Age-related grey matter volume correlates of response inhibition and shifting in Attention Deficit Hyperactivity Disorder

Background Children with attention-deficit hyperactivity disorder (ADHD) have difficulties with executive function and impulse control which may improve with age. Aims To map the brain correlates of executive function in ADHD and determine age-related changes in reaction times and brain volumes. Method Attention-deficit hyperactivity disorder and control groups were compared on the change task measures of response inhibition (stop signal reaction time, SSRT) and shifting (change response reaction time, CRRT). voxel-wise magnetic resonance imaging (MRI) correlations of reaction times and grey matter volume were determined, along with bivariate correlations of reaction times, brain volumes and age.Results Individuals in the ADHD group had longer SSRTs and CRRTs. Anterior cingulate, striatal and medial temporal volumes highly correlated with SSRT. Striatal and cerebellar volumes strongly correlated with CRRT. Older children had faster reaction times and larger regional brain volumes. In controls, orbitofrontal, medial temporal and cerebellar volumes correlated with CRRT but not SSRT. Neither reaction times nor regional brain volumes were strongly age- dependent. Conclusions Our evidence supports delayed brain maturation in ADHD and implies that some features of ADHD improve with age.link_to_subscribed_fulltex

MRI Study of Minor Physical Anomaly in Childhood Autism Implicates Aberrant Neurodevelopment in Infancy

Background: MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective 'window' to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism. Methods: We recruited 91 children aged 7-16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates. Results: Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles. Conclusions: Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to "social brain" dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a "fossil record" of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism. © 2011 Cheung et al.published_or_final_versio

Impaired Communication Between the Motor and Somatosensory Homunculus Is Associated With Poor Manual Dexterity in Autism Spectrum Disorder

ABSTRACTBackgroundFine motor skill impairments are common in autism spectrum disorder (ASD), significantly affecting quality of life. Sensory inputs reaching the primary motor cortex (M1) from the somatosensory cortex (S1) are likely involved in fine motor skill and specifically motor learning. However, the role of these connections has not been directly investigated in humans. This study aimed to investigate, for the first time, the role of the S1-M1 connections in healthy subjects in vivo and whether microstructural alterations are associated with motor impairment in ASD.MethodsSixty right-handed neurotypical adult men aged 18 to 45 years, and 60 right-handed age- and sex-matched subjects diagnosed with ASD underwent fine motor skill assessment and scanning with diffusion tensor imaging (DTI). The streamlines of the hand region connecting S1-M1 of the motor-sensory homunculus were virtually dissected using TrackVis, and diffusion properties were extracted. The face/tongue region connections were used as control tracts.ResultsThe ASD group displayed lower motor performances and altered DTI measurements of the hand-region connection. Behavioral performance correlated with hand-region DTI measures in both groups, but not with the face/tongue connections, indicating anatomical specificity. There was a left-hemisphere association of motor ability in the control group and an atypical rightward shift in the ASD group.ConclusionsThese findings suggest that direct interaction between S1 and M1 may contribute to the human ability to precisely interact with and manipulate the environment. Because electrophysiological evidence indicates that these connections may underpin long-term potentiation in M1, our findings may lead to novel therapeutic treatments for motor skill disorders

Do adults with high functioning autism or Asperger Syndrome differ in empathy and emotion recognition?

The present study examined whether adults with high functioning autism (HFA) showed greater difficulties in (i) their self-reported ability to empathise with others and/or (ii) their ability to read mental states in others’ eyes than adults with Asperger syndrome (AS). The Empathy Quotient (EQ) and ‘Reading the Mind in the Eyes’ Test (Eyes Test) were compared in 43 adults with AS and 43 adults with HFA. No significant difference was observed on EQ score between groups, while adults with AS performed significantly better on the Eyes Test than those with HFA. This suggests that adults with HFA may need more support, particularly in mentalizing and complex emotion recognition, and raises questions about the existence of subgroups within autism spectrum conditions

Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies

Infants born in early term (37-38 weeks gestation) experience slower neurodevelopment than those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain. Here we characterise brain volume and white matter correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome using T2 and diffusion weighted MRI acquired in the neonatal period from a cohort (n = 454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor-based morphometry and tract-based spatial statistics. Neurodevelopment was assessed at age 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Infants born earlier had higher relative ventricular volume and lower relative brain volume in the deep grey matter, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial, and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Regression models predicting outcome from gestational age at birth were significantly improved after adding neuroimaging features associated with gestational age at birth. This work adds to the body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals

BACKGROUND: Autism is a heterogeneous collection of disorders with a complex molecular underpinning. Evidence from postmortem brain studies have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from individuals with autism with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism. METHODS: iPSCs were generated from 9 unrelated individuals with autism without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing control individuals. iPSCs were differentiated toward either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterize iPSCs at different stages of differentiation. RESULTS: A subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to postmortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated toward a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs. CONCLUSIONS: Taken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages

Psychophysiological Markers of Vulnerability to Psychopathology in Men with an Extra X Chromosome (XXY)

Studying genetically defined syndromes associated with increased risk for psychopathology may help in understanding neurodevelopmental mechanisms related to risk for psychopathology. Klinefelter syndrome (47,XXY) is one of the most common sex chromosomal aneuploidies (1 in 650 male births) and associated with increased vulnerability for psychopathology, including psychotic symptoms. Yet, it remains unknown whether this increased risk is associated with underlying psychophysiological mechanisms that are typically deficient in individuals with psychotic disorders. The present study assessed three “classic” psychophysiological markers of psychosis in Klinefelter syndrome (KS): smooth pursuit eye movements (SPEM), prepulse inhibition (PPI) and P50 suppression. Fourteen adults with KS and 15 non-clinical adults participated in the study. Data on SPEM (reflecting visuo-motor control) as well as PPI and P50 suppression (reflecting sensory gating) were collected. Dysfunctions in SPEM were observed in individuals with KS, with less smooth pursuit as expressed in lower position gain. Also, reduced sensory gating in individuals with KS was suggested by significantly reduced prepulse inhibition of the startle response (PPI) (effect size 1.6). No abnormalities were found in suppression of the P50 (effect size 0.6). We speculate that impairments in these psychophysiological mechanisms may reflect core brain dysfunctions that may also mediate the described increased vulnerability for psychotic symptoms in KS. Although speculative, such deficit specific, rather than disorder specific, psychophysiological dysfunctions in KS might convey vulnerability to other types of psychopathology as well. As KS already can be diagnosed prenatally, the predictive value of childhood impairments in prepulse inhibition and smooth pursuit for development of psychopathology later in life could be assessed. In sum, studying individuals with KS may prove to be an avenue of research leading to new hypotheses and insights into “at risk” pathways to psychopathology