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Relapse represents a major limitation to long-term remission of psychopathology (anxiety, addiction). Relapse of anxiety can be modeled in the laboratory as return of fear (ROF) following un-signaled re-presentation of the aversive event (reinstatement, RI) after extinction. In humans, response enhancement to both the CS+ and CS− (generalized RI) or specifically to the CS+ (differential RI) has been described following RI. The (psychological) mechanisms and boundary conditions underlying these different RI qualities were investigated in 76 healthy participants using autonomic measures and functional magnetic resonance imaging. Our results suggest that both processes reflect distinct albeit intertwined (psychological) processes which are reflected in different neural activation patterns. Differential RI was linked to CS+ related hippocampal activation and CS− related disinhibition of the ventromedial prefrontal cortex (vmPFC). The latter likely contributes to robust generalized RI which was mirrored in thalamic and visual areas (as well as the bed nucleus of the striatum and inusula) possibly indicating generally facilitated salience processing. In addition, we also present data on experimental boundary conditions of RI (trial sequence effects, time stability). Taken together, this first comprehensive analysis of RI-induced ROF aids not only experimental research on ROF but also understanding of factors promoting clinical relapse and the role of the vmPFC.