Recent research on classical fear-conditioning in the anxiety disorders has identified overgeneralization of conditioned fear as an important conditioning correlate of anxiety pathology. Unfortunately, only one human neuroimaging study of classically conditioned fear generalization has been conducted, and the neural substrates of this clinically germane process remain largely unknown. The current generalization study employs a clinically validated generalization gradient paradigm, modified for the fMRI environment, to identify neural substrates of classically conditioned generalization that may function aberrantly in clinical anxiety. Stimuli include five rings of gradually increasing size with extreme sizes serving as cues of conditioned danger (CS+) and safety (CS-). The three intermediately sized rings serve as generalization stimuli (GSs) and create a continuum-of-size from CS+ to CS-. Results demonstrate 'positive' generalization gradients, reflected by declines in responding as the presented stimulus differentiates from CS+, in bilateral anterior insula, dorsomedial prefrontal cortex, and bilateral inferior parietal lobule. Conversely, 'negative' gradients, reflected by inclines in responding as the presented stimulus differentiates from CS+ were instantiated in bilateral ventral hippocampus, ventromedial prefrontal cortex and precuneus cortex. These results as well as those from connectivity analyses are discussed in relation to a working neurobiology of conditioned generalization centered on the hippocampus.

In response to recommendations to redefine statistical significance to p ≤ .005, we propose that researchers should transparently report and justify all choices they make when designing a study, including the alpha level.

Classical fear-conditioning is central to many etiologic accounts of panic disorder (PD), but few lab-based conditioning studies in PD have been conducted. One conditioning perspective proposes associative-learning deficits characterized by deficient safety learning among PD patients. The current study of PD assesses acquisition and retention of discriminative aversive conditioning using a fear-potentiated startle paradigm. This paradigm was chosen for its specific capacity to independently assess safety- and danger-learning in the service of characterizing putative anomalies in each type of learning among those with PD. Though no group difference in fear-potentiated startle was found at retention, acquisition results demonstrate impaired discrimination learning among PD patients as indexed by measures of conditioned startle-potentiation to learned safety and danger cues. Importantly, this discrimination deficit was driven by enhanced startle potentiation to the learned safety-cue rather than aberrant reactivity to the danger cue. Consistent with this finding, PD patients relative to healthy individuals reported higher expectancies of dangerous outcomes in the presence of the safety cue, but equal danger expectancies during exposure to the danger cue. Such results link PD to impaired discrimination learning, reflecting elevated fear responding to learned safety-cues.