Associations between brain network, puberty, and behaviors in boys with Klinefelter syndrome.

BACKGROUND: Klinefelter syndrome (KS), also referred to as XXY syndrome, is a significant but inadequately studied risk factor for neuropsychiatric disability. Whether alterations in functional brain connectivity or pubertal delays are associated with aberrant cognitive-behavioral outcomes in individuals with KS is largely unknown. In this observational study, we investigated KS-related alterations in the resting-state brain network, testosterone level, and cognitive-behavioral impairment in adolescents with Klinefelter syndrome. METHODS: We recruited 46 boys with KS, ages 8 to 17 years, and 51 age-matched typically developing (TD) boys. All participants underwent resting-state functional magnetic resonance imaging scans, pubertal, and cognitive-behavioral assessments. Resting-state functional connectivity and regional brain activity of the participants were assessed. RESULTS: We found widespread alterations in global functional connectivity among the inferior frontal gyrus, temporal-parietal area, and hippocampus in boys with KS. Aberrant regional activities, including enhanced fALFF in the motor area and reduced ReHo in the caudate, were also found in the KS group compared to the TD children. Further, using machine learning methods, brain network alterations in these regions accurately differentiated boys with KS from TD controls. Finally, we showed that the alterations of brain network properties not only effectively predict cognitive-behavioral impairment in boys with KS, but also appear to mediate the association between total testosterone level and language ability, a cognitive domain at particular risk for dysfunction in this condition. CONCLUSION: Our results offer an informatic neurobiological foundation for understanding cognitive-behavioral impairments in individuals with KS and contribute to our understanding of the interplay between pubertal status, brain function, and cognitive-behavioral outcome in this population.

Social gaze behavior and hyperarousal in young females with fragile X syndrome: A within-person approach.

Children with fragile X syndrome (FXS) often avoid eye contact, a behavior that is potentially related to hyperarousal. Prior studies, however, have focused on between-person associations rather than coupling of within-person changes in gaze behaviors and arousal. In addition, there is debate about whether prompts to maintain eye contact are beneficial for individuals with FXS. In a study of young females (ages 6-16), we used eye tracking to assess gaze behavior and pupil dilation during social interactions in a group with FXS (n = 32) and a developmentally similar comparison group (n = 23). Participants engaged in semi-structured conversations with a female examiner during blocks with and without verbal prompts to maintain eye contact. We identified a social-behavioral and psychophysiological profile that is specific to females with FXS; this group exhibited lower mean levels of eye contact, significantly increased mean pupil dilation during conversations that included prompts to maintain eye contact, and showed stronger positive coupling between eye contact and pupil dilation. Our findings strengthen support for the perspective that gaze aversion in FXS reflects negative reinforcement of social avoidance behavior. We also found that behavioral skills training may improve eye contact, but maintaining eye contact appears to be physiologically taxing for females with FXS.

Association of Intrinsic Functional Brain Network and Longitudinal Development of Cognitive Behavioral Symptoms in Young Girls With Fragile X Syndrome.

BACKGROUND: Fragile X syndrome (FXS) is an X chromosome-linked genetic disorder characterized by increased risk for behavioral, social, and neurocognitive deficits. Because males express a more severe phenotype than females, research has focused largely on identifying neural abnormalities in all-male or both-sex populations with FXS. Therefore, very little is known about the neural alterations that contribute to cognitive behavioral symptoms in females with FXS. This cross-sectional study aimed to elucidate the large-scale resting-state brain networks associated with the multidomain cognitive behavioral phenotype in girls with FXS. METHODS: We recruited 38 girls with full-mutation FXS (11.58 ± 3.15 years) and 32 girls without FXS (11.66 ± 2.27 years). Both groups were matched on age, verbal IQ, and multidomain cognitive behavioral symptoms. Resting-state functional magnetic resonance imaging data were collected. RESULTS: Compared with the control group, girls with FXS showed significantly greater resting-state functional connectivity of the default mode network, lower nodal strength at the right middle temporal gyrus, stronger nodal strength at the left caudate, and higher global efficiency of the default mode network. These aberrant brain network characteristics map directly onto the cognitive behavioral symptoms commonly observed in girls with FXS. An exploratory analysis suggested that brain network patterns at a prior time point (time 1) were predictive of the longitudinal development of participants' multidomain cognitive behavioral symptoms. CONCLUSIONS: These findings represent the first examination of large-scale brain network alterations in a large sample of girls with FXS, expanding our knowledge of potential neural mechanisms underlying the development of cognitive behavioral symptoms in girls with FXS.

Aberrant Neural Response During Face Processing in Girls With Fragile X Syndrome: Defining Potential Brain Biomarkers for Treatment Studies.

BACKGROUND: Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study, we used functional near-infrared spectroscopy to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population. METHODS: Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function, and autism symptoms. Functional near-infrared spectroscopy was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects. RESULTS: Compared with the control group, girls with FXS showed significant hyperactivation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition, including executive function, autism symptoms, depression, and anxiety. CONCLUSIONS: These findings strongly support a hypothesis of neural hyperactivation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker end point for improving treatment trial evaluation in girls with this condition.

A Pilot randomized trial to examine effects of a hybrid closed-loop insulin delivery system on neurodevelopmental and cognitive outcomes in adolescents with type 1 diabetes.

Type 1 diabetes (T1D) is associated with lower scores on tests of cognitive and neuropsychological function and alterations in brain structure and function in children. This proof-of-concept pilot study (ClinicalTrials.gov Identifier NCT03428932) examined whether MRI-derived indices of brain development and function and standardized IQ scores in adolescents with T1D could be improved with better diabetes control using a hybrid closed-loop insulin delivery system. Eligibility criteria for participation in the study included age between 14 and 17 years and a diagnosis of T1D before 8 years of age. Randomization to either a hybrid closed-loop or standard diabetes care group was performed after pre-qualification, consent, enrollment, and collection of medical background information. Of 46 participants assessed for eligibility, 44 met criteria and were randomized. Two randomized participants failed to complete baseline assessments and were excluded from final analyses. Participant data were collected across five academic medical centers in the United States. Research staff scoring the cognitive assessments as well as those processing imaging data were blinded to group status though participants and their families were not. Forty-two adolescents, 21 per group, underwent cognitive assessment and multi-modal brain imaging before and after the six month study duration. HbA1c and sensor glucose downloads were obtained quarterly. Primary outcomes included metrics of gray matter (total and regional volumes, cortical surface area and thickness), white matter volume, and fractional anisotropy. Estimated power to detect the predicted treatment effect was 0.83 with two-tailed, α = 0.05. Adolescents in the hybrid closed-loop group showed significantly greater improvement in several primary outcomes indicative of neurotypical development during adolescence compared to the standard care group including cortical surface area, regional gray volumes, and fractional anisotropy. The two groups were not significantly different on total gray and white matter volumes or cortical thickness. The hybrid closed loop group also showed higher Perceptual Reasoning Index IQ scores and functional brain activity more indicative of neurotypical development relative to the standard care group (both secondary outcomes). No adverse effects associated with study participation were observed. These results suggest that alterations to the developing brain in T1D might be preventable or reversible with rigorous glucose control. Long term research in this area is needed.

Neuroanatomical Profile of Young Females with Fragile X Syndrome: A Voxel-Based Morphometry Analysis.

Fragile X syndrome is a genetic condition associated with alterations in brain and subsequent cognitive development. However, due to a milder phenotype relative to males, females with fragile X syndrome are underrepresented in research studies. In the current study, we investigate neuroanatomical differences in young females (age range: 6.03-16.32 years) with fragile X syndrome (N = 46) as compared to age-, sex-, and verbal abilities-matched participants (comparison group; N = 35). Between-group analyses of whole-brain and regional brain volumes were assessed using voxel-based morphometry. Results demonstrate significantly larger total gray and white matter volumes in girls with fragile X syndrome compared to a matched comparison group (Ps < 0.001). In addition, the fragile X group showed significantly larger gray matter volume in a bilateral parieto-occipital cluster and a right parieto-occipital cluster (Ps < 0.001). Conversely, the fragile X group showed significantly smaller gray matter volume in the bilateral gyrus rectus (P < 0.03). Associations between these regional brain volumes and key socio-emotional variables provide insight into gene-brain-behavior relationships underlying the fragile X syndrome phenotype in females. These findings represent the first characterization of a neuroanatomical phenotype in a large sample of girls with fragile X syndrome and expand our knowledge about potential neurodevelopmental mechanisms underlying cognitive-behavioral outcomes in this condition.

Impact of Type 1 Diabetes in the Developing Brain in Children: A Longitudinal Study.

OBJECTIVE: To assess whether previously observed brain and cognitive differences between children with type 1 diabetes and control subjects without diabetes persist, worsen, or improve as children grow into puberty and whether differences are associated with hyperglycemia. RESEARCH DESIGN AND METHODS: One hundred forty-four children with type 1 diabetes and 72 age-matched control subjects without diabetes (mean ± SD age at baseline 7.0 ± 1.7 years, 46% female) had unsedated MRI and cognitive testing up to four times over 6.4 ± 0.4 (range 5.3-7.8) years; HbA1c and continuous glucose monitoring were done quarterly. FreeSurfer-derived brain volumes and cognitive metrics assessed longitudinally were compared between groups using mixed-effects models at 6, 8, 10, and 12 years. Correlations with glycemia were performed. RESULTS: Total brain, gray, and white matter volumes and full-scale and verbal intelligence quotients (IQs) were lower in the diabetes group at 6, 8, 10, and 12 years, with estimated group differences in full-scale IQ of -4.15, -3.81, -3.46, and -3.11, respectively (P < 0.05), and total brain volume differences of -15,410, -21,159, -25,548, and -28,577 mm3 at 6, 8, 10, and 12 years, respectively (P < 0.05). Differences at baseline persisted or increased over time, and brain volumes and cognitive scores negatively correlated with a life-long HbA1c index and higher sensor glucose in diabetes. CONCLUSIONS: Detectable changes in brain volumes and cognitive scores persist over time in children with early-onset type 1 diabetes followed longitudinally; these differences are associated with metrics of hyperglycemia. Whether these changes can be reversed with scrupulous diabetes control requires further study. These longitudinal data support the hypothesis that the brain is a target of diabetes complications in young children.

Evaluation of smartphone interactions on drivers' brain function and vehicle control in an immersive simulated environment.

Smartphones and other modern technologies have introduced multiple new forms of distraction that color the modern driving experience. While many smartphone functions aim to improve driving by providing the driver with real-time navigation and traffic updates, others, such as texting, are not compatible with driving and are often the cause of accidents. Because both functions elicit driver attention, an outstanding question is the degree to which drivers' naturalistic interactions with navigation and texting applications differ in regard to brain and behavioral indices of distracted driving. Here, we employed functional near-infrared spectroscopy to examine the cortical activity that occurs under parametrically increasing levels of smartphone distraction during naturalistic driving. Our results highlight a significant increase in bilateral prefrontal and parietal cortical activity that occurs in response to increasingly greater levels of smartphone distraction that, in turn, predicts changes in common indices of vehicle control.

Functional near-infrared spectroscopy detects increased activation of the brain frontal-parietal network in youth with type 1 diabetes.

When considered as a group, children with type 1 diabetes have subtle cognitive deficits relative to neurotypical controls. However, the neural correlates of these differences remain poorly understood. Using functional near-infrared spectroscopy (fNIRS), we investigated the brain functional activations of young adolescents (19 individuals with type 1 diabetes, 18 healthy controls, ages 8-16 years) during a Go/No-Go response inhibition task. Both cohorts had the same performance on the task, but the individuals with type 1 diabetes subjects had higher activations in a frontal-parietal network including the bilateral supramarginal gyri and bilateral rostrolateral prefrontal cortices. The activations in these regions were positively correlated with fewer parent-reported conduct problems (ie, lower Conduct Problem scores) on the Behavioral Assessment System for Children, Second Edition. Lower Conduct Problem scores are characteristic of less rule-breaking behavior suggesting a link between this brain network and better self-control. These findings are consistent with a large functional magnetic resonance imaging (fMRI) study of children with type 1 diabetes using completely different participants. Perhaps surprisingly, the between-group activation results from fNIRS were statistically stronger than the results using fMRI. This pilot study is the first fNIRS investigation of executive function for individuals with type 1 diabetes. The results suggest that fNIRS is a promising functional neuroimaging resource for detecting the brain correlates of behavior in the pediatric clinic.

Impact of Early Diabetic Ketoacidosis on the Developing Brain.

OBJECTIVE: This study examined whether a history of diabetic ketoacidosis (DKA) is associated with changes in longitudinal cognitive and brain development in young children with type 1 diabetes. RESEARCH DESIGN AND METHODS: Cognitive and brain imaging data were analyzed from 144 children with type 1 diabetes, ages 4 to <10 years, who participated in an observational study of the Diabetes Research in Children Network (DirecNet). Participants were grouped according to history of DKA severity (none/mild or moderate/severe). Each participant had unsedated MRI scans and cognitive testing at baseline and 18 months. RESULTS: In 48 of 51 subjects, the DKA event occurred at the time of onset, at an average of 2.9 years before study entry. The moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months compared with the none/mild group. When matched by age at time of enrollment and average HbA1c during the 18-month interval, participants who had a history of moderate/severe DKA compared with none/mild DKA were observed to have significantly lower Full Scale Intelligence Quotient scores and cognitive performance on the Detectability and Commission subtests of the Conners' Continuous Performance Test II and the Dot Locations subtest of the Children's Memory Scale. CONCLUSIONS: A single episode of moderate/severe DKA in young children at diagnosis is associated with lower cognitive scores and altered brain growth. Further studies are needed to assess whether earlier diagnosis of type 1 diabetes and prevention of DKA may reduce the long-term effect of ketoacidosis on the developing brain.

Neuroanatomical abnormalities in fragile X syndrome during the adolescent and young adult years.

Abnormal brain development and cognitive dysfunction have been reported both in children and in adults with fragile X syndrome (FXS). However, few studies have examined neuroanatomical abnormalities in FXS during adolescence. In this study we focus on adolescent subjects with FXS (N = 54) as compared to age- and sex-matched subjects with idiopathic intellectual disability (Comparison Group) (N = 32), to examine neuroanatomical differences during this developmental period. Brain structure was assessed with voxel-based morphometry and independent groups t-test in SPM8 software. Results showed that the FXS group, relative to the comparison group, had significantly larger gray matter volume (GMV) in only one region: the bilateral caudate nucleus, but have smaller GMV in several regions including bilateral medial frontal, pregenual cingulate, gyrus rectus, insula, and superior temporal gyrus. Group differences also were noted in white matter regions. Within the FXS group, lower FMRP levels were associated with less GMV in several regions including cerebellum and gyrus rectus, and less white matter volume (WMV) in pregenual cingulate, middle frontal gyrus, and other regions. Lower full scale IQ within the FXS group was associated with larger right caudate nucleus GMV. In conclusion, adolescents and young adults with FXS demonstrate neuroanatomical abnormalities consistent with those previously reported in children and adults with FXS. These brain variations likely result from reduced FMRP during early neurodevelopment and mediate downstream deleterious effects on cognitive function.

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.

Longitudinal assessment of neuroanatomical and cognitive differences in young children with type 1 diabetes: association with hyperglycemia.

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.

Influence of the X-chromosome on neuroanatomy: evidence from Turner and Klinefelter syndromes.

Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an additional X-chromosome (47XXY). As these disorders essentially represent copy number variants of the sex chromosomes, investigation of brain structure across these disorders allows us to determine whether sex chromosome gene dosage effects exist. We used voxel-based morphometry to investigate this hypothesis in a large sample of children in early puberty, to compare regional gray matter volumes among individuals with one (45X), two (typically developing 46XX females and 46XY males), and three (47XXY) sex chromosomes. Between-group contrasts of TS and KS groups relative to respective sex-matched controls demonstrated highly convergent patterns of volumetric differences with the presence of an additional sex chromosome being associated with relatively decreased parieto-occipital gray matter volume and relatively increased temporo-insular gray matter volumes. Furthermore, z-score map comparisons between TS and KS cohorts also suggested that this effect occurs in a linear dose-dependent fashion. We infer that sex chromosome gene expression directly influences brain structure in children during early stages of puberty, extending our understanding of genotype-phenotype mechanisms underlying sex differences in the brain.

Alterations in white matter structure in young children with type 1 diabetes.

OBJECTIVE: To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children. RESEARCH DESIGN AND METHODS: Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition. RESULTS: Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects. CONCLUSIONS: These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

Neuroanatomical correlates of dysglycemia in young children with type 1 diabetes.

Studies of brain structure in type 1 diabetes (T1D) describe widespread neuroanatomical differences related to exposure to glycemic dysregulation in adults and adolescents. In this study, we investigate the neuroanatomical correlates of dysglycemia in very young children with early-onset T1D. Structural magnetic resonance images of the brain were acquired in 142 children with T1D and 68 age-matched control subjects (mean age 7.0 ± 1.7 years) on six identical scanners. Whole-brain volumetric analyses were conducted using voxel-based morphometry to detect regional differences between groups and to investigate correlations between regional brain volumes and measures of glycemic exposure (including data from continuous glucose monitoring). Relative to control subjects, the T1D group displayed decreased gray matter volume (GMV) in bilateral occipital and cerebellar regions (P < 0.001) and increased GMV in the left inferior prefrontal, insula, and temporal pole regions (P = 0.002). Within the T1D group, hyperglycemic exposure was associated with decreased GMV in medial frontal and temporal-occipital regions and increased GMV in lateral prefrontal regions. Cognitive correlations of intelligence quotient to GMV were found in cerebellar-occipital regions and medial prefrontal cortex for control subjects, as expected, but not for the T1D group. Thus, early-onset T1D affects regions of the brain that are associated with typical cognitive development.

Genomic imprinting effects of the X chromosome on brain morphology.

There is increasing evidence that genomic imprinting, a process by which certain genes are expressed in a parent-of-origin-specific manner, can influence neurogenetic and psychiatric manifestations. While some data suggest possible imprinting effects of the X chromosome on physical and cognitive characteristics in humans, there is no compelling evidence that X-linked imprinting affects brain morphology. To address this issue, we investigated regional cortical volume, thickness, and surface area in 27 healthy controls and 40 prepubescent girls with Turner syndrome (TS), a condition caused by the absence of one X chromosome. Of the young girls with TS, 23 inherited their X chromosome from their mother (X(m)) and 17 from their father (X(p)). Our results confirm the existence of significant differences in brain morphology between girls with TS and controls, and reveal the presence of a putative imprinting effect among the TS groups: girls with X(p) demonstrated thicker cortex than those with X(m) in the temporal regions bilaterally, while X(m) individuals showed bilateral enlargement of gray matter volume in the superior frontal regions compared with X(p). These data suggest the existence of imprinting effects of the X chromosome that influence both cortical thickness and volume during early brain development, and help to explain variability in cognitive and behavioral manifestations of TS with regard to the parental origin of the X chromosome.

White matter aberrations in prepubertal estrogen-naive girls with monosomic Turner syndrome.

Turner syndrome (TS) offers a unique opportunity to investigate associations among genes, the brain, and cognitive phenotypes. In this study, we used 3 complementary analyses of diffusion tensor imaging (DTI) data (whole brain, region of interest, and fiber tractography) and a whole brain volumetric imaging technique to investigate white matter (WM) structure in prepubertal, nonmosaic, estrogen-naive girls with TS compared with age and sex matched typically developing controls. The TS group demonstrated significant WM aberrations in brain regions implicated in visuospatial abilities, face processing, and sensorimotor and social abilities compared with controls. Extensive spatial overlap between regions of aberrant WM structure (from DTI) and regions of aberrant WM volume were observed in TS. Our findings indicate that complete absence of an X chromosome in young females (prior to receiving exogenous estrogen) is associated with WM aberrations in specific regions implicated in characteristic cognitive features of TS.

Neuroanatomical spatial patterns in Turner syndrome.

Turner syndrome (TS) is a highly prevalent genetic condition caused by partial or complete absence of one X-chromosome in a female and is associated with a lack of endogenous estrogen during development secondary to gonadal dysgenesis. Prominent cognitive weaknesses in executive and visuospatial functions in the context of normal overall IQ also occur in affected individuals. Previous neuroimaging studies of TS point to a profile of neuroanatomical variation relative to age and sex matched controls. However, there are no neuroimaging studies focusing on young girls with TS before they receive exogenous estrogen treatment to induce puberty. Information obtained from young girls with TS may help to establish an early neural correlate of the cognitive phenotype associated with the disorder. Further, univariate analysis has predominantly been the method of choice in prior neuroimaging studies of TS. Univariate approaches examine between-group differences on the basis of individual image elements (i.e., a single voxel's intensity or the volume of an a priori defined brain region). This is in contrast to multivariate methods that can elucidate complex neuroanatomical profiles in a clinical population by determining the pattern of between-group differences from many image elements evaluated simultaneously. In this case, individual image elements might not be significantly different between groups but can still contribute to a significantly different overall spatial pattern. In this study, voxel-based morphometry (VBM) of high-resolution magnetic resonance images was used to investigate differences in brain morphology between 13 pediatric, pre-estrogen girls with monosomic TS and 13 age-matched typically developing controls (3.0 T imaging: mean age 9.1±2.1). A similar analysis was performed with an older cohort of 13 girls with monosomic TS and 13 age-matched typically developing controls (1.5 T imaging: mean age 15.8±4.5). A multivariate, linear support vector machine analysis using leave-one-out cross-validation was then employed to discriminate girls with TS from typically developing controls based on differences in neuroanatomical spatial patterns and to assess how accurately such patterns translate across heterogeneous cohorts. VBM indicated that both TS cohorts had significantly reduced gray matter volume in the precentral, postcentral, and supramarginal gyri and enlargement of the left middle and superior temporal gyri. Support vector machine (SVM) classifiers achieved high accuracy for discriminating brain morphology patterns in TS from typically developing controls and also displayed spatial patterns consistent with the VBM results. Furthermore, the SVM classifiers identified additional neuroanatomical variations in individuals with TS, localized in the hippocampus, orbitofrontal cortex, insula, caudate, and cuneus. Our results demonstrate robust spatial patterns of altered brain morphology in developmentally dynamic populations with TS, providing further insight into the neuroanatomical correlates of cognitive-behavioral features in this condition.

Neuroimaging-based approaches in the brain-computer interface.

Techniques to enable direct communication between the brain and computers/machines, such as the brain-computer interface (BCI) or the brain-machine interface (BMI), are gaining momentum in the neuroscientific realm, with potential applications ranging from medicine to general consumer electronics. Noninvasive BCI techniques based on neuroimaging modalities are reviewed in terms of their methodological approaches as well as their similarities and differences. Trends in automated data interpretation through machine learning algorithms are also introduced. Applications of functional neuromodulation techniques to BCI systems would allow for bidirectional communication between the brain and the computer. Such bidirectional interfaces can relay information directly from one brain to another using a computer as a medium, ultimately leading to the concept of a brain-to-brain interface (BBI).