Matthew W. Mosconi

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.

Longitudinal study of amygdala volume and joint attention in 2- to 4-year-old children with autism

CONTEXT Cerebral cortical volume enlargement has been reported in 2- to 4-year-olds with autism. Little is known about the volume of subregions during this period of development. The amygdala is hypothesized to be abnormal in volume and related to core clinical features in autism. OBJECTIVES To examine amygdala volume at 2 years with follow-up at 4 years of age in children with autism and to explore the relationship between amygdala volume and selected behavioral features of autism. DESIGN Longitudinal magnetic resonance imaging study. SETTING University medical setting. PARTICIPANTS Fifty autistic and 33 control (11 developmentally delayed, 22 typically developing) children between 18 and 35 months (2 years) of age followed up at 42 to 59 months (4 years) of age. MAIN OUTCOME MEASURES Amygdala volumes in relation to joint attention ability measured with a new observational coding system, the Social Orienting Continuum and Response Scale; group comparisons including total tissue volume, sex, IQ, and age as covariates. RESULTS Amygdala enlargement was observed in subjects with autism at both 2 and 4 years of age. Significant change over time in volume was observed, although the rate of change did not differ between groups. Amygdala volume was associated with joint attention ability at age 4 years in subjects with autism. CONCLUSIONS The amygdala is enlarged in autism relative to controls by age 2 years but shows no relative increase in magnitude between 2 and 4 years of age. A significant association between amygdala volume and joint attention suggests that alterations to this structure may be linked to a core deficit of autism.

Impaired inhibitory control is associated with higher-order repetitive behaviors in autism spectrum disorders

BACKGROUND Impairments in executive cognitive control, including a reduced ability to inhibit prepotent responses, have been reported in autism spectrum disorders (ASD). These deficits may underlie patterns of repetitive behaviors associated with the disorder. METHOD Eighteen individuals with ASD and 15 age- and IQ-matched healthy individuals performed an antisaccade task and a visually guided saccade control task, each with gap and overlap conditions. Measures of repetitive behaviors were obtained using the Autism Diagnostic Inventory-Revised (ADI-R) and examined in relation to neurocognitive task performance. RESULTS Individuals with an ASD showed increased rates of prosaccade errors (failures to inhibit prepotent responses) on the antisaccade task regardless of task condition (gap/overlap). Prosaccade error rates were associated with the level of higher-order (e.g. compulsions, preoccupations) but not sensorimotor repetitive behaviors in ASD. CONCLUSIONS Neurocognitive disturbances in voluntary behavioral control suggest that alterations in frontostriatal systems contribute to higher-order repetitive behaviors in ASD.

Resting state EEG abnormalities in autism spectrum disorders

Autism spectrum disorders (ASD) are a group of complex and heterogeneous developmental disorders involving multiple neural system dysfunctions. In an effort to understand neurophysiological substrates, identify etiopathophysiologically distinct subgroups of patients, and track outcomes of novel treatments with translational biomarkers, EEG (electroencephalography) studies offer a promising research strategy in ASD. Resting-state EEG studies of ASD suggest a U-shaped profile of electrophysiological power alterations, with excessive power in low-frequency and high-frequency bands, abnormal functional connectivity, and enhanced power in the left hemisphere of the brain. In this review, we provide a summary of recent findings, discuss limitations in available research that may contribute to inconsistencies in the literature, and offer suggestions for future research in this area for advancing the understanding of ASD.

Reduced Behavioral Flexibility in Autism Spectrum Disorders

OBJECTIVE Restricted and repetitive behaviors, and a pronounced preference for behavioral and environmental consistency, are distinctive characteristics of autism spectrum disorders (ASD). Whether these clinical features of ASD are related to fundamental neuropsychological impairments in behavioral flexibility remains to be clarified. METHOD Forty-one individuals with ASD and 37 matched controls performed a probabilistic reversal learning task to assess behavioral flexibility. Participants learned to choose the correct stimulus location from a pair of locations to win points (acquisition). After making the correct choice over multiple trials, the rewarded stimulus location changed without warning (reversal). Feedback was provided on an 80:20 probabilistic schedule, with 80% of correct choices and 20% of incorrect choices randomly reinforced. RESULTS ASD and control participants performed comparably during acquisition. At reversal, ASD participants initially chose the new correct location as quickly as controls, but then more frequently reverted back to the previously preferred response. The ASD group also more frequently shifted back to the previous response choice immediately following intermittent non-reinforcement of the new correct response. The number of regressive errors was positively correlated with independently ascertained clinical ratings of restricted and repetitive behaviors, but not other core features of ASD. CONCLUSIONS Restricted and repetitive behaviors in ASD are associated with neurocognitive deficits in flexible choice behavior. Preclinical research has established that frontostriatal circuitry supports flexibility on reversal learning tasks. Thus, alterations in this circuitry may contribute to behavioral rigidity in ASD and represent a target for therapeutic intervention.

Saccadic eye movement abnormalities in autism spectrum disorder indicate dysfunctions in cerebellum and brainstem

BackgroundIndividuals with autism spectrum disorder (ASD) show atypical scan paths during social interaction and when viewing faces, and recent evidence suggests that they also show abnormal saccadic eye movement dynamics and accuracy when viewing less complex and non-social stimuli. Eye movements are a uniquely promising target for studies of ASD as their spatial and temporal characteristics can be measured precisely and the brain circuits supporting them are well-defined. Control of saccade metrics is supported by discrete circuits within the cerebellum and brainstem - two brain regions implicated in magnetic resonance (MR) morphometry and histopathological studies of ASD. The functional integrity of these distinct brain systems can be examined by evaluating different parameters of visually-guided saccades.MethodsA total of 65 participants with ASD and 43 healthy controls, matched on age (between 6 and 44-years-old), gender and nonverbal IQ made saccades to peripheral targets. To examine the influence of attentional processes, blocked gap and overlap trials were presented. We examined saccade latency, accuracy and dynamics, as well as the trial-to-trial variability of participants’ performance.ResultsSaccades of individuals with ASD were characterized by reduced accuracy, elevated variability in accuracy across trials, and reduced peak velocity and prolonged duration. In addition, their saccades took longer to accelerate to peak velocity, with no alteration in the duration of saccade deceleration. Gap/overlap effects on saccade latencies were similar across groups, suggesting that visual orienting and attention systems are relatively spared in ASD. Age-related changes did not differ across groups.ConclusionsDeficits precisely and consistently directing eye movements suggest impairment in the error-reducing function of the cerebellum in ASD. Atypical increases in the duration of movement acceleration combined with lower peak saccade velocities implicate pontine nuclei, specifically suggesting reduced excitatory activity in burst cells that drive saccades relative to inhibitory activity in omnipause cells that maintain stable fixation. Thus, our findings suggest that both cerebellar and brainstem abnormalities contribute to altered sensorimotor control in ASD.

Neurobehavioral Abnormalities in First-Degree Relatives of Individuals With Autism

CONTEXT Studying sensorimotor and neurocognitive impairments in unaffected family members of individuals with autism may help identify familial pathophysiological mechanisms associated with the disorder. OBJECTIVE To determine whether atypical sensorimotor or neurocognitive characteristics associated with autism are present in first-degree relatives of individuals with autism. DESIGN Case-control comparison of neurobehavioral functions. SETTING University medical center. PARTICIPANTS Fifty-seven first-degree relatives of individuals with autism and 40 age-, sex-, and IQ-matched healthy control participants (aged 8-54 years). MAIN OUTCOME MEASURES Oculomotor tests of sensorimotor responses (saccades and smooth pursuit); procedural learning and response inhibition; neuropsychological tests of motor, memory, and executive functions; and psychological measures of social behavior, communication skills, and obsessive-compulsive behaviors. RESULTS On eye movement testing, family members demonstrated saccadic hypometria, reduced steady-state pursuit gain, and a higher rate of voluntary response inhibition errors relative to controls. They also showed lateralized deficits in procedural learning and open-loop pursuit gain (initial 100 milliseconds of pursuit) and increased variability in the accuracy of large-amplitude saccades that were confined to rightward movements. In neuropsychological studies, only executive functions were impaired relative to those of controls. Family members reported more communication abnormalities and obsessive-compulsive behaviors than controls. Deficits across oculomotor, neuropsychological, and psychological domains were relatively independent from one another. CONCLUSIONS Family members of individuals with autism demonstrate oculomotor abnormalities implicating pontocerebellar and frontostriatal circuits and left-lateralized alterations of frontotemporal circuitry and striatum. The left-lateralized alterations have not been identified in other neuropsychiatric disorders and are of interest given atypical brain lateralization and language development associated with the disorder. Similar oculomotor deficits have been reported in individuals with autism, suggesting that they may be familial and useful for studies of neurophysiological and genetic mechanisms in autism.

Saccade Adaptation Abnormalities Implicate Dysfunction of Cerebellar-Dependent Learning Mechanisms in Autism Spectrum Disorders (ASD)

The cerebellar vermis (lobules VI-VII) has been implicated in both postmortem and neuroimaging studies of autism spectrum disorders (ASD). This region maintains the consistent accuracy of saccadic eye movements and plays an especially important role in correcting systematic errors in saccade amplitudes such as those induced by adaptation paradigms. Saccade adaptation paradigms have not yet been used to study ASD. Fifty-six individuals with ASD and 53 age-matched healthy controls performed an intrasaccadic target displacement task known to elicit saccadic adaptation reflected in an amplitude reduction. The rate of amplitude reduction and the variability of saccade amplitude across 180 adaptation trials were examined. Individuals with ASD adapted slower than healthy controls, and demonstrated more variability of their saccade amplitudes across trials prior to, during and after adaptation. Thirty percent of individuals with ASD did not significantly adapt, whereas only 6% of healthy controls failed to adapt. Adaptation rate and amplitude variability impairments were related to performance on a traditional neuropsychological test of manual motor control. The profile of impaired adaptation and reduced consistency of saccade accuracy indicates reduced neural plasticity within learning circuits of the oculomotor vermis that impedes the fine-tuning of motor behavior in ASD. These data provide functional evidence of abnormality in the cerebellar vermis that converges with previous reports of cellular and gross anatomic dysmorphology of this brain region in ASD.

Rare Inherited A2BP1 Deletion In A Proband With Autism And Developmental Hemiparesis

Ataxin 2 binding protein 1 (A2BP1 aka FOX1, RBFOX1) is an RNA binding protein responsible for regulation of pre‐mRNA splicing events in a number of critical developmental genes expressed in muscle, heart and neuronal cells [Shibata et al. (2000); Mamm Genome 12:595–601; Jin et al. (2003); EMBO J 22:905–912; Underwood et al. (2005); Mol Cell Biol 25:10005–10016]. Rare copy number abnormalities of A2BP1 have been previously associated with cognitive impairment, attention deficit disorder and autism [Martin et al. (2007); Am J Med Gen Part B 144B:869–876; Elia et al. (2010); Mol Psychiatry 15:637–646.]. Using a 1M Illumina SNP microarray, we identified a 1.3 kb deletion in A2BP1, which was subsequently validated by quantitative PCR. Here we present an in depth case study of an individual with autism and mild developmental hemiparesis in whom the deletion was detected. This study provides further support for the possible role of rare copy number variants in A2BP1 in the development of autism and associated motor asymmetries.

Lateralized Response Timing Deficits in Autism

BACKGROUND Procedural learning is an implicit process in which a behavioral response is refined through repeated performance. Neural systems supporting this cognitive process include specific frontostriatal systems responsible for the preparation and timing of planned motor responses. Evaluating performance on procedural learning tasks can provide unique information about neurodevelopmental disorders in which frontostriatal disturbances have been reported, such as autism. METHODS Fifty-two individuals with autism and 54 age-, IQ-, and gender-matched healthy individuals performed an oculomotor serial reaction time task and a sensorimotor control task. RESULTS Whereas the rate of procedural learning and the precision of planned motor responses were unimpaired in autism, a lateralized alteration in the ability to time predictive responses was observed. Rightward saccadic responses were speeded in individuals with autism relative to healthy control subjects. CONCLUSIONS Speeded rightward predictive saccades suggest atypical functioning of left hemisphere striatal chronometric systems in autism.