Atypical functional connectivity between the amygdala and visual, salience regions in infants with genetic liability for autism.

The amygdala undergoes a period of overgrowth in the first year of life, resulting in enlarged volume by 12 months in infants later diagnosed with ASD. The overgrowth of the amygdala may have functional consequences during infancy. We investigated whether amygdala connectivity differs in 12-month-olds at high likelihood (HL) for ASD (defined by having an older sibling with autism), compared to those at low likelihood (LL). We examined seed-based connectivity of left and right amygdalae, hypothesizing that the HL and LL groups would differ in amygdala connectivity, especially with the visual cortex, based on our prior reports demonstrating that components of visual circuitry develop atypically and are linked to genetic liability for autism. We found that HL infants exhibited weaker connectivity between the right amygdala and the left visual cortex, as well as between the left amygdala and the right anterior cingulate, with evidence that these patterns occur in distinct subgroups of the HL sample. Amygdala connectivity strength with the visual cortex was related to motor and communication abilities among HL infants. Findings indicate that aberrant functional connectivity between the amygdala and visual regions is apparent in infants with genetic liability for ASD and may have implications for early differences in adaptive behaviors.

Brain-based sex differences in schizophrenia: A systematic review of fMRI studies.

Schizophrenia is a chronic psychiatric disorder with characteristic symptoms of delusions, hallucinations, lack of motivation, and paucity of thought. Recent evidence suggests that the symptoms of schizophrenia, negative symptoms in particular, vary widely between the sexes and that symptom onset is earlier in males. A better understanding of sex-based differences in functional magnetic resonance imaging (fMRI) studies of schizophrenia may provide a key to understanding sex-based symptom differences. This study aimed to summarize sex-based functional magnetic resonance imaging (fMRI) differences in brain activity of patients with schizophrenia. We searched PubMed and Scopus to find fMRI studies that assessed sex-based differences in the brain activity of patients with schizophrenia. We excluded studies that did not evaluate brain activity using fMRI, did not evaluate sex differences, and were nonhuman or in vitro studies. We found 12 studies that met the inclusion criteria for the current systematic review. Compared to females with schizophrenia, males with schizophrenia showed more blood oxygen level-dependent (BOLD) activation in the cerebellum, the temporal gyrus, and the right precuneus cortex. Male patients also had greater occurrence of low-frequency fluctuations in cerebral blood flow in frontal and parietal lobes and the insular cortex, while female patients had greater occurrence of low-frequency fluctuations in the hippocampus, parahippocampus, and lentiform nucleus. The current study summarizes fMRI studies that evaluated sex-based fMRI brain differences in schizophrenia that may help to shed light on the underlying pathophysiology and further understanding of sex-based differences in the clinical presentation and course of the disorder.

Differential cognitive and behavioral development from 6 to 24 months in autism and fragile X syndrome.

BACKGROUND: Specifying early developmental differences among neurodevelopmental disorders with distinct etiologies is critical to improving early identification and tailored intervention during the first years of life. Recent studies have uncovered important differences between infants with fragile X syndrome (FXS) and infants with familial history of autism spectrum disorder who go on to develop autism themselves (FH-ASD), including differences in brain development and behavior. Thus far, there have been no studies longitudinally investigating differential developmental skill profiles in FXS and FH-ASD infants. METHODS: The current study contrasted longitudinal trajectories of verbal (expressive and receptive language) and nonverbal (gross and fine motor, visual reception) skills in FXS and FH-ASD infants, compared to FH infants who did not develop ASD (FH-nonASD) and typically developing controls. RESULTS: Infants with FXS showed delays on a nonverbal composite compared to FH-ASD (as well as FH-nonASD and control) infants as early as 6 months of age. By 12 months an ordinal pattern of scores was established between groups on all domains tested, such that controls > FH-nonASD > FH-ASD > FXS. This pattern persisted through 24 months. Cognitive level differentially influenced developmental trajectories for FXS and FH-ASD. CONCLUSIONS: Our results demonstrate detectable group differences by 6 months between FXS and FH-ASD as well as differential trajectories on each domain throughout infancy. This work further highlights an earlier onset of global cognitive delays in FXS and, conversely, a protracted period of more slowly emerging delays in FH-ASD. Divergent neural and cognitive development in infancy between FXS and FH-ASD contributes to our understanding of important distinctions in the development and behavioral phenotype of these two groups.

White matter development and language abilities during infancy in autism spectrum disorder.

White matter (WM) fiber tract differences are present in autism spectrum disorder (ASD) and could be important markers of behavior. One of the earliest phenotypic differences in ASD are language atypicalities. Although language has been linked to WM in typical development, no work has evaluated this association in early ASD. Participants came from the Infant Brain Imaging Study and included 321 infant siblings of children with ASD at high likelihood (HL) for developing ASD; 70 HL infants were later diagnosed with ASD (HL-ASD), and 251 HL infants were not diagnosed with ASD (HL-Neg). A control sample of 140 low likelihood infants not diagnosed with ASD (LL-Neg) were also included. Infants contributed expressive language, receptive language, and diffusion tensor imaging data at 6-, 12-, and 24 months. Mixed effects regression models were conducted to evaluate associations between WM and language trajectories. Trajectories of microstructural changes in the right arcuate fasciculus were associated with expressive language development. HL-ASD infants demonstrated a different developmental pattern compared to the HL-Neg and LL-Neg groups, wherein the HL-ASD group exhibited a positive association between WM fractional anisotropy and language whereas HL-Neg and LL-Neg groups showed weak or no association. No other fiber tracts demonstrated significant associations with language. In conclusion, results indicated arcuate fasciculus WM is linked to language in early toddlerhood for autistic toddlers, with the strongest associations emerging around 24 months. To our knowledge, this is the first study to evaluate associations between language and WM development during the pre-symptomatic period in ASD.

A global multicohort study to map subcortical brain development and cognition in infancy and early childhood.

The human brain grows quickly during infancy and early childhood, but factors influencing brain maturation in this period remain poorly understood. To address this gap, we harmonized data from eight diverse cohorts, creating one of the largest pediatric neuroimaging datasets to date focused on birth to 6 years of age. We mapped the developmental trajectory of intracranial and subcortical volumes in ∼2,000 children and studied how sociodemographic factors and adverse birth outcomes influence brain structure and cognition. The amygdala was the first subcortical volume to mature, whereas the thalamus exhibited protracted development. Males had larger brain volumes than females, and children born preterm or with low birthweight showed catch-up growth with age. Socioeconomic factors exerted region- and time-specific effects. Regarding cognition, males scored lower than females; preterm birth affected all developmental areas tested, and socioeconomic factors affected visual reception and receptive language. Brain-cognition correlations revealed region-specific associations.

Comparing narrative storytelling ability in individuals with autism and fetal alcohol spectrum disorders.

BACKGROUND: Narrative discourse, or storytelling, is used in daily conversation and requires higher-level language and social communication skills that are not always captured by standardised assessments of language. Many autistic individuals and individuals with fetal alcohol spectrum disorders (FASD) have difficulties with both social communication and language skills, and narrative discourse analysis offers an ecologically relevant approach to assessing those challenges. AIMS: This study investigated narrative discourse in individuals with autism and FASD, as well as an age- and sex-matched comparison group. METHODS AND PROCEDURES: Narratives from 45 adolescents and adults, 11 with autism, 11 with FASD and 23 age- and sex-matched comparison participants were elicited using a wordless storybook. They were then transcribed orthographically, formatted to the Systematic Analyses of Language Transcript (SALT) convention and scored based on the SALT Narrative Scoring Scheme (NSS), a standardised language analysis protocol. In addition to the NSS total score, which assesses the overall structure and cohesion of the narratives produced, local and global measures of language ability were also employed. The local language measures included the number of mental state and temporal relation terms produced, while the global language measures included mean length of utterance, total different words, total words, total utterances, rate of speech, the number of mazes (e.g., repetitions, 'um', 'uh' or self-corrections) per total word and the NSS total score. OUTCOMES AND RESULTS: Using the SALT Language Sample Analysis tool, our results revealed that on global language measures, group differences were found on rate of speech, number of mazes per total words and the description of conflict/resolution in the narratives produced. The autism group produced significantly more mazes per total word and scored higher on the NSS conflict/resolution category score compared to the FASD and comparison groups. Both the autism and FASD groups spoke at a lower rate than the comparison group. On local language measures of narrative production, all groups were comparable, on average. CONCLUSIONS AND IMPLICATIONS: While many aspects of narrative discourse in the autism and FASD groups were similar to each other and to the comparison group, we observed group differences on global measures of narrative production and significant individual variability within groups, suggesting that narrative abilities considered at an individual level may provide important clinical information for intervention planning. Future research should also consider additional variables that influence narrative discourse, such as motivation, distractibility or decision-making of individual participants. WHAT THIS PAPER ADDS: What is already known on the subject Narrative discourse, or storytelling, is used in daily conversational interactions and reveals higher-level language skills that may not be well captured by standardised assessments of language. Many autistic individuals and individuals with fetal alcohol spectrum disorders (FASD) show difficulty with pragmatic and expressive language skills. What this paper adds to existing knowledge We found that many aspects of the narratives produced by the adolescents/young adults in the autism and FASD groups were comparable to each other and to the neurotypical group. However, the groups differed on three global measures of narrative production: rate of speech, number of mazes per total words and the description of conflict/resolution in the narratives produced. Also, significant variability was observed within groups, suggesting that narrative abilities should be considered at an individual level as opposed to their clinical groups. What are the potential or actual clinical implications of this work? This study showed that narrative discourse is an appropriate task that can be added to routine clinical assessments of language abilities in autistic adolescents/young adults as well as those with FASD or typical development and has the potential to reveal higher-level, real-world language skills. An important clinical implication of this study is that narrative language abilities should be considered at an individual level and individual-tailored interventions based on ability level due to the variability observed across individuals.

Associations between early trajectories of amygdala development and later school-age anxiety in two longitudinal samples.

Amygdala function is implicated in the pathogenesis of autism spectrum disorder (ASD) and anxiety. We investigated associations between early trajectories of amygdala growth and anxiety and ASD outcomes at school age in two longitudinal studies: high- and low-familial likelihood for ASD, Infant Brain Imaging Study (IBIS, n = 257) and typically developing (TD) community sample, Early Brain Development Study (EBDS, n = 158). Infants underwent MRI scanning at up to 3 timepoints from neonate to 24 months. Anxiety was assessed at 6-12 years. Linear multilevel modeling tested whether amygdala volume growth was associated with anxiety symptoms at school age. In the IBIS sample, children with higher anxiety showed accelerated amygdala growth from 6 to 24 months. ASD diagnosis and ASD familial likelihood were not significant predictors. In the EBDS sample, amygdala growth from birth to 24 months was associated with anxiety. More anxious children had smaller amygdala volume and slower rates of amygdala growth. We explore reasons for the contrasting results between high-familial likelihood for ASD and TD samples, grounding results in the broader literature of variable associations between early amygdala volume and later anxiety. Results have the potential to identify mechanisms linking early amygdala growth to later anxiety in certain groups.

Enlarged Perivascular Spaces in Infancy and Autism Diagnosis, Cerebrospinal Fluid Volume, and Later Sleep Problems.

Importance: Perivascular spaces (PVS) and cerebrospinal fluid (CSF) are essential components of the glymphatic system, regulating brain homeostasis and clearing neural waste throughout the lifespan. Enlarged PVS have been implicated in neurological disorders and sleep problems in adults, and excessive CSF volume has been reported in infants who develop autism. Enlarged PVS have not been sufficiently studied longitudinally in infancy or in relation to autism outcomes or CSF volume. Objective: To examine whether enlarged PVS are more prevalent in infants who develop autism compared with controls and whether they are associated with trajectories of extra-axial CSF volume (EA-CSF) and sleep problems in later childhood. Design, Setting, and Participants: This prospective, longitudinal cohort study used data from the Infant Brain Imaging Study. Magnetic resonance images were acquired at ages 6, 12, and 24 months (2007-2017), with sleep questionnaires performed between ages 7 and 12 years (starting in 2018). Data were collected at 4 sites in North Carolina, Missouri, Pennsylvania, and Washington. Data were analyzed from March 2021 through August 2022. Exposure: PVS (ie, fluid-filled channels that surround blood vessels in the brain) that are enlarged (ie, visible on magnetic resonance imaging). Main Outcomes and Measures: Outcomes of interest were enlarged PVS and EA-CSF volume from 6 to 24 months, autism diagnosis at 24 months, sleep problems between ages 7 and 12 years. Results: A total of 311 infants (197 [63.3%] male) were included: 47 infants at high familial likelihood for autism (ie, having an older sibling with autism) who were diagnosed with autism at age 24 months, 180 high likelihood infants not diagnosed with autism, and 84 low likelihood control infants not diagnosed with autism. Sleep measures at school-age were available for 109 participants. Of infants who developed autism, 21 (44.7%) had enlarged PVS at 24 months compared with 48 infants (26.7%) in the high likelihood but no autism diagnosis group (P = .02) and 22 infants in the control group (26.2%) (P = .03). Across all groups, enlarged PVS at 24 months was associated with greater EA-CSF volume from ages 6 to 24 months (ß = 4.64; 95% CI, 0.58-8.72; P = .002) and more frequent night wakings at school-age (F = 7.76; η2 = 0.08; P = .006). Conclusions and Relevance: These findings suggest that enlarged PVS emerged between ages 12 and 24 months in infants who developed autism. These results add to a growing body of evidence that, along with excessive CSF volume and sleep dysfunction, the glymphatic system could be dysregulated in infants who develop autism.

Relationships between GABA, glutamate, and GABA/glutamate and social and olfactory processing in children with autism spectrum disorder.

Theories of altered inhibitory/excitatory signaling in autism spectrum disorder (ASD) suggest that gamma amino butyric acid (GABA) and glutamate (Glu) abnormalities may underlie social and sensory challenges in ASD. Magnetic resonance spectroscopy was used to measure Glu and GABA+ levels in the amygdala-hippocampus region and cerebellum in autistic children (n = 30), a clinical control group with sensory abnormalities (SA) but not ASD (n = 30), and children with typical development (n = 37). All participants were clinically assessed using the Autism Diagnostic Interview-Revised, the Autism Diagnostic Observation Scale-2, and the Child Sensory Profile-2. The Social Responsiveness Scale-2, Sniffin Sticks Threshold Test, and the University of Pennsylvania Smell Identification Test were administered to assess social impairment and olfactory processing. Overall, autistic children showed increased cerebellar Glu levels compared to TYP children. Evidence for altered excitatory/inhibitory signaling in the cerebellum was more clear-cut when analyses were restricted to male participants. Further, lower cerebellar GABA+/Glu ratios were correlated to more severe social impairment in both autistic and SA males, suggesting that the cerebellum may play a transdiagnostic role in social impairment. Future studies of inhibitory/excitatory neural markers, powered to investigate the role of sex, may aid in parsing out disorder-specific neurochemical profiles.

Interpersonal Influences on the Choice to Treat Nausea during Pregnancy with Medication or Cannabis.

OBJECTIVE: This study aimed to better understand the interpersonal influences on a pregnant individual's decision of how to treat nausea and vomiting during pregnancy using a qualitative approach. STUDY DESIGN: A semistructured interview guide was developed to assess pregnancy symptoms, decision-making regarding treating nausea, and interpersonal influences on treatment decisions. Interviews were conducted with 17 individuals enrolled in a neuroimaging and behavioral study of prenatal exposure to cannabis who used medication and/or cannabis to treat symptoms associated with pregnancy. RESULTS: Interviews revealed four groups of stakeholders who influenced participant decision-making: medical providers, partners, family, and friends. Influence was categorized as either positive, negative, neutral, or absent (if not discussed or participant chose not to disclose). Those in the medication group reported only positive or neutral feedback from friends, family, partners, and providers. In contrast, the cannabis group participants reported positive feedback from friends, mixed feedback from family and partners, and negative feedback from providers, which was often felt to be stigmatizing. Many in the cannabis group also reported varying feedback from different medical providers. While the cannabis group frequently reported eliciting feedback from friends, family, and partners, the medication group often did not. CONCLUSION: Medication group participants reported entirely positive feedback from providers and often did not mention any feedback at all from partners, family, and friends. Cannabis group participants reported much more varied feedback, both positive and negative, from a variety of interpersonal contacts and sometimes decided to conceal their treatment choice after receiving or fearing negative feedback. We recommend further research into the health outcomes of pregnant patients who chose not to discuss their treatment decisions with providers, family, partners, or friends. We also suggest further study of possible reasons behind a lack of disclosure, including fear of stigma and/or legal consequences. KEY POINTS: · Providers, partners, family, friends gave feedback.. · Medication group got positive feedback.. · Cannabis group stigmatized by providers.. · Cannabis group got mixed feedback..

Predicting self-injurious behavior at age three among infant siblings of children with autism.

Existing research suggests that self-injurious behavior (SIB) is a relatively common interfering behavior that can occur across the lifespan of individuals with autism spectrum disorder (ASD). We previously reported that SIB or proto-injurious SIB at 12 months was related to increased risk of SIB at 24 months among a preschool sample of children with a high familial likelihood for ASD (Dimian et al., 2017). In the present study, we extend these findings, examine SIB occurrence, and associated potential risk factors at 36 months. The present sample included 149 infants with an older sibling with ASD (65.8% male) who completed assessments at ages 12, 24, and 36 months. Descriptive analyses and binary logistic regression models were utilized. SIB was more prevalent among those children who received a diagnosis of ASD. Logistic regression indicated that presence of SIB, stereotypy, hyper- and hypo- sensory responsivity, and lower intellectual functioning at age 12 months significantly predicted the occurrence of SIB at 36 months. These findings have implications for understanding developmental processes culminating in persistent SIB and may inform prevention programming.

Self-report methodology for quantifying standardized cannabis consumption in milligrams delta-9-tetrahydrocannabinol.

Background: There is currently no format-independent method to determine delta-9-tetrahydrocannabinol (THC) in milligrams for self-report studies.Objectives: Validate self-report method for quantifying mg THC from commercially available cannabis products using product labeling, which includes both net weight and product potency.Methods: 53 adult cannabis users (24 M, 29F), 21-39 years of age (M = 28.38, SD = 4.15), were instructed to report daily use via a weekly survey for two consecutive weeks, provide product label photographs, abstain from use for 24 h, submit a urine sample and complete the Cannabis Use Disorder Identification Test - Revised (CUDIT-R) and the Marijuana Craving Questionnaire - Short Form (MCQ-SF). Milligrams of THC were determined by multiplying quantity of product used by its THC concentration. Urine was analyzed for the urine metabolite 11-nor-carboxy-THC (THC-COOH) via liquid chromatography mass spectroscopy. THC and THC-COOH values were log10 transformed prior to correlational analyses.Results: Median daily THC consumption was 102.53 mg (M = 203.68, SD = 268.13). Thirty-three (62%) of the 53 participants reported using two or more formats over the 2-week period. There was a significant positive correlation between log10 THC-COOH and log10 THC mg (r(41) = .59, p < .001), log10 THC mg and MCQ-SF score (r(41) = .59, p < .001), and log10 THC mg dose and CUDIT-R score, (r(41) = .39, p = .010).Conclusion: Our label-based methodology provides consumption information across all modalities of cannabis use in standard units that can be combined across products for calculation of dose. It is a viable and valid method for quantifying mg of THC consumed and can be utilized in any region where cannabis is legal, and labeling is regulated.

The prevalence and developmental course of auditory processing differences in autistic children.

Auditory processing differences, including hyper- or hyposensitivity to sound, aversions to sound, and difficulty listening under noisy, real-world conditions, are commonly reported in autistic individuals. However, the developmental course and functional impact of these auditory processing differences are unclear. In this study, we investigate the prevalence, developmental trajectory, and functional impact of auditory processing differences in autistic children throughout childhood using a longitudinal study design. Auditory processing differences were measured using the Short Sensory Profile, a caregiver questionnaire, in addition to adaptive behaviors and disruptive/concerning behaviors at 3, 6, and 9 years of age. Our results showed that auditory processing differences were reported in greater than 70% of the autistic children in our sample at all three timepoints, maintained a high prevalence through 9 years of age, and were associated with increased disruptive/concerning behaviors and difficulty with adaptive behaviors. Furthermore, in our sample of children, auditory processing differences at age 3 years predicted disruptive/concerning behaviors and difficulty with adaptive behaviors at age 9 years. These findings warrant further investigations of the potential benefit of incorporating measures of auditory processing during routine clinical evaluations as well as interventions targeting auditory processing differences in autistic children.

Donor perspectives on informed consent and use of biospecimens for brain organoid research.

Debates about the ethics of human brain organoids have proceeded without the input of individuals whose brains are being modeled. Interviews with donors of biospecimens for brain organoid research revealed overall enthusiasm for brain organoids as a tool for biomedical discovery, alongside a desire for ongoing engagement with research teams to learn the results of the research, to allow transfer of decision-making authority over time, and to ensure ethical boundaries are not crossed. Future work is needed to determine the most feasible and resource-efficient way to longitudinally engage donors participating in brain organoid research.

Association of Sex With Neurobehavioral Markers of Executive Function in 2-Year-Olds at High and Low Likelihood of Autism.

Importance: Children with autism and their siblings exhibit executive function (EF) deficits early in development, but associations between EF and biological sex or early brain alterations in this population are largely unexplored. Objective: To investigate the interaction of sex, autism likelihood group, and structural magnetic resonance imaging alterations on EF in 2-year-old children at high familial likelihood (HL) and low familial likelihood (LL) of autism, based on having an older sibling with autism or no family history of autism in first-degree relatives. Design, Setting, and Participants: This prospective cohort study assessed 165 toddlers at HL (n = 110) and LL (n = 55) of autism at 4 university-based research centers. Data were collected from January 1, 2007, to December 31, 2013, and analyzed between August 2021 and June 2022 as part of the Infant Brain Imaging Study. Main Outcomes and Measures: Direct assessments of EF and acquired structural magnetic resonance imaging were performed to determine frontal lobe, parietal lobe, and total cerebral brain volume. Results: A total of 165 toddlers (mean [SD] age, 24.61 [0.95] months; 90 [54%] male, 137 [83%] White) at HL for autism (n = 110; 17 diagnosed with ASD) and LL for autism (n = 55) were studied. The toddlers at HL for autism scored lower than the toddlers at LL for autism on EF tests regardless of sex (mean [SE] B = -8.77 [4.21]; 95% CI, -17.09 to -0.45; η2p = 0.03). With the exclusion of toddlers with autism, no group (HL vs LL) difference in EF was found in boys (mean [SE] difference, -7.18 [4.26]; 95% CI, 1.24-15.59), but EF was lower in HL girls than LL girls (mean [SE] difference, -9.75 [4.34]; 95% CI, -18.32 to -1.18). Brain-behavior associations were examined, controlling for overall cerebral volume and developmental level. Sex differences in EF-frontal (B [SE] = 16.51 [7.43]; 95% CI, 1.36-31.67; η2p = 0.14) and EF-parietal (B [SE] = 17.68 [6.99]; 95% CI, 3.43-31.94; η2p = 0.17) associations were found in the LL group but not the HL group (EF-frontal: B [SE] = -1.36 [3.87]; 95% CI, -9.07 to 6.35; η2p = 0.00; EF-parietal: B [SE] = -2.81 [4.09]; 95% CI, -10.96 to 5.34; η2p = 0.01). Autism likelihood group differences in EF-frontal (B [SE] = -9.93 [4.88]; 95% CI, -19.73 to -0.12; η2p = 0.08) and EF-parietal (B [SE] = -15.44 [5.18]; 95% CI, -25.86 to -5.02; η2p = 0.16) associations were found in girls not boys (EF-frontal: B [SE] = 6.51 [5.88]; 95% CI, -5.26 to 18.27; η2p = 0.02; EF-parietal: B [SE] = 4.18 [5.48]; 95% CI, -6.78 to 15.15; η2p = 0.01). Conclusions and Relevance: This cohort study of toddlers at HL and LL of autism suggests that there is an association between sex and EF and that brain-behavior associations in EF may be altered in children at HL of autism. Furthermore, EF deficits may aggregate in families, particularly in girls.

Sensory Profiles in Relation to Later Adaptive Functioning Among Toddlers at High-Familial Likelihood for Autism.

This study investigated the extent to which sensory responsivity in infancy contributes to adaptive behavior development among toddlers at high-familial likelihood for autism. Prospective, longitudinal data were analyzed for 218 children, 58 of whom received an autism diagnosis. Results indicated that sensory profiles at age one year (hyperresponsivity, sensory seeking) were negatively associated with later adaptive behavior, particularly for socialization, at age 3 years regardless of diagnostic status. These results suggest that early differences in sensory responsivity may have downstream developmental consequences related to social development among young children with high-familial likelihood for autism.

Language exposure during infancy is negatively associated with white matter microstructure in the arcuate fasciculus.

Decades of research have established that the home language environment, especially quality of caregiver speech, supports language acquisition during infancy. However, the neural mechanisms behind this phenomenon remain under studied. In the current study, we examined associations between the home language environment and structural coherence of white matter tracts in 52 typically developing infants from English speaking homes in a western society. Infants participated in at least one MRI brain scan when they were 3, 6, 12, and/or 24 months old. Home language recordings were collected when infants were 9 and/or 15 months old. General linear regression models indicated that infants who heard the most adult words and participated in the most conversational turns at 9 months of age also had the lowest fractional anisotropy in the left posterior parieto-temporal arcuate fasciculus at 24 months. Similarly, infants who vocalized the most at 9 months also had the lowest fractional anisotropy in the same tract at 6 months of age. This is one of the first studies to report significant associations between caregiver speech collected in the home and white matter structural coherence in the infant brain. The results are in line with prior work showing that protracted white matter development during infancy confers a cognitive advantage.

A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

Optimal transport features for morphometric population analysis.

Brain pathologies often manifest as partial or complete loss of tissue. The goal of many neuroimaging studies is to capture the location and amount of tissue changes with respect to a clinical variable of interest, such as disease progression. Morphometric analysis approaches capture local differences in the distribution of tissue or other quantities of interest in relation to a clinical variable. We propose to augment morphometric analysis with an additional feature extraction step based on unbalanced optimal transport. The optimal transport feature extraction step increases statistical power for pathologies that cause spatially dispersed tissue loss, minimizes sensitivity to shifts due to spatial misalignment or differences in brain topology, and separates changes due to volume differences from changes due to tissue location. We demonstrate the proposed optimal transport feature extraction step in the context of a volumetric morphometric analysis of the OASIS-1 study for Alzheimer's disease. The results demonstrate that the proposed approach can identify tissue changes and differences that are not otherwise measurable.

Relationship of Impairments in Associative Learning With Intellectual Disability and Cerebellar Hypoplasia in Autistic Children.

BACKGROUND AND OBJECTIVES: The severity of autism spectrum disorder (ASD) varies widely and is associated with intellectual disability (ID) and brain dysmorphology. We tested the hypothesis that the heterogeneity of ASD can be accounted for, in part, by altered associative learning measured by eye-blink conditioning (EBC) paradigms, used to test for forebrain and cerebellar dysfunction across the full range of ASD severity and intellectual ability. METHODS: Children in this cohort study were diagnosed with ASD or typical development (TD); most children were recruited from a 10-year longitudinal study. Outcome measures were the percentage and timing of conditioned eye-blink responses (CRs) acquired to a tone, recorded photometrically and related to measures of ASD severity, IQ, and age 2 brain morphometry by MRI. A sequence of trace and delay EBC was used. Analysis of variance, t test, and logistic regression (LR) were used. RESULTS: Sixty-two children were studied at school age. Nine children with ASD with ID since age 2 (ASD + ID; IQ = 49 ± 6; 11.9 ± 0.2 years old [±SD]) learned more slowly than 30 children with TD (IQ = 120 ± 16; 10.5 ± 1.5 years old [±SD]) during trace EBC and showed atypically early-onset CRs (1.4 SD pre-TD) related to hypoplasia of the cerebellum at age 2 but not of the amygdala, hippocampus, or cerebral cortex. Conversely, 16 children with ASD with robust intellectual development since age 2 (IQ = 100 ± 3; 12.0 ± 0.4 years old [±SD]) learned typically but showed early-onset CRs only during long-delay EBC (0.8 SD pre-TD) unrelated to hypoplasia of any measured brain area. Using 16 EBC measures, binary LR classified ASD and TD with 80% accuracy (95% CI = 72-88%), 81% sensitivity (95% CI = 69-92%), and 79% specificity (95% CI = 68-91%); multinomial LR more accurately classified children based on ID (94% accuracy, 95% CI = 89-100%) than ASD severity (85% accuracy, 95% CI = 77-93%). Separate analyses of 39 children with MRI (2.1 ± 0.3 years old [±SD]) indicated that cerebellar hypoplasia did not predict ASD + ID over ages 2-4 (Cohen d = 0.3) compared with early-onset CRs during age 11 trace EBC (Cohen d = -1.3). DISCUSSION: Trace EBC reveals the relationship between cerebellar hypoplasia and ASD + ID likely by engaging cerebrocerebellar circuits involved in intellectual ability and implicit timing. Follow-up prospective studies using associative learning can determine whether ID can be predicted in children with early ASD diagnoses.