Cerebellar hypermetabolism disrupts fronto-cerebellar resting-state functional connectivity and associated executive...

Cerebellar hypermetabolism measured with FDG-PET is interpreted as maladaptive plasticity, while increased cerebellar functional connectivity reported in fMRI studies indicates a compensatory role. Using Alcohol Use Disorder (AUD) as a neurobiological model, the combination of PET and fMRI examinations can extend our understanding of cerebellar mechanisms underlying brain reorganization within the fronto-thalamo-cerebellar circuit (FCC) supporting executive functions. The aim of the present study was to investigate resting-state functional connectivity (rs-FC) of the cerebellum and to examine its relationship with cerebellar metabolism, thalamic grey matter volume (GM) as a key node of the FCC, and executive functioning. In AUD patients, stronger negative rs-FC was found between the cerebellar lobule VIII seed and voxels in the left superior frontal gyrus compared with HC. Path analysis conducted in AUD patients indicated that cerebellar hypermetabolism was positively related to fronto-cerebellar rs-FC, and that fronto-cerebellar rs-FC was positively related to inhibition performance. In this model, after controlling for thalamic GM abnormalities, cerebellar hypermetabolism negatively impacted inhibition performance through rs-FC. Cerebellar hypermetabolism disrupts negative fronto-cerebellar rs-FC, resulting in desynchronization within the fronto-cerebellar loop that compromises compensation for executive deficits. Cerebellar hypermetabolism may represent a biomarker of alcohol-related brain dysfunction, as an initial mechanism in the cascade linking fronto-cerebellar desynchronization and executive impairment.