Normative Magnetic Resonance Imaging Data Increase the Sensitivity to Brain Volume Abnormalities in the Classification of Fetal Alcohol Spectrum Disorder.

OBJECTIVE: To evaluate the use of a large magnetic resonance imaging (MRI) normative dataset to quantify structural brain anomalies that may improve diagnostic sensitivity for atypical brain volume in youth with fetal alcohol spectrum disorder (FASD). STUDY DESIGN: Participants included 48 children with prenatal alcohol exposure (PAE) and 43 controls, ages 8-17 years, from the longitudinal Collaborative Initiative on FASD s. Recently published lifespan brain charts were used to quantify participants' (per)centile for brain volumes (cortical and subcortical gray matter and cortical white matter), providing an index of (dis)similarity to typically developing individuals of the same age and sex. RESULTS: Participants with PAE demonstrated lower mean centile scores compared with controls. Participants with PAE and scores ≤ 10th centile on at least 1 brain volume metric demonstrated significantly lower performance on measures of intellectual function and aspects of executive functioning compared with participants with PAE and "typical" volumes (>10th centile). Brain volume centiles explained a greater amount of variance in IQ and improved sensitivity to brain volume anomalies in FASD compared with the most commonly used diagnostic criterion of occipitofrontal circumference (OFC) ≤ 10th. CONCLUSION: Age- and sex-adjusted brain volumes based on a large normative dataset may be useful predictors of functional outcomes and may identify a greater number of individuals with FASD than the currently used criterion of OFC.

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.

Examining the effects of prenatal alcohol exposure on performance of the sustained attention to response task in children with an FASD.

Prenatal alcohol exposure (PAE), the leading known cause of childhood developmental disability, has long-lasting effects extending throughout the lifespan. It is well documented that children prenatally exposed to alcohol have difficulties inhibiting behavior and sustaining attention. Thus, the Sustained Attention to Response Task (SART), a Go/No-go paradigm, is especially well suited to assess the behavioral and neural functioning characteristics of children with PAE. In this study, we utilized neuropsychological assessment, parent/guardian questionnaires, and magnetoencephalography during SART random and fixed orders to assess characteristics of children 8-12 years old prenatally exposed to alcohol compared to typically developing children. Compared to neurotypical control children, children with a Fetal Alcohol Spectrum Disorder (FASD) diagnosis had significantly decreased performance on neuropsychological measures, had deficiencies in task-based performance, were rated as having increased Attention-Deficit/Hyperactivity Disorder (ADHD) behaviors and as having lower cognitive functioning by their caretakers, and had decreased peak amplitudes in Broadmann's Area 44 (BA44) during SART. Further, MEG peak amplitude in BA44 was found to be significantly associated with neuropsychological test results, parent/guardian questionnaires, and task-based performance such that decreased amplitude was associated with poorer performance. In exploratory analyses, we also found significant correlations between total cortical volume and MEG peak amplitude indicating that the reduced amplitude is likely related in part to reduced overall brain volume often reported in children with PAE. These findings show that children 8-12 years old with an FASD diagnosis have decreased amplitudes in BA44 during SART random order, and that these deficits are associated with multiple behavioral measures.

Functional connectivity of cognition-related brain networks in adults with fetal alcohol syndrome.

BACKGROUND: Fetal alcohol syndrome (FAS) can result in cognitive dysfunction. Cognitive functions affected are subserved by few functional brain networks. Functional connectivity (FC) in these networks can be assessed with resting-state functional MRI (rs-fMRI). Alterations of FC have been reported in children and adolescents prenatally exposed to alcohol. Previous reports varied substantially regarding the exact nature of findings. The purpose of this study was to assess FC of cognition-related networks in young adults with FAS. METHODS: Cross-sectional rs-fMRI study in participants with FAS (n = 39, age: 20.9 ± 3.4 years) and healthy participants without prenatal alcohol exposure (n = 44, age: 22.2 ± 3.4 years). FC was calculated as correlation between cortical regions in ten cognition-related sub-networks. Subsequent modelling of overall FC was based on linear models comparing FC between FAS and controls. Results were subjected to a hierarchical statistical testing approach, first determining whether there is any alteration of FC in FAS in the full cognitive connectome, subsequently resolving these findings to the level of either FC within each network or between networks based on the Higher Criticism (HC) approach for detecting rare and weak effects in high-dimensional data. Finally, group differences in single connections were assessed using conventional multiple-comparison correction. In an additional exploratory analysis, dynamic FC states were assessed. RESULTS: Comparing FAS participants with controls, we observed altered FC of cognition-related brain regions globally, within 7 out of 10 networks, and between networks employing the HC statistic. This was most obvious in attention-related network components. Findings also spanned across subcomponents of the fronto-parietal control and default mode networks. None of the single FC alterations within these networks yielded statistical significance in the conventional high-resolution analysis. The exploratory time-resolved FC analysis did not show significant group differences of dynamic FC states. CONCLUSIONS: FC in cognition-related networks was altered in adults with FAS. Effects were widely distributed across networks, potentially reflecting the diversity of cognitive deficits in FAS. However, no altered single connections could be determined in the most detailed analysis level. Findings were pronounced in networks in line with attentional deficits previously reported.

In utero MRI identifies consequences of early-gestation alcohol drinking on fetal brain development in rhesus macaques.

One factor that contributes to the high prevalence of fetal alcohol spectrum disorder (FASD) is binge-like consumption of alcohol before pregnancy awareness. It is known that treatments are more effective with early recognition of FASD. Recent advances in retrospective motion correction for the reconstruction of three-dimensional (3D) fetal brain MRI have led to significant improvements in the quality and resolution of anatomical and diffusion MRI of the fetal brain. Here, a rhesus macaque model of FASD, involving oral self-administration of 1.5 g/kg ethanol per day beginning prior to pregnancy and extending through the first 60 d of a 168-d gestational term, was utilized to determine whether fetal MRI could detect alcohol-induced abnormalities in brain development. This approach revealed differences between ethanol-exposed and control fetuses at gestation day 135 (G135), but not G110 or G85. At G135, ethanol-exposed fetuses had reduced brainstem and cerebellum volume and water diffusion anisotropy in several white matter tracts, compared to controls. Ex vivo electrophysiological recordings performed on fetal brain tissue obtained immediately following MRI demonstrated that the structural abnormalities observed at G135 are of functional significance. Specifically, spontaneous excitatory postsynaptic current amplitudes measured from individual neurons in the primary somatosensory cortex and putamen strongly correlated with diffusion anisotropy in the white matter tracts that connect these structures. These findings demonstrate that exposure to ethanol early in gestation perturbs development of brain regions associated with motor control in a manner that is detectable with fetal MRI.

Facial imaging to screen for fetal alcohol spectrum disorder: A scoping review.

Facial imaging tools have rapidly advanced in recent years and show potential for use in fetal alcohol spectrum disorder (FASD) screening and diagnosis. This scoping review describes the current state of evidence regarding the use of facial imaging being as a screening tool for FASD at a community level. This review follows the guidelines for the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) extension for scoping reviews and is registered with the Open Science Framework (osf.io/e4xw6). An electronic search of five databases was conducted. The time frame was limited to the period 2006 to 2022. The search included any form of imaging of the head, neck, oral cavity, and dentition. Animal and antenatal studies were excluded, as were those using only brain imaging. The search retrieved 730 unique titles. After title, abstract, and full-text screening, 28 primary studies were included in this review. Most studies were conducted with South African participants. Imaging included 2D photographs, 3D stereophotogrammetry, 3D laser scanning, and radiographs. Various measurements and landmarks were used to discriminate FASD from non-FASD participants, which included anthropometry, face shape analysis, and facial curvatures. Methods of data processing, analysis, and modeling ranged from manual methods to fully automated systems utilizing artificial intelligence. The use of facial imaging to screen for and diagnose patients with FASD is a rapidly advancing field. Most studies in the field remain exploratory, attempting to find accurate, reliable, and consistent landmarks and measures across different populations. For community screening, none of the tools in this review in their current form completely fulfill all the identified properties of an ideal screening tool. More research and development are needed prior to advocating for the use of any tool listed and the ethical implications are yet to be fully explored.

Fetal Alcohol Exposure Alters BOLD Activation Patterns in Brain Regions Mediating the Interpretation of Facial Affect.

BACKGROUND: Although deficits in the interpretation of affective facial expressions have been described clinically and in behavioral studies of fetal alcohol spectrum disorders (FASD), effects of prenatal alcohol exposure on the neural networks that mediate affective appraisal have not previously been examined. METHODS: We administered a nonverbal event-related fMRI affective appraisal paradigm to 64 children (mean age = 12.5 years; 18 with fetal alcohol syndrome (FAS) or partial FAS (PFAS), 18 nonsyndromal heavily exposed (HE), and 28 controls). Happy, sad, angry, fearful, and neutral faces and pixelated control images were presented sequentially in a randomized order. The child indicated whether the currently displayed face showed the same or different affect as the previous one. RESULTS: Data from whole-brain analyses showed that all groups activated the appropriate face processing neural networks. Region of interest analyses indicated that, compared to HE and control children, the FAS/PFAS group exhibited greater blood oxygenation level-dependent (BOLD) signal changes when processing neutral faces than pixelated images in 2 regions that form part of the visual sensory social brain network, which plays an important role in the initial processing of facial affect. By contrast, BOLD signal when processing angry faces was weaker for the FAS/PFAS group in a region involved in the processing of facial identity and facial expressions and in a region involved in the recognition and selection of behavioral responses to aggressive behavior. CONCLUSIONS: These findings of greater BOLD signal in the FAS/PFAS group in response to neutral faces suggest less efficient neural processing of more difficult to interpret emotions, and the weaker BOLD response to angry faces suggests altered processing of angry stimuli. Although behavioral performance did not differ in this relatively simple affective appraisal task, these data suggest that in children with FAS and PFAS, the appraisal of neutral affect and anger is likely to be more effortful in more challenging and dynamic social contexts.

Disruptions in global network segregation and integration in adolescents and young adults with fetal alcohol spectrum disorder.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a significant public health problem that is associated with a broad range of physical, neurocognitive, and behavioral effects resulting from prenatal alcohol exposure (PAE). Magnetic resonance imaging (MRI) has been an important tool for advancing our knowledge of abnormal brain structure and function in individuals with FASD. However, whereas only a small number of studies have applied graph theory-based network analysis to resting-state functional MRI (fMRI) data in individuals with FASD additional research in this area is needed. METHODS: Resting-state fMRI data were collected from adolescent and young adult participants (ages 12-22) with fetal alcohol syndrome (FAS) or alcohol-related neurodevelopmental disorder (ARND) and neurotypically developing controls (CNTRL) from previous studies. Group independent components analysis (gICA) was applied to fMRI data to extract components representing functional brain networks. Functional network connectivity (FNC), measured by Pearson correlation of the average independent component (IC) time series, was analyzed under a graph theory framework to compare network modularity, the average clustering coefficient, characteristic path length, and global efficiency between groups. Cognitive intelligence, measured by the Wechsler Abbreviated Scale of Intelligence (WASI), was compared and correlated to global network measures. RESULTS: Group comparisons revealed significant differences in the average clustering coefficient, characteristic path length, and global efficiency. Modularity was not significantly different between groups. The FAS and ARND groups scored significantly lower than the CNTRL group on Full Scale IQ (FS-IQ) and the Vocabulary subtest, but not the Matrix Reasoning subtest. No significant associations between intelligence and graph theory measures were detected. CONCLUSION: Our results partially agree with previous studies examining global graph theory metrics in children and adolescents with FASD and suggest that the exposure to alcohol during prenatal development leads to disruptions in aspects of functional network segregation and integration.

Multivariate models of brain volume for identification of children and adolescents with fetal alcohol spectrum disorder.

Magnetic resonance imaging (MRI) studies of fetal alcohol spectrum disorder (FASD) have shown reductions of brain volume associated with prenatal exposure to alcohol. Previous studies consider regional brain volumes independently but ignore potential relationships across numerous structures. This study aims to (a) identify a multivariate model based on regional brain volume that discriminates children/adolescents with FASD versus healthy controls, and (b) determine if FASD classification performance can be increased by building classification models separately for each sex. Three-dimensional T1-weighted MRI from two independent childhood/adolescent datasets were used for training (79 FASD, aged 5.7-18.9 years, 35 males; 81 controls, aged 5.8-18.5 years, 32 males) and testing (67 FASD, aged 6.0-19.6 years, 38 males; 74 controls, aged 5.2-19.5 years, 42 males) a classification model. Using FreeSurfer, 87 regional brain volumes were extracted for each subject and were used as input into a support vector machine generating a classification model from the training data. The model performed moderately well on the test data with accuracy 77%, sensitivity 64%, and specificity 88%. Regions that contributed heavily to prediction in this model included temporal lobe and subcortical gray matter. Further investigation of two separate models for males and females showed slightly decreased accuracy compared to the model including all subjects (male accuracy 70%; female accuracy 67%), but had different regional contributions suggesting sex differences. This work demonstrates the potential of multivariate analysis of brain volumes for discriminating children/adolescents with FASD and provides indication of the most affected regions.

Asymmetry-index and orthodontic facial analysis of children with foetal alcohol syndrome using 3D-facial scans.

BACKGROUND: The foetal alcohol spectrum disorder (FASD) is a complex and heterogenic disorder, caused by gestational exposure to alcohol. Patients with foetal alcohol syndrome (FAS-most severe form) show abnormal facial features. Our study aims at finding additional reliable and objective parameters for FAS diagnosis. METHODS: Facial three-dimensional scans of 30 children with FAS and 30 controls were analysed. Orthodontic profile analysis (concerning position of upper and lower jaw) was performed. Vertical facial proportions were taken and facial asymmetry index (right to left side) was calculated. RESULTS: Profile type was significantly different for children with FAS (p = 0.001) with lower jaws more frequently in a retral position. Profile angle was significantly larger in the group with FAS (p = 0.009). Children with FAS had shorter middle thirds and longer lower thirds of the face (p < 0.001). Stomion (point between upper and lower lip) was located significantly more caudally in the FAS group (p < 0.001). Facial asymmetry index was not significantly different. CONCLUSIONS: Children with FAS differ significantly from controls in vertical and sagittal facial measurements. Profile analysis and measurement of vertical proportions are easy to apply standard procedures in everyday orthodontic practice and could be time-saving and objective means for additional verification of FAS.

Radiological Findings on Structural Magnetic Resonance Imaging in Fetal Alcohol Spectrum Disorders and Healthy Controls.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) describe a range of physical, behavioral, and cognitive impairments stemming from prenatal alcohol exposure (PAE). Although case studies have demonstrated striking visible brain abnormalities in humans (enlargement of the lateral ventricles, thinning or absence of the corpus callosum, etc.), few studies have systematically determined how these radiological findings generalize to the wider population of individuals living with FASD. METHODS: This study examines rates of structural brain anomalies on magnetic resonance imaging (MRI) as determined by 2 radiologists in a retrospective blinded review of 163 controls and 164 individuals with PAE who were previously scanned as participants of past research studies. Incidental findings were categorized as normal variants, nonclinically significant incidental findings, or clinically significant incidental findings. Rates were compared between diagnostic subgroups using chi-square analysis. RESULTS: There was no significant difference in the overall rate of incidental findings between groups: 75% of controls and 73% of PAE participants had no incidental findings of any kind, and only 1% of controls and 3% of PAE participants had incidental finding of clinical significance (the remaining findings were considered nonsignificant anomalies or normal variants). When the PAE group was split by diagnosis, low-lying cerebellar tonsils, polymicrogyria, and ventricular asymmetry/enlargement were all most prevalent in subjects with fetal alcohol syndrome/partial fetal alcohol syndrome. In addition, the overall rate of incidental findings was higher (41%) in participants with FAS/pFAS, compared to 25% in controls. No participants in this relatively large sample had corpus callosum agenesis. CONCLUSIONS: Although advanced quantitative MRI research has uncovered a range of differences in brain structure associated with FASD, this qualitative radiological study suggests that routine clinical MRI does not reveal a consistent pattern of brain abnormalities that can be used diagnostically in this population.

Reduced Hippocampal Volumes Partially Mediate Effects of Prenatal Alcohol Exposure on Spatial Navigation on a Virtual Water Maze Task in Children.

BACKGROUND: Prenatal alcohol exposure (PAE) has been linked to poorer performance on the Morris water maze (MWM), a test of spatial navigation in rodents that is dependent on hippocampal functioning. We recently confirmed these findings in children with PAE on a human analog of the MWM, the virtual water maze (VWM). Previous studies have shown that the hippocampus is particularly sensitive to PAE. Our aim was to determine whether hippocampal volume mediates the relation between PAE and virtual navigation. METHODS: VWM and MRI hippocampal data were collected from 50 right-handed 10-year-old children in a heavily exposed Cape Town, South African sample. PAE data had been collected from their mothers during pregnancy, and the children were examined by expert fetal alcohol spectrum disorder (FASD) dysmorphologists. In the VWM, the participant attempts to learn the location of a hidden platform in a virtual pool of water across a series of learning trials using only distal room cues. Hippocampal volumes were derived using FreeSurfer from MRI scans administered within 1 week of completing the VWM task. RESULTS: Both the fetal alcohol syndrome (FAS)/partial FAS and nonsyndromal heavy-exposed (HE) groups had smaller hippocampal volumes than controls. PAE was associated with reduced right hippocampal volumes even after control for total intracranial volume (ICV). Hippocampal volume was also positively associated with VWM performance. The relation between PAE and VWM performance was partially mediated by right hippocampal volume but not by total ICV. CONCLUSIONS: These data confirm previous reports linking PAE to poorer spatial navigation on the VWM and are the first to provide direct evidence that volume reductions in this region partially mediate the relation of FASD diagnosis to place learning, suggesting that PAE specifically impairs the ability to encode the spatial information necessary for successful location of the hidden platform on a navigation task.

Fetus morphology changes by second-trimester ultrasound in pregnant women drinking alcohol.

Fetal alcohol spectrum disorders (FASDs) are a group of negative conditions occurring in children exposed to alcohol during gestation. The early discovery of FASD is crucial for mother and infant follow-ups. In this study, we investigated in pregnant women the association between urine ethylglucuronide (EtG-a biomarker of alcohol drinking) and indicators of the physical characteristics of FASD by prenatal ultrasound in the second trimester of gestation. We also correlated these data with the AUDIT-C, T-ACE/TACER-3, TWEAK, and food habit diary, screening questionnaires used to disclose alcohol drinking during pregnancy. Forty-four pregnant women were randomly enrolled and examined for ultrasound investigation during the second trimester of gestation. Urine samples were provided by pregnant women immediately after the routine interviews. EtG determinations were performed with a cutoff established at 100 ng/mL, a value indicating occasional alcohol drinking. Fifteen of the enrolled pregnant women overcame the EtG cutoff (34.09%). Analysis of variance (ANOVA) revealed that the fetuses of the positive EtG pregnant women had significantly longer interorbital distance and also significantly increased frontothalamic distance (P's < 0.02). Quite interestingly, no direct correlation was found between EtG data and both food diary and AUDIT-C. However, a significant correlation was observed between urinary EtG and T-ACE (r = 0.375; P = 0.012) and between urinary EtG and TWEAK (r = 0.512; P < 0.001) and a concordance with all questionnaire for EtG values higher than 500 ng/mL. This study provides clinical evidence that the diagnosis of maternal alcohol consumption during pregnancy by urine EtG may disclose FASD-related damage in the fetus.

White matter microstructure in fetal alcohol spectrum disorders: A systematic review of diffusion tensor imaging studies.

Diffusion tensor imaging (DTI) has revolutionized our understanding of the neural underpinnings of alcohol teratogenesis. This technique can detect alterations in white matter in neurodevelopmental disorders, such as fetal alcohol spectrum disorder (FASD). Using Prisma guidelines, we identified 23 DTI studies conducted on individuals with prenatal alcohol exposure (PAE). These studies confirm the widespread nature of brain damage in PAE by reporting diffusivity alterations in commissural, association, and projection fibers; and in relation to increasing cognitive impairment. Reduced integrity in terms of lower fractional anisotropy (FA) and higher mean diffusivity (MD) and radial diffusivity (RD) is reported more consistently in the corpus callosum, cerebellar peduncles, cingulum, and longitudinal fasciculi connecting frontal and temporoparietal regions. Although these interesting results provide insight into FASD neuropathology, it is important to investigate the clinical diversity of this disorder for better treatment options and prediction of progression. The aim of this review is to provide a summary of different patterns of neural structure between PAE and typically developed individuals. We further discuss the association of alterations in diffusivity with demographic features and symptomatology of PAE. With the accumulated knowledge of the neural correlates of FASD presenting symptoms, a comprehensive understanding of the heterogeneity in FASD will potentially improve the disease management and will highlight the diagnostic challenges and potential areas of future research avenues, where neural markers may be beneficial.

Myelin Water Fraction Imaging of the Brain in Children with Prenatal Alcohol Exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) is linked to alterations of cerebral white matter, including volume and nonspecific diffusion magnetic resonance imaging (MRI) indices of microstructure in humans. Some animal models of PAE have demonstrated myelination deficiencies, but myelin levels have not yet been evaluated in individuals with PAE. Multiecho T2 MRI offers a quantitative method to estimate myelin water fraction (MWF; related to myelin content) noninvasively, which was used here to evaluate brain myelination in children with PAE. METHODS: Participants with PAE (n = 10, 6 females, mean age 13.9 years, range 7 to 18 years) and controls (n = 14, 11 females, mean age 13.2 years, range 9 to 16 years) underwent 3T MRI of the brain. T2 images (15 minutes acquisition for 32 echoes) were used to create MWF maps from which mean MWF was measured in 12 regions of interest (ROIs) including 8 in white matter and 4 in deep gray matter. RESULTS: As expected, across the combined sample, MWF was highest for major white matter tracts such as the internal capsule and genu/splenium of the corpus callosum (10 to 18%) while the caudate and putamen had MWF less than 5%. Mean MWF was similar across 11/12 brain white and gray matter regions for the PAE and control groups (L/R internal capsule, major forceps, putamen, caudate nucleus, L minor forceps, genu and splenium of corpus callosum). In the PAE group, MWF was positively correlated with age in the genu of corpus callosum and right minor forceps, notably 2 frontal tracts. CONCLUSIONS: Given comparable MRI-derived myelination fraction measures in PAE relative to controls, white matter alterations shown in other imaging studies, such as diffusion tensor imaging, may reflect microstructural anomalies related to axon caliber and density.

3D Analysis of Philtrum Depth in Children with Fetal Alcohol Syndrome.

AIMS: Diagnosis of fetal alcohol spectrum disorder (FASD) is complex and difficult. The estimated number of unreported FASD is thus assumed to be substantial. In our cross-sectional study, we aimed to identify possible metric differences in philtrum depth in children with fetal alcohol syndrome (FAS) compared to healthy controls based on non-invasive 3D facial scanning in order to provide an objective, metrical tool improving FASD diagnosis. METHODS: Twenty-five children with confirmed FAS and 30 healthy school children without FAS, both in the mixed dentition, were prospectively recruited and 3D facial scans were performed after recording body length, weight and head circumference. Philtrum surface data were extracted and metric philtrum depth was determined at four geometrically defined measuring points (P1-P4) along the vertical length of the philtrum. RESULTS: Philtrum depths at P1 (P = 0.025), P2 (P = 0.001), P3 (P < 0.001) and P4 (P = 0.001) as well as mean philtrum depth P1-P4 (P < 0.001) differed significantly between patients with and without FAS. Compared to controls, the philtrum was shallower in patients with FAS by on average 0.4 mm at each of the respective points. Whereas no differences could be determined for body height and weight, head circumference was significantly smaller in patients with FAS (P = 0.001), particularly in girls (P = 0.008). CONCLUSIONS: Apart from head circumference, philtrum depth is significantly reduced in children with FAS and can thus be used as diagnostic indicator to aid and confirm FAS diagnosis. In contrast to visual assessments, 3D face scan methods allow a more objective quantification and can thus provide additional evidence in FAS diagnosis.

Sensorimotor network alterations in children and youth with prenatal alcohol exposure.

Children with prenatal alcohol exposure (PAE) often have impaired sensorimotor function. While altered brain structure has been noted in sensorimotor areas, the functional brain alterations remain unclear. This study aims to investigate sensorimotor brain networks in children and youth with PAE using resting-state functional magnetic resonance imaging (rs-fMRI). A parcellation-based network analysis was performed to identify brain networks related to hand/lower limb and face/upper limb function in 59 children and youth with PAE and 50 typically developing controls. Participants with PAE and controls had similar organization of the hand and face areas within the primary sensorimotor cortex, but participants with PAE had altered functional connectivity (FC) between the sensorimotor regions and the rest of the brain. The sensorimotor regions in the PAE group showed less connectivity to certain hubs of the default mode network and more connectivity to areas of the salience network. Overall, our results show that despite similar patterns of organization in the sensorimotor network, subjects with PAE have increased FC between this network and other brain areas, perhaps suggesting overcompensation. These alterations in the sensorimotor network lay the foundation for future studies to evaluate interventions and treatments to improve motor function in children with PAE.

Preserved cortical asymmetry despite thinner cortex in children and adolescents with prenatal alcohol exposure and associated conditions.

Prenatal alcohol exposure (PAE) is associated with reduced overall brain volume. Although this has been reported consistently across studies, the status of cortical thickness after PAE is more variable. The cortex is asymmetric in typical controls, but it is unclear whether the left and right counter parts of the cortical gray matter are unevenly influenced in postpartum brain development after PAE. Brain MRI was acquired in a newly recruited sample of 157 participants (PAE: N = 78, 5.5-18.9 years, 40 females and controls: N = 79, 5.8-18.5 years, 44 females) across four Canadian sites in the NeuroDevNet project. The PAE group had other confounds such as psychiatric co-morbidity, different living environment, and so on, not present in the control group. In agreement with previous studies, the volumes of all brain structures were reduced in PAE compared to controls, including gray and white matter of cerebrum and cerebellum, and all deep gray matter including the hippocampus, amygdala, thalamus, caudate, putamen, and pallidum. The PAE group showed reductions in global and regional cortical thickness, while the pattern and degree of cortical thickness asymmetry were preserved in PAE participants with the greatest rightward asymmetry in the lateral parietal lobe and the greatest leftward asymmetry in the lateral frontal cortex. This persistent asymmetry reflects that the homologous left and right cortical regions followed typical relative developmental patterns in the PAE group despite being thinner bilaterally than controls. Hum Brain Mapp 39:72-88, 2018. © 2017 Wiley Periodicals, Inc.

Combined Face-Brain Morphology and Associated Neurocognitive Correlates in Fetal Alcohol Spectrum Disorders.

BACKGROUND: Since the 1970s, a range of facial, neurostructural, and neurocognitive adverse effects have been shown to be associated with prenatal alcohol exposure. Typically, these effects are studied individually and not in combination. Our objective is to improve the understanding of the teratogenic effects of prenatal alcohol exposure by simultaneously considering face-brain morphology and neurocognitive measures. METHODS: Participants were categorized as control (n = 47), fetal alcohol syndrome (FAS, n = 22), or heavily exposed (HE) prenatally, but not eligible for a FAS diagnosis (HE, n = 50). Structural brain MRI images and high-resolution 3D facial images were analyzed using dense surface models of features of the face and surface shape of the corpus callosum (CC) and caudate nucleus (CN). Asymmetry of the CN was evaluated for correlations with neurocognitive measures. RESULTS: (i) Facial growth delineations for FAS, HE, and controls are replicated for the CN and the CC. (ii) Concordance of clinical diagnosis and face-based control-FAS discrimination improves when the latter is combined with specific brain regions. In particular, midline facial regions discriminate better when combined with a midsagittal profile of the CC. (iii) A subset of HE individuals was identified with FAS-like CN dysmorphism. The average of this HE subset was FAS-like in its facial dysmorphism. (iv) Right-left asymmetry found in the CNs of controls is not apparent for FAS, is diminished for HE, and correlates with neurocognitive measures in the combined FAS and HE population. CONCLUSIONS: Shape analysis which combines facial regions with the CN, and with the CC, better identify those with FAS. CN asymmetry was reduced for FAS compared to controls and is strongly associated with general cognitive ability, verbal learning, and recall in those with prenatal alcohol exposure. This study further extends the brain-behavior relationships known to be vulnerable to alcohol teratogenesis.

Functional MRI of Human Eyeblink Classical Conditioning in Children with Fetal Alcohol Spectrum Disorders.

Prenatal alcohol exposure has been linked to a broad range of developmental deficits, with eyeblink classical conditioning (EBC) among the most sensitive endpoints. This fMRI study compared EBC-related brain activity in 47 children with fetal alcohol syndrome (FAS), partial FAS (PFAS), heavily exposed (HE) non-syndromal children, and healthy controls. All of the children had previously participated in two EBC studies conducted as part of our longitudinal study of fetal alcohol spectrum disorders. Although learning-related behavioral differences were seen in all groups during the scans, controls showed more conditioned responses (CR) than the alcohol-exposed groups. Despite lower conditioning levels relative to controls, the exposed groups exhibited extensive cerebellar activations. Specifically, children with FAS/PFAS showed increased activation of cerebellar lobule VI in session 2, while HE children showed increased activation in session 1. Continuous measures of prenatal alcohol use correlated with learning-related activations in cerebellum and frontal cortices. Only controls showed significant cerebellar activation-CR correlations in the deep nuclei and lateral lobule VI, suggesting that these key regions supporting EBC may be functionally disorganized in alcohol-exposed children. These findings are the first to characterize abnormalities in brain function associated with the behavioral conditioning deficits seen in children with prenatal alcohol exposure.