Functional connectivity of the sensorimotor cerebellum in autism: associations with sensory over-responsivity.

The cerebellum has been consistently shown to be atypical in autism spectrum disorder (ASD). However, despite its known role in sensorimotor function, there is limited research on its association with sensory over-responsivity (SOR), a common and impairing feature of ASD. Thus, this study sought to examine functional connectivity of the sensorimotor cerebellum in ASD compared to typically developing (TD) youth and investigate whether cerebellar connectivity is associated with SOR. Resting-state functional connectivity of the sensorimotor cerebellum was examined in 54 ASD and 43 TD youth aged 8-18 years. Using a seed-based approach, connectivity of each sensorimotor cerebellar region (defined as lobules I-IV, V-VI and VIIIA&B) with the whole brain was examined in ASD compared to TD youth, and correlated with parent-reported SOR severity. Across all participants, the sensorimotor cerebellum was functionally connected with sensorimotor and visual regions, though the three seed regions showed distinct connectivity with limbic and higher-order sensory regions. ASD youth showed differences in connectivity including atypical connectivity within the cerebellum and increased connectivity with hippocampus and thalamus compared to TD youth. More severe SOR was associated with stronger connectivity with cortical regions involved in sensory and motor processes and weaker connectivity with cognitive and socio-emotional regions, particularly prefrontal cortex. These results suggest that atypical cerebellum function in ASD may play a role in sensory challenges in autism.

Associations between thalamocortical functional connectivity and sensory over-responsivity in infants at high likelihood for ASD.

Despite growing evidence implicating thalamic functional connectivity atypicalities in autism spectrum disorder (ASD), it remains unclear how such alterations emerge early in human development. Because the thalamus plays a critical role in sensory processing and neocortical organization early in life, its connectivity with other cortical regions could be key for studying the early onset of core ASD symptoms. Here, we investigated emerging thalamocortical functional connectivity in infants at high (HL) and typical (TL) familial likelihood for ASD in early and late infancy. We report significant thalamo-limbic hyperconnectivity in 1.5-month-old HL infants, and thalamo-cortical hypoconnectivity in prefrontal and motor regions in 9-month-old HL infants. Importantly, early sensory over-responsivity (SOR) symptoms in HL infants predicted a direct trade-off in thalamic connectivity whereby stronger thalamic connectivity with primary sensory regions and basal ganglia was inversely related to connectivity with higher order cortices. This trade-off suggests that ASD may be characterized by early differences in thalamic gating. The patterns reported here could directly underlie atypical sensory processing and attention to social vs. nonsocial stimuli observed in ASD. These findings lend support to a theoretical framework of ASD whereby early disruptions in sensorimotor processing and attentional biases early in life may cascade into core ASD symptomatology.

An Observed Assessment of Sensory Responsivity in Autism Spectrum Disorders: Associations with Diagnosis, Age, and Parent Report.

Sensory features are common and impairing in autism spectrum disorder (ASD), but there are few observational sensory assessments that are valid across ages. We used the Sensory Processing 3-Dimensional (SP3-D) observed Assessment and parent-reported Inventory to examine sensory responsivity in 41 ASD and 33 typically-developing (TD) youth across 7-17 years. ASD youth had higher and more variable observed and reported sensory responsivity symptoms compared to TD, but the two measures were not correlated. Observed sensory over-responsivity (SOR) and sensory craving (SC) decreased with age in ASD, though SOR remained higher in ASD versus TD through adolescence. Results suggest that in ASD, the SP3-D Assessment can identify SOR through adolescence, and that there is value in integrating multiple sensory measures.

Atypical cerebellar functional connectivity at 9 months of age predicts delayed socio-communicative profiles in infants at high and low risk for autism.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

Effects of sensory distraction and salience priming on emotion identification in autism: an fMRI study.

BACKGROUND: Social interaction often occurs in noisy environments with many extraneous sensory stimuli. This is especially relevant for youth with autism spectrum disorders (ASD) who commonly experience sensory over-responsivity (SOR) in addition to social challenges. However, the relationship between SOR and social difficulties is still poorly understood and thus rarely addressed in interventions. This study investigated the effect of auditory sensory distracters on neural processing of emotion identification in youth with ASD and the effects of increasing attention to social cues by priming participants with their own emotional faces. METHODS: While undergoing functional magnetic resonance imaging (fMRI), 30 youth with ASD and 24 typically developing (TD) age-matched controls (ages 8-17 years) identified faces as happy or angry with and without simultaneously hearing aversive environmental noises. Halfway through the task, participants also viewed videos of their own emotional faces. The relationship between parent-rated auditory SOR and brain responses during the task was also examined. RESULTS: Despite showing comparable behavioral performance on the task, ASD and TD youth demonstrated distinct patterns of neural activity. Compared to TD, ASD youth showed greater increases in amygdala, insula, and primary sensory regions when identifying emotions with noises compared to no sounds. After viewing videos of their own emotion faces, ASD youth showed greater increases in medial prefrontal cortex activation compared to TD youth. Within ASD youth, lower SOR was associated with reduced increased activity in subcortical regions after the prime and greater increased activity in the ventromedial prefrontal cortex after the prime, particularly in trials with noises. CONCLUSIONS: The results suggest that the sensory environment plays an important role in how ASD youth process social information. Additionally, we demonstrated that increasing attention to relevant social cues helps ASD youth engage frontal regions involved in higher-order social cognition, a mechanism that could be targeted in interventions. Importantly, the effect of the intervention may depend on individual differences in SOR, supporting the importance of pre-screening youth for sensory challenges prior to social interventions.

Coming of age in the frontal cortex: The role of puberty in cortical maturation.

Across species, adolescence is a period of growing independence that is associated with the maturation of cognitive, social, and affective processing. Reorganization of neural circuits within the frontal cortex is believed to contribute to the emergence of adolescent changes in cognition and behavior. While puberty coincides with adolescence, relatively little is known about which aspects of frontal cortex maturation are driven by pubertal development and gonadal hormones. In this review, we highlight existing work that suggests puberty plays a role in the maturation of specific cell types in the medial prefrontal cortex (mPFC) of rodents, and highlight possible routes by which gonadal hormones influence frontal cortical circuit development.

Emerging atypicalities in functional connectivity of language-related networks in young infants at high familial risk for ASD.

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.

Sex and Pubertal Status Influence Dendritic Spine Density on Frontal Corticostriatal Projection Neurons in Mice.

In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends into adolescence. This maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how specific cell types in the frontal cortex mature or whether puberty plays a role in the maturation of some cell types but not others. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project through the corpus collosum to the dorsomedial striatum. We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in male mice.

Autoimmune receptor encephalitis in mice induced by active immunization with conformationally stabilized holoreceptors.

Autoimmunity to membrane proteins in the central nervous system has been increasingly recognized as a cause of neuropsychiatric disease. A key recent development was the discovery of autoantibodies to N-methyl-d-aspartate (NMDA) receptors in some cases of encephalitis, characterized by cognitive changes, memory loss, and seizures that could lead to long-term morbidity or mortality. Treatment approaches and experimental studies have largely focused on the pathogenic role of these autoantibodies. Passive antibody transfer to mice has provided useful insights but does not produce the full spectrum of the human disease. Here, we describe a de novo autoimmune mouse model of anti-NMDA receptor encephalitis. Active immunization of immunocompetent mice with conformationally stabilized, native-like NMDA receptors induced a fulminant encephalitis, consistent with the behavioral and pathologic characteristics of human cases. Our results provide evidence for neuroinflammation and immune cell infiltration as components of the autoimmune response in mice. Use of transgenic mice indicated that mature T cells and antibody-producing cells were required for disease induction. This active immunization model may provide insights into disease induction and a platform for testing therapeutic approaches.

Epinephrine promotes COX-2-dependent immune suppression in myeloid cells and cancer tissues.

Activation of the sympathetic nervous system (e.g., due to stress) has been implicated in cancer progression and recurrence, but its cancer-promoting effects have been variable between different studies. Here, we report that although catecholamines, mediators of systemic sympathetic activity, display only weak immunosuppressive impact on their own, their combination with inflammatory signals leads to the induction of COX-2 and multiple COX-2-dependent suppressive factors in human myeloid cells and cancer tissues. Human macrophages exposed to epinephrine and TNFα, or macrophages generated in 6day cultures in the presence of epinephrine, expressed high levels of COX-2, IDO and IL-10, and strongly suppressed both the proliferation and IFNγ production of CD8+ T cells. These suppressive effects of epinephrine were counteracted by celecoxib, a selective inhibitor of COX-2 activity, which inhibited the induction of immunosuppressive factors (including the elevated expression of COX-2 itself) and the ability of epinephrine-exposed macrophages to suppress CD8+ T cell responses. The activation of the COX-2/PGE2 system and COX-2-dependent suppressive events were also observed in ex vivo human breast and colon cancer explant cultures and were similarly counteracted by celecoxib. Our preliminary data also indicate elevated COX-2 expression in mammary tumors of chronic stress-exposed mice. The current demonstration of the interplay between inflammation and the induction of immunosuppressive factors by catecholamines suggest a contextual impact of stress, helping to explain variable results of epidemiologic studies of the link between sympathetic activity and cancer progression, and implicating COX-2 blockade as a potential means to mitigate stress-related immune suppression.