Abstract Background Narcolepsy Type 1 is a chronic sleep disorder caused by a deficiency of orexin (hypocretin). In addition to sleep regulation, orexin is important for motivated control processes. Weight gain and obesity are common in narcolepsy. However, the neurocognitive processes associated with food-related control and overeating in orexin-deficient patients are unknown. We explored the neural correlates of general and food-related attentional control in narcolepsy patients (n=23) and healthy BMI-matched controls (n=20). In secondary analyses, we included patients with idiopathic hypersomnia (n=15) to assess sleepiness-related influences. Methods We measured attentional bias to food words with a Food Stroop task and general executive control with a Classic Stroop task during fMRI. Moreover, with correlational analyses, we assessed the relative contribution of the neural findings on the Food Stroop and Classic Stroop tasks to spontaneous snack intake. Results Relative to healthy controls, narcolepsy patients showed enhanced ventral medial prefrontal cortex responses and connectivity with motor cortex during the Food Stroop task, but attenuated dorsal medial prefrontal cortex responses during the Classic Stroop task. The ventral medial prefrontal cortex responses on the Food Stroop task, not the dorsal medial prefrontal cortex responses on the Classic Stroop task, were a significant predictor of snack intake. Comparing the narcolepsy patients with idiopathic hypersomnia patients revealed similar results. Conclusions These findings demonstrate that orexin deficiency is associated with decreased dorsal medial prefrontal cortex responses during general executive control and enhanced ventral medial prefrontal cortex responses during food-driven attention, with the latter predicting increases in food intake. Statement of Significance Patients with orexin (hypocretin) deficient narcolepsy type-1 often suffer from obesity as well as increased food craving, in addition to the sleep symptoms. However, whether and how orexin deficiency relates to neural differences in food-directed attention is unclear. We employed a Food Stroop task during fMRI and provide experimental evidence that the ventral medial prefrontal cortex responds more strongly to food words in narcolepsy patients than in controls. The hypothesis that this mechanism contributes to weight problems in narcolepsy is strengthened by the observation that ventral medial prefrontal cortex responses during the Food Stroop task were predictive of snack intake. These mechanistic data might thus advance the development of treatment targets for obesity in narcolepsy.

Enhanced food-related responses in the ventral medial prefrontal cortex in orexin-deficient patients