Voxel-based morphometry study on brain structure in children with high-functioning autism

Earlier studies have suggested abnormal brain volumes in autism, but inconsistencies exist. Using voxel-based morphometry, we compared global and regional brain volumes in 17 high-functioning autistic children with 15 matched controls. We identified significant reduction in left white matter volume and white/gray matter ratio in autism. Regional brain volume reductions were detected for right anterior cingulate, left superior parietal lobule white matter volumes, and right parahippocampal gyrus gray matter volume, whereas enlargements in bilateral supramarginal gyrus, right postcentral gyrus, right medial frontal gyrus, and right posterior lobe of cerebellum gray matter in autism. Our findings showed global and regional brain volumes abnormality in high-functioning autism.     

Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study

OBJECTIVE: To quantify developmental abnormalities in cerebral and cerebellar volume in autism. METHODS: The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. RESULTS: Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 +/- 1.3 cm versus clinical norms: 34.6 +/- 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI-VII than normal controls. CONCLUSIONS: Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism.     

Neural correlates of communication skill and symptom severity in autism: A voxel-based morphometry study

Although many studies have compared the brains of normal controls and individuals with autism, especially older, higher-functioning individuals with autism, little is known of the neural correlates of the vast clinical heterogeneity characteristic of the disorder. In this study, we used voxel-based morphometry (VBM) to examine gray matter correlates of variation in communication skill and symptom severity within a heterogeneous group of 33 children with autism ranging in age from 3.4 to 11.4 years. Greater gray matter (GM) volume was associated with better communication skills in numerous frontal regions, especially in the left middle frontal gyrus. Further, greater GM volume in the right inferior frontal gyrus was associated with reduced severity of symptoms of autism. However, increased total GM volume was correlated with more severe symptoms of autism at a trend level, consistent with other studies, suggesting that while increased total GM volume is generally predictive of greater autistic severity, specific local increases in GM volume result in a reduction in symptoms. Our results suggest that communication and symptom severity have distinct neuroanatomic correlates and draw attention to the importance of studying the neuroanatomy of clinical heterogeneity within the autistic population.     

Hippocampus and amygdala volumes in parents of children with autistic disorder

OBJECTIVE: Structural and functional abnormalities in the medial temporal lobe, particularly the hippocampus and amygdala, have been described in people with autism. The authors hypothesized that parents of children with a diagnosis of autistic disorder would show similar changes in these structures. METHOD: Magnetic resonance imaging scans were performed in 17 biological parents of children with a diagnosis of DSM-IV autistic disorder. The scans were compared with scans from 15 adults with autistic disorder and 17 age-matched comparison subjects with no personal or familial history of autism. The volumes of the hippocampus, amygdala, and total brain were measured in all participants. RESULTS: The volume of the left hippocampus was larger in both the parents of children with autistic disorder and the adults with autistic disorder, relative to the comparison subjects. The hippocampus was significantly larger in the adults with autistic disorder than in the parents of children with autistic disorder. The left amygdala was smaller in the adults with autistic disorder, relative to the other two groups. No differences in total brain volume were observed between the three groups. CONCLUSIONS: The finding of larger hippocampal volume in autism is suggestive of abnormal early neurodevelopmental processes but is partly consistent with only one prior study and contradicts the findings of several others. The finding of larger hippocampal volume for the parental group suggests a potential genetic basis for hippocampal abnormalities in autism.     

Anthroposophic therapy for chronic depression: a four-year prospective cohort study

Background

Although differences in brain anatomy in autism have been difficult to replicate using manual tracing methods, automated whole brain analyses have begun to find consistent differences in regions of the brain associated with the social cognitive processes that are often impaired in autism. We attempted to replicate these whole brain studies and to correlate regional volume changes with several autism symptom measures.

Methods

We performed MRI scans on 24 individuals diagnosed with DSM-IV autistic disorder and compared those to scans from 23 healthy comparison subjects matched on age. All participants were male. Whole brain, voxel-wise analyses of regional gray matter volume were conducted using voxel-based morphometry (VBM).

Results

Controlling for age and total gray matter volume, the volumes of the medial frontal gyri, left pre-central gyrus, right post-central gyrus, right fusiform gyrus, caudate nuclei and the left hippocampus were larger in the autism group relative to controls. Regions exhibiting smaller volumes in the autism group were observed exclusively in the cerebellum. Significant partial correlations were found between the volumes of the caudate nuclei, multiple frontal and temporal regions, the cerebellum and a measure of repetitive behaviors, controlling for total gray matter volume. Social and communication deficits in autism were also associated with caudate, cerebellar, and precuneus volumes, as well as with frontal and temporal lobe regional volumes.

Conclusion

Gray matter enlargement was observed in areas that have been functionally identified as important in social-cognitive processes, such as the medial frontal gyri, sensorimotor cortex and middle temporal gyrus. Additionally, we have shown that VBM is sensitive to associations between social and repetitive behaviors and regional brain volumes in autism.     

Slower cortisol response during ACTH stimulation test in autistic children

Autism is a hereditary, pervasive neurodevelopmental disorder that starts early in life. The main characteristics of the autism are impairment in social interactions, difficulties in adapting to novel environmental situations and improper reaction to stress. Since the Hypothalamic-Pituitary-Adrenocortical (HPA) axis plays a key role in the response to stress and because the previous research found abnormalities in HPA system, we conducted a study to test several elements of the HPA axis. Because autism is a heritable disorder, autistic subjects were studied as well as their parents. Cortisol circadian rhythm, cortisol daily secretion and its suppression response to dexamethasone had been measured from saliva or urine samples of the autistic children and their parents. Cortisol secretion response after ACTH stimulation was done with the autistic children only. The cortisol elevation after ACTH stimulation among the autistic individuals was slower (P = 0.017) than in healthy controls. No differences were found in salivary cortisol circadian rhythm or suppression response, as well as in cortisol daily excretion. These data indicate that, compared to healthy subjects, autistic individuals have fine differences in cortisol response to ACTH stimulation or possibly to other types of stress.     

White matter reduced streamline coherence in young men with autism and mental retardation

Background and purpose:  It has been proposed that white matter alterations might play a role in autistic disorders; however, published data are mainly limited to high-functioning autism. The goal of this study was to apply diffusion tensor imaging (DTI) and fiber tractography (FT) to study white matter in low-functioning autism and the relationship between white matter and cognitive impairment.
Methods:  Ten low-functioning males with autism (mean age: 19.7 ± 2.83 years) and 10 age-matched healthy males (mean age: 19.9 ± 2.64 years) underwent DTI-MRI scanning. fractional anisotropy (FA) maps were analyzed with whole brain voxel-wise and tract-of-interest statistics. Using FT algorithms, white matter tracts connecting the orbitofrontal cortex (OFC) with other brain regions were identified and compared between the two groups. FA mean values of the autistic group were correlated with intelligence quotient (IQ) scores.
Results:  Low-functioning autistic subjects showed a reduced tract volume and lower mean FA values in the left OFC network compared with controls. In the autistic group, lower FA values were associated with lower IQ scores.
Conclusions:  We showed evidence of OFC white matter network abnormalities in low-functioning autistic individuals. Our results point to a relationship between the severity of the intellectual impairment and the extent of white matter alterations.     

Brain growth rate abnormalities visualized in adolescents with autism

Autism spectrum disorder is a heterogeneous disorder of brain development with wide ranging cognitive deficits. Typically diagnosed before age 3, autism spectrum disorder is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared with those of typically developing children and adolescents. Using tensor‐based morphometry, we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and seven typically developing boys (mean age/interscan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (P = 0.03, corrected), especially in the parietal (P = 0.008), temporal (P = 0.03), and occipital lobes (P = 0.02). We also visualized abnormal overgrowth in autism in gray matter structures such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. Tensor‐based morphometry revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Increased left parietal volumes relate to delayed language development in autism: a structural mri study

The neural basis of language and motor deficits in autism is still not completely clear. The aim of this study was to explore the involvement of the parietal lobe in language and motor development in autism, in view of the recognized role of this region in language and imitation functions. Twenty-eight autistic children underwent an extensive clinical assessment and an MRI examination. A significant direct correlation between age at first word and left parietal gray matter volumes was found (r=0.50, p=0.007). Conversely, age at reaching milestones of motor development, such as the ability to sit and to walk unaided, was not significantly associated with parietal size, after correcting for chronological age and for gender. To the best of our knowledge, this is the first structural MRI report demonstrating a role of left parietal gray matter volumes in delayed language development in autistic children representative of the 'real world' autistic population.     

Assessment of Neural Cell Adhesion Molecule (NCAM) in Autistic Serum and Postmortem Brain

Studies have identified structural abnormalities in areas of the autistic brain, with a pattern suggesting that a neurodevelopmental anomaly took place. Neural cell adhesion molecule (NCAM), which is involved in development of the central nervous system, was previously shown to be decreased in the serum of autistic individuals. In the present study, we measured NCAM protein in the sera from controls, patients with autism, siblings of autistic patients, and individuals with other neurologic disorders, but found no significant differences. We also measured NCAM protein in autistic postmortem brain samples and found the longest isoform, NCAM-180, to be significantly decreased. In addition, we investigated the mRNA expression of NCAM in these brain samples using cDNA microarrays and RT-PCR. Results show that NCAM mRNA levels are not altered in autism.     

The neuroanatomy of the autistic phenotype

The autism phenotype is associated with an excess of brain volume due in part to decreased pruning during development. Here we aimed at assessing brain volume early in development to further elucidate previous findings in autism and determine whether this pattern is restricted to idiopathic autism or shared within the autistic phenotype (fragile X syndrome [FXS]). We investigated brain volume in 37 participants, using the fully automated Civet pipeline anatomical magnetic resonance imaging. 3 groups with intellectual deficiency: autism (AUT); its most associated FXS; and its most opposite Williams syndrome (WS) were compared with each other and with normal controls (NC). We report increased total and regional gray and white matter brain volume in AUT and FXS relative to WS and NC. These findings are discussed in light of the possibilities leading for the enlarged brain volume in children with the AUT phenotype. We speculate that this excess suggests reduced regression of neuronal processes “pruning” in cortical and subcortical regions in AUT/FXS, which may be due to a mutation in specific genes involved in pruning and/or a lack of socio-emotional environmental experience during a critical developmental period.     

Cortical gray and white brain tissue volume in adolescents and adults with autism.

BACKGROUND: A number of studies have found brain enlargement in autism, but there is disagreement as to whether this enlargement is limited to early development or continues into adulthood. In this study, cortical gray and white tissue volumes were examined in a sample of adolescents and adults with autism who had demonstrated total brain enlargement in a previous magnetic resonance imaging (MRI) study. METHODS: An automated tissue segmentation program was applied to structural MRI scans to obtain volumes of gray, white, and cerebrospinal fluid (CSF) tissue on a sample of adolescent and adult males ages 13-29 with autism (n = 23) and controls (n = 15). Regional differences for brain lobes and brain hemispheres were also examined. RESULTS: Significant enlargement in gray matter volume was found for the individuals with autism, with a disproportionate increase in left-sided gray matter volume. Lobe volume enlargements were detected for frontal and temporal, but not parietal or occipital lobes, in the subjects with autism. Age and nonverbal IQ effects on tissue volume were also observed. CONCLUSIONS: These findings give evidence for left-lateralized gray tissue enlargement in adolescents and adults with autism, and demonstrate a regional pattern of cortical lobe volumes underlying this effect.     

Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years

CONTEXT: While the neuroanatomical basis of autism is not yet known, evidence suggests that brain enlargement may be characteristic of this disorder. Inferences about the timing of brain enlargement have recently come from studies of head circumference (HC). OBJECTIVES: To examine brain volume and HC in individuals with autism as compared with control individuals. DESIGN: A cross-sectional study of brain volume was conducted at the first time point in an ongoing longitudinal magnetic resonance imaging study of brain development in autism. Retrospective longitudinal HC measurements were gathered from medical records on a larger sample of individuals with autism and local control individuals. SETTING: Clinical research center. PARTICIPANTS: The magnetic resonance imaging study included 51 children with autism and 25 control children between 18 and 35 months of age (the latter included both developmentally delayed and typically developing children). Retrospective, longitudinal HC data were examined from birth to age 3 years in 113 children with autism and 189 local control children. MAIN OUTCOME MEASURES: Cerebral cortical (including cortical lobes) and cerebellar gray and white matter magnetic resonance imaging brain volumes as well as retrospective HC data from medical records were studied. RESULTS: Significant enlargement was detected in cerebral cortical volumes but not cerebellar volumes in individuals with autism. Enlargement was present in both white and gray matter, and it was generalized throughout the cerebral cortex. Head circumference appears normal at birth, with a significantly increased rate of HC growth appearing to begin around 12 months of age. CONCLUSIONS: Generalized enlargement of gray and white matter cerebral volumes, but not cerebellar volumes, are present at 2 years of age in autism. Indirect evidence suggests that this increased rate of brain growth in autism may have its onset postnatally in the latter part of the first year of life.     

Relationship of autistic traits between parents and children with and without autism spectrum disorder

BackgroundAlthough parents with a child with autism spectrum disorder (ASD) have usually been identified as having the “broader autism phenotype”, empirical research on the differences in autistic-like characteristics between parents with and without ASD children has yielded inconsistent results.MethodThis survey of the autistic traits of parents and children was conducted in 119 parents with ASD children and 108 parents with typically developing (TD) children. Parents’ autistic traits were quantified using the Autism-Spectrum Quotient and children’s autistic traits were quantified using the Autism Spectrum Quotient—Children’s Version.ResultsThe autistic traits of ASD children were significantly higher than those of the TD children; however, autistic traits were similar between parents in the two groups. Furthermore, the correlations of autistic traits between parents and children were only significant for the TD group and not for the ASD group.ConclusionsThe current findings indicate that the relationship of autistic traits between parents and children exists in the TD group, and that the Autism-Spectrum Quotient may be used for parents as a screening aid to identify children who should be further screened for autistic traits.     

Voxel-based morphometric gray matter correlates of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is associated with functional abnormalities within a neurocircuitry that includes the hippocampus, amygdala, and medial prefrontal cortex. Evidence of structural abnormalities within these regions, and their association with PTSD severity and symptom burden is, however, sparse. The present study evaluated the relation between indices of gray matter volume and PTSD symptom severity using voxel-based morphometry. Fifteen individuals meeting DSM-IV criteria for PTSD completed the Clinician Administered PTSD Scale and underwent structural magnetic resonance imaging. Greater PTSD severity and avoidance/numbing were correlated with increased gray matter volume of the right amygdala–hippocampal complex. Greater hyper-arousal was associated with reduced gray matter volume in the left superior medial frontal gyrus. Findings are consistent with current neurocircuitry models of PTSD, which posit that the disorder is associated with structural and functional variance within this distributed network.     

Abnormal asymmetry in language association cortex in autism

Autism is a neurodevelopmental disorder affecting cognitive, language, and social functioning. Although language and social communication abnormalities are characteristic, prior structural imaging studies have not examined language-related cortex in autistic and control subjects. Subjects included 16 boys with autism (aged 7-11 years), with nonverbal IQ greater than 80, and 15 age- and handedness-matched controls. Magnetic resonance brain images were segmented into gray and white matter; cerebral cortex was parcellated into 48 gyral-based divisions per hemisphere. Asymmetry was assessed a priori in language-related inferior lateral frontal and posterior superior temporal regions and assessed post hoc in all regions to determine specificity of asymmetry abnormalities. Boys with autism had significant asymmetry reversal in frontal language-related cortex: 27% larger on the right in autism and 17% larger on the left in controls. Only one additional region had significant asymmetry differences on post hoc analysis: posterior temporal fusiform gyrus (more left-sided in autism), whereas adjacent fusiform gyrus and temporooccipital inferior temporal gyrus both approached significance (more right-sided in autism). These inferior temporal regions are involved in visual face processing. In boys with autism, language and social/face processing-related regions displayed abnormal asymmetry. These structural abnormalities may relate to language and social disturbances observed in autism.     

The Broad Autism Phenotype Questionnaire

The broad autism phenotype (BAP) is a set of personality and language characteristics that reflect the phenotypic expression of the genetic liability to autism, in non-autistic relatives of autistic individuals. These characteristics are milder but qualitatively similar to the defining features of autism. A new instrument designed to measure the BAP in adults, the Broad Autism Phenotype Questionnaire (BAPQ), was administered to 86 parents of autistic individuals and 64 community control parents. Sensitivity and specificity of the BAPQ for detecting the BAP were high (>70%). Parents of children with autism had significantly higher scores on all three subscales: aloof personality, rigid personality, and pragmatic language. This instrument provides a valid and efficient measure for characterizing the BAP.     

Cerebral volumetric analysis over time in children with malformations of cortical development: a quantitative investigation

Malformations of cortical development are common neurological disorders characterized by disruptions in the normal development of cerebral gray and white matter during fetal life. We performed a quantitative, partly longitudinal investigation of cerebral volumes in a cohort of children with cortical malformations to investigate how their anatomical abnormalities change over time. Cortical malformation subjects showed volumetric curves that were comparable with those reported for healthy individuals, and reached peak cerebral volume, gray matter volume, and white matter volume at ages similar to those reported for healthy children. Volumes of heterotopic gray matter, however, demonstrated increases that were out of proportion to changes in cortical volume or caudate nucleus volume, suggesting that misplaced gray matter can have a unique pattern of maturation. Our findings demonstrate that overall brain growth in children with cortical malformations appears to mirror that of the healthy population, although malformed regions can show distinct growth patterns.     

Autism and diagnostic substitution: evidence from a study of adults with a history of developmental language disorder

Rates of diagnosis of autism have risen since 1980, raising the question of whether some children who previously had other diagnoses are now being diagnosed with autism. We applied contemporary diagnostic criteria for autism to adults with a history of developmental language disorder, to discover whether diagnostic substitution has taken place. A total of 38 adults (aged 15–31y; 31 males, seven females) who had participated in studies of developmental language disorder during childhood were given the Autism Diagnostic Observation Schedule - Generic. Their parents completed the Autism Diagnostic Interview - Revised, which relies largely on symptoms present at age 4 to 5 years to diagnose autism. Eight individuals met criteria for autism on both instruments, and a further four met criteria for milder forms of autistic spectrum disorder. Most individuals with autism had been identified with pragmatic impairments in childhood. Some children who would nowadays be diagnosed unambiguously with autistic disorder had been diagnosed with developmental language disorder in the past. This finding has implications for our understanding of the epidemiology of autism.     

Broader Autism Phenotype in Parents of Autistic Children: Reality or Myth?

The finding that relatives of individuals with autism show mild autistic traits is referred to as the broader autism phenotype (BAP). In the current study, 25 parents with a child with high-functioning autism and 25 parents with typically developed children were compared on: (1) the Block Design Test, (2) the Autism-Spectrum Quotient (AQ), and (3) a reaction time task to examine reflexive covert visual orienting to social (eyes) and non-social (arrows) cues. The parent groups were scored similar on the Block Design Test and the AQ. However, fathers with an autistic child demonstrated a different reaction time pattern and responded slower on the social cues than control fathers. These results partly support and further elaborate on the BAP in parents with an autistic child.