Stephen R. Dager

Brain structural abnormalities in young children with autism spectrum disorder

Objective To explore the specific gross neuroanatomic substrates of this brain developmental disorder, the authors examine brain morphometric features in a large sample of carefully diagnosed 3- to 4-year-old children with autism spectrum disorder (ASD) compared with age-matched control groups of typically developing (TD) children and developmentally delayed (DD) children. Methods Volumes of the cerebrum, cerebellum, amygdala, and hippocampus were measured from three-dimensional coronal MR images acquired from 45 children with ASD, 26 TD children, and 14 DD children. The volumes were analyzed with respect to age, sex, volume of the cerebrum, and clinical status. Results Children with ASD were found to have significantly increased cerebral volumes compared with TD and DD children. Cerebellar volume for the ASD group was increased in comparison with the TD group, but this increase was proportional to overall increases in cerebral volume. The DD group had smaller cerebellar volumes compared with both of the other groups. Measurements of amygdalae and hippocampi in this group of young children with ASD revealed enlargement bilaterally that was proportional to overall increases in total cerebral volume. There were similar findings of cerebral enlargement for both girls and boys with ASD. For subregion analyses, structural abnormalities were observed primarily in boys, although this may reflect low statistical power issues because of the small sample (seven girls with ASD) studied. Among the ASD group, structural findings were independent of nonverbal IQ. In a subgroup of children with ASD with strictly defined autism, amygdalar enlargement was in excess of increased cerebral volume. Conclusions These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

Differences in White Matter Fiber Tract Development Present From 6 to 24 Months in Infants With Autism

OBJECTIVE Evidence from prospective studies of high-risk infants suggests that early symptoms of autism usually emerge late in the first or early in the second year of life after a period of relatively typical development. The authors prospectively examined white matter fiber tract organization from 6 to 24 months in high-risk infants who developed autism spectrum disorders (ASDs) by 24 months. METHOD The participants were 92 high-risk infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months; a majority contributed additional imaging data at 12 and/or 24 months. At 24 months, 28 infants met criteria for ASDs and 64 infants did not. Microstructural properties of white matter fiber tracts reported to be associated with ASDs or related behaviors were characterized by fractional anisotropy and radial and axial diffusivity. RESULTS The fractional anisotropy trajectories for 12 of 15 fiber tracts differed significantly between the infants who developed ASDs and those who did not. Development for most fiber tracts in the infants with ASDs was characterized by higher fractional anisotropy values at 6 months followed by slower change over time relative to infants without ASDs. Thus, by 24 months of age, those with ASDs had lower values. CONCLUSIONS These results suggest that aberrant development of white matter pathways may precede the manifestation of autistic symptoms in the first year of life. Longitudinal data are critical to characterizing the dynamic age-related brain and behavior changes underlying this neurodevelopmental disorder.

Defining the broader phenotype of autism: genetic, brain, and behavioral perspectives.

Achieving progress in understanding the cause, nature, and treatment of autism requires an integration of concepts, approaches, and empirical findings from genetic, cognitive neuroscience, animal, and clinical studies. The need for such integration has been a fundamental tenet of the discipline of developmental psychopathology from its inception. It is likely that the discovery of autism susceptibility genes will depend on the development of dimensional measures of broader phenotype autism traits. It is argued that knowledge of the cognitive neuroscience of social and language behavior will provide a useful framework for defining such measures. In this article, the current state of knowledge of the cognitive neuroscience of social and language impairments in autism is reviewed. Following from this, six candidate broader phenotype autism traits are proposed: (a) face processing, including structural encoding of facial features and face movements, such as eye gaze; (b) social affiliation or sensitivity to social reward, pertaining to the social motivational impairments found in autism; (c) motor imitation ability, particularly imitation of body actions; (d) memory, specifically those aspects of memory mediated by the medial temporal lobe-prefrontal circuits; (e) executive function, especially planning and flexibility; and (f) Language ability, particularly those aspects of language that overlap with specific language impairment, namely, phonological processing.

The developmental neurobiology of autism spectrum disorder.

Editor’s Note: Two reviews in this week’s issue examine the rapidly expanding interest in autism research in the neuroscience community. Moldin et al. provide a brief prospective on the overall state of research in autism. DiCicco-Bloom and colleagues summarize their presentations at the

Consensus Paper: Pathological Role of the Cerebellum in Autism

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Frontal lobe gray matter density decreases in bipolar I disorder.

BACKGROUND This study was conducted to explore differences in gray and white matter density between bipolar and healthy comparison groups using voxel-based morphometry (VBM). METHODS Brain magnetic resonance imaging was performed for 39 subjects with bipolar I disorder and 43 comparison subjects. Images were registered into a proportional stereotaxic space and segmented into gray matter, white mater, and cerebrospinal fluid. Statistical parametric mapping was used to calculate differences in gray and white matter density between groups. RESULTS Bipolar subjects had decreased gray matter density in left anterior cingulate gyrus (Brodmanns area [BA] 32, 7.3% decrease), an adjacent left medial frontal gyrus (BA 10, 6.9% decrease), right inferior frontal gyrus (BA 47, 9.2% decrease), and right precentral gyrus (BA 44, 6.2% decrease), relative to comparison subjects. CONCLUSIONS The observation of a gray matter density decrease in the left anterior cingulate, which processes emotions, in bipolar subjects is consistent with prior reports that used region-of-interest analytic methods. Decreased gray matter density in the right inferior frontal gyrus, which processes nonverbal and intrinsic functions, supports nondominant hemisphere dysfunction as a component of bipolar disorder.

Placebo-controlled study of gabapentin treatment of panic disorder.

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of panic disorder. One hundred three patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 600 and 3,600 mg/day) or placebo for 8 weeks. No overall drug/placebo difference was observed in scores on the Panic and Agoraphobia Scale (PAS) (p = 0.606). A post hoc analysis was used to evaluate the more severely ill patients as defined by the primary outcome measure (PAS score > or = 20). In this population, the gabapentin-treated patients showed significant improvement in the PAS change score (p = 0.04). In patients with a PAS score of 20 or greater, women showed a greater response than men regardless of treatment. Adverse events were consistent with the known side effect profile of gabapentin and included somnolence, headache, and dizziness. One patient experienced a serious adverse event during the study. No deaths were reported. The results of this study suggest that gabapentin may have anxiolytic effects in more severely ill patients with panic disorder.

Enhancement of BOLD-contrast sensitivity by single-shot multi-echo functional MR imaging.

Improved data acquisition and processing strategies for blood oxygenation level‐dependent (BOLD)‐contrast functional magnetic resonance imaging (fMRI), which enhance the functional contrast‐to‐noise ratio (CNR) by sampling multiple echo times in a single shot, are described. The dependence of the CNR on T2*, the image encoding time, and the number of sampled echo times are investigated for exponential fitting, echo summation, weighted echo summation, and averaging of correlation maps obtained at different echo times. The method is validated in vivo using visual stimulation and turbo proton echoplanar spectroscopic imaging (turbo‐PEPSI), a new single‐shot multi‐slice MR spectroscopic imaging technique, which acquires up to 12 consecutive echoplanar images with echo times ranging from 12 to 213 msec. Quantitative T2*‐mapping significantly increases the measured extent of activation and the mean correlation coefficient compared with conventional echoplanar imaging. The sensitivity gain with echo summation, which is computationally efficient provides similar sensitivity as fitting. For all data processing methods sensitivity is optimum when echo times up to 3.2 T2* are sampled. This methodology has implications for comparing functional sensitivity at different magnetic field strengths and between brain regions with different magnetic field inhomogeneities. Magn Reson Med 42:87–97, 1999.

Regional brain chemical alterations in young children with autism spectrum disorder

Objective: The authors evaluated regional brain chemistry for evidence of increased neuronal packing density in autism. Methods: Forty-five 3- to 4-year-old children with autism spectrum disorder (ASD), 13 children with typical development (TD), and 15 children with delayed development (DD) were studied using dual-echo proton echoplanar spectroscopic imaging (32 × 32 matrix-1 cm3 voxels) to measure brain chemical concentrations and relaxation times. Chemical quantification was corrected for tissue partial volume and relative measures of chemical relaxation (T2r) were calculated from the paired echoes. Measures from averaged and individual regions were compared using analysis of variance corrected for multiple comparisons. Results: ASD subjects demonstrated reduced N-acetylaspartate (NAA) (−10%), creatine (Cre) (−8%), and myo-inositol (−13%) concentrations compared to TD controls and prolonged NAA T2r relative to TD (7%) and DD (9%) groups. Compared to DD subjects, children with ASD also demonstrated prolonged T2r for choline (10%) and Cre (9%). Regional analyses demonstrated subtle patterns of chemical alterations in ASD compared to the TD and DD groups. Conclusions: Brain chemical abnormalities are present in ASD at 3 to 4 years of age. However, the direction and widespread distribution of these abnormalities do not support hypothesis of diffuse increased neuronal packing density in ASD.

Early brain development in infants at high risk for autism spectrum disorder

Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6–12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.