Volumetric grey matter alterations in adolescents and adults born very preterm suggest accelerated brain maturation.

Previous research investigating structural neurodevelopmental alterations in individuals who were born very preterm demonstrated a complex pattern of grey matter changes that defy straightforward summary. Here we addressed this problem by characterising volumetric brain alterations in individuals who were born very preterm from adolescence to adulthood at three hierarchically related levels - global, modular and regional. We demarcated structural components that were either particularly resilient or vulnerable to the impact of very preterm birth. We showed that individuals who were born very preterm had smaller global grey matter volume compared to controls, with subcortical and medial temporal regions being particularly affected. Conversely, frontal and lateral parieto-temporal cortices were relatively resilient to the effects of very preterm birth, possibly indicating compensatory mechanisms. Exploratory analyses supported this hypothesis by showing a stronger association between lateral parieto-temporal volume and IQ in the very preterm group compared to controls. We then related these alterations to brain maturation processes. Very preterm individuals exhibited a higher maturation index compared to controls, indicating accelerated brain maturation and this was specifically associated with younger gestational age. We discuss how the findings of accelerated maturation might be reconciled with evidence of delayed maturation at earlier stages of development.

A multimodal imaging study of recognition memory in very preterm born adults.

Very preterm (<32 weeks of gestation) birth is associated with structural brain alterations and memory impairments throughout childhood and adolescence. Here, we used functional MRI (fMRI) to study the neuroanatomy of recognition memory in 49 very preterm-born adults and 50 controls (mean age: 30 years) during completion of a task involving visual encoding and recognition of abstract pictures. T1-weighted and diffusion-weighted images were also collected. Bilateral hippocampal volumes were calculated and tractography of the fornix and cingulum was performed and assessed in terms of volume and hindrance modulated orientational anisotropy (HMOA). Online recognition memory task performance, assessed with A scores, was poorer in the very preterm compared with the control group. Analysis of fMRI data focused on differences in neural activity between the recognition and encoding trials. Very preterm born adults showed decreased activation in the right middle frontal gyrus and posterior cingulate cortex/precuneus and increased activation in the left inferior frontal gyrus and bilateral lateral occipital cortex (LOC) compared with controls. Hippocampi, fornix and cingulum volume was significantly smaller and fornix HMOA was lower in very preterm adults. Among all the structural and functional brain metrics that showed statistically significant group differences, LOC activation was the best predictor of online task performance (P = 0.020). In terms of association between brain function and structure, LOC activation was predicted by fornix HMOA in the preterm group only (P = 0.020). These results suggest that neuroanatomical alterations in very preterm born individuals may be underlying their poorer recognition memory performance. Hum Brain Mapp 38:644-655, 2017. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Real-Life Impact of Executive Function Impairments in Adults Who Were Born Very Preterm.

OBJECTIVES: Children and adolescents who were born very preterm (≤32 weeks' gestation) are vulnerable to experiencing cognitive problems, including in executive function. However, it remains to be established whether cognitive deficits are evident in adulthood and whether these exert a significant effect on an individual's real-lifeachievement. METHODS: Using a cross-sectional design, we tested a range of neurocognitive abilities, with a focus on executive function, in a sample of 122 very preterm individuals and 89 term-born controls born between 1979 and 1984. Associations between executive function and a range of achievement measures, indicative of a successful transition to adulthood, were examined. RESULTS: Very preterm adults performed worse compared to controls on measures of intellectual ability and executive function with moderate to large effect sizes. They also demonstrated significantly lower achievement levels in terms of years spent in education, employment status, and on a measure of functioning in work and social domains. Results of regression analysis indicated a stronger positive association between executive function and real-life achievement in the very preterm group compared to controls. CONCLUSIONS: Very preterm born adults demonstrate executive function impairments compared to full-term controls, and these are associated with lower achievement in several real-life domains. (JINS, 2017, 23, 381-389).

In vivo translocator protein in females with autism spectrum disorder: a pilot study.

Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [11C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [11C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [11C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [11C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [11C]PBR28 SUVR across time in both groups. Elevated regional [11C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [11C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.

Epigenetics of Autism Spectrum Disorder: Histone Deacetylases.

The etiology of autism spectrum disorder (ASD) remains unknown, but gene-environment interactions, mediated through epigenetic mechanisms, are thought to be a key contributing factor. Prenatal environmental factors have been shown to be associated with both increased risk of ASD and altered histone deacetylases (HDACs) or acetylation levels. The relationship between epigenetic changes and gene expression in ASD suggests that alterations in histone acetylation, which lead to changes in gene transcription, may play a key role in ASD. Alterations in the acetylome have been demonstrated for several genes in ASD, including genes involved in synaptic function, neuronal excitability, and immune responses, which are mechanisms previously implicated in ASD. We review preclinical and clinical studies that investigated HDACs and autism-associated behaviors and discuss risk genes for ASD that code for proteins associated with HDACs. HDACs are also implicated in neurodevelopmental disorders with a known genetic etiology, such as 15q11-q13 duplication and Phelan-McDermid syndrome, which share clinical features and diagnostic comorbidities (e.g., epilepsy, anxiety, and intellectual disability) with ASD. Furthermore, we highlight factors that affect the behavioral phenotype of acetylome changes, including sensitive developmental periods and brain region specificity in the context of epigenetic programming.

Spatial gradients of healthy aging: a study of myelin-sensitive maps.

Protracted development of a brain network may entail greater susceptibility to aging decline, supported by evidence of an earlier onset of age-related changes in late-maturing anterior areas, that is, an anterior-to-posterior gradient of brain aging. Here we analyzed the spatiotemporal features of age-related differences in myelin content across the human brain indexed by magnetization transfer (MT) concentration in a cross-sectional cohort of healthy adults. We described age-related spatial gradients in MT, which may reflect the reversal of patterns observed in development. We confirmed an anterior-to-posterior gradient of age-related MT decrease and also showed a lateral-to-ventral gradient inversely mirroring the sequence of connectivity development and myelination. MT concentration in the lateral white matter regions continued to increase up to the age of 45 years and decreased moderately following a peak. In contrast, ventral white matter regions reflected life-long stable MT concentration levels, followed by a rapid decrease at a later age. We discussed our findings in relation with existing theories of brain aging, including the lack of support for the proposal that areas which mature later decline at an accelerated rate.

Verbal Fluency Is Affected by Altered Brain Lateralization in Adults Who Were Born Very Preterm.

Language difficulties have been reported in children and adolescents who were born very preterm (<32 weeks' gestation) and associated with an atypical lateralization of language processing, i.e., increased right-hemispheric engagement. This study used functional magnetic resonance imaging (fMRI) and spherical deconvolution tractography to study the hemodynamic responses associated with verbal fluency processing (easy and hard letter trials) and verbal fluency-related white matter fiber tracts in 64 very preterm born adults and 36 adult controls (mean age: 30 years). Tractography of the arcuate fasciculus (AF) and frontal aslant tract (FAT) was performed. Tracts were quantified in terms of mean volume, hindrance modulated orientational anisotropy, and lateralization, assessed using a laterality index (LI) to indicate hemispheric dominance. During verbal fluency fMRI, very preterm participants displayed decreased hemodynamic response suppression in both the Easy > Rest and Hard > Rest conditions, compared to controls, in superior temporal gyrus (STG), insula, thalamus, and sensorimotor cortex, particularly in the right hemisphere. At the whole-group level, decreased hemodynamic response suppression in the right sensorimotor cortex was associated with worse on-line performance on the hard letter trials. Increased left-laterality in the AF was present alongside increased right hemispheric hemodynamic response suppression in controls. When only right-handed participants were considered, decreased hemodynamic response suppression in the right STG during hard letter trials was related to weaker left and right FAT white matter integrity in the preterm group only. These results show that verbal fluency is affected by altered functional lateralization in adults who were born very preterm.

Altered cortical structures and tract integrity of the mirror neuron system in association with symptoms of schizophrenia.

The mirror neuron system (MNS) may be implicated in schizophrenia. This study investigated MNS structures, including the pars opercularis (Pop), the supramarginal gyrus (SMg), the third branch of the superior longitudinal fasciculus, and callosal fibers interconnecting bilateral Pop (CC-Pop) and SMg (CC-SMg), and clarified their relationships with positive and negative symptoms of schizophrenia. Participants comprised 32 schizophrenia patients and 32 matched controls who received T1-weighted structural magnetic resonance imaging (MRI, T1WI) and diffusion spectrum imaging (DSI). The cortical measures were computed from the T1WI data. Tract integrity was assessed using a tractography-based analysis of the generalized fractional anisotropy (GFA) derived from the DSI data. Pearson׳s correlations and multiple linear regression analysis were used to investigate the associations between MNS structures and positive and negative symptom scores of schizophrenia. Cortical thickness in bilateral Pop and SMg were significantly thinner and mean GFA of CC-Pop was significantly decreased in patients. Negative symptoms were significantly correlated with left SMg volume, and positive symptoms were significantly correlated with right SMg thickness. Multiple linear regression analysis showed left SMg volume to be the strongest contributor to the negative symptoms. The association between left SMg volume and negative symptoms may reflect the degree of social cognition impairment in schizophrenia.