Influences of RASopathies on Neuroanatomical Variation in Children.

BACKGROUND: RASopathies are a group of disorders characterized by pathogenic mutations in the Ras/mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder and attention-deficit/hyperactivity disorder. METHODS: This study examined the effect of RASopathies (NS and NF1) on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes. Using vertex-based analysis for cortical measures and Desikan region of interest parcellation for subcortical volumes, we compared structural T1-weighted images of children with RASopathies (n = 91, mean age = 8.81 years, SD = 2.12) to those of sex- and age-matched typically developing children (n = 74, mean age = 9.07 years, SD = 1.77). RESULTS: Compared with typically developing children, RASopathies had convergent effects on SA and CT, exhibiting increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus. RASopathies exhibited divergent effects on subcortical volumes, with syndrome-specific influences from NS and NF1. Overall, children with NS showed decreased volumes in striatal and thalamic structures, and children with NF1 displayed increased volumes in the hippocampus, amygdala, and thalamus. CONCLUSIONS: Our study reveals the converging and diverging neuroanatomical effects of RASopathies on human neurodevelopment. The convergence of cortical effects on SA and CT indicates a shared influence of Ras/MAPK hyperactivation on the human brain. Therefore, considering these measures as objective outcome indicators for targeted treatments is imperative.

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d's < -0.8), and extensive effects on SA (d's > |0.8|) and CT (d's > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: 1. How Ras-MAPK activating variants of PTPN11 / SOS1 protein-coding genes affect brain anatomy. 2. The relationship between PTPN11 gene expression levels and brain anatomy, and 3. The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 ( n = 30) or SOS1 ( n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA) and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area ( d 's<-0.8), and extensive effects on SA ( d 's>|0.8|) and CT ( d 's>|0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

PTPN11 Mutations in the Ras-MAPK Signaling Pathway Affect Human White Matter Microstructure.

We examined whether PTPN11 mutations affect the white matter connectivity of the developing human brain. Germline activating mutations to the PTPN11 gene cause overactivation of the Ras-Mitogen-Activated Protein Kinase pathway. Activating mutations cause Noonan syndrome (NS), a developmental disorder associated with hyperactivity and cognitive weakness in attention, executive function, and memory. In mouse models of NS, PTPN11 mutations cause reduced axon myelination and white matter formation, while the effects of PTPN11 mutations on human white matter are largely unknown. For the first time, we assessed 17 children with NS (9 females, mean age, 8.68 ± 2.39) and 17 age- and sex-matched controls (9 female, mean age, 8.71 ± 2.40) using diffusion brain imaging for white matter connectivity and structural magnetic resonance imaging to characterize brain morphology. Children with NS showed widespread reductions in fractional anisotropy (FA; 82 613 voxels, t = 1.49, P < 0.05) and increases in radial diffusivity (RD; 94 044 voxels, t = 1.22, P < 0.05), denoting decreased white matter connectivity. In NS, the FA of the posterior thalamic radiation correlated positively with inhibition performance, whereas connectivity in the genu of the corpus callosum was inversely associated with auditory attention performance. Additionally, we observed negative and positive correlations, respectively, between memory and the cingulum hippocampus, and memory and the cingulum cingulate gyrus. These findings elucidate the neural mechanism underpinning the NS cognitive phenotype, and may serve as a brain-based biomarker.

Genetic and Environmental Influences on Lobar Brain Structures in Twins With Autism.

This investigation examined whether the variation of cerebral structure is associated with genetic or environmental factors in children with autism spectrum disorder (ASD) compared with typically developing (TD) controls. T1-weighted magnetic resonance imaging scans were obtained from twin pairs (aged 6-15 years) in which at least one twin was diagnosed with ASD or both were TD. Good quality data were available from 30 ASD, 18 discordant, and 34 TD pairs (n = 164). Structural measures (volume, cortical thickness, and surface area) were generated with FreeSurfer, and ACE modeling was completed. Lobar structures were primarily genetically mediated in TD twins (a2 = 0.60-0.89), except thickness of the temporal (a2 = 0.33 [0.04, 0.63]) and occipital lobes (c2 = 0.61 [0.45, 0.77]). Lobar structures were also predominantly genetically mediated in twins with ASD (a2 = 0.70-1.00); however, thickness of the frontal (c2 = 0.81 [0.71, 0.92]), temporal (c2 = 0.77 [0.60, 0.93]), and parietal lobes (c2 = 0.87 [0.77, 0.97]), and frontal gray matter (GM) volume (c2 = 0.79 [0.63, 0.95]), were associated with environmental factors. Conversely, occipital thickness (a2 = 0.93 [0.75, 1.11]) did not exhibit the environmental contributions that were found in controls. Differences in GM volume were associated with social communication impairments for the frontal (r = 0.52 [0.18, 0.75]), temporal (r = 0.61 [0.30, 0.80]), and parietal lobes (r = 0.53 [0.19, 0.76]). To our knowledge, this is the first investigation to suggest that environmental factors influence GM to a larger extent in children with ASD, especially in the frontal lobe.

Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder.

Atypical growth patterns of the brain have been previously reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on brain development. Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6-15 years) were recruited to participate in this study. T1-weighted MRIs (n = 164) were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across diagnostic groups. ACE modeling was also completed. Structural brain measures, including cerebral and cerebellar gray matter (GM) and white matter (WM) volume, surface area, and cortical thickness, were primarily influenced by genetic factors in TD twins; however, mean curvature appeared to be primarily influenced by environmental factors. Similarly, genetic factors accounted for the majority of variation in brain size in twins with ASD, potentially to a larger extent regarding curvature and subcortical GM; however, there were also more environmental contributions in twins with ASD on some structural brain measures, such that cortical thickness and cerebellar WM volume were primarily influenced by environmental factors. These findings indicate potential neurobiological outcomes of the genetic and environmental risk factors that have been previously associated with ASD and, although preliminary, may help account for some of the previously outlined neurobiological heterogeneity across affected individuals. This is especially relevant regarding the role of genetic and environmental factors in the development of ASD, in which certain brain structures may be more sensitive to specific influences.

Genetic and environmental influences on corticostriatal circuits in twins with autism

Background: Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs. Methods: We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6­15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity. Results: Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated. Limitations: We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors. Conclusion: Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.

Persistence of abnormalities in white matter in children with type 1 diabetes.

AIMS/HYPOTHESIS: Prior studies suggest white matter growth is reduced and white matter microstructure is altered in the brains of young children with type 1 diabetes when compared with brains of non-diabetic children, due in part to adverse effects of hyperglycaemia. This longitudinal observational study examines whether dysglycaemia alters the developmental trajectory of white matter microstructure over time in young children with type 1 diabetes. METHODS: One hundred and eighteen children, aged 4 to <10 years old with type 1 diabetes and 58 age-matched, non-diabetic children were studied at baseline and 18 months, at five Diabetes Research in Children Network clinical centres. We analysed longitudinal trajectories of white matter using diffusion tensor imaging. Continuous glucose monitoring profiles and HbA1c levels were obtained every 3 months. RESULTS: Axial diffusivity was lower in children with diabetes at baseline (p = 0.022) and at 18 months (p = 0.015), indicating that differences in white matter microstructure persist over time in children with diabetes. Within the diabetes group, lower exposure to hyperglycaemia, averaged over the time since diagnosis, was associated with higher fractional anisotropy (p = 0.037). Fractional anisotropy was positively correlated with performance (p < 0.002) and full-scale IQ (p < 0.02). CONCLUSIONS/INTERPRETATION: These results suggest that hyperglycaemia is associated with altered white matter development, which may contribute to the mild cognitive deficits in this population.

A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder.

Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with 1H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.

Altered Brain Network Segregation in Fragile X Syndrome Revealed by Structural Connectomics.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder, is associated with significant behavioral, social, and neurocognitive deficits. Understanding structural brain network topology in FXS provides an important link between neurobiological and behavioral/cognitive symptoms of this disorder. We investigated the connectome via whole-brain structural networks created from group-level morphological correlations. Participants included 100 individuals: 50 with FXS and 50 with typical development, age 11-23 years. Results indicated alterations in topological properties of structural brain networks in individuals with FXS. Significantly reduced small-world index indicates a shift in the balance between network segregation and integration and significantly reduced clustering coefficient suggests that reduced local segregation shifted this balance. Caudate and amygdala were less interactive in the FXS network further highlighting the importance of subcortical region alterations in the neurobiological signature of FXS. Modularity analysis indicates that FXS and typically developing groups' networks decompose into different sets of interconnected sub networks, potentially indicative of aberrant local interconnectivity in individuals with FXS. These findings advance our understanding of the effects of fragile X mental retardation protein on large-scale brain networks and could be used to develop a connectome-level biological signature for FXS.

The moderating effects of sex on insula subdivision structure in youth with posttraumatic stress symptoms.

BACKGROUND: The insula is involved in interoceptive processing, emotion awareness, and attention to salient stimuli. Research suggests that these functions are specific-albeit overlapping-within insula subdivisions. Additional studies also imply that sexual dimorphism and different rates of development occur within these subdivisions in youth. The purpose of this study was to examine potential insula subdivision structure differences in youth with PTSD symptoms as compared to controls and test sex as a moderator of these differences. METHODS: Insula structure (volume, surface area, and thickness) was measured with structural magnetic resonance imaging (sMRI) and calculated using Freesurfer software. We compared insula structure across age- and sex-matched boys and girls with (30 with and 29 without) PTSD symptoms while also controlling for age and whole brain measurements. RESULTS: Differences were specific to the insula's anterior circular sulcus. Within this subregion, boys with PTSD symptoms demonstrated larger volume and surface area than control boys, while girls with PTSD symptoms demonstrated smaller volume and surface area than control girls. DISCUSSION: Findings indicate a potential neurobiological explanation for sex differences in youth with PTSD symptoms.

Surface-based morphometry reveals distinct cortical thickness and surface area profiles in Williams syndrome.

Morphometric investigations of brain volumes in Williams syndrome (WS) consistently show significant reductions in gray matter volume compared to controls. Cortical thickness (CT) and surface area (SA) are two constituent parts of cortical gray matter volume that are considered genetically distinguishable features of brain morphology. Yet, little is known about the independent contribution of cortical CT and SA to these volumetric differences in WS. Thus, our objectives were: (i) to evaluate whether the microdeletion in chromosome 7 associated with WS has a distinct effect on CT and SA, and (ii) to evaluate age-related variations in CT and SA within WS. We compared CT and SA values in 44 individuals with WS to 49 age- and sex-matched typically developing controls. Between-group differences in CT and SA were evaluated across two age groups: young (age range 6.6-18.9 years), and adults (age range 20.2-51.5 years). Overall, we found contrasting effects of WS on cortical thickness (increases) and surface area (decreases). With respect to brain topography, the between-group pattern of CT differences showed a scattered pattern while the between-group surface area pattern was widely distributed throughout the brain. In the adult subgroup, we observed a cluster of increases in cortical thickness in WS across the brain that was not observed in the young subgroup. Our findings suggest that extensive early reductions in surface area are the driving force for the overall reduction in brain volume in WS. The age-related cortical thickness findings might reflect delayed or even arrested development of specific brain regions in WS.

Sex differences in amygdala shape: Insights from Turner syndrome.

OBJECTIVE: Sex differences in the manifestation of psychiatric disorders, including anxiety disorders, are among the most prominent findings in psychiatry. The study of Turner syndrome (TS), caused by X-monosomy, has the potential to reveal mechanisms that underline male/female differences in neuropsychiatric disorders. The amygdala has been implicated in numerous neuropsychiatric disorders. Previous studies suggest an effect of TS on amygdala volume as well as on amygdala-related behaviors such as anxiety. Our objective is to investigate the amygdala shape in TS. Specifically, we tested whether amygdala enlargements in TS are localized to specific nuclei implicated in anxiety, such as the basomedial nucleus. EXPERIMENTAL DESIGN: We use a surface-based analytical modeling approach to contrast 41 pre-estrogen treatment girls with TS (mean age 8.6 ± 2.4) with 34 age-and sex-matched typically developing (TD) controls (mean age 8.0 ± 2.8). Anxiety symptoms were assessed using the Revised Children's Manifest Anxiety Scale - 2 (RCMAS-2) in both groups. PRINCIPAL OBSERVATIONS: TS was associated with anomalous enlargement of the amygdala. Surface-based modeling revealed shape differences (increased radial-distances) in bilateral basal and basomedial nuclei within the basolateral complex. RCMAS-2 Total Anxiety t-score was significantly higher in participants with TS compared with TD controls (P = 0.012). CONCLUSIONS: Group differences in global amygdala volumes were driven by local morphological increases in areas that are critically involved in face emotion processing and anxiety. In the context of increased amygdala volumes in TS, our results also showed increased worry and social anxiety in young girls with TS compared with TD.

Variations in Brain Volume and Growth in Young Children With Type 1 Diabetes.

Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4-10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (±SD) HbA1c level was 7.9 ± 0.9% (63 ± 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes.

The cognitive developmental profile associated with fragile X syndrome: A longitudinal investigation of cognitive strengths and weaknesses through childhood and adolescence.

Few studies have investigated developmental strengths and weaknesses within the cognitive profile of children and adolescents with fragile X syndrome (FXS), a single-gene cause of inherited intellectual impairment. With a prospective longitudinal design and using normalized raw scores (Z scores) to circumvent floor effects, we measured cognitive functioning of 184 children and adolescents with FXS (ages 6 to 16) using the Wechsler Scale of Intelligence for Children on one to three occasions for each participant. Participants with FXS received lower raw scores relative to the Wechsler Scale of Intelligence for Children normative sample across the developmental period. Verbal comprehension, perceptual organization, and processing speed Z scores were marked by a widening gap from the normative sample, while freedom from distractibility Z scores showed a narrowing gap. Key findings include a relative strength for verbal skills in comparison with visuospatial-constructive skills arising in adolescence and a discrepancy between working memory (weakness) and processing speed (strength) in childhood that diminishes in adolescence. Results suggest that the cognitive profile associated with FXS develops dynamically from childhood to adolescence. Findings are discussed within the context of aberrant brain morphology in childhood and maturation in adolescence. We argue that assessing disorder-specific cognitive developmental profiles will benefit future disorder-specific treatment research.

Estimating individual contribution from group-based structural correlation networks.

Coordinated variations in brain morphology (e.g., cortical thickness) across individuals have been widely used to infer large-scale population brain networks. These structural correlation networks (SCNs) have been shown to reflect synchronized maturational changes in connected brain regions. Further, evidence suggests that SCNs, to some extent, reflect both anatomical and functional connectivity and hence provide a complementary measure of brain connectivity in addition to diffusion weighted networks and resting-state functional networks. Although widely used to study between-group differences in network properties, SCNs are inferred only at the group-level using brain morphology data from a set of participants, thereby not providing any knowledge regarding how the observed differences in SCNs are associated with individual behavioral, cognitive and disorder states. In the present study, we introduce two novel distance-based approaches to extract information regarding individual differences from the group-level SCNs. We applied the proposed approaches to a moderately large dataset (n=100) consisting of individuals with fragile X syndrome (FXS; n=50) and age-matched typically developing individuals (TD; n=50). We tested the stability of proposed approaches using permutation analysis. Lastly, to test the efficacy of our method, individual contributions extracted from the group-level SCNs were examined for associations with intelligence scores and genetic data. The extracted individual contributions were stable and were significantly related to both genetic and intelligence estimates, in both typically developing individuals and participants with FXS. We anticipate that the approaches developed in this work could be used as a putative biomarker for altered connectivity in individuals with neurodevelopmental disorders.

Specific effect of the fragile-X mental retardation-1 gene (FMR1) on white matter microstructure.

BACKGROUND: Fragile-X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability and neurobiological abnormalities including white matter microstructural differences. White matter differences have been found relative to neurotypical individuals. AIMS: To examine whether FXS white matter differences are related specifically to FXS or more generally to the presence of intellectual disability. METHOD: We used voxel-based and tract-based analytic approaches to compare individuals with FXS (n = 40) with gender- and IQ-matched controls (n = 30). RESULTS: Individuals with FXS had increased fractional anisotropy and decreased radial diffusivity values compared with IQ-matched controls in the inferior longitudinal, inferior fronto-occipital and uncinate fasciculi. CONCLUSIONS: The genetic variation associated with FXS affects white matter microstructure independently of overall IQ. White matter differences, found in FXS relative to IQ-matched controls, are distinct from reported differences relative to neurotypical controls. This underscores the need to consider cognitive ability differences when investigating white matter microstructure in neurodevelopmental disorders.

Right arcuate fasciculus abnormality in chronic fatigue syndrome.

PURPOSE: To identify whether patients with chronic fatigue syndrome (CFS) have differences in gross brain structure, microscopic structure, or brain perfusion that may explain their symptoms. MATERIALS AND METHODS: Fifteen patients with CFS were identified by means of retrospective review with an institutional review board-approved waiver of consent and waiver of authorization. Fourteen age- and sex-matched control subjects provided informed consent in accordance with the institutional review board and HIPAA. All subjects underwent 3.0-T volumetric T1-weighted magnetic resonance (MR) imaging, with two diffusion-tensor imaging (DTI) acquisitions and arterial spin labeling (ASL). Open source software was used to segment supratentorial gray and white matter and cerebrospinal fluid to compare gray and white matter volumes and cortical thickness. DTI data were processed with automated fiber quantification, which was used to compare piecewise fractional anisotropy (FA) along 20 tracks. For the volumetric analysis, a regression was performed to account for differences in age, handedness, and total intracranial volume, and for the DTI, FA was compared piecewise along tracks by using an unpaired t test. The open source software segmentation was used to compare cerebral blood flow as measured with ASL. RESULTS: In the CFS population, FA was increased in the right arcuate fasciculus (P = .0015), and in right-handers, FA was also increased in the right inferior longitudinal fasciculus (ILF) (P = .0008). In patients with CFS, right anterior arcuate FA increased with disease severity (r = 0.649, P = .026). Bilateral white matter volumes were reduced in CFS (mean ± standard deviation, 467 581 mm(3) ± 47 610 for patients vs 504 864 mm(3) ± 68 126 for control subjects, P = .0026), and cortical thickness increased in both right arcuate end points, the middle temporal (T = 4.25) and precentral (T = 6.47) gyri, and one right ILF end point, the occipital lobe (T = 5.36). ASL showed no significant differences. CONCLUSION: Bilateral white matter atrophy is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA may serve as a biomarker for CFS.

Aberrant parietal cortex developmental trajectories in girls with Turner syndrome and related visual-spatial cognitive development: a preliminary study.

Turner syndrome (TS) arises from partial or complete absence of the X-chromosome in females. Girls with TS show deficits in visual-spatial skills as well as reduced brain volume and surface area in the parietal cortex which supports these cognitive functions. Thus, measuring the developmental trajectory of the parietal cortex and the associated visual-spatial cognition in TS may provide novel insights into critical brain-behavior associations. In this longitudinal study, we acquired structural MRI data and assessed visual-spatial skills in 16 (age: 8.23 ± 2.5) girls with TS and 13 age-matched controls over two time-points. Gray and white matter volume, surface area and cortical thickness were calculated from surfaced based segmentation of bilateral parietal cortices, and the NEPSY Arrows subtest was used to assess visual-spatial ability. Volumetric and cognitive scalars were modeled to obtain estimates of age-related change. The results show aberrant growth of white matter volume (P = 0.011, corrected) and surface area (P = 0.036, corrected) of the left superior parietal regions during childhood in girls with TS. Other parietal sub-regions were significantly smaller in girls with TS at both time-points but did not show different growth trajectories relative to controls. Furthermore, we found that visual-spatial skills showed a widening deficit for girls with TS relative to controls (P = 0.003). Young girls with TS demonstrate an aberrant trajectory of parietal cortical and cognitive development during childhood. Elucidating aberrant neurodevelopmental trajectories in this population is critical for determining specific stages of brain maturation that are particularly dependent on TS-related genetic and hormonal factors.

Cognitive and behavioral correlates of caudate subregion shape variation in fragile X syndrome.

Individuals with fragile X syndrome (FXS) exhibit frontal lobe-associated cognitive and behavioral deficits, including impaired general cognitive abilities, perseverative behaviors, and social difficulties. Neural signals related to these functions are communicated through frontostriatal circuits, which connect with distinct regions of the caudate nucleus (CN). Enlargement of the CN is the most robust and reproduced neuroanatomical abnormality in FXS, but very little is known on how this affects behavioral/cognitive outcomes in this condition. Here, we investigated topography within focal regions of the CN associated with prefrontal circuitry and its link with aberrant behavior and intellect in FXS. Imaging data were acquired from 48 individuals with FXS, 28 IQ-matched controls without FXS (IQ-CTL), and 36 typically developing controls (TD-CTL). Of the total participant count, cognitive and behavioral assessment data were obtained from 44 individuals with FXS and 27 participants in the IQ-CTL group. CN volume and topography were compared between groups. Correlations were performed between CN topography and cognitive as well as behavioral measures within FXS and IQ-CTL groups. As expected, the FXS group had larger CN compared with both IQ-CTL and TD-CTL groups. Correlations between focal CN topography and frontal lobe-associated cognitive and behavioral deficits in the FXS group supported the hypothesis that CN enlargement is related to abnormal orbitofrontal-caudate and dorsolateral-caudate circuitry in FXS. These findings deepen our understanding of neuroanatomical mechanisms underlying cognitive-behavioral problems in FXS and hold promise for informing future behavioral and psychopharmacological interventions targeting specific neural pathways.