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.

Brain morphology correlates of interindividual differences in conditioned fear acquisition and extinction learning.

The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear.

Behavioral and central correlates of contextual fear learning and contextual modulation of cued fear in posttraumatic stress disorder.

Patients with posttraumatic stress disorder (PTSD) show persistent fear responses to trauma cues in contexts in which these cues no longer predict danger. This might be related to deficient context and enhanced cue conditioning. To test this hypothesis, we examined context conditioning directly followed by a cue conditioning phase against the background of the previously conditioned context in 12 patients with PTSD, 14 traumatized control subjects without PTSD and 11 matched never-traumatized controls. We used differential context and cue conditioning paradigms, with rooms as contexts and geometric figures as cues, and assessed valence, arousal and contingency ratings as well as brain responses using functional magnetic resonance imaging. The PTSD patients showed more hippocampal activation and differentiated the threat and safe contexts less in their contingency ratings than the healthy controls during context acquisition. In the subsequent cue acquisition against the background of the conditioned context, they displayed similar threat versus safe cue differentiation in contingency ratings as the two control groups. Moreover, PTSD patients failed to extinguish the differential conditioned context and cued fear responses and showed increased fear to both the dangerous and the safe conditioned contexts and cues in some ratings. This study provides evidence for a dissociation of brain responses and contingency awareness in PTSD which represents impaired context learning and a deficient contextual modulation of cue-related associations. In addition, extinction and extinction recall were impaired in PTSD. These changes were related to PTSD symptoms and suggest that contextual learning deficits may contribute to PTSD.

Neuropsychological measures of hippocampal function.

The role of the medial temporal lobe, specifically the hippocampus, in learning and memory has been consistently demonstrated over the past years and has led to the identification of the hippocampus as a target imaging marker for several neurological and psychiatric disorders. Hippocampal dysfunctions and smaller hippocampal volumes have been reported as characteristic for these disorders, and hippocampal asymmetry has been shown to be associated with memory deficits in older adults. These findings underline the importance of screenings for memory functions using neuropsychological cognitive test batteries within the clinical context. To the best of our knowledge, there has been no comprehensive review that has presented neuropsychological tests related to the hippocampus in detail. However, we did not aim to provide a complete overview of neuropsychological tests related to hippocampal function, which would fail in the light of the widespread area. This chapter focuses on neuropsychological tests that assess cognitive functions that depend on the hippocampus in a state-of-the-art fashion and additionally provide the link to several disorders for which hippocampal abnormalities are a common characteristic.