Ryan L. Muetzel

White matter integrity predicts delay discounting behavior in 9-to 23-year-olds: A diffusion tensor imaging study

Healthy participants (n = 79), ages 9–23, completed a delay discounting task assessing the extent to which the value of a monetary reward declines as the delay to its receipt increases. Diffusion tensor imaging (DTI) was used to evaluate how individual differences in delay discounting relate to variation in fractional anisotropy (FA) and mean diffusivity (MD) within whole-brain white matter using voxel-based regressions. Given that rapid prefrontal lobe development is occurring during this age range and that functional imaging studies have implicated the prefrontal cortex in discounting behavior, we hypothesized that differences in FA and MD would be associated with alterations in the discounting rate. The analyses revealed a number of clusters where less impulsive performance on the delay discounting task was associated with higher FA and lower MD. The clusters were located primarily in bilateral frontal and temporal lobes and were localized within white matter tracts, including portions of the inferior and superior longitudinal fasciculi, anterior thalamic radiation, uncinate fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, and splenium of the corpus callosum. FA increased and MD decreased with age in the majority of these regions. Some, but not all, of the discounting/DTI associations remained significant after controlling for age. Findings are discussed in terms of both developmental and age-independent effects of white matter organization on discounting behavior.

The development of corpus callosum microstructure and associations with bimanual task performance in healthy adolescents

Cross-sectional and longitudinal volumetric studies suggest that the corpus callosum (CC) continues to mature structurally from infancy to adulthood. Diffusion tensor imaging (DTI) provides in vivo information about the directional organization of white matter microstructure and shows potential for elucidating even more subtle brain changes during adolescent development. We used DTI to examine CC microstructure in healthy right-handed adolescents (n=92, ages 9-24 years) and correlated the imaging data with motor task performance. The primary DTI variable was fractional anisotropy (FA), which reflects the degree of white matters directional organization. Participants completed an alternating finger tapping test to assess interhemispheric transfer and motor speed. Task performance was significantly correlated with age. Analyses of variance indicated that 9- to 11-year-olds generally performed worse than each of the older groups. Males outperformed females. Significant positive correlations between age and FA were observed in the splenium of the CC, which interconnects posterior cortical regions. Analyses of variance indicated that individuals older than 18 years had significantly higher FA than 9- to 11-year-olds. FA levels in the genu and splenium correlated significantly with task performance. Regression analyses indicated that bimanual coordination was significantly predicted by age, gender, and splenium FA. Decreases in alternating finger tapping time and increases in FA likely reflect increased myelination in the CC and more efficient neuronal signal transmission. These findings expand upon existing neuroimaging reports of CC development by showing associations between bimanual coordination and white matter microstructural organization in an adolescent sample.

Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study

BACKGROUND Thyroid hormone is involved in the regulation of early brain development. Since the fetal thyroid gland is not fully functional until week 18-20 of pregnancy, neuronal migration and other crucial early stages of intrauterine brain development largely depend on the supply of maternal thyroid hormone. Current clinical practice mostly focuses on preventing the negative consequences of low thyroid hormone concentrations, but data from animal studies have shown that both low and high concentrations of thyroid hormone have negative effects on offspring brain development. We aimed to investigate the association of maternal thyroid function with child intelligence quotient (IQ) and brain morphology. METHODS In this population-based prospective cohort study, embedded within the Generation R Study (Rotterdam, Netherlands), we investigated the association of maternal thyroid function with child IQ (assessed by non-verbal intelligence tests) and brain morphology (assessed on brain MRI scans). Eligible women were those living in the study area at their delivery date, which had to be between April 1, 2002, and Jan 1, 2006. For this study, women with available serum samples who presented in early pregnancy (<18 weeks) were included. Data for maternal thyroid-stimulating hormone, free thyroxine, thyroid peroxidase antibodies (at weeks 9-18 of pregnancy), and child IQ (assessed at a median of 6·0 years of age [95% range 5·6-7·9 years]) or brain MRI scans (done at a median of 8·0 years of age [6·2-10·0]) were obtained. Analyses were adjusted for potential confounders including concentrations of human chorionic gonadotropin and child thyroid-stimulating hormone and free thyroxine. FINDINGS Data for child IQ were available for 3839 mother-child pairs, and MRI scans were available from 646 children. Maternal free thyroxine concentrations showed an inverted U-shaped association with child IQ (p=0·0044), child grey matter volume (p=0·0062), and cortex volume (p=0·0011). For both low and high maternal free thyroxine concentrations, this association corresponded to a 1·4-3·8 points reduction in mean child IQ. Maternal thyroid-stimulating hormone was not associated with child IQ or brain morphology. All associations remained similar after the exclusion of women with overt hypothyroidism and overt hyperthyroidism, and after adjustment for concentrations of human chorionic gonadotropin, child thyroid-stimulating hormone and free thyroxine or thyroid peroxidase antibodies (continuous or positivity). INTERPRETATION Both low and high maternal free thyroxine concentrations during pregnancy were associated with lower child IQ and lower grey matter and cortex volume. The association between high maternal free thyroxine and low child IQ suggests that levothyroxine therapy during pregnancy, which is often initiated in women with subclinical hypothyroidism during pregnancy, might carry the potential risk of adverse child neurodevelopment outcomes when the aim of treatment is to achieve high-normal thyroid function test results. FUNDING The Netherlands Organisation for Health Research and Development (ZonMw) and the European Communitys Seventh Framework Programme.

Longitudinal Changes in Behavioral Approach System Sensitivity and Brain Structures Involved in Reward Processing during Adolescence.

Figure 2 was distorted in production. The correct version is presented in the erratum.] Adolescence is a period of radical normative changes and increased risk for substance use, mood disorders, and physical injury. Researchers have proposed that increases in reward sensitivity (i.e., sensitivity of the behavioral approach system [BAS]) and/or increases in reactivity to all emotional stimuli (i.e., reward and threat sensitivities) lead to these phenomena. The present study is the first longitudinal investigation of changes in reward (i.e., BAS) sensitivity in 9- to 23-year-olds across a 2-year follow-up. Support was found for increased reward sensitivity from early to late adolescence, and evidence was found for decline in the early 20s. This decline is combined with a decrease in left nucleus accumbens (Nacc) volume, a key structure for reward processing, from the late teens into the early 20s. Furthermore, we found longitudinal increases in sensitivity to reward to be predicted by individual differences in the Nacc and medial orbitofrontal cortex (OFC) volumes at baseline in this developmental sample. Similarly, increases in sensitivity to threat (i.e., behavioral inhibition system sensitivity) were qualified by sex, with only females participants experiencing this increase, and predicted by individual differences in lateral OFC volumes at baseline.

Microstructural Corpus Callosum Anomalies in Children With Prenatal Alcohol Exposure: An Extension of Previous Diffusion Tensor Imaging Findings

BACKGROUND Several studies have now shown corpus callosum abnormalities using diffusion tensor imaging (DTI) in children with fetal alcohol spectrum disorders (FASD) in comparison with nonexposed controls. The data suggest that posterior regions of the callosum may be disproportionately affected. The current study builds on previous efforts, including our own work, and moves beyond midline corpus callosum to probe major inter-hemispheric white matter pathways with an improved DTI tractographic method. This study also expands on our prior work by evaluating a larger sample and by incorporating children with a broader range of clinical effects including full-criteria fetal alcohol syndrome (FAS). METHODS Participants included 33 children with FASD (8 FAS, 23 partial FAS, 2 static encephalopathy) and 19 nonexposed controls between the ages of 10 and 17 years. Participants underwent DTI scans and intelligence testing. Groups (FASD vs. controls) were compared on fractional anisotropy (FA) and mean diffusivity (MD) in 6 white matter tracts projected through the corpus callosum. Exploratory analyses were also conducted examining the relationships between DTI measures in the corpus callosum and measures of intellectual functioning and facial dysmorphology. RESULTS In comparison with the control group, the FASD group had significantly lower FA in 3 posterior tracts of the corpus callosum: the posterior mid-body, the isthmus, and the splenium. A trend-level finding also suggested lower FA in the genu. Measures of white matter integrity and cognition were correlated and suggest some regional specificity, in that only posterior regions of the corpus callosum were associated with visual-perceptual skills. Correlations between measures of facial dysmorphology and posterior regions of the corpus callosum were nonsignificant. CONCLUSIONS Consistent with previous DTI studies, these results suggest that microstructural posterior corpus callosum abnormalities are present in children with prenatal alcohol exposure and cognitive impairment. These abnormalities are clinically relevant because they are associated with cognitive deficits and appear to provide evidence of abnormalities associated with prenatal alcohol exposure independent of dysmorphic features. As such, they may yield important diagnostic and prognostic information not provided by the traditional facial characteristics.

White matter and neurocognitive changes in adults with chronic traumatic brain injury.

Diffusion tensor imaging was used to investigate white matter (WM) integrity in adults with traumatic brain injury (TBI) and healthy adults as controls. Adults with TBI had sustained severe vehicular injuries on the average of 7 years earlier. A multivariate analysis of covariance with verbal IQ as the covariate revealed that adults with TBI had lower fractional anisotropy and higher mean diffusivity than controls, specifically in the three regions of interest (ROIs), the centrum semiovale (CS), the superior frontal (SPF), and the inferior frontal (INF). Adults with TBI averaged in the normal range in motor speed and two of three executive functions and were below average in delayed verbal recall and inhibition, whereas controls were above average. Time since injury, but not age, was associated with WM changes in the SPF ROI, whereas age, but not time since injury, was associated with WM changes in the INF ROI, suggesting that the effects of WM on time since injury may interact with age. To understand the utility of WM changes in chronic recovery, larger sample sizes are needed to investigate associations between cognition and WM integrity of severely injured individuals who have substantial cognitive impairment compared to severely injured individuals with little cognitive impairment. (JINS, 2009, 15, 130-136.).

Effects of alcohol use initiation on brain structure in typically developing adolescents

Abstract Background: Alcohol use in excessive quantities has deleterious effects on brain structure and behavior in adults and during periods of rapid neurodevelopment, such as prenatally. Whether similar outcomes characterize other developmental periods, such as adolescence, and in the context of less extensive use is unknown. Recent cross-sectional studies suggest that binge drinking as well as alcohol use disorders in adolescence are associated with disruptions in white matter microstructure and gray matter volumes. Objectives: The current study followed typically developing adolescents from a baseline assessment, where no experience with alcohol was present, through two years, after which some individuals transitioned into regular use. Methods: Participants (n = 55) completed MRI scans and behavioral assessments. Results: Alcohol initiators (n = 30; mean baseline age 16.7 ± 1.3 years), compared to non-users (n = 25; mean baseline age 17.1 ± 1.2 years), showed altered patterns of neurodevelopment. They showed greater-than-expected decreases in cortical thickness in the right middle frontal gyrus from baseline to follow-up as well as blunted development of white matter in the right hemisphere precentral gyrus, lingual gyrus, middle temporal gyrus and anterior cingulate. Diffusion tensor imaging revealed a relative decrease over time in fractional anisotropy in the left caudate/thalamic region as well as in the right inferior frontal occipital fasciculus. Alcohol initiators did not differ from non-users at the baseline assessment; the groups were largely similar in other premorbid characteristics. Conclusions: Subclinical alcohol use during mid-to-late adolescence is associated with deviations in neurodevelopment across several brain tissue classes. Implications for continued development and behavior are discussed.

High Connectivity Between Reduced Cortical Thickness and Disrupted White Matter Tracts in Long-Standing Type 1 Diabetes

OBJECTIVE Previous studies have observed disruptions in brain white and gray matter structure in individuals with type 1 diabetes, and these structural differences have been associated with neurocognitive testing deficiencies. This study investigated the relationship between cerebral cortical thickness reductions and white matter microstructural integrity loss in a group of patients with type 1 diabetes and in healthy control subjects using diffusion tensor imaging (DTI). RESEARCH DESIGN AND METHODS Twenty-five subjects with type 1 diabetes for at least 15 years and 25 age- and sex-matched control subjects underwent structural T1 and proton-density and DTI on a 3.0 Tesla scanner. Fractional anisotropy measurements were made on major cerebral white matter tracts, and DTI tractography was performed to identify cortical regions with high connectivity to these tracts. RESULTS Posterior white matter tracts with reduced fractional anisotropy (optic radiations, posterior corona radiata, and the splenium region of the corpus callosum) were found to have high connectivity with a number of posterior cortical regions, including the cuneus, precuneus, fusiform, and posterior parietal cortical regions. A significant reduction in cortical thickness in the diabetic group was observed in the regions with high connectivity to the optic radiations and posterior corona radiata tracts (P < 0.05). CONCLUSIONS The direct relationship between white and gray matter structural pathology has not been previously demonstrated in subjects with long-standing type 1 diabetes. The relationship between posterior white matter microstructural integrity disruption and lower cortical thickness demonstrated using a novel DTI connectivity technique suggests a common or interrelated pathophysiological mechanism in type 1 diabetes.

Associations between cortical thickness and verbal fluency in childhood, adolescence, and young adulthood

Neuroimaging studies of normative human brain development indicate that the brain matures at differing rates across time and brain regions, with some areas maturing into young adulthood. In particular, changes in cortical thickness may index maturational progressions from an overabundance of neuropil toward efficiently pruned neural networks. Developmental changes in structural MRI measures have rarely been examined in relation to discrete neuropsychological functions. In this study, healthy right-handed adolescents completed MRI scanning and the Controlled Oral Word Association Test (COWAT). Associations of task performance and cortical thickness were assessed with cortical-surface-based analyses. Significant correlations between increasing COWAT performances and decreasing cortical thickness were found in left hemisphere language regions, including perisylvian regions surrounding Wernickes and Brocas areas. Task performance was also correlated with regions associated with effortful verbal processing, working memory, and performance monitoring. Structure-function associations were not significantly different between older and younger subjects. Decreases in cortical thicknesses in regions that comprise the language network likely reflect maturation toward adult-like cortical organization and processing efficiency. The changes in cortical thicknesses that support verbal fluency are apparent by middle childhood, but with regionally separate developmental trajectories for males and females, consistent with other studies of adolescent development.

Global Functional Connectivity Abnormalities in Children with Fetal Alcohol Spectrum Disorders

BACKGROUND Previous studies, including those employing diffusion tensor imaging (DTI), have revealed significant disturbances in the white matter of individuals with fetal alcohol spectrum disorders (FASD). Both macrostructural and microstructural abnormalities have been observed across levels of FASD severity. Emerging evidence suggests that these white matter abnormalities are associated with functional deficits. This study used resting-state functional MRI (fMRI) to evaluate the status of network functional connectivity in children with FASD compared with control subjects. METHODS Participants included 24 children with FASD, ages 10 to 17, and 31 matched controls. Neurocognitive tests were administered including Wechsler Intelligence Scales, California Verbal Learning Test (CVLT), and Behavior Rating Inventory of Executive Functioning. High-resolution anatomical MRI data and 6-minute resting-state fMRI data were collected. The resting-state fMRI data were subjected to a graph theory analysis, and 4 global measures of cortical network connectivity were computed: characteristic path length, mean clustering coefficient, local efficiency, and global efficiency. RESULTS Results revealed significantly altered network connectivity in those with FASD. The characteristic path length was 3.1% higher (p = 0.04, Cohens d = 0.47), and global efficiency was 1.9% lower (p = 0.04, d = 0.63) in children with FASD compared with controls, suggesting decreased network capacity that may have implications for integrative cognitive functioning. Global efficiency was significantly positively correlated with cortical thickness in frontal (r = 0.38, p = 0.005), temporal (r = 0.28, p = 0.043), and parietal (r = 0.36, p = 0.008) regions. No relationship between facial dysmorphology and functional connectivity was observed. Exploratory correlations suggested that global efficiency and characteristic path length are associated with capacity for immediate verbal memory on the CVLT (r = 0.41, p = 0.05 and r = 0.41, p = 0.01, respectively) among those with FASD. CONCLUSIONS Resting-state functional connectivity measures provide new insight into the integrity of brain networks in clinical populations such as FASD. Results demonstrate that children with FASD have alterations in core components of network function and that these aspects of brain integrity are related to measures of structure and cognitive functioning.