Enhancing fetal alcohol spectrum disorders diagnosis with a classifier based on the intracerebellar gradient of volumetric undersizing

Justine Fraize (1, 2, 3, 4, 5) , Clara Fischer (6, 2, 3, 4) , Monique Elmaleh-Bergès (1, 7) , Eliot Kerdreux (3, 2, 4, 5, 1) , Anita Beggiato (8) , Alexandra Ntorkou (7) , Edouard Duchesnay (3, 2, 4, 6) , Dhaif Bekha (3, 2, 4, 5, 1) , Odile Boespflug-Tanguy (1) , Richard Delorme (8) , Lucie Hertz-Pannier (3, 2, 4, 5, 1) , David Germanaud (3, 2, 4, 5, 1, 9)

1 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
2 JOLIOT - Institut des Sciences du Vivant Frédéric JOLIOT
3 CEA - CEA- Saclay
4 NEUROSPIN - Service NEUROSPIN
5 UNIACT - Unité de recherche en NeuroImagerie Applicative Clinique et Translationnelle
6 BAOBAB - Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields
7 AP-HP Hôpital universitaire Robert-Debré [Paris]
8 Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré]
9 Département de génétique [Robert Debré]

In fetal alcohol spectrum disorders (FASD), brain growth deficiency is a hallmark of subjects both with fetal alcohol syndrome (FAS) and with non-syndromic FASD (NS-FASD, i.e., those without specific diagnostic features). However, although the cerebellum was suggested to be more severely undersized than the rest of the brain, it has not yet been given a specific place in the FASD diagnostic criteria where neuroanatomical features still count for little if anything in diagnostic specificity. We applied a combination of cerebellar segmentation tools on a 1.5 T 3DT1 brain MRI dataset from a monocentric population of 89 FASD (52 FAS, 37 NS-FASD) and 126 typically developing controls (6–20 years old), providing 8 volumes: cerebellum, vermis and 3 lobes (anterior, posterior, inferior), plus total brain volume. After adjustment of confounders, the allometric scaling relationship between these cerebellar volumes (V i ) and the total brain or cerebellum volume (V t) was fitted (V i = bVt^a), and the effect of group (FAS, control) on allometric scaling was evaluated. We then estimated for each cerebellar volume in the FAS population the deviation from the typical scaling (v DTS) learned in the controls. Lastly, we trained and tested two classifiers todiscriminate FAS from controls, one based on the total cerebellum v DTS only, the other based on all the cerebellar v DTS, comparing their performance both in the FAS and the NS-FASD group. Allometric scaling was significantly different between FAS and control group for all the cerebellar volumes (p < .001). We confirmed the excess of total cerebellum volume deficit (v DTS = 10.6%) and revealed an antero-inferior-posterior gradient of volumetric undersizing in the hemispheres (12.4%, 1.1%, 2.0%, repectively) and the vermis (16.7%, 9.2%, 8.6%, repectively). The classifier based on the intracerebellar gradient of v DTS performed more efficiently than the one based on total cerebellum v DTS only (AUC = 92% vs. 82%, p = .001). Setting a high probability threshold for >95% specificity of the classifiers, the gradient-based classifier identified 35% of the NS-FASD to have a FAS cerebellar phenotype, compared to 11% with the cerebellum-only classifier (pFISHER = 0.027). In a large series of FASD, this study details the volumetric undersizing within the cerebellum at the lobar and vermian level using allometric scaling, revealing an anterior-inferior-posterior gradient of vulnerability to prenatal alcohol exposure. It also strongly suggests that this intra-cerebellar gradient of volumetric undersizing may be a reliable neuroanatomical signature of FAS that could be used to improve the specificity of the diagnosis of NS-FASD.

Mots clés: cerebellum morphometry; diagnostic imaging; fetal alcohol spectrum disorders; fetal alcohol syndrome; microcephaly; prenatal alcohol exposure; scaling analysis

Domaines: Médecine humaine et pathologie; Imagerie médicale

Justine Fraize, Clara Fischer, Monique Elmaleh-Bergès, Eliot Kerdreux, Anita Beggiato, et al.. Enhancing fetal alcohol spectrum disorders diagnosis with a classifier based on the intracerebellar gradient of volumetric undersizing. Human Brain Mapping, 2023, 44 (11), pp.4321-4336. ⟨10.1002/hbm.26348⟩. ⟨inserm-04102112⟩