1. Amatachaya A, Jensen MP, Patjanasoontorn N, Auvichayapat N, Suphakunpinyo C, Janjarasjitt S, Ngernyam N, Aree-Uea B, Auvichayapat P. {{The short-term effects of transcranial direct current stimulation on electroencephalography in children with autism: a randomized crossover controlled trial}}. {Behav Neurol};2015;2015:928631.
Abnormal synaptic maturation and connectivity are possible etiologies of autism. Previous studies showed significantly less alpha activity in autism than normal children. Therefore, we studied the effects of anodal tDCS on peak alpha frequency (PAF) related to autism treatment evaluation checklist (ATEC). Twenty male children with autism were randomly assigned in a crossover design to receive a single session of both active and sham tDCS stimulation (11 mA) over F3 (left dorsolateral prefrontal cortex). Pre- to postsession changes in a measure of cortical activity impacted by tDCS (PAF) and ATEC were compared between groups. We also examined the associations between pre- and postsession changes in the PAF and ATEC. The results show significant pre- to postsession improvements in two domains of ATEC (social and health/behavior domains) following active tDCS, relative to sham treatment. PAF also significantly increased at the stimulation site, and an increase in PAF was significantly associated with improvements in the two domains of ATEC impacted by tDCS. The findings suggest that a single session of anodal tDCS over the F3 may have clinical benefits in children with autism and that those benefits may be related to an increase in PAF.
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2. Conti E, Calderoni S, Marchi V, Muratori F, Cioni G, Guzzetta A. {{The first 1000 days of the autistic brain: a systematic review of diffusion imaging studies}}. {Front Hum Neurosci};2015;9:159.
There is overwhelming evidence that autism spectrum disorder (ASD) is related to altered brain connectivity. While these alterations are starting to be well characterized in subjects where the clinical picture is fully expressed, less is known on their earlier developmental course. In the present study we systematically reviewed current knowledge on structural connectivity in ASD infants and toddlers. We searched PubMed and Medline databases for all English language papers, published from year 2000, exploring structural connectivity in populations of infants and toddlers whose mean age was below 30 months. Of the 264 papers extracted, four were found to be eligible and were reviewed. Three of the four selected studies reported higher fractional anisotropy values in subjects with ASD compared to controls within commissural fibers, projections fibers, and association fibers, suggesting brain hyper-connectivity in the earliest phases of the disorder. Similar conclusions emerged from the other diffusion parameters assessed. These findings are reversed to what is generally found in studies exploring older patient groups and suggest a developmental course characterized by a shift toward hypo-connectivity starting at a time between two and four years of age.
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3. Dickinson A, Bruyns-Haylett M, Jones M, Milne E. {{Increased peak gamma frequency in individuals with higher levels of autistic traits}}. {Eur J Neurosci};2015 (Apr 8)
Individual differences in orientation discrimination threshold are related to both visually-induced peak gamma frequency and the presence of autistic traits. The relationship between peak gamma frequency and orientation discrimination thresholds may be due to both of these factors being mediated by levels of neural inhibition. No study has previously measured the relationship between peak gamma frequency and levels of autistic traits. Thus, this was the aim of the present study. We measured orientation discrimination thresholds and autistic traits in a neurotypical human sample (N = 33), and separately recorded electroencephalography to measure visually induced gamma activity. In line with our prediction, we found a significant relationship between peak gamma frequency and level of autistic traits. Consistent with previous work we also found significant relationships between orientation discrimination thresholds and level of autistic traits and between orientation discrimination thresholds and peak gamma frequency. Our results demonstrate that individuals with individuals with higher levels of autistic personality traits have a higher peak-gamma frequency and are better at discriminating between visual stimuli based on orientation. As both higher peak gamma frequency and lower orientation discrimination thresholds have been linked to higher levels of neural inhibition, this suggests that autistic traits co-occur with increased neural inhibition. This discovery is significant as it challenges the currently-held view that autism spectrum conditions are associated with increased neural excitation.
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4. Fieremans N, Van Esch H, de Ravel T, Van Driessche J, Belet S, Bauters M, Froyen G. {{Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features}}. {Eur J Med Genet};2015 (Apr 7)
Intellectual disability (ID) is a very heterogeneous disorder with over 100 ID genes located on the X chromosome alone. Of these, KDM5C and IQSEC2 are located adjacent to each other at the Xp11.22 locus. While mutations in either of these genes are associated with severe ID in males, female carriers are mostly unaffected. Here, we report on a female patient with severe ID and autistic features carrying a de novo 0.4 Mb deletion containing six coding genes including KDM5C and IQSEC2. X-inactivation analysis revealed skewing in a lymphocyte-derived cell line from this patient with preferential inactivation of the mutant X chromosome. As the brain-expressed KDM5C and IQSEC2 genes escape X-inactivation, deletion of these alleles could still be detrimental despite skewing of X-inactivation. Indeed, mutations in either of both genes have been reported in a few female ID patients. Expression analysis in the patients’ cell line revealed decreased KDM5C mRNA levels compared to female controls. IQSEC2 levels could not be compared due to very low expression in blood. Overall, our data suggest that heterozygous loss-of-function of the escape genes KDM5C and/or IQSEC2 can contribute to severe ID in female patients and should be taken into account in diagnostics.
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5. Kenmuir C, Richardson M, Ghearing G. {{Surgical treatment for medically refractory focal epilepsy in a patient with fragile X syndrome}}. {Brain Dev};2015 (Apr 7)
RATIONALE: Medication resistant temporal lobe epilepsy occurs in a small population of patients with fragile X syndrome. We present the case of a 24-year-old man with medically refractory temporal lobe epilepsy and fragile X syndrome who underwent left anterior temporal lobectomy resulting in cessation of seizures. METHODS: Our patient was diagnosed with fragile X syndrome with a fully mutated, fully methylated FMR1 gene resulting in 572 CGG repeats. He developed seizures initially controlled with Depakote monotherapy, but progressed to become medically refractive to combination treatment with Depakote, lamotrigine and zonisamide. Prolonged video EEG monitoring revealed interictal left temporal sharp waves and slowing as well as subclinical and clinical seizures, each with left temporal onset. 3T MRI was consistent with left mesial temporal sclerosis. After discussing the case in our multidisciplinary surgical epilepsy conference, he was referred for presurgical evaluation including neuropsychological testing and Wada testing. RESULTS: He underwent an asleep left anterior temporal lobectomy, sparing the superior temporal gyrus. Pathology showed neuronal loss and gliosis in the hippocampus and amygdala. Twelve months after surgery, the patient has not experienced a seizure. He is described by his parents as less perseverative and less restless. CONCLUSIONS: We have presented the case of a 24year-old-man with fragile X syndrome who underwent successful left anterior temporal lobectomy for the treatment of medically refractory epilepsy who is now seizure free without further functional impairment. This case report demonstrates the feasibility of surgical treatment for a patient with comorbid fragile X syndrome and mesial temporal sclerosis.
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6. Neuhofer D, Henstridge CM, Dudok B, Sepers M, Lassalle O, Katona I, Manzoni OJ. {{Functional and structural deficits at accumbens synapses in a mouse model of Fragile X}}. {Front Cell Neurosci};2015;9:100.
Fragile X is the most common cause of inherited intellectual disability and a leading cause of autism. The disease is caused by mutation of a single X-linked gene called fmr1 that codes for the Fragile X mental retardation protein (FMRP), a 71 kDa protein, which acts mainly as a translation inhibitor. Fragile X patients suffer from cognitive and emotional deficits that coincide with abnormalities in dendritic spines. Changes in spine morphology are often associated with altered excitatory transmission and long-term plasticity, the most prominent deficit in fmr1-/y mice. The nucleus accumbens, a central part of the mesocortico-limbic reward pathway, is now considered as a core structure in the control of social behaviors. Although the socio-affective impairments observed in Fragile X suggest dysfunctions in the accumbens, the impact of the lack of FMRP on accumbal synapses has scarcely been studied. Here we report for the first time a new spike timing-dependent plasticity paradigm that reliably triggers NMDAR-dependent long-term potentiation (LTP) of excitatory afferent inputs of medium spiny neurons (MSN) in the nucleus accumbens core region. Notably, we discovered that this LTP was completely absent in fmr1-/y mice. In the fmr1-/y accumbens intrinsic membrane properties of MSNs and basal excitatory neurotransmission remained intact in the fmr1-/y accumbens but the deficit in LTP was accompanied by an increase in evoked AMPA/NMDA ratio and a concomitant reduction of spontaneous NMDAR-mediated currents. In agreement with these physiological findings, we found significantly more filopodial spines in fmr1-/y mice by using an ultrastructural electron microscopic analysis of accumbens core medium spiny neuron spines. Surprisingly, spine elongation was specifically due to the longer longitudinal axis and larger area of spine necks, whereas spine head morphology and postsynaptic density size on spine heads remained unaffected in the fmr1-/y accumbens. These findings together reveal new structural and functional synaptic deficits in Fragile X.
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7. Pisula E, Kawa R, Danielewicz D, Pisula W. {{The Relationship between Temperament and Autistic Traits in a Non-Clinical Students Sample}}. {PLoS One};2015;10(4):e0124364.
Since temperament affects the development of social behaviours and interpersonal relations, the possible links between autistic traits and temperament are of particular interest. The purpose of the study was to explore the relationships between autistic traits and temperamental characteristics in the framework of the Regulative Temperament Theory by Strelau, and the Emotionality, Activity and Sociability theory by Buss and Plomin, with particular emphasis on gender differences. The Autism Spectrum Quotient (AQ), Formal Characteristics of Behaviour – Temperament Inventory and Temperament Survey for Adults were administered. The participants were 593 university students, including 364 females and 229 males. Results showed positive correlations between autistic traits and Emotional Reactivity, Perseveration, Distress, Fear and Anger, and negative correlations with Activity, Briskness, Endurance and Sociability. The results of multiple regression analyses involving the Autism Spectrum Quotient score as a dependent measure were different for females and males. Results of exploratory PCA analysis showed that AQ score, Sociability and Activity loaded one factor (with AQ loading being opposite to two others). High AQ scorers demonstrated higher Emotional Reactivity, Perseveration, Distress and Anger, and lower Briskness, Endurance, Activity and Sociability as compared to norms for the general population. In this study we showed that temperament measures were able to identify items that correlated in parts with autistic traits, while other items were obverse. The relationships between temperament and autistic traits differ slightly between genders. We assume that with regard to the broader autism phenotype, temperaments might be helpful in characterizing healthy control samples.
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8. Pozzo-Miller L, Pati S, Percy AK. {{Rett Syndrome: Reaching for Clinical Trials}}. {Neurotherapeutics};2015 (Apr 11)
Rett syndrome (RTT) is a syndromic autism spectrum disorder caused by loss-of-function mutations in MECP2. The methyl CpG binding protein 2 binds methylcytosine and 5-hydroxymethycytosine at CpG sites in promoter regions of target genes, controlling their transcription by recruiting co-repressors and co-activators. Several preclinical studies in mouse models have identified rational molecular targets for drug therapies aimed at correcting the underlying neural dysfunction. These targeted therapies are increasingly translating into human clinical trials. In this review, we present an overview of RTT and describe the current state of preclinical studies in methyl CpG binding protein 2-based mouse models, as well as current clinical trials in individuals with RTT.
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9. Tsai SJ. {{Is riluzole a potential therapy for Rett syndrome?}}. {Med Hypotheses};2015 (Apr 4)
Rett syndrome (RTT) is a severe neurodevelopmental disorder with autistic features and is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) in the majority of cases. Besides symptomatic treatment, no therapeutic trials have shown effectiveness for RTT. Some perspectives in the treatment of RTT have been provided by recent works showing a phenotypic reversal by increasing brain-derived neurotrophic factor (BDNF) expression in a RTT mouse model. Glutamate may also play an important role in the primary pathogenesis in Rett syndrome through the excitotoxic neuronal injury in experimental models. Riluzole, an agent currently approved for the treatment of amyotrophic lateral sclerosis, is a glutamatergic modulator and BDNF enhancer with neuroprotective properties. For these reasons, riluzole could potentially play an important role in the treatment of RTT symptoms. Several points regarding the use of riluzole in RTT are discussed. Further evaluation of the therapeutic effects of this agent in RTT animal models is needed before clinical trials can begin.
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10. Yoo HJ, Woo RS, Cho SC, Kim BN, Kim JW, Shin MS, Park TW, Son JW, Chung US, Park S, Park M, Kim SA. {{Genetic association analyses of neuregulin 1 gene polymorphism with endopheontype for sociality of Korean autism spectrum disorders family}}. {Psychiatry Res};2015 (Mar 23)
To determine the genetic association between qualitative and quantitative traits of autism spectrum disorder (ASD) and neuregulin 1 (NRG1)-a schizophrenia candidate gene-we examined six single nucleotide polymorphisms (SNPs) in NRG1 using a family-based association test (FBAT) in Korean families with ASD. rs35753505 and rs6994992 SNPs in NRG1 revealed a statistically significant family-based association with three quantitative traits for sociality.
