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.

Executive task-based brain function in children with type 1 diabetes: An observational study.

BACKGROUND: Optimal glycemic control is particularly difficult to achieve in children and adolescents with type 1 diabetes (T1D), yet the influence of dysglycemia on the developing brain remains poorly understood. METHODS AND FINDINGS: Using a large multi-site study framework, we investigated activation patterns using functional magnetic resonance imaging (fMRI) in 93 children with T1D (mean age 11.5 ± 1.8 years; 45.2% female) and 57 non-diabetic (control) children (mean age 11.8 ± 1.5 years; 50.9% female) as they performed an executive function paradigm, the go/no-go task. Children underwent scanning and cognitive and clinical assessment at 1 of 5 different sites. Group differences in activation occurring during the contrast of "no-go > go" were examined while controlling for age, sex, and scan site. Results indicated that, despite equivalent task performance between the 2 groups, children with T1D exhibited increased activation in executive control regions (e.g., dorsolateral prefrontal and supramarginal gyri; p = 0.010) and reduced suppression of activation in the posterior node of the default mode network (DMN; p = 0.006). Secondary analyses indicated associations between activation patterns and behavior and clinical disease course. Greater hyperactivation in executive control regions in the T1D group was correlated with improved task performance (as indexed by shorter response times to correct "go" trials; r = -0.36, 95% CI -0.53 to -0.16, p < 0.001) and with better parent-reported measures of executive functioning (r values < -0.29, 95% CIs -0.47 to -0.08, p-values < 0.007). Increased deficits in deactivation of the posterior DMN in the T1D group were correlated with an earlier age of T1D onset (r = -0.22, 95% CI -0.41 to -0.02, p = 0.033). Finally, exploratory analyses indicated that among children with T1D (but not control children), more severe impairments in deactivation of the DMN were associated with greater increases in hyperactivation of executive control regions (T1D: r = 0.284, 95% CI 0.08 to 0.46, p = 0.006; control: r = 0.108, 95% CI -0.16 to 0.36, p = 0.423). A limitation to this study involves glycemic effects on brain function; because blood glucose was not clamped prior to or during scanning, future studies are needed to assess the influence of acute versus chronic dysglycemia on our reported findings. In addition, the mechanisms underlying T1D-associated alterations in activation are unknown. CONCLUSIONS: These data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN, ultimately facilitating cognitive and behavioral performance levels that are equivalent to that of non-diabetic controls. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted.

Longitudinal assessment of hippocampus structure in children with type 1 diabetes.

The extant literature finds that children with type 1 diabetes mellitus (T1D) experience mild cognitive alterations compared to healthy age-matched controls. The neural basis of these cognitive differences is unclear but may relate in part to the effects of dysglycemia on the developing brain. We investigated longitudinal changes in hippocampus volume in young children with early-onset T1D. Structural magnetic resonance imaging data were acquired from 142 children with T1D and 65 age-matched control subjects (4-10 years of age at study entry) at 2 time points, 18 months apart. The effects of diabetes and glycemic exposure on hippocampal volume and growth were examined. Results indicated that although longitudinal hippocampus growth did not differ between children with T1D and healthy control children, slower growth of the hippocampus was associated with both increased exposure to hyperglycemia (interval HbA1c) and greater glycemic variability (MAGE) in T1D. These observations indicate that the current practice of tolerating some hyperglycemia to minimize the risk of hypoglycemia in young children with T1D may not be optimal for the developing brain. Efforts that continue to assess the factors influencing neural and cognitive development in children with T1D will be critical in minimizing the deleterious effects of diabetes.

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.

Topological methods reveal high and low functioning neuro-phenotypes within fragile X syndrome.

Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability as well as the most common single-gene risk factor for autism. Our goal was to examine variation in brain structure in FXS with topological data analysis (TDA), and to assess how such variation is associated with measures of IQ and autism-related behaviors. To this end, we analyzed imaging and behavioral data from young boys (n = 52; aged 1.57-4.15 years) diagnosed with FXS. Application of topological methods to structural MRI data revealed two large subgroups within the study population. Comparison of these subgroups showed significant between-subgroup neuroanatomical differences similar to those previously reported to distinguish children with FXS from typically developing controls (e.g., enlarged caudate). In addition to neuroanatomy, the groups showed significant differences in IQ and autism severity scores. These results suggest that despite arising from a single gene mutation, FXS may encompass two biologically, and clinically separable phenotypes. In addition, these findings underscore the potential of TDA as a powerful tool in the search for biological phenotypes of neuropsychiatric disorders.

Cortical brain morphology in young, estrogen-naive, and adolescent, estrogen-treated girls with Turner syndrome.

Turner syndrome (TS) is a genetic condition that permits direct investigation of the complex interaction among genes, hormones, behavior, and brain development. Here, we used automated segmentation and surface-based morphometry to characterize the differences in brain morphology in children (n = 30) and adolescents (n = 16) with TS relative to age- and sex-matched control groups (n = 21 and 24, respectively). Our results show that individuals with TS, young and adolescent, present widespread reduction of gray matter volume, white matter volume and surface area (SA) over both parietal and occipital cortices bilaterally, as well as enlarged amygdala. In contrast to the young cohort, adolescents with TS showed significantly larger mean cortical thickness and significantly smaller total SA compared with healthy controls. Exploratory developmental analyses suggested aberrant regional brain maturation in the parahippocampal gyrus and orbitofrontal regions from childhood to adolescence in TS. These findings show the existence of abnormal brain morphology early in development in TS, but also suggest the presence of altered neurodevelopmental trajectories in some regions, which could potentially be the consequences of estrogen deficiency, both pre- and postnatally.

High success rates of sedation-free brain MRI scanning in young children using simple subject preparation protocols with and without a commercial mock scanner--the Diabetes Research in Children Network (DirecNet) experience.

BACKGROUND: The ability to lie still in an MRI scanner is essential for obtaining usable image data. To reduce motion, young children are often sedated, adding significant cost and risk. OBJECTIVE: We assessed the feasibility of using a simple and affordable behavioral desensitization program to yield high-quality brain MRI scans in sedation-free children. MATERIALS AND METHODS: 222 children (4-9.9 years), 147 with type 1 diabetes and 75 age-matched non-diabetic controls, participated in a multi-site study focused on effects of type 1 diabetes on the developing brain. T1-weighted and diffusion-weighted imaging (DWI) MRI scans were performed. All children underwent behavioral training and practice MRI sessions using either a commercial MRI simulator or an inexpensive mock scanner consisting of a toy tunnel, vibrating mat, and video player to simulate the sounds and feel of the MRI scanner. RESULTS: 205 children (92.3%), mean age 7 ± 1.7 years had high-quality T1-W scans and 174 (78.4%) had high-quality diffusion-weighted scans after the first scan session. With a second scan session, success rates were 100% and 92.5% for T1-and diffusion-weighted scans, respectively. Success rates did not differ between children with type 1 diabetes and children without diabetes, or between centers using a commercial MRI scan simulator and those using the inexpensive mock scanner. CONCLUSION: Behavioral training can lead to a high success rate for obtaining high-quality T1-and diffusion-weighted brain images from a young population without sedation.

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.

Brain Function Differences in Children With Type 1 Diabetes: A Functional MRI Study of Working Memory.

Glucose is a primary fuel source to the brain, yet the influence of dysglycemia on neurodevelopment in children with type 1 diabetes remains unclear. We examined brain activation using functional MRI in 80 children with type 1 diabetes (mean ± SD age 11.5 ± 1.8 years; 46% female) and 47 children without diabetes (control group) (age 11.8 ± 1.5 years; 51% female) as they performed a visuospatial working memory (N-back) task. Results indicated that in both groups, activation scaled positively with increasing working memory load across many areas, including the frontoparietal cortex, caudate, and cerebellum. Between groups, children with diabetes exhibited reduced performance on the N-back task relative to children in the control group, as well as greater modulation of activation (i.e., showed greater increase in activation with higher working memory load). Post hoc analyses indicated that greater modulation was associated in the diabetes group with better working memory function and with an earlier age of diagnosis. These findings suggest that increased modulation may occur as a compensatory mechanism, helping in part to preserve working memory ability, and further, that children with an earlier onset require additional compensation. Future studies that test whether these patterns change as a function of improved glycemic control are warranted.

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.

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.

Aberrant face and gaze habituation in fragile x syndrome.

OBJECTIVE: The authors sought to investigate neural system habituation to face and eye gaze in fragile X syndrome, a disorder characterized by eye-gaze aversion, among other social and cognitive deficits. METHOD: Participants (ages 15-25 years) were 30 individuals with fragile X syndrome (females, N=14) and a comparison group of 25 individuals without fragile X syndrome (females, N=12) matched for general cognitive ability and autism symptoms. Functional MRI (fMRI) was used to assess brain activation during a gaze habituation task. Participants viewed repeated presentations of four unique faces with either direct or averted eye gaze and judged the direction of eye gaze. RESULTS: Four participants (males, N=4/4; fragile X syndrome, N=3) were excluded because of excessive head motion during fMRI scanning. Behavioral performance did not differ between the groups. Less neural habituation (and significant sensitization) in the fragile X syndrome group was found in the cingulate gyrus, fusiform gyrus, and frontal cortex in response to all faces (direct and averted gaze). Left fusiform habituation in female participants was directly correlated with higher, more typical levels of the fragile X mental retardation protein and inversely correlated with autism symptoms. There was no evidence for differential habituation to direct gaze compared with averted gaze within or between groups. CONCLUSIONS: Impaired habituation and accentuated sensitization in response to face/eye gaze was distributed across multiple levels of neural processing. These results could help inform interventions, such as desensitization therapy, which may help patients with fragile X syndrome modulate anxiety and arousal associated with eye gaze, thereby improving social functioning.

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.