Trouble du spectre de l'alcoolisation fœtale : vers des marqueurs neuroanatomiques en imagerie

Alcohol-related neurodevelopmental disorders are a major cause of cognitive and behavioral disability in France but are poorly recognized, partly due to the lack of specificity in the clinical diagnosis of fetal alcohol spectrum disorders (FASD) in the absence of all clinical features of the fetal alcohol syndrome (FAS). Furthermore, clinical phenotype and level of alcohol exposure do not explain prognosis. Cerebral growth deficiency is a near-constant feature of FASD, sometimes associated with focal brain damage, encouraging the search for neuroanatomical markers of the FASD. Recent MRI-assisted neuroanatomical studies have broadened the scope of brain damage associated with FASD, but many of these findings remain elusive and no marker has yet emerged that is useful for the diagnosis of non-specific forms of FASD (NS-FASD) or for functional prognosis. Our aim was to identify neuroanatomical markers that could be characterized at the individual level and integrated into the current clinical approach. Thus, we created a database of subjects with FASD from a large monocentric clinical recruitment of patients extensively clinically and cognitively described and imaged in high resolution (T1 and diffusion MRI). This series was compared with over a hundred typically developing control subjects. Markers were sought using simple manual measurements, followed by computerized object morphometry (automatic segmentation, identification and measurement of brain regions or structures). We studied in detail the cerebellum and its lobar sub-parts, as well as the corpus callosum and each of its segments. A special effort was made to generate and use original complementary anatomical segmentation tools for cross-validation of results, in order to limit methodological biases. In addition, the analysis of size variance must take into account the fact that homotheticity (zooming) is not the rule between brains of different sizes with typical development, particularly in comparative studies of FASD where brains are on average "too small". We have modeled the allometry (change in proportions with size) using a power law. To translate to the clinical approach, we identified candidate markers in subjects with FAS and, using combinations and automated learning tools, to study their diagnostic value in the NS-FASD population. We have shown that it is possible to characterize a neuroanatomical signature of FAS and to find it in part in NS-FASD, including at the individual level, which could help to strengthen diagnostic certainty and potentially predict functional prognosis. In addition to its clinical value in FASD, this work could shed light on the understanding of developmental alcohol toxicity by revealing the sensitivity or relative preservation of certain neuroanatomical structures.Les troubles neurodéveloppementaux liés à l'alcool sont une cause majeure de handicap cognitif et comportemental mal reconnue en France, en partie à cause du manque de spécificité du diagnostic clinique des troubles du spectre de l'alcoolisation foetale (TSAF) en l'absence de l'ensemble des éléments malformatifs du syndrome d'alcoolisation foetale (SAF). Par ailleurs, le phénotype clinique et le niveau d'exposition à l'alcool expliquent mal le pronostic. Le déficit de croissance cérébrale est quasi constant dans les TSAF, parfois associé à des atteintes cérébrales focales, encourageant à rechercher des marqueurs neuroanatomiques de la maladie. Les récentes études de neuroanatomie assistée par ordinateur en IRM ont étendu le champ des atteintes cérébrales associées aux TSAF, mais beaucoup de ces résultats restent équivoques et aucun marqueur n'a pour l'heure émergé qui soit utile au diagnostic des formes non spécifiques de TSAF (TSAF-NS) ou au pronostic fonctionnel en général. Notre but était d'identifier des marqueurs neuroanatomiques, caractérisables à l'échelle individuelle et intégrables à la démarche clinique actuelle. Ainsi, nous avons créé une base de données sur des sujets ayant un TSAF à partir d'un large recrutement clinique monocentrique de patients extensivement phénotypés sur le plan clinique et cognitif, et imagés en haute résolution (IRM T1 et de diffusion). Cette série a été comparée à plus d'une centaine de sujets contrôles au développement typique. Les marqueurs ont été recherchés avec des mesures manuelles simples puis par morphométrie objet informatisée (segmentation automatique, identification et mesure de régions ou structures cérébrales). Nous avons étudié en détail le cervelet et ses sous-parties lobaires ainsi que le corps calleux et chacun de ces segments. Un effort particulier a été fourni pour générer et utiliser des outils de segmentation anatomique complémentaires originaux pour une validation croisée des résultats, afin de limiter les biais méthodologiques. De plus, l'analyse de la variance de taille doit l'intégrer que l'homothétie (zoom) n'est pas la règle entre les cerveaux de tailles différentes au développement pourtant typique, en particulier dans des études comparatives portant sur les TSAF où les cerveaux sont en moyenne « trop petits ». Nous avons modélisé les phénomènes d'allométrie (changement des proportions avec la taille) sur la base d'une loi de puissance. Dans l'optique de la translation à la démarche clinique, nous avons identifié des candidats marqueurs chez les sujets avec un SAF et grâce à des combinaisons et des outils d'apprentissage automatisé, d'étudier leur intérêt diagnostic dans la population des sujets TSAF-NS. Nous avons montré qu'il était possible de caractériser une signature neuroanatomique des SAF et de la retrouver en partie chez les TSAF-NS y compris à l'échelle individuelle, ce qui pourrait aider à renforcer la certitude diagnostic et potentiellement à prédire le pronostic fonctionnel. A côté de l'intérêt clinique dans la prise en charge des TSAF, ce travail pourrait éclairer la compréhension de la toxicité développementale de l'alcool en révélant la sensibilité ou la relative préservation de certaines structures neuroanatomiques

Fetal alcohol spectrum disorder : towards neuroanatomical markers in imaging

Les troubles neurodéveloppementaux liés à l'alcool sont une cause majeure de handicap cognitif et comportemental mal reconnue en France, en partie à cause du manque de spécificité du diagnostic clinique des troubles du spectre de l'alcoolisation foetale (TSAF) en l'absence de l'ensemble des éléments malformatifs du syndrome d'alcoolisation foetale (SAF). Par ailleurs, le phénotype clinique et le niveau d'exposition à l'alcool expliquent mal le pronostic. Le déficit de croissance cérébrale est quasi constant dans les TSAF, parfois associé à des atteintes cérébrales focales, encourageant à rechercher des marqueurs neuroanatomiques de la maladie. Les récentes études de neuroanatomie assistée par ordinateur en IRM ont étendu le champ des atteintes cérébrales associées aux TSAF, mais beaucoup de ces résultats restent équivoques et aucun marqueur n'a pour l'heure émergé qui soit utile au diagnostic des formes non spécifiques de TSAF (TSAF-NS) ou au pronostic fonctionnel en général. Notre but était d'identifier des marqueurs neuroanatomiques, caractérisables à l'échelle individuelle et intégrables à la démarche clinique actuelle. Ainsi, nous avons créé une base de données sur des sujets ayant un TSAF à partir d'un large recrutement clinique monocentrique de patients extensivement phénotypés sur le plan clinique et cognitif, et imagés en haute résolution (IRM T1 et de diffusion). Cette série a été comparée à plus d'une centaine de sujets contrôles au développement typique. Les marqueurs ont été recherchés avec des mesures manuelles simples puis par morphométrie objet informatisée (segmentation automatique, identification et mesure de régions ou structures cérébrales). Nous avons étudié en détail le cervelet et ses sous-parties lobaires ainsi que le corps calleux et chacun de ces segments. Un effort particulier a été fourni pour générer et utiliser des outils de segmentation anatomique complémentaires originaux pour une validation croisée des résultats, afin de limiter les biais méthodologiques. De plus, l'analyse de la variance de taille doit l'intégrer que l'homothétie (zoom) n'est pas la règle entre les cerveaux de tailles différentes au développement pourtant typique, en particulier dans des études comparatives portant sur les TSAF où les cerveaux sont en moyenne « trop petits ». Nous avons modélisé les phénomènes d'allométrie (changement des proportions avec la taille) sur la base d'une loi de puissance. Dans l'optique de la translation à la démarche clinique, nous avons identifié des candidats marqueurs chez les sujets avec un SAF et grâce à des combinaisons et des outils d'apprentissage automatisé, d'étudier leur intérêt diagnostic dans la population des sujets TSAF-NS. Nous avons montré qu'il était possible de caractériser une signature neuroanatomique des SAF et de la retrouver en partie chez les TSAF-NS y compris à l'échelle individuelle, ce qui pourrait aider à renforcer la certitude diagnostic et potentiellement à prédire le pronostic fonctionnel. A côté de l'intérêt clinique dans la prise en charge des TSAF, ce travail pourrait éclairer la compréhension de la toxicité développementale de l'alcool en révélant la sensibilité ou la relative préservation de certaines structures neuroanatomiques.Alcohol-related neurodevelopmental disorders are a major cause of cognitive and behavioral disability in France but are poorly recognized, partly due to the lack of specificity in the clinical diagnosis of fetal alcohol spectrum disorders (FASD) in the absence of all clinical features of the fetal alcohol syndrome (FAS). Furthermore, clinical phenotype and level of alcohol exposure do not explain prognosis. Cerebral growth deficiency is a near-constant feature of FASD, sometimes associated with focal brain damage, encouraging the search for neuroanatomical markers of the FASD. Recent MRI-assisted neuroanatomical studies have broadened the scope of brain damage associated with FASD, but many of these findings remain elusive and no marker has yet emerged that is useful for the diagnosis of non-specific forms of FASD (NS-FASD) or for functional prognosis. Our aim was to identify neuroanatomical markers that could be characterized at the individual level and integrated into the current clinical approach. Thus, we created a database of subjects with FASD from a large monocentric clinical recruitment of patients extensively clinically and cognitively described and imaged in high resolution (T1 and diffusion MRI). This series was compared with over a hundred typically developing control subjects. Markers were sought using simple manual measurements, followed by computerized object morphometry (automatic segmentation, identification and measurement of brain regions or structures). We studied in detail the cerebellum and its lobar sub-parts, as well as the corpus callosum and each of its segments. A special effort was made to generate and use original complementary anatomical segmentation tools for cross-validation of results, in order to limit methodological biases. In addition, the analysis of size variance must take into account the fact that homotheticity (zooming) is not the rule between brains of different sizes with typical development, particularly in comparative studies of FASD where brains are on average "too small". We have modeled the allometry (change in proportions with size) using a power law. To translate to the clinical approach, we identified candidate markers in subjects with FAS and, using combinations and automated learning tools, to study their diagnostic value in the NS-FASD population. We have shown that it is possible to characterize a neuroanatomical signature of FAS and to find it in part in NS-FASD, including at the individual level, which could help to strengthen diagnostic certainty and potentially predict functional prognosis. In addition to its clinical value in FASD, this work could shed light on the understanding of developmental alcohol toxicity by revealing the sensitivity or relative preservation of certain neuroanatomical structures

Perturbation of Fiedler vector: interest for graph measures and shape analysis

In this paper we investigate some properties of the Fiedler vector, the so-called first non-trivial eigenvector of the Laplacian matrix of a graph. There are important results about the Fiedler vector to identify spectral cuts in graphs but far less is known about its extreme values and points. We propose a few results and conjectures in this direction. We also bring two concrete contributions, i) by defining a new measure for graphs that can be interpreted in terms of extremality (inverse of centrality), ii) by applying a small perturbation to the Fiedler vector of cerebral shapes such as the corpus callosum to robustify their parameterization

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

IntroductionFetal 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.MethodsWe 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).ResultsWe 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.ConclusionWe 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

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

International audienceIntroduction 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

Combining neuroanatomical features to support diagnosis of fetal alcohol spectrum disorders

International audienceAbstractAim: 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

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

International audienceIntroduction 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 (η 2 = 6.5%, p FDR = 0.032) callosal parcel and % of the cortical parcel (η 2 = 8.9%, p FDR = 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 (η 2 = 5.7%, p FDR = 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 (p FDR &lt; 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

International audienceIn 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 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

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

International audienceIntroduction: 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