Biological Psychiatry : Cortical Function and Social Deficits in Autism (Avril 2016)

mardi 19 avril 2016

Le numéro d’avril 2016 de Biological Psychiatry est consacré aux fonctions du cortex cérébral et aux déficits sociaux dans l’autisme.

1. Tebartz van Elst L, Riedel A, Maier S. Autism as a Disorder of Altered Global Functional and Structural Connectivity. Biological Psychiatry ;2016 ;79(8):626-627.

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2. Gandal MJ, Geschwind DH. The Genetics-Driven Revival in Neuropsychiatric Drug Development. Biological Psychiatry ;2016 ;79(8):628-630.

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3. Herpertz SC, Bertsch K. Oxytocin Effects on Brain Functioning in Humans. Biological Psychiatry ;2016 ;79(8):631-632.

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4. Nebel MB, Eloyan A, Nettles CA, Sweeney KL, Ament K, Ward RE, Choe AS, Barber AD, Pekar JJ, Mostofsky SH. Intrinsic Visual-Motor Synchrony Correlates With Social Deficits in Autism. Biological Psychiatry ;2016 ;79(8):633-641.

AbstractBackground Imitation, which is impaired in children with autism spectrum disorder (ASD) and critically depends on the integration of visual input with motor output, likely impacts both motor and social skill acquisition in children with ASD ; however, it is unclear what brain mechanisms contribute to this impairment. Children with ASD also exhibit what appears to be an ASD-specific bias against using visual feedback during motor learning. Does the temporal congruity of intrinsic activity, or functional connectivity, between motor and visual brain regions contribute to ASD-associated deficits in imitation, motor, and social skills ? Methods We acquired resting-state functional magnetic resonance imaging scans from 100 8- to 12-year-old children (50 ASD). Group independent component analysis was used to estimate functional connectivity between visual and motor systems. Brain-behavior relationships were assessed by regressing functional connectivity measures with social deficit severity, imitation, and gesture performance scores. Results We observed increased intrinsic asynchrony between visual and motor systems in children with ASD and replicated this finding in an independent sample from the Autism Brain Imaging Data Exchange. Moreover, children with more out-of-sync intrinsic visual-motor activity displayed more severe autistic traits, while children with greater intrinsic visual-motor synchrony were better imitators. Conclusions Our twice replicated findings confirm that visual-motor functional connectivity is disrupted in ASD. Furthermore, the observed temporal incongruity between visual and motor systems, which may reflect diminished integration of visual consequences with motor output, was predictive of the severity of social deficits and may contribute to impaired social-communicative skill development in children with ASD.

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5. Muotri AR. The Human Model : Changing Focus on Autism Research. Biological Psychiatry ;2016 ;79(8):642-649.

Abstract The lack of live human brain cells for research has slowed progress toward understanding the mechanisms underlying autism spectrum disorders. A human model using reprogrammed patient somatic cells offers an attractive alternative, as it captures a patient’s genome in relevant cell types. Despite the current limitations, the disease-in-a-dish approach allows for progressive time course analyses of target cells, offering a unique opportunity to investigate the cellular and molecular alterations before symptomatic onset. Understanding the current drawbacks of this model is essential for the correct data interpretation and extrapolation of conclusions applicable to the human brain. Innovative strategies for collecting biological material and clinical information from large patient cohorts are important for increasing the statistical power that will allow for the extraction of information from the noise resulting from the variability introduced by reprogramming and differentiation methods. Working with large patient cohorts is also important for understanding how brain cells derived from diverse human genetic backgrounds respond to specific drugs, creating the possibility of personalized medicine for autism spectrum disorders.

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6. Wendland JR, Ehlers MD. Translating Neurogenomics Into New Medicines. Biological Psychiatry ;2016 ;79(8):650-656.

Abstract Brain disorders remain one of the defining challenges of modern medicine and among the most poorly served with new therapeutics. Advances in human neurogenetics have begun to shed light on the genomic architecture of complex diseases of mood, cognition, brain development, and neurodegeneration. From genome-wide association studies to rare variants, these findings hold promise for defining the pathogenesis of brain disorders that have resisted simple molecular description. However, the path from genetics to new medicines is far from clear and can take decades, even for the most well-understood genetic disorders. In this review, we define three challenges for the field of neurogenetics that we believe must be addressed to translate human genetics efficiently into new therapeutics for brain disorders.

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7. Pierce K, Marinero S, Hazin R, McKenna B, Barnes CC, Malige A. Eye Tracking Reveals Abnormal Visual Preference for Geometric Images as an Early Biomarker of an Autism Spectrum Disorder Subtype Associated With Increased Symptom Severity. Biological Psychiatry ;2016 ;79(8):657-666.

AbstractBackground Clinically and biologically, autism spectrum disorder (ASD) is heterogeneous. Unusual patterns of visual preference as indexed by eye tracking are hallmarks ; however, whether they can be used to define an early biomarker of ASD as a whole or leveraged to define a subtype is unclear. To begin to examine this issue, large cohorts are required. Methods A sample of 334 toddlers from six distinct groups (115 toddlers with ASD, 20 toddlers with ASD features, 57 toddlers with developmental delay, 53 toddlers with other conditions [e.g., premature birth, prenatal drug exposure], 64 toddlers with typical development, and 25 unaffected toddlers with siblings with ASD) was studied. Toddlers watched a movie containing geometric and social images. Fixation duration and number of saccades within each area of interest and validation statistics for this independent sample were computed. Next, to maximize power, data from our previous study (n = 110) were added for a total of 444 subjects. A subset of toddlers repeated the eye-tracking procedure. Results As in the original study, a subset of toddlers with ASD fixated on geometric images >69% of the time. Using this cutoff, sensitivity for ASD was 21%, specificity was 98%, and positive predictive value was 86%. Toddlers with ASD who strongly preferred geometric images had 1) worse cognitive, language, and social skills relative to toddlers with ASD who strongly preferred social images and 2) fewer saccades when viewing geometric images. Unaffected siblings of ASD probands did not show evidence of heightened preference for geometric images. Test-retest reliability was good. Examination of age effects suggested that this test may not be appropriate with children >4 years old. Conclusions Enhanced visual preference for geometric repetition may be an early developmental biomarker of an ASD subtype with more severe symptoms.

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8. Luongo FJ, Horn ME, Sohal VS. Putative Microcircuit-Level Substrates for Attention Are Disrupted in Mouse Models of Autism. Biological Psychiatry ;2016 ;79(8):667-675.

AbstractBackground Deep layer excitatory circuits in the prefrontal cortex represent the strongest locus for genetic convergence in autism, but specific abnormalities within these circuits that mediate key features of autism, such as cognitive or attentional deficits, remain unknown. Attention normally increases the sensitivity of neural populations to incoming signals by decorrelating ongoing cortical circuit activity. Here, we investigated whether mechanisms underlying this phenomenon might be disrupted within deep layer prefrontal circuits in mouse models of autism. Methods We isolated deep layer prefrontal circuits in brain slices then used single-photon GCaMP imaging to record activity from many (50 to 100) neurons simultaneously to study patterns of spontaneous activity generated by these circuits under normal conditions and in two etiologically distinct models of autism : mice exposed to valproic acid in utero and Fmr1 knockout mice. Results We found that modest doses of the cholinergic agonist carbachol normally decorrelate spontaneous activity generated by deep layer prefrontal networks. This effect was disrupted in both valproic acid-exposed and Fmr1 knockout mice but intact following other manipulations that did not model autism. Conclusions Our results suggest that cholinergic modulation may contribute to attention by acting on local cortical microcircuits to decorrelate spontaneous activity. Furthermore, defects in this mechanism represent a microcircuit-level endophenotype that could link diverse genetic and developmental disruptions to attentional deficits in autism. Future studies could elucidate pathways leading from various etiologies to this circuit-level abnormality or use this abnormality itself as a target and identify novel therapeutic strategies that restore normal circuit function.

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9. Solso S, Xu R, Proudfoot J, Hagler Jr DJ, Campbell K, Venkatraman V, Carter Barnes C, Ahrens-Barbeau C, Pierce K, Dale A, Eyler L, Courchesne E. Diffusion Tensor Imaging Provides Evidence of Possible Axonal Overconnectivity in Frontal Lobes in Autism Spectrum Disorder Toddlers. Biological Psychiatry ;2016 ;79(8):676-684.

AbstractBackground Theories of brain abnormality in autism spectrum disorder (ASD) have focused on underconnectivity as an explanation for social, language, and behavioral deficits but are based mainly on studies of older autistic children and adults. Methods In 94 ASD and typical toddlers ages 1 to 4 years, we examined the microstructure (indexed by fractional anisotropy) and volume of axon pathways using in vivo diffusion tensor imaging of fronto-frontal, fronto-temporal, fronto-striatal, and fronto-amygdala axon pathways, as well as posterior contrast tracts. Differences between ASD and typical toddlers in the nature of the relationship of age to these measures were tested. Results Frontal tracts in ASD toddlers displayed abnormal age-related changes with greater fractional anisotropy and volume than normal at younger ages but an overall slower than typical apparent rate of continued development across the span of years. Posterior cortical contrast tracts had few significant abnormalities. Conclusions Frontal fiber tracts displayed deviant early development and age-related changes that could underlie impaired brain functioning and impact social and communication behaviors in ASD.

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10. Been LE, Moore KM, Kennedy BC, Meisel RL. Metabotropic Glutamate Receptor and Fragile X Signaling in a Female Model of Escalated Aggression. Biological Psychiatry ;2016 ;79(8):685-692.

AbstractBackground Escalated aggression is a behavioral sign of numerous psychiatric disorders characterized by a loss of control. The neurobiology underlying escalated aggression is unknown and is particularly understudied in females. Research in our laboratory demonstrated that repeated aggressive experience in female hamsters resulted in an escalated response to future aggressive encounters and an increase in dendritic spine density on nucleus accumbens (NAc) neurons. We hypothesized that the activation of group I metabotropic glutamate receptor signaling though the fragile X mental retardation protein (FMRP) pathway may underlie synaptic plasticity associated with aggression escalation. Methods Female hamsters were given five daily aggression tests with or without prior treatment with the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)-pyridine. Following aggression testing, messenger RNA expression and protein levels were measured in the nucleus accumbens for postsynaptic density protein 95 (PSD-95) and SAP90/PSD-95-associated protein 3, as well as the levels of phosphorylated FMRP. Results Experience-dependent escalation of aggression in female hamsters depends on activation of mGluR5 receptors. Furthermore, aggressive experience decreases phosphorylation of FMRP in the NAc, which is coupled to a long-term increase in the expression of the synaptic scaffolding proteins PSD-95 and SAP90/PSD-95-associated protein 3. Finally, the experience-dependent increase in PSD-95 is prevented by antagonism of the mGluR5 receptor. Conclusions Activation of the FMRP pathway by group I metabotropic glutamate receptors is involved in regulating synaptic plasticity following aggressive experience. The NAc is a novel target for preclinical studies of the treatment of escalated aggression, with the added benefit that emerging therapeutic approaches are likely to be effective in treating pathologic aggression in both female and male subjects.

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11. Paloyelis Y, Doyle OM, Zelaya FO, Maltezos S, Williams SC, Fotopoulou A, Howard MA. A Spatiotemporal Profile of In Vivo Cerebral Blood Flow Changes Following Intranasal Oxytocin in Humans. Biological Psychiatry ;2016 ;79(8):693-705.

AbstractBackground Animal and human studies highlight the role of oxytocin in social cognition and behavior and the potential of intranasal oxytocin (IN-OT) to treat social impairment in individuals with neuropsychiatric disorders such as autism. However, extensive efforts to evaluate the central actions and therapeutic efficacy of IN-OT may be marred by the absence of data regarding its temporal dynamics and sites of action in the living human brain. Methods In a placebo-controlled study, we used arterial spin labeling to measure IN-OT-induced changes in resting regional cerebral blood flow (rCBF) in 32 healthy men. Volunteers were blinded regarding the nature of the compound they received. The rCBF data were acquired 15 min before and up to 78 min after onset of treatment onset (40 IU of IN-OT or placebo). The data were analyzed using mass univariate and multivariate pattern recognition techniques. Results We obtained robust evidence delineating an oxytocinergic network comprising regions expected to express oxytocin receptors, based on histologic evidence, and including core regions of the brain circuitry underpinning social cognition and emotion processing. Pattern recognition on rCBF maps indicated that IN-OT-induced changes were sustained over the entire posttreatment observation interval (25–78 min) and consistent with a pharmacodynamic profile showing a peak response at 39–51 min. Conclusions Our study provides the first visualization and quantification of IN-OT-induced changes in rCBF in the living human brain unaffected by cognitive, affective, or social manipulations. Our findings can inform theoretical and mechanistic models regarding IN-OT effects on typical and atypical social behavior and guide future experiments (e.g., regarding the timing of experimental manipulations).

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12. Bohland JW. Toward a Multimodal, Multiscale Understanding of White Matter Abnormalities in Autism Spectrum Disorder. Biological Psychiatry ;2016 ;79(8):e47-e48.

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13. Quintana DS, Woolley JD. Intranasal Oxytocin Mechanisms Can Be Better Understood, but Its Effects on Social Cognition and Behavior Are Not to Be Sniffed At. Biological Psychiatry ;2016 ;79(8):e49-e50.

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14. Leng G, Ludwig M. Reply to : Intranasal Oxytocin Mechanisms Can Be Better Understood, but Its Effects on Social Cognition and Behavior Are Not to Be Sniffed At. Biological Psychiatry ;2016 ;79(8):e51-e52.

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15. Carson DS, Yuan H, Labuschagne I. Improving Research Standards to Restore Trust in Intranasal Oxytocin. Biological Psychiatry ;2016 ;79(8):e53-e54.

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16. Leng G, Ludwig M. Reply to : Improving Research Standards to Restore Trust in Intranasal Oxytocin. Biological Psychiatry ;2016 ;79(8):e55-e56.

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