1. Abdelmageed RI, Youssef AM, Rihan LS, Abdelaziz AW. Validation of the autism behavior checklist in Egyptian children with autism spectrum disorder. Child Neuropsychol;2024 (Jan 26):1-16.

This study was designed to validate the Arabic version of the Autism Behavior Checklist (ABC) for the Egyptian population. A total of 500 mothers of children aged 4-14 years, of whom 150 had a diagnosis of ASD, 100 with intellectual disability, and 250 typically developing children completed the ABC. The factor analysis showed that 48 of 57 ABC items yielded a five-dimensional factor structure. The ABC-Arabic version indicated acceptable internal consistency (α = 0.85) and test – retest reliability (0.82). Also, the ABC exhibited good concurrent validity and discriminative validity. A cutoff score of 58 obtained a sensitivity of 94.7% and a specificity of 92.14% for detecting children with ASD. Our findings support the use of the ABC as a valid screening measure for ASD cases, and it may promote the use of the ABC for clinical and research purposes among Arabic-speaking communities.

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2. Asgarihafshejani A, Raveendran VA, Pressey JC, Woodin MA. LTP is Absent in the CA1 Region of the Hippocampus of Male and Female Rett Syndrome Mouse Models. Neuroscience;2024 (Jan 26);537:189-204.

Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, resulting in severe deficits in learning and memory. Alterations in synaptic plasticity have been reported in RTT, however most electrophysiological studies have been performed in male mice only, despite the fact that RTT is primarily found in females. In addition, most studies have focused on excitation, despite the emerging evidence for the important role of inhibition in learning and memory. Here, we performed an electrophysiological characterization in the CA1 region of the hippocampus in both males and females of RTT mouse models with a focus on neurogliaform (NGF) interneurons, given that they are the most abundant dendrite-targeting interneuron subtype in the hippocampus. We found that theta-burst stimulation (TBS) failed to induce long-term potentiation (LTP) in either pyramidal neurons or NGF interneurons in male or female RTT mice, with no apparent changes in short-term plasticity (STP). This failure to induce LTP was accompanied by excitation/inhibition (E/I) imbalances and altered excitability, in a sex- and cell-type specific manner. Specifically, NGF interneurons of male RTT mice displayed increased intrinsic excitability, a depolarized resting membrane potential, and decreased E/I balance, while in female RTT mice, the resting membrane potential was depolarized. Understanding the role of NGF interneurons in RTT animal models is crucial for developing targeted treatments to improve cognition in individuals with this disorder.

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3. Camacho-Morales A, Cárdenas-Tueme M. Prenatal Programming of Monocyte Chemotactic Protein-1 Signaling in Autism Susceptibility. Mol Neurobiol;2024 (Jan 26)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that involves functional and structural defects in selective central nervous system (CNS) regions, harming the individual capability to process and respond to external stimuli, including impaired verbal and non-verbal communications. Etiological causes of ASD have not been fully clarified; however, prenatal activation of the innate immune system by external stimuli might infiltrate peripheral immune cells into the fetal CNS and activate cytokine secretion by microglia and astrocytes. For instance, genomic and postmortem histological analysis has identified proinflammatory gene signatures, microglia-related expressed genes, and neuroinflammatory markers in the brain during ASD diagnosis. Active neuroinflammation might also occur during the developmental stage, promoting the establishment of a defective brain connectome and increasing susceptibility to ASD after birth. While still under investigation, we tested the hypothesis whether the monocyte chemoattractant protein-1 (MCP-1) signaling is prenatally programmed to favor peripheral immune cell infiltration and activate microglia into the fetal CNS, setting susceptibility to autism-like behavior. In this review, we will comprehensively provide the current understanding of the prenatal activation of MCP-1 signaling by external stimuli during the developmental stage as a new selective node to promote neuroinflammation, brain structural alterations, and behavioral defects associated to ASD diagnosis.

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4. Diamanti T, Trobiani L, Mautone L, Serafini F, Gioia R, Ferrucci L, Lauro C, Bianchi S, Perfetto C, Guglielmo S, Sollazzo R, Giorda E, Setini A, Ragozzino D, Miranda E, Comoletti D, Di Angelantonio S, Cacci E, De Jaco A. Glucocorticoids rescue cell surface trafficking of R451C Neuroligin3 and enhance synapse formation. Traffic;2024 (Jan);25(1):e12930.

Neuroligins are synaptic cell adhesion proteins with a role in synaptic function, implicated in neurodevelopmental disorders. The autism spectrum disorder-associated substitution Arg451Cys (R451C) in NLGN3 promotes a partial misfolding of the extracellular domain of the protein leading to retention in the endoplasmic reticulum (ER) and the induction of the unfolded protein response (UPR). The reduced trafficking of R451C NLGN3 to the cell surface leads to altered synaptic function and social behavior. A screening in HEK-293 cells overexpressing NLGN3 of 2662 compounds (FDA-approved small molecule drug library), led to the identification of several glucocorticoids such as alclometasone dipropionate, desonide, prednisolone sodium phosphate, and dexamethasone (DEX), with the ability to favor the exit of full-length R451C NLGN3 from the ER. DEX improved the stability of R451C NLGN3 and trafficking to the cell surface, reduced the activation of the UPR, and increased the formation of artificial synapses between HEK-293 and hippocampal primary neurons. The effect of DEX was validated on a novel model system represented by neural stem progenitor cells and differentiated neurons derived from the R451C NLGN3 knock-in mouse, expressing the endogenous protein. This work shows a potential rescue strategy for an autism-linked mutation affecting cell surface trafficking of a synaptic protein.

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5. Hickey EJ, DaWalt LS, Hong J, Taylor JL, Mailick MR. Trajectories of Competitive Employment of Autistic Adults through Late Midlife. Healthcare (Basel);2024 (Jan 20);12(2)

Autistic adults experience challenges in maintaining employment; however, little is known about patterns of competitive employment through late midlife. This longitudinal study examined the change in hours of competitive employment for a cohort of autistic adults over a 22-year period. The study’s aims were to provide a fine-grained analysis of competitive employment patterns, to determine whether there was age-related change, and to test whether trajectories differed between those with and without intellectual disability (ID). Using an accelerated longitudinal design, trajectories of hours of competitive employment were estimated from young adulthood through late midlife in a community-based cohort (n = 341; 1327 observations). Results indicated a significant curvilinear trajectory of age-related change in hours of competitive employment, with differences between those with and without ID. For those without ID, the number of competitive employment hours increased from young adulthood until early midlife, then leveled off and decreased into late midlife. For those with ID, engagement in competitive employment was low throughout. Although competitive employment is just one option for vocational engagement, it is a goal often articulated by autistic adults who seek entry into the general workforce. The present research reveals their degree of engagement in the competitive workforce across the decades of adulthood.

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6. Kamp-Becker I. Autism spectrum disorder in ICD-11-a critical reflection of its possible impact on clinical practice and research. Mol Psychiatry;2024 (Jan 25)

This perspective article compares and contrasts the conceptualization of Autism Spectrum Disorder (ASD) in ICD-11 and DSM-5. By guiding the user through the ICD-11 text, it is argued that, in contrast to DSM-5, ICD-11 allows a high variety in symptom combinations, which results in an operationalization of ASD that is in favor of an extreme diverse picture, yet possibly at the expense of precision, including unforeseeable effects on clinical practice, care, and research. The clinical utility is questionable as this conceptualization can hardly be differentiated from other mental disorders and autism-like traits. It moves away from an observable, behavioral, and neurodevelopmental disorder to a disorder of inner experience that can hardly be measured objectively. It contains many vague and subjective concepts that lead to non-falsifiable diagnoses. This bears a large danger of false positive diagnoses, of further increased prevalence rates, limitations of access to ASD-specific services and of increasing the non-specificity of treatments. For research, the hypothesis is that the specificity of ASD will be reduced and this will additional increase the already high heterogeneity with the effect that replication of studies will be hampered. This could limit our understanding of etiology and biological pathways of ASD and bears the risk that precision medicine, i.e., a targeted approach for individual treatment strategies based on precise diagnostic markers, is more far from becoming reality. Thus, a more precise, quantitative description and more objective measurement of symptoms are suggested that define the clinical ASD phenotype. Identification of core ASD subtypes/endophenotypes and a precise description of symptoms is the necessary next step to advance diagnostic classification systems. Therefore, employing a more finely grained, objective, clinical symptom characterization which is more relatable to neurobehavioral concepts is of central significance.

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7. Key AP, Thompson EC, Benítez-Barrera C, Feldman JI, Woynaroski T, Picou E, Tharpe AM. Electrophysiological Measures of Listening-in-Noise With and Without Remote Microphone System Use in Autistic and Non-Autistic Youth. Ear Hear;2024 (Jan 26)

OBJECTIVES: This study examined the neural mechanisms by which remote microphone (RM) systems might lead to improved behavioral performance on listening-in-noise tasks in autistic and non-autistic youth. DESIGN: Cortical auditory evoked potentials (CAEPs) were recorded in autistic (n = 25) and non-autistic (n = 22) youth who were matched at the group level on chronological age (M = 14.21 ± 3.39 years) and biological sex. Potentials were recorded during an active syllable identification task completed in quiet and in multi-talker babble noise with and without the use of an RM system. The effects of noise and RM system use on speech-sound-evoked P1-N1-P2 responses and the associations between the cortical responses and behavioral performance on syllable identification were examined. RESULTS: No group differences were observed for behavioral or CAEP measures of speech processing in quiet or in noise. In the combined sample, syllable identification in noise was less accurate and slower than in the quiet condition. The addition of the RM system to the noise condition restored accuracy, but not the response speed, to the levels observed in quiet. The CAEP analyses noted amplitude reductions and latency delays in the noise compared with the quiet condition. The RM system use increased the N1 amplitude as well as reduced and delayed the P2 response relative to the quiet and noise conditions. Exploratory brain-behavior correlations revealed that larger N1 amplitudes in the RM condition were associated with greater behavioral accuracy of syllable identification. Reduced N1 amplitude and accelerated P2 response were associated with shorter syllable identification response times when listening with the RM system. CONCLUSIONS: Findings suggest that although listening-in-noise with an RM system might remain effortful, the improved signal to noise ratio facilitates attention to the sensory features of the stimuli and increases speech sound identification accuracy.

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8. Lacroix A, Harquel S, Mermillod M, Garrido M, Barbosa L, Vercueil L, Aleysson D, Dutheil F, Kovarski K, Gomot M. Sex modulation of faces prediction error in the autistic brain. Commun Biol;2024 (Jan 25);7(1):127.

Recent research suggests that autistic females may have superior socio-cognitive abilities compared to autistic males, potentially contributing to underdiagnosis in females. However, it remains unclear whether these differences arise from distinct neurophysiological functioning in autistic males and females. This study addresses this question by presenting 41 autistic and 48 non-autistic adults with a spatially filtered faces oddball paradigm. Analysis of event-related potentials from scalp electroencephalography reveal a neurophysiological profile in autistic females that fell between those of autistic males and non-autistic females, highlighting sex differences in autism from the initial stages of face processing. This finding underscores the urgent need to explore neurophysiological sex differences in autism and encourages efforts toward a better comprehension of compensation mechanism and a clearer definition of what is meant by camouflaging.

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9. Li H, Dodd-Butera T, Beaman ML, Burtea R. Immediate Caregiving Environment of Young Children with Autism: Findings from the U.S. National Survey of Children’s Health. Int J Environ Res Public Health;2023 (Dec 21);21(1)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disability that negatively affects children’s learning, motor behavior, social communication, and interaction. It was estimated that, in 2020, 1 in 36 children aged 8 years in the United States had ASD. Caring for children with ASD might exert significant psychological and emotional distress on parents. Receiving parental emotional support and fostering positive parent-child interactions at home have been identified as beneficial for the immediate caregiving environment for children with ASD. The current secondary analysis of the 2019-2020 National Survey of Children’s Health examined parent-child interactions and accessible sources of emotional support for parents caring for 3-5-year-old children diagnosed with ASD (N = 243). Children with the following characteristics had higher odds of having ASD: male gender; having no private insurance or uninsured; and having less than excellent general health. Among parents, higher odds of caring for children with ASD were associated with accessing emotional support from various sources, especially from healthcare professionals and peers, and spending more time telling stories and/or singing to their children. Given these significant health disparities, educational interventions and strategies are needed to foster a positive home caregiving environment for young children with ASD, including equitable access to parent resources.

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10. Margedari P, Goudarzi I, Sepehri H. The protective role of prenatal administration of ascorbic acid on autistic-like behavior in a rat model of autism. IBRO Neurosci Rep;2024 (Jun);16:78-85.

BACKGROUND: Autism is a complicated neurodevelopmental disorder characterized by several behavioral impairments. The pathology of autism is complex and not fully known. Several recent studies have shown alterations in the activities of antioxidant enzymes in autism. Vitamin C is a potent antioxidant that is present in high concentrations in the brain and acts as a neuromodulator. Prefrontal abnormality has been hypothesized to underlie autistic symptoms. The present study investigated the protective effect of prenatally Vitamin C on autistic-like behaviors, oxidative stress status, and histopathological change of prefrontal in valproic acid (VPA) rat model of autism. METHOD: The model of autism was induced by subcutaneous administration of Valproic acid (600 mg/kg) to pregnant rats at gestational day 12.5. Vitamin C was administered 600 mg/L in drinking water from the 5th day of gestaion (GD5) up to postnatal day 23 (PND23). Thirty-two rat offspring were divided into four groups: Control, Vitamin C, VPA, and Vitamin C + VPA. The offspring were tested for repetitive behaviors and cognitive ability with a Y-maze task and social interaction with a play behavior task on 31st of Postnatal days. Glutathione (GSH), superoxide dismutase (SOD) activity, and the histological change in the prefrontal lobe were assessed at the end of the study. The number of neurons from the left prefrontal lobe was counted in duplicate from slides stained with hematoxylin-eosin. RESULTS: In the Y-maze apparatus, spontaneous alteration significantly decreased in the prenatal VPA treated rats compared to control rats showing autistic-like behavior; pre and postnatal Vitamin C treatment increased the alternation indicated benefit effect of Vitamin C. Prenatal VPA treatment impaired play behavior such as sniffing, grooming and darting. Vitamin C treatment attenuated the problems in male offspring social behavior. Histological examination showed an increase in the number of cells in the prefrontal cortex of valproic acid offspring rats compared to other groups. Moreover, prenatal VPA decreased antioxidant enzyme activities in the cortex (PFC) attenuated by Vitamin C administration. CONCLUSION: The present study showed that valproic acid induced oxidative stress and neural changes in the prefrontal lobe when administered prenatally which in turn may cause the development of some autistic-like behaviors, and vitamin C may reduce this symptom with its antioxidant effects.

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11. Pérez-Vigil A, Ilzarbe D, Garcia-Delgar B, Morer A, Pomares M, Puig O, Lera-Miguel S, Rosa M, Romero M, Calvo Escalona R, Lázaro L. Theory of mind in neurodevelopmental disorders: beyond autistic spectrum disorder. Neurologia (Engl Ed);2024 (Jan 23)

INTRODUCTION: Theory of mind (ToM) is the human ability to perceive, interpret, and attribute the mental states of other people, and the alteration of this cognitive function is a core symptom of autistic spectrum disorder (ASD). In such other neurodevelopmental disorders as childhood-onset obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) that can present with cognitive dysfunctions, ToM has been less extensively studied, especially in the young population. The aim of the study was to compare advanced ToM between groups of young people diagnosed with OCD, TS, or ASD and a control group. METHODS: Clinical interviews were conducted with male patients aged between 11 and 17 years with a main diagnosis of OCD (n = 19), TS (n = 14), or ASD (n = 18), and a control group (n = 20). We administered instruments for estimating intelligence quotient and severity of psychiatric symptoms, and tasks to evaluate ToM (the « Stories from everyday life » task and the « Reading the mind in the eyes » test). RESULTS: Young people with TS and with ASD present similar difficulties in solving advanced ToM tasks, whereas patients with childhood-onset OCD present similar results to controls. CONCLUSIONS: ToM is altered in other neurodevelopmental disorders beyond ASD, such as TS.

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12. Persico T, Tranquillo ML, Seracchioli R, Zuccarello D, Sorrentino U. PGT-M for Premature Ovarian Failure Related to CGG Repeat Expansion of the FMR1 Gene. Genes (Basel);2023 (Dec 19);15(1)

Primary ovarian failure (POF) is caused by follicle exhaustion and is associated with menstrual irregularities and elevated gonadotropin levels, which lead to infertility before the age of 40 years. The etiology of POI is mostly unknown, but a heterogeneous genetic and familial background can be identified in a subset of cases. Abnormalities in the fragile X mental retardation 1 gene (FMR1) are among the most prevalent monogenic causes of POI. These abnormalities are caused by the expansion of an unstable CGG repeat in the 5′ untranslated region of FMR1. Expansions over 200 repeats cause fragile X syndrome (FXS), whereas expansions between 55 and 200 CGG repeats, which are defined as a fragile X premutation, have been associated with premature ovarian failure type 1 (POF1) in heterozygous females. Preimplantation genetic testing for monogenic diseases (PGT-M) can be proposed when the female carries a premutation or a full mutation. In this narrative review, we aim to recapitulate the clinical and molecular features of POF1 and their implications in the context of PGT-M.

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13. Pervin M, Hansmann NM, Hagmayer Y. Attitudes Toward and Usage of Evidence-Based Mental Health Practices for Autistic Youth in Bangladesh and Germany: A Cross-Cultural Comparison. J Autism Dev Disord;2024 (Jan 26)

The implementation of evidence-based practices (EBPs) for autistic youth is a critical concern worldwide. Research examining factors facilitating the implementation of EBPs found that providers’ attitudes are an important factor. In this study, we evaluated cross-cultural differences in attitudes toward and use of EBPs. We tested socio-demographic factors as predictors of attitudes, and attitudes as predictors of EBPs use among mental health professionals working with autistic youth in Bangladesh and Germany. We used purposeful sampling. Two-hundred-ninety-two professionals who worked in a clinical setting responded to the survey and fulfilled the inclusion criteria (101 in Bangladesh, 191 in Germany). Participants were asked to respond to nine subscales of the Evidence-Based Practice Attitude Scale-36 (EBPAS-36), to indicate which of nine types of treatments they used, and to provide sociodemographic data. Measurement invariance across countries could be established for four subscales of the EBPAS-36. Comparative analyses of attitudes showed that professionals in both countries were open to using EBPs, but German practitioners were more likely to use EBPs when they appealed to them. By contrast, Bangladeshi professionals claimed to be more likely to adopt an EBP when required and to be more willing to learn EBPs to enhance job security. The relationship between caseload and attitudes varied between countries. A broader variety of EBPs was used in Germany. The findings highlight the importance of considering country-specific factors when implementing EBPs. Directions for conducting comparative studies on mental health professionals’ attitudes towards EBP including methodological considerations are discussed.

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14. Piro-Gambetti B, Greenlee J, Bolt D, Papp LM, Hartley SL. Parent-couple satisfaction, parent depression, and child mental health in families with autistic children. Front Psychiatry;2023;14:1306456.

INTRODUCTION: Within two-parent households, the parent-couple subsystem (marital or romantic partner relationship) is posited to shape the mental health of both parents and children. Autistic children and their parents have an elevated-risk for mental health problems. The present study longitudinally examined the mediating role of the quality of the parent-couple relationship in time-ordered pathways between changes in the mental health problems of autistic children and in parent depression symptoms at a within-family level. METHODOLOGY: Using four time points of data collected on 188 families of autistic children (aged 5-12 years) across 3 years, the bidirectional associations between parent-couple relationship satisfaction, parent depressive symptoms, and child internalizing and externalizing mental health problems were investigated. Two multi-group (grouped by parent gender) complete longitudinal mediation models in structural equation modeling using Mplus software were conducted. RESULTS: Parent-couple relationship satisfaction mediated: (1) the association between higher parent depressive symptoms and higher child internalizing mental health problems 12 months later for both mothers and fathers, and (2) the association between higher child externalizing mental health problems and higher father depression symptoms 12 months later. Father depression symptoms mediated a pathway from lower parent-couple satisfaction to higher child internalizing mental health problems 12 months later, and mother depression symptoms mediated the pathway from higher child externalizing mental health problems to lower parent-couple satisfaction 12 months later. CONCLUSION: Findings highlight the bidirectional and complex ways that parent and child mental health and the quality of the parent-couple relationship are entwined across time in families of autistic children. Family-wide interventions that address the needs of multiple family members and family systems are best suited to improve the mental health of parents and autistic children.

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15. Santa Paola S, Di Blasi FD, Borgione E, Lo Giudice M, Giuliano M, Pettinato R, Di Stefano V, Brighina F, Lupica A, Scuderi C. Aromatic L-Amino Acid Decarboxylase Deficiency: A Genetic Screening in Sicilian Patients with Neurological Disorders. Genes (Basel);2024 (Jan 21);15(1)

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare autosomal recessive neurometabolic disorder caused by AADC deficiency, an enzyme encoded by the DDC gene. Since the enzyme is involved in the biosynthesis of serotonin and dopamine, its deficiency determines the lack of these neurotransmitters, but also of norepinephrine and epinephrine. Onset is early and the key signs are hypotonia, movement disorders (oculogyric crises, dystonia and hypokinesia), developmental delay and autonomic dysfunction. Taiwan is the site of a potential founder variant (IVS6+4A>T) with a predicted incidence of 1/32,000 births, while only 261 patients with this deficit have been described worldwide. Actually, the number of affected persons could be greater, given that the spectrum of clinical manifestations is broad and still little known. In our study we selected 350 unrelated patients presenting with different neurological disorders including heterogeneous neuromuscular disorders, cognitive deficit, behavioral disorders and autism spectrum disorder, for which the underlying etiology had not yet been identified. Molecular investigation of the DDC gene was carried out with the aim of identifying affected patients and/or carriers. Our study shows a high frequency of carriers (2.57%) in Sicilian subjects with neurological deficits, with a higher concentration in northern and eastern Sicily. Assuming these data as representative of the general Sicilian population, the risk may be comparable to some rare diseases included in the newborn screening programs such as spinal muscular atrophy, cystic fibrosis and phenylketonuria.

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16. Schweizer T, Endres D, Dziobek I, Tebartz van Elst L. Psychosocial therapeutic approaches for high-functioning autistic adults. Front Psychiatry;2023;14:1265066.

Autism spectrum disorder (ASD) is characterized by impaired social interaction and communication skills, repetitive behaviors, restricted interests, and specific sensory processing. Particularly, adults with high-functioning ASD often remain unrecognized, presumably due to their high compensatory skills, but at the cost of high stress, which is often linked to anxiety and depression. This may further explain the significantly high suicide rates and reduced life expectancy among individuals with ASD. Thus, providing support to high-functioning autistic adults in managing core symptoms, as well as co-occurring anxiety and depression, appears essential. To date, only a limited number of evidence-based psychosocial therapeutic options are available, and very few of them have undergone rigorous evaluation in a clinical context. To obtain a comprehensive understanding, a systematic literature search was conducted according to the PRISMA checklist, and only studies demonstrating robust methodological quality were included and discussed in this review article. Although promising initial key factors and methods have been identified, additional evidence-based studies are imperative to ascertain the optimal treatment and evaluate the long-term outcomes for adults with high-functioning ASD.

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17. Soghomonian JJ. The cortico-striatal circuitry in autism-spectrum disorders: a balancing act. Front Cell Neurosci;2023;17:1329095.

The basal ganglia are major targets of cortical inputs and, in turn, modulate cortical function via their projections to the motor and prefrontal cortices. The role of the basal ganglia in motor control and reward is well documented and there is also extensive evidence that they play a key role in social and repetitive behaviors. The basal ganglia influence the activity of the cerebral cortex via two major projections from the striatum to the output nuclei, the globus pallidus internus and the substantia nigra, pars reticulata. This modulation involves a direct projection known as the direct pathway and an indirect projection via the globus pallidus externus and the subthalamic nucleus, known as the indirect pathway. This review discusses the respective contribution of the direct and indirect pathways to social and repetitive behaviors in neurotypical conditions and in autism spectrum disorders.

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18. Song Y, Hupfeld KE, Davies-Jenkins CW, Zöllner HJ, Murali-Manohar S, Mumuni AN, Crocetti D, Yedavalli V, Oeltzschner G, Alessi N, Batschelett MA, Puts NAJ, Mostofsky SH, Edden RAE. Brain glutathione and GABA+ levels in autistic children. Autism Res;2024 (Jan 26)

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered neurometabolite levels, including glutathione (GSH) and gamma-aminobutyric acid (GABA), have been proposed as potential contributors to the biology underlying ASD. This study investigated whether cerebral GSH or GABA levels differ between a cohort of children aged 8-12 years with ASD (n = 52) and typically developing children (TDC, n = 49). A comprehensive analysis of GSH and GABA levels in multiple brain regions, including the primary motor cortex (SM1), thalamus (Thal), medial prefrontal cortex (mPFC), and supplementary motor area (SMA), was conducted using single-voxel HERMES MR spectroscopy at 3T. The results revealed no significant differences in cerebral GSH or GABA levels between the ASD and TDC groups across all examined regions. These findings suggest that the concentrations of GSH (an important antioxidant and neuromodulator) and GABA (a major inhibitory neurotransmitter) do not exhibit marked alterations in children with ASD compared to TDC. A statistically significant positive correlation was observed between GABA levels in the SM1 and Thal regions with ADHD inattention scores. No significant correlation was found between metabolite levels and hyper/impulsive scores of ADHD, measures of core ASD symptoms (ADOS-2, SRS-P) or adaptive behavior (ABAS-2). While both GSH and GABA have been implicated in various neurological disorders, the current study provides valuable insights into the specific context of ASD and highlights the need for further research to explore other neurochemical alterations that may contribute to the pathophysiology of this complex disorder.

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19. Taheri F, Joushi S, Mohammadipoor-Ghasemabad L, Rad I, Esmaeilpour K, Sheibani V. Effects of music on cognitive behavioral impairments in both sex of adult rats exposed prenatally to valproic acid. Birth Defects Res;2024 (Jan);116(1):e2300.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive behaviors and interests. In previous studies, music has been identified as an intervention therapy for children with ASD. OBJECTIVES: The present study evaluated the effects of music on cognitive behavioral impairments in both sexes of adult rats exposed prenatally to Valproic acid. METHODS: For induction of autism, pregnant female rats were pretreated with either saline or VPA (600 mg/kg.i.p.) at gestational day (GD) 12.5. Male and female offspring were divided into Saline.Non-Music, VPA.Non-Music, Saline.Music, and VPA.Music groups. The adult rats in the music groups were exposed to Mozart’s piano sonata K.448 for 30 days (4 h/day), from postnatal day (PND) 60 to 90. Social interaction and Morris water maze (MWM) tasks were tested at PND 90. RESULTS: Our results revealed that prenatal exposure to VPA decreased sociability and social memory performance in both sexes of adult rats. Moreover, prenatal exposure to VPA created learning and memory impairments in both sexes of adult rats in the MWM task. Music intervention improved sociability in both sexes of VPA-exposed rats and social memory in both sexes of VPA-exposed rats, especially in females. Furthermore, our results revealed that music ameliorated learning impairments in VPA-exposed female rats in the MWM task. In addition, music improved spatial memory impairments in VPA-exposed rats of both sexes, especially in females, which needs more investigation in molecular and histological fields in future studies. CONCLUSION: Music intervention improved sociability and social memory in adult VPA-exposed rats, especially in female animals. Furthermore, music improved memory impairments in VPA-exposed rats of both sexes. It seems that music had a better influence on female rats. However, future studies need more investigations in molecular and histological fields.

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20. Toll SA, Flore LA, Gorsi HS, Marupudi NI, Mody S, Kupsky W, Wang ZJ. Intracranial Germinoma in Two Caucasian American Siblings With Autism Spectrum Disorder. J Pediatr Hematol Oncol;2024 (Jan 29)

Intracranial germ cell tumors (IGCTs) comprise 3% to 5% of all pediatric brain tumors in the West, with a significantly higher prevalence in Asia. Although these tumors are histologically diverse, repeated somatic variants have been demonstrated. Chromosomal aneuploidies, such as Klinefelter and Down syndromes, are associated with IGCTs, but no familial germline tumor syndromes are currently known. Here, we report the novel case of 2 American siblings with underlying autism spectrum disorder who developed intracranial germinoma within months of each other, in the absence of external risk factors. Extensive genetic testing was performed, including karyotyping, chromosomal microarray, and whole exome and whole genome sequencing, and did not identify any variants accounting for the phenotypes. Despite the absence of overlapping variants, a recent retrospective review demonstrated a threefold greater prevalence of autism spectrum disorder in patients with intracranial germinoma compared with national prevalence. This report highlights the complexity of tumor development, as well as the need for further research regarding IGCTs in a neurodivergent population.

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21. Torenvliet C, Groenman AP, Agelink van Rentergem JA, Radhoe TA, Geurts HM. When mind and measurement diverge; the interplay between subjective cognitive complaints (SCCs), objective cognition, age, and depression in autistic adults. Psychiatry Res;2024 (Jan 26);333:115759.

While the increased incidence of dementia and subjective cognitive complaints (SCCs) suggests that autistic adults may face cognitive challenges at older age, the extent to which SCCs predict (future) cognitive functioning remains uncertain. This uncertainty is complicated by associations with variables like depression. The current study aims to unravel the interplay of age, depression, cognitive performance, and SCCs in autism. Using a large cross-sectional cohort of autistic (n=202) and non-autistic adults (n=247), we analyzed associations of SCCs with age, depression, and cognitive performance across three domains (visual memory, verbal memory, and fluency). Results showed a strong significant association between depression and SCCs in both autistic and non-autistic adults. Cognitive performance was not significantly associated with SCCs, except for a (modest) association between visual memory performance and SCCs in autistic adults only. Follow-up regression tree analysis indicated that depression and being autistic were considerably more predictive of SCCs than objective cognitive performance. Age nor sex was significantly associated with SCCs. These findings indicate that self-reported cognitive functioning does not equal cognitive performance, and should be interpreted with care, especially in individuals with high rates of depression. Longitudinal investigations are needed to understand SCCs’ role in dementia and cognitive health in autism.

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22. Travers BG, Surgent O, Guerrero-Gonzalez J, Dean DC, 3rd, Adluru N, Kecskemeti SR, Kirk GR, Alexander AL, Zhu J, Skaletski EC, Naik S, Duran M. Role of autonomic, nociceptive, and limbic brainstem nuclei in core autism features. Autism Res;2024 (Jan 26)

Although multiple theories have speculated about the brainstem reticular formation’s involvement in autistic behaviors, the in vivo imaging of brainstem nuclei needed to test these theories has proven technologically challenging. Using methods to improve brainstem imaging in children, this study set out to elucidate the role of the autonomic, nociceptive, and limbic brainstem nuclei in the autism features of 145 children (74 autistic children, 6.0-10.9 years). Participants completed an assessment of core autism features and diffusion- and T1-weighted imaging optimized to improve brainstem images. After data reduction via principal component analysis, correlational analyses examined associations among autism features and the microstructural properties of brainstem clusters. Independent replication was performed in 43 adolescents (24 autistic, 13.0-17.9 years). We found specific nuclei, most robustly the parvicellular reticular formation-alpha (PCRtA) and to a lesser degree the lateral parabrachial nucleus (LPB) and ventral tegmental parabrachial pigmented complex (VTA-PBP), to be associated with autism features. The PCRtA and some of the LPB associations were independently found in the replication sample, but the VTA-PBP associations were not. Consistent with theoretical perspectives, the findings suggest that individual differences in pontine reticular formation nuclei contribute to the prominence of autistic features. Specifically, the PCRtA, a nucleus involved in mastication, digestion, and cardio-respiration in animal models, was associated with social communication in children, while the LPB, a pain-network nucleus, was associated with repetitive behaviors. These findings highlight the contributions of key autonomic brainstem nuclei to the expression of core autism features.

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23. Wood JJ, Wood KS, Rosenau KA, Cho AC, Johnson AR, Muscatello VS, Tien IS, Straus J, Wolpe S, Zeldin A, Kazlauskas K, McLeod BD. Practitioner Adherence and Competence in MEYA, a Free Online Self-Instruction Program in Modular Psychotherapy and Counseling for Children’s Autism-Related Clinical Needs. J Autism Dev Disord;2024 (Jan 26)

The quality of care in public schools and other community settings for school-aged youths on the autism spectrum is variable and often not evidence-based. Training practitioners in these settings to deliver evidence-based practices (EBPs) may improve the quality of care. We developed a free internet-based training and clinical guidance system synthesizing multiple EBPs for youth on the autism spectrum addressing a range of mental health needs and autism-related behaviors, entitled Modular EBPs for Youth on the Autism Spectrum (MEYA; meya.ucla.edu). A multiple baseline study was conducted with seven practitioners recruited from mental health practice settings across the United States who were providing services to children on the autism spectrum (aged 6 to 17 years). Practitioners were randomly assigned to undergo baseline conditions of 2 to 8 weeks. Once online training in MEYA commenced, practitioners engaged in algorithm-guided self-instruction in EBPs for autism. Participants video-recorded sessions. Independent coders used the MEYA Fidelity Scale (MEYA-FS) to rate adherence and competence in EBPs for autism. Practitioners also completed measures pertaining to implementation outcomes and parents rated youth outcomes on personalized target behaviors. Five of seven practitioners increased their adherence to MEYA practices (i.e., MEYA-FS scores) following MEYA training. Findings for competence were similar, though somewhat less robust. Practitioners generally viewed MEYA as feasible, understandable, and acceptable. Most youth outcomes improved during MEYA. A randomized, controlled trial of MEYA would be helpful in characterizing its effectiveness for supporting practitioner EBP implementation and youth outcomes in school and community service settings.

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24. Xie CTY, Pastore SF, Vincent JB, Frankland PW, Hamel PA. Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt N-Glycosylation and Reduce Protein Stability. Cells;2024 (Jan 21);13(2)

PTCHD1 has been implicated in Autism Spectrum Disorders (ASDs) and/or intellectual disability, where copy-number-variant losses or loss-of-function coding mutations segregate with disease in an X-linked recessive fashion. Missense variants of PTCHD1 have also been reported in patients. However, the significance of these mutations remains undetermined since the activities, subcellular localization, and regulation of the PTCHD1 protein are currently unknown. This paucity of data concerning PTCHD1 prevents the effective evaluation of sequence variants identified during diagnostic screening. Here, we characterize PTCHD1 protein binding partners, extending previously reported interactions with postsynaptic scaffolding protein, SAP102. Six rare missense variants of PTCHD1 were also identified from patients with neurodevelopmental disorders. After modelling these variants on a hypothetical three-dimensional structure of PTCHD1, based on the solved structure of NPC1, PTCHD1 variants harboring these mutations were assessed for protein stability, post-translational processing, and protein trafficking. We show here that the wild-type PTCHD1 post-translational modification includes complex N-glycosylation and that specific mutant proteins disrupt normal N-link glycosylation processing. However, regardless of their processing, these mutants still localized to PSD95-containing dendritic processes and remained competent for complexing SAP102.

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25. Zhu Y, Li J, Pan Y, Huang W, Xi H, Duan R. Attitudes of medical professionals toward fragile X carrier screening and genetic counseling in China. J Community Genet;2024 (Jan 26)

Fragile X syndrome is the most common inherited cause of intellectual disability. Considering China’s low prevalence, distinct healthcare system, middle-income economic status, and unique culture, China cannot simply replicate the screening systems in European and American countries. In this study, we investigated the attitudes of 450 Chinese medical professionals who received fragile X training on fragile X carrier screening and genetic counseling. Before the training, 57.6% of the respondents were unfamiliar with FXS. After the training, 7.3% of participants are unable to fully master the knowledge. Furthermore, 71.8% believe that the absence of phenotypes during the reproductive age and the availability of simple and feasible testing methods are prerequisites for screening. The presence of the phenotype would still require screening. Regarding the target population, over 90% of the participants support fragile X carrier screening in high-risk pregnant women. As for influencing factors, they consider cost as the most influential factor in pregnant women’s decision to undergo screening. The acceptable price range for screening is determined to be ￥200-1000 ($30-150). In terms of the issues and challenges of screening, most medical professionals support the need for genetic counseling for intermediate alleles and 55-60 repeat premutation results. Additionally, some respondents believe that informing patients’ family members of positive screening results is necessary. It is also recognized that positive results may lead to anxiety for patients. The findings of this study will provide valuable information for the establishment of fragile X carrier screening system, particularly for low-prevalence or middle-income countries.

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