CATECHOL-O-METHYLTRANSFERASE GENOTYPE MODIFIES EXECUTIVE FUNCTIONING AND PREFRONTAL FUNCTIONAL CONNECTIVITY IN WOMEN WITH ANOREXIA NERVOSA.

Background: Anorexia nervosa (AN) is characterised by high levels of perseveration and inflexibility which interfere with successful treatments. Dopamine signalling seems to play a key role in modulating the prefrontal cortex, since both dopamine deficiency and excess negatively influences the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase gene on the set-shifting abilities and prefrontal functional connectivity of patients with AN. Methods: All subjects of the study (166 subjects with DSM-IV lifetime AN and 140 healthy women) performed the Wisconsin Card Sorting Task, and a subsample (33 AN patients and 30 controls) underwent resting-state functional magnetic resonance imaging scanning. Results: Both underweight and weight-recovered AN patients showed high levels of perseveration, but only in the underweight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased dopamine signalling in the prefrontal cortex. Underweight AN patients who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity, indicating abnormal regional cortical processing. Limitations: Although our data show that grey matter reduction in starving AN did not explain our findings, the cross-sectional design of the present study did not allow to distinguish between the effects of starvation and those of low estrogen levels. Conclusions: Starvation affects dopamine release in the prefrontal cortex of AN patients with different effects on executive functioning and prefrontal functional connectivity according to catechol-O-methyltransferase genotype. This observation has several therapeutic implications that need to be addressed by future studies.