Clinical-biological Alzheimer's disease stage concordance: insights from cohorts and autopsy data.

Deficits in forming and retrieving fear extinction memories are implicated in anxiety-related disorders, including posttraumatic stress disorder (PTSD; (–). Exposure-based therapy, which involves many of the principles of extinction (), is a gold-standard psychotherapy for PTSD. However, only half of patients who undergo exposure therapy experience lasting symptom improvement (,). Strategies that enhance extinction might inform how to improve psychotherapy (–), particularly if they strengthen the retrieval of safety memories. Animal research has identified interconnected regions involved in the formation, consolidation, and retrieval of extinction memories, including connections between the ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC) (,). Human neuroimaging research has translated these findings, showing activity within these regions may be abnormal in PTSD, possibly contributing to extinction memory retrieval deficits (–). Whether augmented extinction strategies, such as counterconditioning, can rescue extinction memory retrieval deficits in PTSD remains unclear. Here, we compare the long-term item-level fidelity of counterconditioning versus standard extinction memory traces using multivariate pattern analysis (MVPA) of fMRI data in adults with and without PTSD symptoms. One behavioral approach to enhance the learning and retention of safety memories involves replacing an expected aversive outcome (e.g., electrical shock) with a positive/rewarding outcome, a paradigm known as counterconditioning (). The new association between the conditioned stimulus (CS) and unconditioned stimulus (US), formed during counterconditioning, diminishes defensive-related behavior (,). Counterconditioning may result in stronger alternative CS associations than simply omitting the aversive US (), creating more durable safety memories than standard extinction. In a recent within-subjects neuroimaging study in healthy adults, our lab found counterconditioning outperformed standard extinction in reducing BOLD response in brain regions associated with threat appraisal and expression after 24-hour delay (). Trial-unique semantic exemplars from two superordinate categories (animals and tools) served as conditioned stimuli paired with shock. New exemplars from one category underwent standard extinction, while exemplars from the other category underwent counterconditioning, where shock was replaced by positively valanced pictures. Twenty-four hours and 1-month later, participants returned for tests of extinction/counterconditioning recall consisting of new category exemplars. Compared to standard extinction, counterconditioning reduced BOLD response in regions associated with threat learning, appraisal, and expression, including the dACC (,). This suggests counterconditioning might create a more stable memory trace relying on distinct neurocircuitry from standard extinction, at least in adults without PTSD ().