1. Bjørk MH, Zoega H, Leinonen MK, Cohen JM, Dreier JW, Furu K, Gilhus NE, Gissler M, Hálfdánarson Ó, Igland J, Sun Y, Tomson T, Alvestad S, Christensen J. Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability. JAMA neurology. 2022.

IMPORTANCE: Women with epilepsy frequently need antiseizure medication (ASM) to prevent seizures in pregnancy. Risk of neurodevelopmental disorders after prenatal exposure to AMSs is uncertain. OBJECTIVE: To determine whether children exposed prenatally to ASMs in monotherapy and duotherapy have increased risk of neurodevelopmental disorders. DESIGN, SETTING, AND PARTICIPANTS: The Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017; analysis performed February 2022). From 4 702 774 alive-born children with available mother-child identities and maternal prescription data, this study included 4 494 926 participants. Children from a multiple pregnancy or with chromosomal disorders or uncertain pregnancy length were excluded (n = 207 848). EXPOSURES: Prenatal exposure to ASM determined from maternal prescription fills between last menstrual period and birth. MAIN OUTCOMES AND MEASURES: We estimated cumulative incidence at age 8 years in exposed and unexposed children. Cox regression adjusted for potential confounders yielded adjusted hazard ratios (aHRs) with 95% CIs for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID). RESULTS: A total of 4 494 926 children were included; 2 306 993 (51.3%) were male, and the median (IQR) age at end of follow-up was 8 (4.0-12.1) years. Among 21 634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% (numerators were not available because of personal data regulations in Denmark) of ID by age 8 years. In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID. The aHRs for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and after valproate exposure were 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7). The aHRs were elevated with higher ASM doses compared with children from the general population. The duotherapies levetiracetam with carbamazepine and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders in children of women with epilepsy: levetiracetam with carbamazepine: 8-year cumulative incidence, 5.7%; aHR, 3.5; 95% CI, 1.5-8.2; lamotrigine with topiramate: 8-year cumulative incidence, 7.5%; aHR, 2.4; 95% CI, 1.1-4.9. No increased risk was associated with levetiracetam with lamotrigine (8-year cumulative incidence, 1.6%; aHR, 0.9; 95% CI, 0.3-2.5). No consistently increased risks were observed for neurodevelopmental disorders after prenatal exposure to monotherapy with lamotrigine, levetiracetam, carbamazepin, oxcarbazepine, gapapentin, pregabalin, clonazepam, or phenobarbital.

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2. Cahart MS, Amad A, Draper SB, Lowry RG, Marino L, Carey C, Ginestet CE, Smith MS, Williams SCR. The effect of learning to drum on behavior and brain function in autistic adolescents. Proceedings of the National Academy of Sciences of the United States of America. 2022; 119(23): e2106244119.

SignificanceThere is an acknowledged need for improved service provision in the context of autism spectrum disorders. Previous studies have demonstrated the positive role drum training can play in improving behavioral outcomes for children and adolescents with emotional and behavioral difficulties. However, to date, none of these studies has explored how these behavioral changes translate at the neural level. Our study provides strong evidence that drumming not only reduces hyperactivity and inattention in autistic adolescents but also strengthens functional connectivity in brain regions responsible for inhibitory control and action outcome monitoring.

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3. Cornell M. A fine balance: Best interests in the context of invasive treatment and autism: Manchester University NHS Foundation Trust v William Verden [2022] EWCOP 9. Medical law review. 2022.

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4. Davis P, Takach K, Maski K, Levin A. A circuit-level biomarker of Rett syndrome based on ectopic phase-amplitude coupling during slow-wave-sleep. Cerebral cortex (New York, NY : 1991). 2022.

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of purposeful hand use and spoken language following an initial period of normal development. Although much is known about the genetic and molecular underpinnings of RTT, less is known about the circuit-level etiopathology. Coupling of oscillations during slow-wave-sleep (SWS) underlies important neurocognitive processes in adulthood, yet its emergence has yet to be described in early typical development (TD) or in RTT. We therefore addressed these unknowns by describing SWS cross-frequency coupling in both RTT and early TD using a retrospective study design. We found that in TD, phase-amplitude coupling (PAC) during SWS was dominated by coupling of slow-wave (0.5-2 Hz) phase to theta amplitude (5-8 Hz, « SW:T ») as well as slow-wave to spindle-range (12-15 Hz, « SW:S »). Coupling exhibited characteristic vertex-prominent spatial topography, which emerged during an early developmental window. This topography failed to develop in patients with RTT due to persistent ectopic coupling. Furthermore, we found that subtypes of RTT exhibit distinct PAC topographic profiles, and that ectopic PAC correlates with clinical severity. These findings suggest that altered PAC dynamics and spatial organization during SWS may underlie the circuit-level pathophysiology of RTT and suggest that ectopic coupling may contribute to RTT pathogenesis.

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5. Kong HE, Lim J, Linsalata A, Kang Y, Malik I, Allen EG, Cao Y, Shubeck L, Johnston R, Huang Y, Gu Y, Guo X, Zwick ME, Qin Z, Wingo TS, Juncos J, Nelson DL, Epstein MP, Cutler DJ, Todd PK, Sherman SL, Warren ST, Jin P. Identification of PSMB5 as a genetic modifier of fragile X-associated tremor/ataxia syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2022; 119(22): e2118124119.

SignificanceExpansion of 55-200 CGG repeats in the 5′ untranslated region of FMR1 predisposes carriers to fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. FXTAS demonstrates incomplete penetrance, which strongly suggests the presence of genetic modifiers. We performed whole-genome sequencing (WGS) on male premutation carriers (CGG(55-200)) followed by a functional screen in Drosophila and identified PSMB5 as a strong suppressor of CGG-associated neurodegeneration, thereby presenting a therapeutic strategy for FXTAS.

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6. Lee CH, Bartholomay KL, Marzelli MJ, Miller JG, Bruno JL, Lightbody AA, Reiss AL. Neuroanatomical Profile of Young Females with Fragile X Syndrome: A Voxel-Based Morphometry Analysis. Cerebral cortex (New York, NY : 1991). 2022; 32(11): 2310-20.

Fragile X syndrome is a genetic condition associated with alterations in brain and subsequent cognitive development. However, due to a milder phenotype relative to males, females with fragile X syndrome are underrepresented in research studies. In the current study, we investigate neuroanatomical differences in young females (age range: 6.03-16.32 years) with fragile X syndrome (N = 46) as compared to age-, sex-, and verbal abilities-matched participants (comparison group; N = 35). Between-group analyses of whole-brain and regional brain volumes were assessed using voxel-based morphometry. Results demonstrate significantly larger total gray and white matter volumes in girls with fragile X syndrome compared to a matched comparison group (Ps < 0.001). In addition, the fragile X group showed significantly larger gray matter volume in a bilateral parieto-occipital cluster and a right parieto-occipital cluster (Ps < 0.001). Conversely, the fragile X group showed significantly smaller gray matter volume in the bilateral gyrus rectus (P < 0.03). Associations between these regional brain volumes and key socio-emotional variables provide insight into gene-brain-behavior relationships underlying the fragile X syndrome phenotype in females. These findings represent the first characterization of a neuroanatomical phenotype in a large sample of girls with fragile X syndrome and expand our knowledge about potential neurodevelopmental mechanisms underlying cognitive-behavioral outcomes in this condition.

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7. Liufu T, Zheng Y, Yu J, Yuan Y, Wang Z, Deng J, Hong D. The polyG diseases: a new disease entity. Acta neuropathologica communications. 2022; 10(1): 79.

Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats in the 5′ untranslated region has been found in neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDMs). Although the upstream open reading frame has not been elucidated in OPML and OPDMs, polyglycine (polyG) translated by expanded CGG repeats is reported to be as a primary pathogenesis in FXTAS and NIID. Collectively, these findings indicate a new disease entity, the polyG diseases. In this review, we state the common clinical manifestations, pathological features, mechanisms, and potential therapies in these diseases, and provide preliminary opinions about future research in polyG diseases.

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8. Morin M, Rivard M, Morin D, Mello C, Coulombe P. Parents’ satisfaction with a Canadian pilot clinic to reduce waiting lists for the assessment and diagnosis of autism spectrum disorder and intellectual disability in young children. Journal of applied research in intellectual disabilities : JARID. 2022.

BACKGROUND: A large body of evidence suggest that parents of young children with autism spectrum disorder or intellectual disability experience low levels of satisfaction with the diagnostic evaluation process. This study sought to document parents’ satisfaction with the services of a pilot clinic implemented in Québec, Canada. METHOD: Two-hundred fifty-nine (259) parents were recruited following their child’s diagnosis. A mixed methods approach was used to investigate parents’ satisfaction globally and with specific aspects of the assessment process. RESULTS: Parents expressed overall high satisfaction with the assessment process. Parental satisfaction with specific aspects of the assessment process was negatively related to paternal stress, fathers’ unemployment and household income and positively related to maternal stress. CONCLUSIONS: This pilot clinic could meet parents’ needs at this crucial moment in their care and services trajectory. The factors associated with satisfaction in the present study may inform future improvements to its services.

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9. Spackman E, Lerh JW, Rodgers J, Hollocks MJ, South M, McConachie H, Ozsivadjian A, Vaughan Van Hecke A, Libove R, Hardan AY, Leekam SR, Simonoff E, Frazier TW, Alvares GA, Schwartzman JM, Magiati I, Uljarević M. Understanding the heterogeneity of anxiety in autistic youth: A person-centered approach. Autism research : official journal of the International Society for Autism Research. 2022.

The present study aimed to examine anxiety profiles among children and adolescents on the autism spectrum. It further aimed to characterize the association between the identified anxiety profiles and key clinical and developmental variables. The Spence Children’s Anxiety Scale-Parent Version (SCAS-P) data from a large international pooled sample of 870 caregivers of autistic children and adolescents (M(age) = 11.6 years, SD(age) = 2.77; 107 females) was used. Latent profile analysis identified a three-anxiety profile solution exhibiting high entropy (0.80) and high latent profile probabilities, with good classification accuracy. Identified profiles fell along the severity spectrum and were named as the mild (n = 498), moderate (n = 272) and severe (n = 100) anxiety profiles. There were no statistically significant differences between the three anxiety profiles in terms of sex distribution. Participants in the mild profile were significantly younger than those in the severe profile, had significantly fewer social communication difficulties than youth in the moderate anxiety profile group and had significantly fewer restricted and repetitive behaviors and lower cognitive functioning scores compared to participants in moderate and severe anxiety profiles. This is the first study to move beyond identifying associations and group-level differences to exploring and identifying characteristics of anxiety-based subgroups at an individual level that differ on key clinical and developmental variables. The subgroups identified in this study are a preliminary, yet important, first step towards informing future assessment and individualized interventions aiming to support young people on the autism spectrum to reduce and manage anxiety. LAY SUMMARY: This study tried to understand if there are subgroups of autistic young people who may have similar anxiety profiles. We found that we could meaningfully group young people into three groups based on how severe the anxiety symptoms their caregivers reported were: a group with low levels of anxiety, those with moderate anxiety, and those with more severe anxiety. We also found that the young people in the mild group were younger, had fewer autism traits and lower levels of intellectual functioning than young people in the other two groups.

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10. Yang JH, Strodl E, Wu CA, Hou XY, Yin XN, Wen GM, Sun DL, Xian DX, Chen JY, Chen YJ, Chen J, Chen WQ. Maternal exposure to cooking oil fumes during pregnancy and autistic-like behaviors in Chinese preschoolers. Environmental science and pollution research international. 2022.

There is growing evidence that cooking oil fumes (COFs) are harmful indoor air pollutants. However, there is a dearth of research investigating whether maternal COFs exposure during pregnancy may affect children’s autistic-like behaviors in China. This study aimed to explore this association, and examine the effects of different cooking fuels and ventilation methods used by mothers on the presence of autistic-like behaviors. This study analyzed the survey data of the Longhua Child Cohort Study in 2017 with a total of 62,372 mothers enrolled in this study. A self-administrative questionnaire was used to collect information on socio-demographic characteristics, cooking habits during pregnancy, and autistic-like behaviors (measured using the Autism Behavior Checklist). After adjusting for potential confounders, the results showed that compared with children whose mothers never cooked during pregnancy, children whose mothers cooked sometimes, often, always during pregnancy had the higher risk of autistic-like behaviors. As the amounts of COFs exposed to and the frequency of cooking during pregnancy increased, the risk of a child’s autistic-like behaviors also increased. Mothers using natural gas as cooking fuels had a lower risk of their child having autistic-like behaviors, compared with mothers using coal or other cooking fuels. Furthermore, pregnant women using ventilation measures during cooking significantly decreased likelihood of the presence of autistic-like behaviors in their children. These results suggest that maternal exposure to COFs during pregnancy may increase the likelihood of the presence of autistic-like behaviors in offspring. These findings support a recommendation that pregnant women should avoid exposure to COFs and use clean fuels and ventilation equipment in kitchens to reduce the risk of autistic-like behaviors in children.

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11. Zhao S, Liu Y, Wei K. Pupil-Linked Arousal Response Reveals Aberrant Attention Regulation among Children with Autism Spectrum Disorder. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2022.

Autism spectrum disorder (ASD) is a developmental disorder that is characterized by difficulties with social interaction and interpersonal communication. It has been argued that abnormal attentional function to exogenous stimuli precedes and contributes to the core ASD symptoms. Notably, the locus ceruleus (LC) and its noradrenergic projections throughout the brain modulate attentional function, but the extent to which this locus ceruleus-norepinephrine (LC-NE) system influences attention in individuals with ASD, who frequently exhibit dysregulated alerting and attention orienting, is unknown. We examined dynamic attention control in girls and boys with ASD at rest using the pupil dilation response (PDR) as a noninvasive measure of LC-NE activity. When gender- and age-matched neurotypical participants were passively exposed to an auditory stream, their PDR decreased for recurrent stimuli but remained sensitive to surprising deviant stimuli. In contrast, children with ASD showed less habituation to recurrent stimuli as well as a diminished phasic response to deviants, particularly those containing social information. Their tonic habituation impairment predicts their phasic orienting impairment, and both impairments correlated with the severity of ASD symptom. Because of the fact that these pupil-linked responses are observed when individuals passively listen without any task engagement, our findings imply that the intricate and dynamic attention allocation mechanism, mediated by the subcortical LC-NE system, is impaired in ASD.SIGNIFICANCE STATEMENTAutistic individuals show attentional abnormalities to even simple sensory inputs, which emerge even before formal diagnosis. One possible mechanism behind these abnormalities is a malfunctioning pacemaker of their attention system, the locus ceruleus-norepinephrine pathway. Here we found, according to the pupillary response (a noradrenergic activity proxy), autistic children are hypersensitive to repeated sounds but hyposensitive to surprising deviant sounds when compared with age-matched controls. Importantly, hypersensitivity to repetitions predicts hyposensitivity to deviant sounds, and both abnormalities positively correlate to the severity of autistic symptoms. This provides strong evidence that autistic children have faulty noradrenergic regulation, which might underly the attentional atypicalities previously evidenced in various cortical responses in autistic individuals.

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