The effect of Alcohol Withdrawal Syndrome severity on sleep, brain and cognition Running title: The harmful effects of drinking cessation

International audienceIn alcohol use disorder, drinking cessation is frequently associated with an alcohol withdrawal syndrome. Early in abstinence (within the first two months after drinking cessation), when patients do not exhibit physical signs of alcohol withdrawal syndrome anymore (such as nausea, tremor or anxiety), studies report various brain, sleep and cognitive alterations, highly heterogeneous from one patient to another. While the acute neurotoxicity of alcohol withdrawal syndrome is well known, its contribution to structural brain alterations, sleep disturbances and neuropsychological deficits observed early in abstinence has never been investigated and is addressed in this study. We included 54 alcohol use disorder patients early in abstinence (from 4 to 21 days of sobriety) and 50 healthy controls. When acute physical signs of alcohol withdrawal syndrome were no longer present, patients performed a detailed neuropsychological assessment, a T1-weighted MRI, and a polysomnography for a subgroup of patients. According to the severity of the clinical symptoms collected during the acute withdrawal period, patients were subsequently classified as mild alcohol withdrawal syndrome (mild-AWS) patients (Cushman score 4, no benzodiazepine prescription, N=17) or moderate alcohol withdrawal syndrome (moderate-AWS) patients (Cushman score > 4, benzodiazepine prescription, N=37). Patients with severe withdrawal complications (delirium tremens or seizures) were not included. Mild-AWS patients presented similar gray matter volume and sleep quality as healthy controls, but lower processing speed and episodic memory performance. Compared to healthy controls, moderate-AWS patients presented non-rapid eye movement sleep alterations, widespread gray matter shrinkage and lower performance for all the cognitive domains assessed (processing speed, short-term memory, executive functions and episodic memory). ModerateAWS patients presented a lower percentage of slow wave sleep, gray matter atrophy in frontoinsular and thalamus/hypothalamus regions, and lower short-term memory and executive performance than mild-AWS patients. Mediation analyses revealed both direct and indirect (via fronto-insular and thalamus/hypothalamus atrophy) relationships between poor sleep quality and cognitive performance. Alcohol withdrawal syndrome severity, which reflects neurotoxic hyperglutamatergic activity, should be considered as a critical factor for the development of non-rapid eye movement sleep alterations, fronto-insular atrophy and executive impairments in recently detoxified alcohol use disorder patients. The glutamatergic activity is involved in sleep-wake circuits and may thus contribute to molecular mechanisms underlying alcoholrelated brain damage, resulting in cognitive deficits. Alcohol withdrawal syndrome severity and sleep quality deserve special attention for a better understanding and treatment of brain and cognitive alterations observed early in abstinence, and ultimately for more efficient relapse prevention strategies