Spectral-based thickness profiling of the corpus callosum enhances anomaly detection in fetal alcohol spectrum disorders.

Introduction: Fetal alcohol spectrum disorders (FASD) range from fetal alcohol syndrome (FAS) to non-syndromic forms (NS-FASD). The neuroanatomical consequences of prenatal alcohol exposure are mainly the reduction in brain size, but also focal abnormalities such as those of the corpus callosum (CC). We previously showed a narrowing of the CC for brain size, using manual measurement and its usefulness to improve diagnostic certainty. Our aim was to automate these measurements of the CC and identify more recurrent abnormalities in FAS subjects, independently of brain size reduction. Methods: We developed a fast, automated, and normalization-free method based on spectral analysis to generate thicknesses of the CC continuously and at singular points (genu, body, isthmus, and splenium), and its length (LCC). We applied it on midsagittal section of the CC extracted from T1-anatomical brain MRI of 89 subjects with FASD (52 FAS, 37 NS-FASD) and 126 with typically development (6-20 y-o). After adjusting for batch effect, we compared the mean profiles and thicknesses of the singular points across the 3 groups. For each parameter, we established variations with age (growth charts) and brain size in the control group (scaling charts), then identified participants with abnormal measurements (<10th percentile). Results: We confirmed the slimming of the posterior half of the CC in both FASD groups, and of the genu section in the FAS group, compared to the control group. We found a significant group effect for the LCC, genu, median body, isthmus, and splenium thicknesses (p < 0.05). We described a body hump whose morphology did not differ between groups. According to the growth charts, there was an excess of FASD subjects with abnormal LCC and isthmus, and of FAS subjects with abnormal genu and splenium. According to the scaling charts, this excess remained only for LCC, isthmus and splenium, undersized for brain size. Conclusion: We characterized size-independent anomalies of the posterior part of the CC in FASD, with an automated method, confirming and extending our previous study. Our new tool brings the use of a neuroanatomical criterion including CC damage closer to clinical practice. Our results suggest that an FAS signature identified in NS-FASD, could improve diagnosis specificity.

Questioning cognitive heterogeneity and intellectual functioning in fetal alcohol spectrum disorders from the Wechsler intelligence scale for children.

Introduction: Fetal Alcohol Spectrum Disorders (FASD) are characterized by a variety of multiple cognitive and behavioral impairments, with intellectual, attentional, and executive impairments being the most commonly reported. In populations with multiple neurodevelopmental disorders, the Full Scale Intelligence Quotient (FSIQ) may not be a proper measure of intellectual abilities, rarely interpreted in FASD clinical practice because the heterogeneity of the cognitive profile is deemed too strong. We propose a quantitative characterization of this heterogeneity, of the strengths and weaknesses profile, and a differential analysis between global cognitive (FSIQ) and elementary reasoning abilities in a large retrospective monocentric FASD sample. Methods: Using clinical and cognitive data (Wechsler Intelligence Scale for Children) from 107 children with FASD, we characterized subject heterogeneity (variance and scatter of scaled/composite scores), searched for strengths and weaknesses, and specified intellectual functioning in terms of FSIQ and elementary reasoning (General Abilities Index, Highest Reasoning Scaled Score), in comparison with standardization norms and a Monte-Carlo-simulated sample from normalization data. Results: Performance of children with FASD was lower on all subtests, with a significant weakness in working memory and processing speed. We found no increase in the variance and scatter of the scores, but a discordance between the assessment of global cognitive functioning (28% borderline, 23% deficient) and that of global and elementary reasoning abilities (23-9% borderline, 15-14% deficient). Conclusion: Our results question the notion of WISC profile heterogeneity in FASD and point to working memory and processing speed over-impairment, with global repercussions but most often preserved elementary reasoning abilities.

Mapping corpus callosum surface reduction in fetal alcohol spectrum disorders with sulci and connectivity-based parcellation.

Introduction: Fetal alcohol spectrum disorders (FASD) range from fetal alcohol syndrome (FAS) to non-syndromic non-specific forms (NS-FASD) that are still underdiagnosed and could benefit from new neuroanatomical markers. The main neuroanatomical manifestation of prenatal alcohol exposure on developmental toxicity is the reduction in brain size, but repeated imaging observations have long driven the attention on the corpus callosum (CC), without being all convergent. Our study proposed a new segmentation of the CC that relies on both a sulci-based cortical segmentation and the "hemispherotopic" organization of the transcallosal fibers. Methods: We collected a monocentric series of 37 subjects with FAS, 28 with NS-FASD, and 38 with typical development (6 to 25 years old) using brain MRI (1.5T). Associating T1- and diffusion-weighted imaging, we projected a sulci-based cortical segmentation of the hemispheres on the midsagittal section of the CC, resulting in seven homologous anterior-posterior parcels (frontopolar, anterior and posterior prefrontal, precentral, postcentral, parietal, and occipital). We measured the effect of FASD on the area of callosal and cortical parcels by considering age, sex, and brain size as linear covariates. The surface proportion of the corresponding cortical parcel was introduced as an additional covariate. We performed a normative analysis to identify subjects with an abnormally small parcel. Results: All callosal and cortical parcels were smaller in the FASD group compared with controls. When accounting for age, sex, and brain size, only the postcentral (η2 = 6.5%, pFDR = 0.032) callosal parcel and % of the cortical parcel (η2 = 8.9%, pFDR = 0.007) were still smaller. Adding the surface proportion (%) of the corresponding cortical parcel to the model, only the occipital parcel was persistently reduced in the FASD group (η2 = 5.7%, pFDR = 0.014). In the normative analysis, we found an excess of subjects with FASD with abnormally small precentral and postcentral (peri-isthmic) and posterior-splenial parcels (pFDR < 0.05). Conclusion: The objective sulcal and connectivity-based method of CC parcellation proved to be useful not only in confirming posterior-splenial damage in FASD but also in the narrowing of the peri-isthmic region strongly associated with a specific size reduction in the corresponding postcentral cortical region (postcentral gyrus). The normative analysis showed that this type of callosal segmentation could provide a clinically relevant neuroanatomical endophenotype, even in NS-FASD.

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

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 (Vi ) and the total brain or cerebellum volume (Vt ) was fitted (Vi = 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 to discriminate 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%, respectively) 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 intracerebellar 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.

Combining neuroanatomical features to support diagnosis of fetal alcohol spectrum disorders.

AIM: To identify easily accessible neuroanatomical abnormalities useful for diagnosing fetal alcohol spectrum disorders (FASD) in fetal alcohol syndrome (FAS) but more importantly for the probabilistic diagnosis of non-syndromic forms (NS-FASD). METHOD: We retrospectively collected monocentric data from 52 individuals with FAS, 37 with NS-FASD, and 94 paired typically developing individuals (6-20 years, 99 males, 84 females). On brain T1-weighted magnetic resonance imaging, we measured brain size, corpus callosum length and thicknesses, vermis height, then evaluated vermis foliation (Likert scale). For each parameter, we established variations with age and brain size in comparison individuals (growth and scaling charts), then identified participants with abnormal measurements (<10th centile). RESULTS: According to growth charts, there was an excess of FAS with abnormally small brain, isthmus, splenium, and vermis. According to scaling charts, this excess remained only for isthmus thickness and vermis height. The vermis foliation was pathological in 18% of those with FASD but in no comparison individual. Overall, 39% of those with FAS, 27% with NS-FASD, but only 2% of comparison individuals presented with two FAS-recurrent abnormalities, and 19% of those with FAS had all three. Considering the number of anomalies, there was a higher likelihood of a causal link with alcohol in 14% of those with NS-FASD. INTERPRETATION: Our results suggest that adding an explicit composite neuroanatomical-radiological criterion for FASD diagnosis may improve its specificity, especially in NS-FASD. WHAT THIS PAPER ADDS: Neuroanatomical anomalies independent of microcephaly can be measured with clinical-imaging tools. Small-for-age brain, small-for-brain-size callosal isthmus or vermian height, and disrupted vermis foliation are fetal alcohol syndrome (FAS)-recurrent anomalies. Associations of these anomalies are frequent in fetal alcohol spectrum disorder (FASD) even without FAS, while exceptional in typically developing individuals. These associations support higher likelihood of causal link with alcohol in some individuals with non-syndromic FASD. A new explicit and composite neuroanatomical-radiological criterion can improve the specificity of FASD diagnosis.