Pierre-Yves Postic ^1,2,3* Yann Leprince ¹ Soraya Brosset ^4,5 Laure Drutel ^6,7 Emeline Peyric ⁸ Ines Ben-Abdallah ^4,5 Dhaif Bekha ^4,5 Sara Neumane ^4,5,9 Edouard Duchesnay ¹⁰ Mickael Dinomais ¹¹ Mathilde Chevignard ^12,13,3 Lucie Hertz-Pannier ^1,2

• ¹ UNIACT, Neurospin, Gif-sur-Yvette, France
• ² InDEV, INSERM UMR1141 Neurodiderot, Paris, France
• ³ INSERM U1146 Laboratoire d'Imagerie Biomédicale, Paris, Île-de-France, France
• ⁴ Neurospin, Gif-sur-Yvette, Île-de-France, France
• ⁵ INSERM UMR1141 Neurodiderot, Paris, France
• ⁶ EA1285 Laboratoire de Psychologie, Cognition, Comportement, Communication (LP3C), Rennes, France
• ⁷ French National Reference Center for Pediatric Stroke, CHU de Saint-Etienne, Saint-Etienne, France
• ⁸ Hospices Civils de Lyon, Lyon, Rhône-Alpes, France
• ⁹ Departement of Pediatric Physical Medicine and Rehabilitation, Hôpital Raymond-Poincaré, Garches, France
• ¹⁰ BAOBAB, Neurospin, Gif-sur-Yvette, Île-de-France, France
• ¹¹ Department of Physical Medicine and Rehabilitation, Centre Hospitalier Universitaire d'Angers, Angers, Pays de la Loire, France
• ¹² Rehabilitation Department for Children with Acquired Brain Injury, Hôpitaux de Saint-Maurice, Saint-Maurice, France
• ¹³ GRC 24 Handicap Moteur Cognitif et Réadaptation (HaMCRe), Sorbonne University, Paris, France

Early focal brain injuries lead to long-term disabilities with frequent cognitive impairments, suggesting global dysfunction beyond the lesion. While plasticity of the immature brain promotes better learning, outcome variability across individuals is multifactorial. Males are more vulnerable to early injuries and neurodevelopmental disorders than females, but long-term sex differences in brain growth after an early focal lesion have not been described yet. With this MRI longitudinal morphometry study of brain development after a Neonatal Arterial Ischemic Stroke (NAIS), we searched for differences between males and females in the trajectories of ipsi- and contralesional grey matter growth in childhood and adolescence, accounting for lesion characteristics. We relied on a longitudinal cohort (AVCnn) of patients with unilateral NAIS who underwent clinical and MRI assessments at 7 and 16 and were compared to age-matched controls. Non-lesioned volumes of grey matter (hemispheres, lobes, regions, deep structures, cerebellum) were extracted from segmented T1 MRI images at 7 (Patients: 23 M, 16 F ; Controls : 17 M, 18 F) and 16 (Patients : 18 M, 11 F ; Controls : 16 M, 15 F). These volumes were analyzed using a Linear Mixed Model accounting for age, sex, and lesion characteristics. Whole hemisphere volumes were reduced at both ages in patients compared to controls (grey matter volume : -16% in males, -10% in females). In ipsilesional hemisphere, cortical grey matter and thalamic volume losses (average -13%) mostly depended on lesion severity, suggesting diaschisis, with minimal effect of patient sex. In the contralesional hemisphere however, we consistently found sex differences in grey matter volumes, as only males volumes were smaller (average -7.5%), mostly in territories mirroring the contralateral lesion. Females did not significantly deviate from the typical trajectories of controls. Similar sex differences were found in both cerebellar hemispheres. These results suggests sex-dependant compensation trajectories after an early brain lesion. The similarity of this pattern between age 7 and 16 evokes that puberty has little effect on these trajectories, and that most of the deviation in males occurs in early childhood, in line with the well described perinatal vulnerability of the  male brain, with no compensation thereafter.