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Altered functional connectivity has been reported in infants with prenatal exposure to opioids, which significantly interrupts and influences endogenous neurotransmitter/receptor signaling during fetal programming. Better birth outcomes and long-term developmental outcomes are associated with medication for opioid use disorder (MOUD) during pregnancy, but the neural mechanisms underlying these benefits are largely unknown. We aimed to characterize effects of prenatal opioid/other drug exposure (PODE) and the neural basis for the reported beneficial effects of MOUD by examining neonatal brain functional organization. A cohort of 109 human newborns, 42 PODE, 39 with prenatal exposure to drugs excluding opioids (PDE), 28 drug-free controls (males and females) underwent resting-state fMRI at 2 weeks of age. To examine neural effects of MOUD, PODE infants were separated into subgroups based on whether mothers received MOUD (n= 31) or no treatment (n= 11). A novel heatmap analysis was designed to characterize PODE-associated functional connectivity alterations and MOUD-related effects, and permutation testing identified regions of interest with significant effects. PODE neonates showed alterations beyond those associated with PDE, particularly in reward-related frontal-sensory connectivity. MOUD was associated with a significant reduction of PODE-related alterations in key regions of endogenous opioid pathways including limbic and frontal connections. However, significant residual effects in limbic and subcortical circuitry were observed. These findings confirm altered brain functional organization associated with PODE. Importantly, widespread normalization effects associated with MOUD reveal, for the first time, the potential brain basis of the beneficial effects of MOUD on the developing brain and underscore the importance of this treatment intervention for better developmental outcomes.SIGNIFICANCE STATEMENTThis is the first study to reveal the potential neural mechanisms underlying the beneficial effects on the neonate brain associated with MOUD during pregnancy. We identified both normalization and residual effects of MOUD on brain functional architecture by directly comparing neonates prenatally exposed to opioids with MOUD and those exposed to opioids but without MOUD. Our findings confirm altered brain functional organization associated with prenatal opioid exposure and demonstrate that although significant residual effects remain in reward circuitry, MOUD confers significant normalization effects on functional connectivity of regions associated with socioemotional development and reward processing. Together, our results highlight the importance of MOUD intervention for better neurodevelopmental outcomes.

While the cerebellum is traditionally known for its role in sensorimotor control, emerging research shows that particular subregions, such as right Crus I (RCrusI), support language and social processing. Indeed, cerebellar atypicalities are commonly reported in autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by socio-communicative impairments. However, the cerebellum's contribution to early socio-communicative development remains virtually unknown.Here, we characterized functional connectivity within cerebro-cerebellar networks implicated in language/social functions in 9-month-old infants who exhibit distinct 3-year socio-communicative developmental profiles. We employed a data-driven clustering approach to stratify our sample of infants at high (n = 82) and low (n = 37) familial risk for ASD into three cohorts-Delayed, Late-Blooming, and Typical-who showed unique socio-communicative trajectories. We then compared the cohorts on indices of language and social development. Seed-based functional connectivity analyses with RCrusI were conducted on infants with fMRI data (n = 66). Cohorts were compared on connectivity estimates from a-priori regions, selected on the basis of reported coactivation with RCrusI during language/social tasks.The three trajectory-based cohorts broadly differed in social communication development, as evidenced by robust differences on numerous indices of language and social skills. Importantly, at 9 months, the cohorts showed striking differences in cerebro-cerebellar circuits implicated in language/social functions. For all regions examined, the Delayed cohort exhibited significantly weaker RCrusI connectivity compared to both the Late-Blooming and Typical cohorts, with no significant differences between the latter cohorts.We show that hypoconnectivity within distinct cerebro-cerebellar networks in infancy predicts altered socio-communicative development before delays overtly manifest, which may be relevant for early detection and intervention. As the cerebellum is implicated in prediction, our findings point to probabilistic learning as a potential intermediary mechanism that may be disrupted in infancy, cascading into alterations in social communication.

Converging evidence from neuroimaging studies has revealed altered connectivity in cortical–subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical–subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here, we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and low-risk controls (LR). Resting-state functional connectivity and diffusion tensor imaging data were acquired in 52 6-week-old infants. Functional connectivity was examined between 6 cortical seeds—prefrontal, motor, somatosensory, temporal, parietal, and occipital regions—and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared with LR infants. Notably, aberrant connectivity indices at 6 weeks predicted atypical social development between 9 and 36 months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as 6 weeks of age, providing a possible early marker of risk for ASD.

ObjectiveSensory overresponsivity (SOR), an atypical negative reaction to sensory stimuli, is highly prevalent in autism spectrum disorder (ASD). Previous work has related SOR to increased brain response in sensory-limbic regions. This study investigated where these atypical responses fall in three fundamental stages of sensory processing: arousal (i.e., initial response), habituation (i.e., change in response over time), and generalization of response to novel stimuli. Different areas of atypical response would require distinct intervention approaches.MethodsFunctional MRI was used to examine these patterns of neural habituation to two sets of similar mildly aversive auditory and tactile stimuli in 42 high-functioning children and adolescents with ASD (21 with high levels of SOR and 21 with low levels of SOR) and 27 age-matched typically developing youths (ages 8-17). The relationship between SOR and change in amygdala-prefrontal functional connectivity across the sensory stimulation was also examined.ResultsAcross repeated sensory stimulation, high-SOR participants with ASD showed reduced ability to maintain habituation in the amygdala and relevant sensory cortices and to maintain inhibition of irrelevant sensory cortices. These results indicate that sensory habituation is a dynamic, time-varying process dependent on sustained regulation across time, which is a particular deficit in high-SOR participants with ASD. However, low-SOR participants with ASD also showed distinct, nontypical neural response patterns, including reduced responsiveness to novel but similar stimuli and increases in prefrontal-amygdala regulation across the sensory exposure.ConclusionsThe results suggest that all children with autism have atypical brain responses to sensory stimuli, but whether they express atypical behavioral responses depends on top-down regulatory mechanisms. Results are discussed in terms of targeted intervention approaches.

Converging evidence implicates disrupted brain connectivity in autism spectrum disorder (ASD); however, the mechanisms linking altered connectivity early in development to the emergence of ASD symptomatology remain poorly understood. Here we examined whether atypicalities in the Salience Network (SN) – an early-emerging neural network involved in orienting attention to the most salient aspects of one’s internal and external environment – may predict the development of ASD markers such as reduced social attention and atypical sensory processing. Six-week-old infants at high-risk for ASD exhibited stronger SN connectivity with sensorimotor regions; low-risk infants demonstrated stronger SN connectivity with prefrontal regions involved in social attention. Infants with higher connectivity with sensorimotor regions had lower connectivity with prefrontal regions, suggesting a direct tradeoff between attention to basic sensory versus socially-relevant information. Early alterations in SN connectivity predicted subsequent ASD symptomatology, providing a plausible mechanistic account for the unfolding of atypical developmental trajectories associated with ASD risk.

Highlights • Heatmaps quantify degrees of developmental changes in functional connectivity. • More changes are observed in the first than second postnatal year, driven by girls. • Most change is observed from ages 2–4 compared with any other age span. • Limbic and subcortical areas show more changes than primary sensory regions. • Consistent trajectories of functional connectivity are found across validations., Different functional networks exhibit distinct longitudinal trajectories throughout development, but the timeline of the dynamics of functional connectivity across the whole brain remains to be elucidated. Here we used resting-state fMRI to investigate the development of voxel-level changes in functional connectivity across the first six years of life. Globally, we found that developmental changes in functional connectivity are nonlinear with more changes during the first postnatal year than the second, followed by most significant changes from ages 2–4 and from ages 4–6. However, the overall global difference observed between the first and second year appears to have been driven by girls. Limbic and subcortical areas consistently demonstrated the most substantial changes, whereas primary sensory areas were the most stable. These patterns were consistent in full-term and preterm subgroups. Validation on randomly divided subsamples as well as in an independent cross-sectional sample revealed global patterns consistent with the main results. Overall, the derived developmental heatmaps reveal novel dynamics underlying functional circuit development during the first 6 years of life.

Word segmentation is a fundamental aspect of language learning, since identification of word boundaries in continuous speech must occur before the acquisition of word meanings can take place. We previously used functional magnetic resonance imaging (fMRI) to show that youth with autism spectrum disorder (ASD) are less sensitive to statistical and speech cues that guide implicit word segmentation. However, little is known about the neural mechanisms underlying this process during infancy and how this may be associated with ASD risk. Here, we examined early neural signatures of language-related learning in 9-month-old infants at high (HR) and low familial risk (LR) for ASD. During natural sleep, infants underwent fMRI while passively listening to three speech streams containing strong statistical and prosodic cues, strong statistical cues only, or minimal statistical cues to word boundaries. Compared to HR infants, LR infants showed greater activity in the left amygdala for the speech stream containing statistical and prosodic cues. While listening to this same speech stream, LR infants also showed more learning-related signal increases in left temporal regions as well as increasing functional connectivity between bilateral primary auditory cortex and right anterior insula. Importantly, learning-related signal increases at 9 months positively correlated with expressive language outcome at 36 months in both groups. In the HR group, greater signal increases were additionally associated with less severe ASD symptomatology at 36 months. These findings suggest that early differences in the neural networks underlying language learning may predict subsequent language development and altered trajectories associated with ASD risk.

The hippocampus is a key limbic region involved in higher-order cognitive processes including learning and memory. Although both typical and atypical functional connectivity patterns of the hippocampus have been well-studied in adults, the developmental trajectory of hippocampal connectivity during infancy and how it relates to later working memory performance remains to be elucidated. Here we used resting state fMRI (rsfMRI) during natural sleep to examine the longitudinal development of hippocampal functional connectivity using a large cohort (N = 202) of infants at 3 weeks (neonate), 1 year, and 2 years of age. Next, we used multivariate modeling to investigate the relationship between both cross-sectional and longitudinal growth in hippocampal connectivity and 4-year working memory outcome. Results showed robust local functional connectivity of the hippocampus in neonates with nearby limbic and subcortical regions, with dramatic maturation and increasing connectivity with key default mode network (DMN) regions resulting in adult-like topology of the hippocampal functional connectivity by the end of the first year. This pattern was stabilized and further consolidated by 2 years of age. Importantly, cross-sectional and longitudinal measures of hippocampal connectivity in the first year predicted subsequent behavioral measures of working memory at 4 years of age. Taken together, our findings provide insight into the development of hippocampal functional circuits underlying working memory during this early critical period.

Converging evidence from neuroimaging studies has revealed altered connectivity in cortical-subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical-subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and lowrisk controls (LR). Resting-state functional connectivity (rs-fcMRI) and diffusion tensor imaging (DTI) data were acquired 52 six-week-old infants. Functional connectivity was examined between six cortical seeds –prefrontal, motor, somatosensory, temporal, parietal, and occipital regions– and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared to LR infants. Notably, aberrant rs-fcMRI and DTI connectivity indices at 6 weeks predicted atypical social development between 6 and 36 months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as six weeks of age, providing a possible early marker of risk for ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by lack of attention to social cues in the environment, including speech. Hypersensitivity to sensory stimuli, such as loud noises, is also extremely common in youth with ASD. While a link between sensory hypersensitivity and impaired social functioning has been hypothesized, very little is known about the neural mechanisms whereby exposure to distracting sensory stimuli may interfere with the ability to direct attention to socially-relevant information. Here, we used functional magnetic resonance imaging (fMRI) in youth with and without ASD (N=54, age range 8-18 years) to (1) examine brain responses during presentation of brief social interactions (i.e., two-people conversations) shrouded in ecologically-valid environmental noises, and (2) assess how brain activity during encoding might relate to later accuracy in identifying what was heard. During exposure to conversation-in-noise (vs. conversation or noise alone), both neurotypical youth and youth with ASD showed robust activation of canonical language networks. However, the extent to which youth with ASD activated temporal language regions, including voice-selective cortex (i.e., posterior superior temporal sulcus), predicted later discriminative accuracy in identifying what was heard. Further, relative to neurotypical youth, ASD youth showed significantly greater activity in left-hemisphere speech-processing cortex (i.e., angular gyrus) while listening to conversation-in-noise (vs. conversation or noise alone). Notably, in youth with ASD, increased activity in this region was associated with higher social motivation and better social cognition measures. This heightened activity in voice-selective/speech-processing regions may serve as a compensatory mechanism allowing youth with ASD to hone in on the conversations they heard in the context of non-social distracting stimuli. These findings further suggest that focusing on social and non-social stimuli simultaneously may be more challenging for youth with ASD requiring the recruitment of additional neural resources to encode socially-relevant information.

Prior studies have demonstrated that infants and toddlers who later go on to develop autism spectrum disorder (ASD) show atypical functional connectivity as well as altered neural processing of language and other auditory stimuli, but the timeline underlying the emergence of these altered developmental trajectories is still unclear. Here we used resting-state fMRI (rsfMRI) during natural sleep to examine the longitudinal development of functional connectivity in language-related networks from 1.5 to 9 months of age. We found that functional connectivity of networks that underlie the integration of sensory and motor representations, which is crucial for language development, is disrupted in infants at high familial risk (HR) for developing ASD as early as 1.5 months of age. By 9 months of age, HR infants showed hyperconnectivity between auditory and somatosensory regions whereas low risk (LR) infants displayed greater intrahemispheric connectivity between auditory cortex and higher-order temporal regions as well as the hippocampus. Furthermore, while LR infants showed robust changes in functional connectivity during the first year of life with increasing long-range connectivity accompanied by decreasing short-range connectivity over time, HR infants displayed limited developmental changes. Our findings demonstrate that early disruptions in the development of language-related network connectivity may provide an early marker for the later emergence of ASD symptomatology.

Altered structural connectivity has been identified as a possible biomarker of autism spectrum disorder (ASD) risk in the developing brain. Core features of ASD include impaired social communication and early language delay. Thus, examining white matter tracts associated with language may lend further insight into early signs of ASD risk and the mechanisms that underlie language impairments associated with the disorder. Evidence of altered structural connectivity has previously been detected in 6-month-old infants at high familial risk for developing ASD. However, as language processing begins in utero, differences in structural connectivity between language regions may be present in the early infant brain shortly after birth. Here we investigated key white matter pathways of the dorsal language network in 6-week-old infants at high (HR) and low (LR) risk for ASD to identify atypicalities in structural connectivity that may predict altered developmental trajectories prior to overt language delays and the onset of ASD symptomatology. Compared to HR infants, LR infants showed higher fractional anisotropy (FA) in the left superior longitudinal fasciculus (SLF); in contrast, in the right SLF, HR infants showed higher FA than LR infants. Additionally, HR infants showed more rightward lateralization of the SLF. Across both groups, measures of FA and lateralization of these pathways at 6 weeks of age were related to later language development at 18 months of age as well as ASD symptomatology at 36 months of age. These findings indicate that early differences in the structure of language pathways may provide an early predictor of future language development and ASD risk.

Spatiotemporal interpolation (STI) refers to perception of complete objects from fragmentary information across gaps in both space and time. It differs from static interpolation in that requirements for interpolation are not met in any static frame. It has been found that STI produced objective performance advantages in a shape discrimination paradigm for both illusory and occluded objects when contours met conditions of spatiotemporal relatability. Here we report psychophysical studies testing whether spatiotemporal interpolation allows recovery of metric properties of objects. Observers viewed virtual triangles specified only by sequential partial occlusions of background elements by their vertices (the STI condition) and made forced choice judgments of the object’s size relative to a reference standard. We found that length could often be accurately recovered for conditions where fragments were relatable and formed illusory triangles. In the first control condition, three moving dots located at the vertices provided the same spatial and timing information as the virtual object in the STI condition but did not induce perception of interpolated contours or a coherent object. In the second control condition oriented line segments were added to the dots and mid-points between the dots in a way that did not induce perception of interpolated contours. Control stimuli did not lead to accurate size judgments. We conclude that spatiotemporal interpolation can produce representations, from fragmentary information, of metric properties in addition to shape.

High-voltage activated Ca channels participate in multiple cellular functions, including transmitter release, excitation, and gene transcription. Ca channels are heteromeric proteins consisting of a pore-forming α(1) subunit and auxiliary α(2)δ and β subunits. Although there are reports of α(2)δ(4) subunit mRNA in the mouse retina and localization of the α(2)δ(4) subunit immunoreactivity to salamander photoreceptor terminals, there is a limited overall understanding of its expression and localization in the retina. α(2)δ(4) subunit expression and distribution in the mouse and rat retina were evaluated by using reverse transcriptase polymerase chain reaction, western blot, and immunohistochemistry with specific primers and a well-characterized antibody to the α(2)δ(4) subunit. α(2)δ(4) subunit mRNA and protein are present in mouse and rat retina, brain, and liver homogenates. Immunostaining for the α(2)δ(4) subunit is mainly localized to Muller cell processes and endfeet, photoreceptor terminals, and photoreceptor outer segments. This subunit is also expressed in a few displaced ganglion cells and bipolar cell dendrites. These findings suggest that the α(2)δ(4) subunit participates in the modulation of L-type Ca(2+) current regulating neurotransmitter release from photoreceptor terminals and Ca(2+)-dependent signaling pathways in bipolar and Muller cells.

Compared to deep brain electrical stimulation, which has been applied to treating pathological brain diseases, little work has been done on the effect of deep brain light stimulation. A fiber-coupled laser stimulator at 840 nm wavelength and 130 Hz pulse repetition rate is developed in this work for deep brain light stimulation in a rat model. Concentration changes in glutamate and dopamine in the striatum are observed using a microdialysis probe when the subthalamic nucleus (STN) is stimulated at various optical power levels. Experimental results show that light stimulation causes the concentration of glutamate to decrease while that of dopamine is increased. This suggests that deep brain light stimulation of the STN is a promising therapeutic strategy for dopamine-related diseases such as Parkinson’s disease. The stimulator developed for this work is useful for deep brain light stimulation in biomedical research.

High-voltage activated Ca channels participate in multiple cellular functions, including transmitter release, excitation, and gene transcription. Ca channels are heteromeric proteins consisting of a pore-forming α(1) subunit and auxiliary α(2)δ and β subunits. Although there are reports of α(2)δ(4) subunit mRNA in the mouse retina and localization of the α(2)δ(4) subunit immunoreactivity to salamander photoreceptor terminals, there is a limited overall understanding of its expression and localization in the retina. α(2)δ(4) subunit expression and distribution in the mouse and rat retina were evaluated by using reverse transcriptase polymerase chain reaction, western blot, and immunohistochemistry with specific primers and a well-characterized antibody to the α(2)δ(4) subunit. α(2)δ(4) subunit mRNA and protein are present in mouse and rat retina, brain, and liver homogenates. Immunostaining for the α(2)δ(4) subunit is mainly localized to Müller cell processes and endfeet, photoreceptor terminals, and photoreceptor outer segments. This subunit is also expressed in a few displaced ganglion cells and bipolar cell dendrites. These findings suggest that the α(2)δ(4) subunit participates in the modulation of L-type Ca(2+) current regulating neurotransmitter release from photoreceptor terminals and Ca(2+)-dependent signaling pathways in bipolar and Müller cells.

High-voltage-activated calcium channels are hetero-oligomeric protein complexes that mediate multiple cellular processes, including the influx of extracellular Ca(2+), neurotransmitter release, gene transcription, and synaptic plasticity. These channels consist of a primary α(1) pore-forming subunit, which is associated with an extracellular α(2)δ subunit and an intracellular β auxiliary subunit, which alter the gating properties and trafficking of the calcium channel. The cellular localization of the α(2)δ(3) subunit in the mouse and rat retina is unknown. In this study using RT-PCR, a single band at ∼ 305 bp corresponding to the predicted size of the α(2)δ(3) subunit fragment was found in mouse and rat retina and brain homogenates. Western blotting of rodent retina and brain homogenates showed a single 123-kDa band. Immunohistochemistry with an affinity-purified antibody to the α(2)δ(3) subunit revealed immunoreactive cell bodies in the ganglion cell layer and inner nuclear layer and immunoreactive processes in the inner plexiform layer and the outer plexiform layer. α(2)δ(3) immunoreactivity was localized to multiple cell types, including ganglion, amacrine, and bipolar cells and photoreceptors, but not horizontal cells. The expression of the α(2)δ(3) calcium channel subunit to multiple cell types suggests that this subunit participates widely in Ca-channel-mediated signaling in the retina.