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Background: Although deficits in affective processing are a core component of anorexia nervosa (AN), we lack a detailed characterization of the neurobiological underpinnings of emotion regulation impairment in AN. Moreover, it remains unclear whether these neural correlates scale with clinical outcomes. Methods: We investigated the neural correlates of negative emotion regulation in a sample of young women receiving day-hospital treatment for AN (n = 21) and healthy controls (n = 21). We aimed to determine whether aberrant brain activation patterns during emotion regulation predicted weight gain following treatment in AN patients and were linked to AN severity. To achieve this, participants completed a cognitive reappraisal paradigm during functional magnetic resonance imaging. Skin conductance response, as well as subjective distress ratings, were recorded to corroborate task engagement. Results: Compared to controls, patients with AN showed reduced activation in the dorsolateral prefrontal cortex (dlPFC) during cognitive reappraisal [pFWE<0.05, threshold-free cluster enhancement (TFCE) corrected]. Importantly, psycho–physiological interaction analysis revealed reduced functional connectivity between the dlPFC and the amygdala in AN patients during emotion regulation (pFWE<0.05, TFCE corrected), and dlPFC-amygdala uncoupling was associated with emotion regulation deficits (r = −0.511, p = 0.018) and eating disorder severity (r = −0.565, p =.008) in the AN group. Finally, dlPFC activity positively correlated with increases in body mass index (r = 0.471, p = 0.042) and in body fat mass percentage (r = 0.605, p = 0.008) following 12 weeks of treatment. Conclusions: Taken together, our findings indicate that individuals with AN present altered fronto-amygdalar response during cognitive reappraisal and that this response may serve as a predictor of response to treatment and be linked to clinical severity. [ABSTRACT FROM AUTHOR]