Targeting the Manifestations of Subclinical and Overt Hypothyroidism Within the Hippocampus.

BACKGROUND: The past decade has witnessed a surge of articles describing the neurocognitive sequelae and associated structural and functional brain abnormalities of patients with overt (OH) and subclinical hypothyroidism (SCH). Findings show effects primarily within the frontal lobes with usually worse outcomes for OH than SCH. Several recent studies have also indicated hypothyroid patients may have smaller hippocampi, a key structure for memory. CONTEXT: The current JCEM paper by T. Zhang and colleagues applies two novel approaches for analyzing hippocampal structure and function. One uses an automated processing tool that segments the hippocampus into distinct subregions and the other, performs connectivity analysis to assess the relationships between specific hippocampal subregions and cortical areas. Relatively large samples of OH and SCH patients and healthy controls received a test of global cognitive functioning and structural and functional MRIs. Results showed hypothyroid groups scored significantly below controls on the memory scale and also had smaller hippocampal volumes in selective subregions. Effects were stronger for SCH than OH groups, who also showed different patterns of interconnectivity between hippocampal subregions and specific frontal-lobe areas. INTERPRETATION: To make sense of these findings, I explored the rodent and human literatures on thyroid hormone's role in hippocampal functioning and on hippocampal subfields and their purported functions and interconnections. Because current results suggest SCH may represent a distinct clinical entity with unique brain manifestations, I hypothesized two explanations for these findings, one involving transporter defects in the brain barriers and the other, differential neurodegeneration of the blood-brain-barrier vascular unit.

Growth Hormone Supplementation and Psychosocial Functioning to Adult Height in Turner Syndrome: A Questionnaire Study of Participants in the Canadian Randomized Trial.

Despite the long-held belief that growth hormone supplementation provides psychosocial benefits to patients with Turner syndrome (TS), this assumption has never been rigorously tested in a randomized control trial. As a sub-study of the Canadian growth-hormone trial, parent-, and patient-completed standardized questionnaires were used to compare 70 girls with TS who received injections (GH group) and 61 similarly followed untreated TS controls (C) on multiple facets of psychosocial functioning. Questionnaires were given (i) at baseline (session 1, mean age = 10.4 y), (ii) before estrogen therapy for puberty induction (session 2, mean age = 13.0 y), (iii) after 1 year of estrogen therapy (session 3, mean age = 14.4 y), and (iv) when growth stopped (session 4, mean age = 16.3 y). Groups were compared for multiple facets of psychosocial function within social, behavioral, self-esteem, and academic domains. Results were also correlated with indices of adult height. We found no global (i.e., across-session) group differences on any scales or subscales of the four domains. In both GH and C groups, age-related improvements were seen for social problems, externalizing behavior problems, and school functioning and age-related declines for social competence and social relations. Both parents and patients claimed GH received less teasing than C but C had more friends than GH. Results from analyses conducted within individual sessions showed that while GH at early sessions claimed to be more popular, more socially engaged, better adapted, and to have higher self-esteem than C, C was reported to be less anxious, depressed, and withdrawn than GH at adult height. The correlation analyses revealed different effects of adult height and height gain on outcome for the two groups. In GH, both height parameters were correlated with multiple parent- and/or self-reported indices from the four psychosocial domains, whereas in C, only adult height and two indices (viz., total self-concept and school functioning), were correlated. The observed modest gains in psychosocial functioning for patients with TS treated with GH highlight the need for alternative approaches to assist them in coping with the challenges of their condition.

Everyday memory difficulties in children and adolescents with Fetal Alcohol Spectrum Disorder.

Purpose: To investigate whether significant differences exist in everyday memory between youth with Fetal Alcohol Spectrum (FASD) compared with a nonexposed (NE) control group, while controlling for socioeconomic status and other comorbidities. Methods: Caregiver ratings using the Everyday Memory Questionnaire were obtained for 105 youth (9-17 years of age). Scores were compared between youth with a FASD diagnosis (N = 41; 56% male) and the NE group (N = 64; 53% male) using multivariate analysis of variance. Results: Significantly poorer scores were found across all domains of everyday memory in youth with FASD (p<0.01 for all comparisons). Findings maintained significance after controlling for group differences in socioeconomic status, presence of learning, and attention disorders, as well as exposure to other teratogens. Conclusions: This study provides important insights regarding the memory issues that underlie daily functional challenges faced by youth with FASD and the need for future intervention research.

Preliminary Findings that a Targeted Intervention Leads to Altered Brain Function in Children with Fetal Alcohol Spectrum Disorder.

Children with fetal alcohol spectrum disorder (FASD) exhibit behavioral dysregulation, executive dysfunction, and atypical function in associated brain regions. Previous research shows early intervention mitigates these outcomes but corresponding brain changes were not studied. Given the Alert® Program for Self-Regulation improves behavioral regulation and executive function in children with FASD, we asked if this therapy also improves their neural functioning in associated regions. Twenty-one children with FASD aged 8-12 years were randomized to the Alert®-treatment (TXT; n = 10) or waitlist-control (WL; n = 11) conditions. They were assessed with a Go-NoGo functional magnetic resonance imaging (fMRI) paradigm before and after training or the wait-out period. Groups initially performed equivalently and showed no fMRI differences. At post-test, TXT outperformed WL on NoGo trials while fMRI in uncorrected results with a small-volume correction showed less activation in prefrontal, temporal, and cingulate regions. Groups also demonstrated different patterns of change over time reflecting reduced signal at post-test in selective prefrontal and parietal regions in TXT and increased in WL. In light of previous evidence indicating TXT at post-test perform similar to non-exposed children on the Go-NoGo fMRI paradigm, our findings suggest Alert® does improve functional integrity in the neural circuitry for behavioral regulation in children with FASD.

Neurodevelopmental profile of Fetal Alcohol Spectrum Disorder: A systematic review.

BACKGROUND: In an effort to improve the screening and diagnosis of individuals with Fetal Alcohol Spectrum Disorder (FASD), research has focused on the identification of a unique neurodevelopmental profile characteristic of this population. The objective of this review was to identify any existing neurodevelopmental profiles of FASD and review their classification function in order to identify gaps and limitations of the current literature. METHODS: A systematic search for studies published up to the end of December 2016 reporting an identified neurodevelopmental profile of FASD was conducted using multiple electronic bibliographic databases. The search was not limited geographically or by language of publication. Original research published in a peer-reviewed journal that involved the evaluation of the classification function of an identified neurodevelopmental profile of FASD was included. RESULTS: Two approaches have been taken to determine the pathognomonic neurodevelopmental features of FASD, namely the utilization of i) behavioral observations/ratings by parents/caregivers and ii) subtest scores from standardized test batteries assessing a variety of neurodevelopmental domains. Both approaches show some promise, with the former approach (which is dominated by research on the Neurobehavioral Screening Tool) having good sensitivity (63% to 98%), but varying specificity (42% to 100%), and the latter approach having good specificity (72% to 96%), but varying sensitivity (60% to 88%). CONCLUSIONS: The current review revealed that research in this area remains limited and a definitive neurodevelopmental profile of FASD has not been established. However, the identification of a neurodevelopmental profile will aid in the accurate identification of individuals with FASD, by adding to the armamentarium of clinicians. The full review protocol is available in PROSPERO ( http://www.crd.york.ac.uk/PROSPERO/ ); registration number CRD42016039326; registered 20 May 2016.

[Formula: see text]Dorsal and ventral visual streams: Typical and atypical development.

The literature on visuospatial processing describes two distinct pathways within the brain: a dorsal route extending from the visual cortex into the parietal lobes that is critical for spatial processing and a ventral route extending from the visual cortex into the temporal lobes that is critical for form perception. These visual streams appear to differ in their developmental trajectories and their vulnerabilities to diverse neurodevelopmental conditions. The present work aims to investigate development and vulnerability in two aspects of dorsal and ventral visual-stream function, namely attention to location and attention to identity. In Study 1, we compare typically-developing (TD) youth aged 9 to 16 years with young adults aged 18 to 22 years on computerized location and identity tasks. In Study 2, we compare children and adolescents who have congenital hypothyroidism (CH), a pediatric endocrine disorder, with age-matched TD controls on the same tasks. The results from Study 1 show that the youths were less accurate than the adults at judging identity, whereas both groups were equally accurate at judging location. The results from Study 2 show that the youths with CH were slower but not less accurate than the TD youths in making both identity and location judgments. The results are interpreted as signifying later development of ventral (identity) stream functions compared to dorsal (location) but equal vulnerability of both functions in CH.

[Formula: see text]Social perception in children with fetal alcohol spectrum disorder.

Although the profile of social cognitive difficulties is well recognized in children with certain neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), this profile is not as well established in other clinical pediatric populations. The objective of the present study is to examine patterns of social perception in children with fetal alcohol spectrum disorder (FASD) compared to typically-developing (TD) control children. A total of 56 children between 8 and 12 years of age-35 with FASD and 21 TD-completed the Reading the Mind in the Eyes Task - Children's Version (RMET-C). The RMET-C accuracy scores were compared between groups and also by item difficulty and emotional valence. The relation between cognitive functioning, age, FASD severity, and RMET-C performance was also investigated. The children in the FASD group did not perform as well as the children in the TD group on the RMET-C Total score and Easy items, as well as the Positive, Negative, and Neutral emotional valence items. When age and IQ were investigated, there was a significant effect of age on the Positive items in the TD group, with scores increasing with age. With regard to FASD severity, children with alcohol-related neurodevelopmental disorder were outperformed by children with full/partial fetal alcohol syndrome on the Positive and Negative items. Overall, these results further the understanding of the social cognitive profile in children with FASD and how this profile relates to other childhood-onset neurodevelopmental disorders.

Preliminary Findings Show Maternal Hypothyroidism May Contribute to Abnormal Cortical Morphology in Offspring.

In rodents, insufficient thyroid hormone (TH) gestationally has adverse effects on cerebral cortex development. Comparable studies of humans examining how TH insufficiency affects cortical morphology are limited to children with congenital hypothyroidism or offspring of hypothyroxinemic women; effects on cortex of children born to women with clinically diagnosed hypothyroidism are not known. We studied archived MRI scans from 22 children aged 10-12 years born to women treated for preexisting or de novo hypothyroidism in pregnancy (HYPO) and 24 similar age and sex controls from euthyroid women. FreeSurfer Image Analysis Suite software was used to measure cortical thickness (CT) and a vertex-based approach served to compare HYPO versus control groups and Severe versus Mild HYPO subgroups as well as to perform regression analyses examining effects of trimester-specific maternal TSH on CT. Results showed that relative to controls, HYPO had multiple regions of both cortical thinning and thickening, which differed for left and right hemispheres. In HYPO, thinning was confined to medial and mid-lateral regions of each hemisphere and thickening to superior regions (primarily frontal) of the left hemisphere and inferior regions (particularly occipital and temporal) of the right. The Severe HYPO subgroup showed more thinning than Mild in frontal and temporal regions and more thickening in bilateral posterior and frontal regions. Maternal TSH values predicted degree of thinning and thickening within multiple brain regions, with the pattern and direction of correlations differing by trimester. Notably, some correlations remained when cases born to women with severe hypothyroidism were removed from the analyses, suggesting that mild variations of maternal TH may permanently affect offspring cortex. We conclude that maternal hypothyroidism during pregnancy has long-lasting manifestations on the cortical morphology of their offspring with specific effects reflecting both severity and timing of maternal TH insufficiency.

Hippocampal Functioning and Verbal Associative Memory in Adolescents with Congenital Hypothyroidism.

Thyroid hormone (TH) is essential for normal development of the hippocampus, which is critical for memory and particularly for learning and recalling associations between visual and verbal stimuli. Adolescents with congenital hypothyroidism (CH), who lack TH in late gestation and early life, demonstrate weak verbal recall abilities, reduced hippocampal volumes, and abnormal hippocampal functioning for visually associated material. However, it is not known if their hippocampus functions abnormally when remembering verbal associations. Our objective was to assess hippocampal functioning in CH using functional magnetic resonance imaging (fMRI). Fourteen adolescents with CH and 14 typically developing controls (TDC) were studied. Participants studied pairs of words and then, during fMRI acquisition, made two types of recognition decisions: in one they judged whether the pairs were the same as when seen originally and in the other, whether individual words were seen before regardless of pairing. Hippocampal activation was greater for pairs than items in both groups, but this difference was only significant in TDC. When we directly compared the groups, the right anterior hippocampus was the primary region in which the TDC and CH groups differed for this pair memory effect. Results signify that adolescents with CH show abnormal hippocampal functioning during verbal memory processing.

Social Perspective Taking and Empathy in Children with Fetal Alcohol Spectrum Disorders.

Children with fetal alcohol spectrum disorders (FASD) show sociobehavioral impairments; however, the social cognitive profile contributing to these impairments is poorly understood. This study compared social perspective taking and empathy in children with FASD versus typically developing controls (TDC). Thirty-seven children with FASD and 21 TDC participated. Measures included parent-rated CBCL and SSIS, and NEPSY-II Theory of Mind, Test of Social Cognition and Index of Empathy. Parents rated the FASD group higher than TDC on indices of behavior problems and lower on indices of social skills and empathy. Children with FASD scored significantly below TDC on tasks requiring complex social cognition. The majority of correlations between social cognition and parent-ratings were not significant in FASD and TDC, with the exception of a negative correlation between self-reported empathy and parent-rated behavior difficulties in TDC. FASD subgroup analyses revealed lower theory of mind and empathy scores among children with ARND than pFAS/FAS. With regard to sex, males with FASD were rated as having more behavior difficulties than females, whereas TDC females obtained higher empathy ratings than males. In both groups, females scored higher on theory of mind and empathy indices. On theory of mind tasks, older children with FASD performed below younger, whereas younger TDC children performed more poorly than older. Children with FASD show reduced functioning on indices of sociobehavioral and social cognition, and the effects are influenced by sex and age. These findings provide insight into the clinical and social profile of children with FASD.

Neurodevelopment of children prenatally exposed to selective reuptake inhibitor antidepressants: Toronto sibling study.

BACKGROUND: The reproductive safety of selective reuptake inhibitor (SRI) antidepressants needs to be established to provide optimal control of maternal depression while protecting the fetus. OBJECTIVE: To define a child's neurodevelopment following prenatal exposure to SRIs and to account for genetic and environmental confounders in a sibling design using the Toronto Motherisk prospective database. METHOD: Intelligence and behavior of siblings prenatally exposed and unexposed to SRIs were assessed by using the Wechsler Preschool and Primary Scale of Intelligence-Third Edition, Child Behavior Checklist, and Conners Parent Rating Scale-Revised and subsequently compared. Mothers, diagnosed with depression using DSM-IV, were assessed for intelligence quotient (IQ) and for severity of depressive symptoms with the Center for Epidemiologic Studies Depression scale. Prenatal drug doses and durations of exposure, child's age, child's sex, birth order, severity of maternal depression symptoms, and Full Scale IQ, the primary outcome measure, of both the mother and the child were considered in the analyses. RESULTS: Forty-five sibling pairs (ages 3 years to 6 years 11 months, prenatally exposed and unexposed to SRIs) did not differ in their mean ± SD Full Scale IQs (103 ± 13 vs 106 ± 12; P = .30; 95% CI, -7.06 to 2.21) or rates of problematic behaviors. Significant predictor of children's intelligence was maternal IQ (P = .043, ß = 0.306). Severity of maternal depression was a significant predictor of Child Behavior Checklist Internalizing (P = .019, ß = 0.366), Externalizing (P = .003, ß = 0.457), and Total scores (P = .001, ß = 0.494). Drug doses and durations of exposure during pregnancy did not predict any outcomes of interest in the exposed siblings. CONCLUSIONS: SRI antidepressants were not found to be neurotoxic. Maternal depression may risk the child's future psychopathology. The sibling design in behavioral teratology aids in separating the effects of maternal depression from those of SRIs, providing stronger evidence in clinical decision-making.

Do children with congenital hypothyroidism exhibit abnormal cortical morphology?

BACKGROUND: Given thyroid hormone (TH)'s essential role in multiple aspects of early brain development, children with congenital hypothyroidism (CH) detected and treated early may still display subtle cognitive and behavioral impairments as well as brain abnormalities. However, effects on their cortical development are not yet known. We used an automated neuroimaging technique to determine if these children differ in cortical thickness (CT) from typically developing controls (TDC) and if the regions showing CT differences reflect severity of initial hypothyroidism and predict later neuropsychological functioning. METHODS: FreeSurfer Image Analysis Suite was used on archived MRI scans from 41 CH and 42 TDC children aged 9-16 y. Vertex-based procedures were used to compare groups and perform correlations between CT and indices of disease severity and neuropsychological outcome. RESULTS: The CH group showed multiple regions of cortical thinning or cortical thickening within right and left hemispheres relative to TDC. CT values were significantly correlated with early T4 and thyroid-stimulating hormone (TSH) levels and current neuropsychological test indices. CONCLUSION: The developing cortex is sensitive to early TH loss in CH. Different patterns of cortical thinning or cortical thickening among brain regions may reflect timing of TH deficiency relative to timing of cortical development.

Self-regulation therapy increases frontal gray matter in children with fetal alcohol spectrum disorder: evaluation by voxel-based morphometry.

Children with fetal alcohol spectrum disorder show executive function (EF) deficits, particularly in self-regulation skills, and abnormalities in brain regions critical for these skills. None of the validated EF interventions for these children has been evaluated with regards to impacts on brain structure. Twenty-nine children with FASD were assigned to either an immediate-treatment (TX) or delayed-treatment control (DTC) group (DTC). Nineteen typically developing children served as healthy controls (CT). All received a structural MRI scan and baseline neuropsychological testing, following which the TX group underwent 12 weekly 1.5-h sessions of the Alert Program for Self-Regulation(®). After treatment or a period of ~14 weeks, all received a repeat scan and post-intervention testing. Whole-brain and region-of-interest analyses using voxel-based morphometry evaluated group differences and changes over time in gray matter (GM). Exploratory analyses revealed significant group changes: (1) At baseline, combined TX and DTC groups demonstrated global GM reductions compared with the CT group. (2) Region-of-interest analysis using a frontal mask, comparing post-intervention to pre-intervention results, showed significantly increased GM in the left middle frontal gyrus (BA10), right frontal pole (BA11), and right anterior cingulate (BA32) in the TX group. Similar results were not found in the DTC or CT groups. (3) At post-intervention, both TX and CT groups showed larger GM volumes than the DTC group in the left superior frontal gyrus (BA9), which was smaller in the FASD group at baseline. These results suggested that Alert led to improvements in post-intervention testing of self-regulation skills and typical brain development in treated children.

Children born to women treated for hypothyroidism during pregnancy show abnormal corpus callosum development.

BACKGROUND: Thyroid hormone (TH) is essential for the developing brain, and because the fetal thyroid develops relatively late in gestation, the maternal TH supply is critical for fetal brain development. However, if the mother has hypothyroidism during pregnancy, fetal brain and neuropsychological development may be compromised. Rodents experiencing maternal TH insufficiency show abnormal corpus callosum (CC) morphology, but it is not known if children born to women treated for hypothyroidism (HYPO) show similar effects. The purpose of the current study was to investigate HYPO for CC morphology and morphometry and to determine whether any specific CC abnormalities were associated aspects of maternal hypothyroidism and were correlated with reduced neuropsychological functioning in the children. METHODS: ANALYZE software was used to trace CCs in archived magnetic resonance imaging scans from 22 HYPO and 22 matched controls. Areas of two sub-regions and six segments and different shape metrics (angles, lengths, ratios) were determined. CC parameters were correlated with maternal thyrotropin (TSH) values and number of hypothyroid trimesters as well as the child's neuropsychological test performance. RESULTS: HYPO showed a smaller anterior CC and genu and larger posterior CC and splenium areas than controls as well as shape abnormalities in genu and splenium. Results were correlated with the duration of maternal hypothyroidism. Executive function skills were positively associated with genu size in HYPO, while verbal comprehension skills were negatively associated with splenium and overall posterior CC sizes. CONCLUSIONS: Maternal hypothyroidism contributes to CC abnormalities in the offspring, and effects differ for anterior versus posterior CC regions.

Spatial function in adolescents and young adults with congenital adrenal hyperplasia: clinical phenotype and implications for the androgen hypothesis.

Females with the classic form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are said to perform better than unaffected female controls on tests of mental rotation or other visuospatial abilities, but findings are conflicting. We studied 31 adolescents and young adults with CAH and 19 unaffected sibling controls, who were given standardized spatial tests and tests of other sexually differentiated cognitive functions (verbal fluency, perceptual speed). The possible role of CAH subtype (salt-wasting or simple-virilizing) was evaluated. Only females with the more severe, salt-wasting form of CAH, but not females with the simple-virilizing form, performed significantly better than sex-matched sibling controls on measures of mental rotation. Subtype differences were not significant for verbal fluency or perceptual speed. Severity of prenatal genital virilization, but not postnatal age when medication was started, predicted accuracy on the Mental Rotations Test. Results are consistent with the possibility of an organizational effect of androgens in the central nervous system that impacts the development of spatial abilities. Implications for the timing of the hypothetical critical period are discussed.

Improving executive functioning in children with fetal alcohol spectrum disorders.

An extensive body of literature has documented executive function (EF) impairments in children with fetal alcohol spectrum disorders (FASD); however, few studies have aimed specifically at improving EF. One treatment program that shows promise for children with FASD is the Alert Program for Self-Regulation®, which is a 12-week treatment specifically designed to target self-regulation, a component of EF. The present study sought to examine if Alert would produce improvements in self-regulation that would generalize to other aspects of EF, behavior, and social skills in children with FASD. Twenty-five children aged 8-12 years diagnosed with an FASD were assigned in alternating sequence to either an immediate treatment (TXT) or a delayed treatment control (DTC) group. Both groups received a comprehensive evaluation of EF at baseline and upon completing therapy (TXT), or after a 12- to 14-week interval from baseline (DTC). Parents also completed questionnaires assessing EF and behavior at both time points. For the TXT group only, parent questionnaires were readministered at 6-month follow-up. At the 12-week follow-up, the TXT group displayed significant improvements in inhibitory control and social cognition. Parents of children in the TXT group reported improved behavioral and emotional regulation, as well as reduced externalizing behavior problems. These behavioral improvements along with further improved parent-rated inhibitory control was maintained at the 6-month follow-up. The EF disabilities in children with FASD can be remediated through a targeted treatment approach aimed at facilitating self-regulation skills.

The role of thyroid hormones for brain development and cognitive function.

Through its actions on regulatory genes that form, grow and sculpt the brain, thyroid hormone (TH) is essential for human brain development. Although much of what we know about these effects is based on research with rodents, recent studies of children exposed to TH insufficiencies during critical stages of early development provide preliminary evidence on how and when the human brain needs TH. This paper reviews some of the major studies from both the rodent research and research on offspring of women with hypothyroidism during pregnancy and children with congenital hypothyroidism (CH) who were assessed using neuropsychological tests and with advanced neuroimaging techniques. The final section will compare findings from children lacking TH due to maternal hypothyroidism and CH conditions, whose loss of TH at different times represents unique time windows for examining TH effects in the human brain.