Alterations in the functional neural circuitry supporting flexible choice behavior in autism spectrum disorders.

Restricted and repetitive behaviors, and a pronounced preference for behavioral and environmental consistency, are distinctive characteristics of autism spectrum disorder (ASD). Alterations in frontostriatal circuitry that supports flexible behavior might underlie this behavioral impairment. In an functional magnetic resonance imaging study of 17 individuals with ASD, and 23 age-, gender- and IQ-matched typically developing control participants, reversal learning tasks were used to assess behavioral flexibility as participants switched from one learned response choice to a different response choice when task contingencies changed. When choice outcome after reversal was uncertain, the ASD group demonstrated reduced activation in both frontal cortex and ventral striatum, in the absence of task performance differences. When the outcomes of novel responses were certain, there was no difference in brain activation between groups. Reduced activation in frontal cortex and ventral striatum suggest problems in decision-making and response planning, and in processing reinforcement cues, respectively. These processes, and their integration, are essential for flexible behavior. Alterations in these systems may therefore contribute to a rigid adherence to preferred behavioral patterns in individuals with an ASD. These findings provide an additional impetus for the use of reversal learning paradigms as a translational model for treatment development targeting the domain of restricted and repetitive behaviors in ASD.

Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome.

Sensory hypersensitivities are common, clinically distressing features of Fragile X Syndrome (FXS). Preclinical evidence suggests this abnormality may result from synaptic hyper-excitability in sensory systems. This model predicts reduced sensory habituation to repeated stimulus presentation. Fourteen adolescents and adults with FXS and 15 age-matched controls participated in a modified auditory gating task using trains of 4 identical tones during dense array electroencephalography (EEG). Event-related potential and single trial time-frequency analyses revealed decreased habituation of the N1 event-related potential response in FXS, and increased gamma power coupled with decreases in gamma phase-locking during the early-stimulus registration period. EEG abnormalities in FXS were associated with parent reports of heightened sensory sensitivities and social communication deficits. Reduced habituation and altered gamma power and phase-locking to auditory cues demonstrated here in FXS patients parallels preclinical findings with Fmr1 KO mice. Thus, the EEG abnormalities seen in FXS patients support the model of neocortical hyper-excitability in FXS, and may provide useful translational biomarkers for evaluating novel treatment strategies targeting its neural substrate.

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.

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.