Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

The maturation of auditory responses in infants and young children: a cross-sectional study from 6 to 59 months

Background: An understanding of the maturation of auditory cortex responses in typically developing infants and toddlers is needed to later identify auditory processing abnormalities in infants at risk for neurodevelopmental disorders. The availability of infant and young child magnetoencephalography (MEG) systems may now provide near optimal assessment of left and right hemisphere auditory neuromagnetic responses in young populations. To assess the performance of a novel whole-head infant MEG system, a cross-sectional study examined the maturation of left and right auditory cortex responses in children 6- to 50-months of age. Methods: Blocks of 1000Hz (1st and 3rd blocks) and 500Hz tones (2nd block) were presented while MEG data were recorded using an infant/young child biomagnetometer (Artemis 123). Data were obtained from 29 children (11 males; 6 months to 59 months). Latency measures were obtained for the first positive-to-negative evoked response waveform complex in each hemisphere. Latency and age associations as well as frequency and hemisphere latency differences were examined. For the 1000 Hz tone, measures of reliability were computed. Results: For the first response - a response with a ‘P2m’ topography - latencies decreased as a function of age. For the second response - a response with a ‘N2m’ topography - no N2m latency and age relationships were observed. A main effect of tone frequency showed earlier P2m responses for 1st 1000 Hz (150 ms) and 2nd 1000 Hz (148 ms) versus 500 Hz tones (162 ms). A significant main effect of hemisphere showed earlier N2m responses for 2nd 1000 Hz (226 ms) versus 1st 1000 Hz (241 ms) versus 500 Hz tones (265 ms). P2m and N2m interclass correlation coefficient latency findings were as follows: left P2m (0.72, p < 0.001), right P2m (0.84, p < 0.001), left N2m (0.77, p < 0.001), and right N2m (0.77, p < 0.01).Conclusions: Findings of strong age and latency associations, sensitivity to tone frequency, and good test-retest reliability support the viability of longitudinal infant MEG studies that include younger as well as older participants as well as studies examining auditory processing abnormalities in infants at risk for neurodevelopmental disorders

Multimodal Diffusion-MRI and MEG Assessment of Auditory and Language System Development in Autism Spectrum Disorder

Background: Auditory processing and language impairments are prominent in children with autism spectrum disorder (ASD). The present study integrated diffusion MR measures of white-matter microstructure and magnetoencephalography (MEG) measures of cortical dynamics to investigate associations between brain structure and function within auditory and language systems in ASD. Based on previous findings, abnormal structure-function relationships in auditory and language systems in ASD were hypothesized. Methods: Evaluable neuroimaging data was obtained from 44 typically developing (TD) children (mean age 10.4±2.4years) and 95 children with ASD (mean age 10.2±2.6years). Diffusion MR tractography was used to delineate and quantitatively assess the auditory radiation and arcuate fasciculus segments of the auditory and language systems. MEG was used to measure (1) superior temporal gyrus auditory evoked M100 latency in response to pure-tone stimuli as an indicator of auditory system conduction velocity, and (2) auditory vowel-contrast mismatch field (MMF) latency as a passive probe of early linguistic processes. Results: Atypical development of white matter and cortical function, along with atypical lateralization, were present in ASD. In both auditory and language systems, white matter integrity and cortical electrophysiology were found to be coupled in typically developing children, with white matter microstructural features contributing significantly to electrophysiological response latencies. However, in ASD, we observed uncoupled structure-function relationships in both auditory and language systems. Regression analyses in ASD indicated that factors other than white-matter microstructure additionally contribute to the latency of neural evoked responses and ultimately behavior. Results also indicated that whereas delayed M100 is a marker for ASD severity, MMF delay is more associated with language impairment. Conclusion: Present findings suggest atypical development of primary auditory as well as auditory language systems in ASD. Findings demonstrate the need for additional multimodal studies to better characterize the different structural features (white matter, gray matter, neurochemical concentration) that contribute to brain activity, both in typical development and in ASD. Finally, the neural latency measures were found to be of clinical significance, with M100 associated with overall ASD severity, and with MMF latency associated with language performance

Maturation of auditory cortex neural responses during infancy and toddlerhood

The infant auditory system rapidly matures across the first years of life, with a primary goal of obtaining ever-more-accurate real-time representations of the external world. Our understanding of how left and right auditory cortex neural processes develop during infancy, however, is meager, with few studies having the statistical power to detect potential hemisphere and sex differences in primary/secondary auditory cortex maturation. Using infant magnetoencephalography (MEG) and a cross-sectional study design, left and right auditory cortex P2m responses to pure tones were examined in 114 typically developing infants and toddlers (66 males, 2 to 24 months). Non-linear maturation of P2m latency was observed, with P2m latencies decreasing rapidly as a function of age during the first year of life, followed by slower changes between 12 and 24 months. Whereas in younger infants auditory tones were encoded more slowly in the left than right hemisphere, similar left and right P2m latencies were observed by ∼21 months of age due to faster maturation rate in the left than right hemisphere. No sex differences in the maturation of the P2m responses were observed. Finally, an earlier left than right hemisphere P2m latency predicted better language performance in older infants (12 to 24 months). Findings indicate the need to consider hemisphere when examining the maturation of auditory cortex neural activity in infants and toddlers and show that the pattern of left–right hemisphere P2m maturation is associated with language performance

Auditory Evoked M100 Response Latency is Delayed in Children with 16p11.2 Deletion but not 16p11.2 Duplication

Individuals with the 16p11.2 BP4-BP5 copy number variant (CNV) exhibit a range of behavioral phenotypes that may include mild impairment in cognition and clinical diagnoses of autism spectrum disorder (ASD). To better understand auditory processing impairments in populations with this chromosomal variation, auditory evoked responses were examined in children with the 16p11.2 deletion, 16p11.2 duplication, and age-matched controls. Stimuli consisted of sinusoidal binaural tones presented passively while children underwent recording with magnetoencephalography (MEG). The primary indicator of auditory processing impairment was the latency of the ∼100-ms "M100" auditory response detected by MEG, with the 16p11.2 deletion population exhibiting profoundly delayed M100 latencies relative to controls. This delay remained even after controlling for potential confounds such as age and cognitive ability. No significant difference in M100 latency was observed between 16p11.2 duplication carriers and controls. Additionally, children meeting diagnostic criteria for ASD (16p11.2 deletion carriers) exhibited nonsignificant latency delays when compared with the corresponding CNV carriers not meeting criteria for ASD. Present results indicate that 16p11.2 deletion is associated with auditory processing delays analogous to (but substantially more pronounced than) those previously reported in "idiopathic" ASD

Initial Clinical Guidelines for Co-Occurring Autism Spectrum Disorder and Gender Dysphoria or Incongruence in Adolescents

Evidence indicates an overrepresentation of youth with co-occurring autism spectrum disorders (ASD) and gender dysphoria (GD). The clinical assessment and treatment of adolescents with this co-occurrence is often complex, related to the developmental aspects of ASD. There are no guidelines for clinical care when ASD and GD co-occur; however, there are clinicians and researchers experienced in this co-occurrence. This study develops initial clinical consensus guidelines for the assessment and care of adolescents with co-occurring ASD and GD, from the best clinical practices of current experts in the field. Expert participants were identified through a comprehensive international search process and invited to participate in a two-stage Delphi procedure to form clinical consensus statements. The Delphi Method is a well-studied research methodology for obtaining consensus among experts to define appropriate clinical care. Of 30 potential experts identified, 22 met criteria as expert in co-occurring ASD and GD youth and participated. Textual data divided into the following data nodes: guidelines for assessment; guidelines for treatment; six primary clinical/psychosocial challenges: social functioning, medical treatments and medical safety, risk of victimization/safety, school, and transition to adulthood issues (i.e., employment and romantic relationships). With a cutoff of 75% consensus for inclusion, identified experts produced a set of initial guidelines for clinical care. Primary themes include the importance of assessment for GD in ASD, and vice versa, as well as an extended diagnostic period, often with overlap/blurring of treatment and assessment