Minicolumnar pathology in autism

OBJECTIVE: To determine whether differences exist in the configuration of minicolumns between the brains of autistic and control patients. BACKGROUND: Autism is a severe and pervasive developmental disturbance of childhood characterized by disturbances in both social interactions and communication, as well as stereotyped patterns of interests, activities, and behaviors. Postmortem neuropathologic studies remain inconclusive. METHODS: The authors used a computerized imaging program to measure details of cell column morphologic features in area 9 of the prefrontal cortex and areas 21 and posterior 22 (Tpt) within the temporal lobe of nine brains of autistic patients and controls. RESULTS: The authors found significant differences between brains of autistic patients and controls in the number of minicolumns, in the horizontal spacing that separates cell columns, and in their internal structure, that is, relative dispersion of cells. Specifically, cell columns in brains of autistic patients were more numerous, smaller, and less compact in their cellular configuration with reduced neuropil space in the periphery. CONCLUSIONS: In autism, there are minicolumnar abnormalities in the frontal and temporal lobes of the brain.     

Clinical, morphological, and biochemical correlates of head circumference in autism.

BACKGROUND: Head growth rates are often accelerated in autism. This study is aimed at defining the clinical, morphological, and biochemical correlates of head circumference in autistic patients. METHODS: Fronto-occipital head circumference was measured in 241 nonsyndromic autistic patients, 3 to 16 years old, diagnosed according to DSM-IV criteria. We assessed 1) clinical parameters using the Autism Diagnostic Observation Schedule, Autism Diagnostic Interview-Revised, Vineland Adaptive Behavioral Scales, intelligence quotient measures, and an ad hoc clinical history questionnaire; 2) height and weight; 3) serotonin (5-HT) blood levels and peptiduria. RESULTS: The distribution of cranial circumference is significantly skewed toward larger head sizes (p < .00001). Macrocephaly (i.e., head circumference >97th percentile) is generally part of a broader macrosomic endophenotype, characterized by highly significant correlations between head circumference, weight, and height (p < .001). A head circumference >75th percentile is associated with more impaired adaptive behaviors and with less impairment in IQ measures and motor and verbal language development. Surprisingly, larger head sizes are significantly associated with a positive history of allergic/immune disorders both in the patient and in his/her first-degree relatives. CONCLUSIONS: Our study demonstrates the existence of a macrosomic endophenotype in autism and points toward pathogenetic links with immune dysfunctions that we speculate either lead to or are associated with increased cell cycle progression and/or decreased apoptosis.     

Behavioral correlates of epileptiform abnormalities in autism

There is a high incidence of epileptiform abnormalities in children with autism even in the absence of clinical seizures. These findings are most prominent during sleep recordings. The significance of these abnormalities is unclear. Although studies do not all agree, there may be some association between cognitive function, behavior, and the presence or absence of epileptiform discharges. Small studies of anticonvulsant treatment mostly suggest an improvement in certain aspects of cognitive or behavioral functioning in these children, but larger and more comprehensive studies are needed to determine the potential relationship between epileptiform discharges on EEG, cognitive and behavioral functioning, and treatment effects in the population with autism.This article is part of a Special Issue entitled “Autism and Epilepsy”.     

Clinical correlates of the pathology underlying parkinsonism: a population perspective.

We correlated the clinical features with pathological findings in an autopsy series of cases of incident parkinsonism. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all incident cases of parkinsonism in Olmsted County, MN, for the years 1976 to 1990. Medical histories were abstracted in a standardized manner. Included in this study were those incident cases who died and underwent autopsy. Brain sections were studied with routine histology and special stainings. A neuropathologist blinded to any clinical information assigned cases to neuropathological categories. We found 364 incident cases of parkinsonism of which 235 were deceased at the time of this study; there were 39 autopsied brains available for analysis (17% of deceased cases). Of the 16 patients diagnosed pathologically with Lewy body disease, documentation indicated that 8 had an early dementia, 3 had prominent dysautonomia, and 2 had prominent ataxia. Of the 7 patients diagnosed pathologically with progressive supranuclear palsy, 4 had no documentation of supranuclear gaze palsy, and 3 had no documentation of early falls. Of the 3 patients diagnosed pathologically with multiple system atrophy, none had prominent ataxia or dysautonomia documented. Of the 5 patients with vascular disease at pathology, none had been given the clinical diagnosis of vascular parkinsonism. Of the 8 cases given the clinical diagnosis of drug-induced parkinsonism, 6 were found to have basal ganglia pathology. The autopsied cases in this study were not representative of all patients with parkinsonism, because atypical cases are more likely to come to autopsy than typical ones. Despite this selection bias, the retrospective data collection, and the small sample size, we made several observations that illustrate the difficulty in achieving an accurate antemortem diagnosis of parkinsonism.     

Neural correlates of moral reasoning in autism spectrum disorder

In our study, we tried to clarify whether patients with autism spectrum disorder (ASD) reveal different moral decision patterns as compared to healthy subjects and whether common social interaction difficulties in ASD are reflected in altered brain activation during different aspects of moral reasoning. 28 patients with high-functioning ASD and 28 healthy subjects matched for gender, age and education took part in an event-related functional magnetic resonance imaging study. Participants were confronted with textual dilemma situations followed by proposed solutions to which they could agree or disagree. On a neural level, moral decision making was associated with activation in anterior medial prefrontal regions, the temporo-parietal junction and the precuneus for both groups. However, while patients and healthy controls did not exhibit significant behavioral differences, ASD patients showed decreased activation in limbic regions, particularly the amygdala, as well as increased activation in the anterior and the posterior cingulate gyrus during moral reasoning. Alterations of brain activation in patients might thus indicate specific impairments in empathy. However, activation increases in brain regions associated with the ‘default mode network’ and self-referential cognition also provide evidence for an altered way of patients’ cerebral processing with regard to decision making based on social information.     

The role of cerebellar genes in pathology of autism and schizophrenia

Schizophrenia and autism are neurodevelopmental diseases that have genetic as well as environmental etiologies. Both disorders have been associated with prenatal viral infection. Brain imaging and postmortem studies have found alterations in the structure of the cerebellum as well as changes in gene expression. Our laboratory has developed an animal model using prenatal infection of mice with human influenza virus that has demonstrated changes in behavior, pharmacology, structure, and gene expression in the brains of exposed offspring. In the current communication we describe altered expression of cerebellar genes associated with development of brain disorder in a mouse model for schizophrenia and autism and correlate these changes with those involved in the pathology of these two disorders.     

Neuroanatomic correlates of autism and stereotypy in children with Down syndrome

We conducted semiautomated, atlas-based analyses of regional brain volume changes on MRIs of children and adolescents with Down syndrome (DS) (N=15), DS with comorbid autism spectrum disorder (ASD) (N=15), and age-matched or sex-matched typically developing controls (N=22). Selective volumetric changes were correlated with neurobehavioral measures to determine their functional significance. DS involved selective reduction of frontal and parietal gray matter volumes, beyond the global microencephaly typically observed in this condition. DS with comorbid ASD involved relative hyperplasia of white matter in the cerebellum and brainstem compared with DS only. Cerebellar white matter volumes were positively correlated with severity of stereotypies, a distinctive feature of ASD in DS.     

Hierarchical self-organization of minicolumnar receptive fields.

We study self-organization of receptive fields (RFs) of cortical minicolumns. Input driven self-organization is induced by Hebbian synaptic plasticity of afferent fibers to model minicolumns based on spiking neurons and background oscillations. If input in the form of spike patterns is presented during learning, the RFs of minicolumns hierarchically specialize to increasingly small groups of similar RFs in a series of nested group subdivisions. In a number of experiments we show that the system finds clusters of similar spike patterns, that it is capable of evenly cover the input space if the input is continuously distributed, and that it extracts basic features from input consisting of superpositions of spike patterns. With a continuous version of the bars test we, furthermore, demonstrate the system's ability to evenly cover the space of extracted basic input features. The hierarchical nature and its flexibility with respect to input distinguishes the presented type of self-organization from others including similar but non-hierarchical self-organization as discussed in [Lucke J., & von der Malsburg, C. (2004). Rapid processing and unsupervised learning in a model of the cortical macrocolumn. Neural Computation 16, 501-533]. The capabilities of the presented system match crucial properties of the plasticity of cortical RFs and we suggest it as a model for their hierarchical formation.     

Functional correlates of macroscopic high-frequency brain activity in the human visual system

The present article reviews empirical findings of large-scale gamma oscillations in the human brain, in the context of their functional correlates. Evidence supporting the fact that high-frequency neuronal oscillations are involved in several aspects of visual processing is presented, with a focus on bottom-up and top-down visual feature processing, selective attention, and emotional evaluation. This evidence suggests that visual processing involves the integrated activity of wide spread neuronal assemblies that can be studied with respect to time course and topography, employing frequency-domain analyses. Possible mechanisms underlying these phenomena are considered. Furthermore, the effects of attention and motivation, as well as characteristics of experimental paradigms are discussed as determinants of reliability and validity of measures of high-frequency oscillations.     

Neural correlates of eye-gaze detection in young children with autism

Various reports have demonstrated difficulties in eye-gaze processing in older children and adults with autism. However, little is known about the neural or developmental origin of such difficulties. In the present study, we used high-density Event-Related Potentials (HD-ERPs) to record the neural correlates of gaze processing in young children with autism, and their age-matched controls. In addition, to determine normal gaze processing development we also tested a non-autism adult group. The data obtained from the children with autism resembled that previously observed in typical 4-month old infants. In contrast, the control group showed the same pattern as typical adults. These findings suggest that the neural correlates of gaze direction processing may be delayed in young children with autism.     

Electrophysiological correlates of progressive sensorineural pathology in carboplatin-treated chinchillas

Carboplatin produces progressive damage to auditory nerve fibers, spiral ganglion neurons (SGNs) and inner hair cells (IHC) in the chinchilla cochlea but leaves outer hair cells intact. Within 1 h after injection, many afferent terminals beneath IHCs and myelin lamellae surrounding SGN processes are vacuolated. One day after injection, approximately half of the nerve fibers are missing. IHCs are intact at 2 days, but 20-30% are missing at 3 days. We studied the electrophysiological correlates of this progressive morphological damage by recording cochlear microphonics (CM), distortion product otoacoustic emissions (DPOAE), summating potentials (SP), compound action potentials (CAP) and midbrain evoked potentials (IC-EVP) before and 1 h, 12 h, 1 days, 3 days, 5 days, 7 days and 14 days after carboplatin injection (75 mg/kg IP) in four chinchillas. CM and DPOAEs tended to be unchanged or enhanced. CAP and SP showed little change until Day 3, when amplitudes were reduced in all animals and CAP thresholds were elevated by 9 dB; amplitudes declined further between Days 3 and 5 but not thereafter. IC-EVP amplitudes decreased on Days 3 or 5 but thresholds were relatively unchanged. All animals showed some recovery of IC-EVP between Days 7 and 14, including one with 70% enhancement on Day 14. The results indicate that threshold and amplitude measures fail to detect peripheral pathology until some relatively high threshold level of damage has been exceeded. This has important implications for monitoring peripheral damage and interpreting electrophysiological test results in animals and humans.     

Sensory correlates of difficult temperament characteristics in preschool children with autism

This study was aimed to investigate the rate of co-occurring sensory processing (SP) dysfunction in children with autism who had a difficult temperament characteristics, and the relationship between SP dysfunction and temperament characteristics in preschool children with autism. A total of 111 children aged 48-84 months, 67 children with autism and 44 age-matched typically developing children, participated in this study. Results of the study indicated that SP dysfunction was prevalent in children with autism who had difficult temperament characteristics, and that different SP patterns were associated with different temperament characteristics in preschool children with autism. In summary, the present findings highlight the importance of evaluating SP patterns in addition to assessing temperament in children with autism in order for clinicians to plan appropriate intervention programs and support children's participation in their daily lives. Furthermore, the knowledge of the relationship between difficult temperament characteristics and SP dysfunction of the child can foster parental appreciation of individual differences in children, provide parents effective strategies to manage children's behaviors, and promote adaptive parent-child interaction.     

A comparison of neural correlates underlying social cognition in Klinefelter syndrome and autism

Klinefelter syndrome (KS) is a genetic syndrome characterized by the presence of an extra X chromosome that appears to increase the risk of psychopathology, such as autism symptoms. This study used functional magnetic resonance imaging to determine underlying mechanisms related to this risk, with the aim of gaining insight into neural mechanisms behind social-cognitive dysfunction in KS and autism, and understanding similarities and differences in social information processing deficits. Fourteen boys with KS, seventeen boys with autism spectrum disorders (ASD) and nineteen non-clinical male controls aged 10–18 years were scanned while matching and labeling facial expressions (i.e. face processing and affect labeling, respectively). No group differences in neural activation were found during face processing. However, during affect labeling, the ASD group showed increased activation in the amygdala compared with controls, while the KS group showed increased activation in frontal areas compared with both controls and the ASD group. No group differences in task performance were found. Although behavioral symptoms of social dysfunction appear similar both in boys with KS and ASD, this is the first study to demonstrate different underlying etiologies. These results may aid in identifying different pathways to autism symptoms, which may help understanding variability within the ASD spectrum.     

The phenotype and neural correlates of language in autism: an integrative review

Although impaired communication is one of the defining criteria in autism, linguistic functioning is highly variable among people with this disorder. Accumulating evidence shows that language impairments in autism are more extensive than commonly assumed and described by formal diagnostic criteria and are apparent at various levels. Phenotypically, most people with autism have semantic, syntactic and pragmatic deficits, a smaller number are known to have phonological deficits. Neurophysiologically, abnormal processing of low-level linguistic information points to perceptual difficulties. Also, abnormal high-level linguistic processing of the frontal and temporal language association cortices indicates more self-reliant and less connected neural subsystems. Early sensory impairments and subsequent atypical neural connectivity are likely to play a part in abnormal language acquisition in autism. This paper aims to review the available data on the phenotype of language in autism as well as a number of structural, electrophysiological and functional brain-imaging studies to provide a more integrated view of the linguistic phenotype and its underlying neural deficits, and to provide new directions for research and therapeutic and experimental applications.