stress, PTSD-patients compared to NPTSD displayed more activation of the rostral anterior cingulate cortex and decreased neural activity in brain areas associated with pain perception. However heart rate increase during stress and blood pressure decrease post-stress was lower in PTSD pointing to a dysregulation of the cardiovascular system in response to stress. LIMITATIONS: The small sample size represents a limiting factor in interpreting the results and might have led to low levels of significance for the group differences in BOLD response changes. CONCLUSIONS: These findings show enhanced stress reactivity and accompanying reduced pain perception in PTSD-patients in contrast to traumatized participants without PTSD. The results suggest that the previously reported enhanced analgesic response after trauma-related stress in PTSD transfers to trauma-unrelated stressors.