Autism Spectrum Disorder (ASD) is a heterogenous condition that has no biologically relevant subtypes yet. Here, we utilized a multidimensional approach considering social deficits in ASD alongside negative valence and empathy dysfunction to distinguish ASD from Neurotypicals (NT) and to generate ASD subtypes using machine learning approaches. 114 subjects were analyzed, with 70 being NT and 44 ASD, all male with an IQ greater than 70, with 5 domains of personality (NEO-PI-r) and Reading the Mind the Eyes Test (RMET) scores included in the main classifier. We then used a multitude of behavioral (such as IQ, Broader Autism Phenotype, Autism Quotient, Interpersonal Reactivity Index) and clinical measures such as Autism Diagnostic Interview-Revised (ADI-R) alongside biological methods including DNA methylation of OXTR gene and resting-state functional connectivity (rsFC) to validate the putative subtypes. 30 ASD who received IN-OXT in a randomized, placebo-controlled, within-subject design and 17 new NT were part of the rs-FC analysis. A random forest tree algorithm was used to classify NT and ASD and Shapley Additive Explanation Values were used to describe the model and to cluster ASD subtypes using K-Means clustering. Three subtypes were generated with two of them being highly distinctive in behavioral and brain functional traits. One subtype named NASA (or Negative Affect and Social Aloofness) was characterized by high Neuroticism and Low warmth alongside lower rsFC between networks involved in social cognition, self-awareness, and sensory processing, such as Superior Temporal Sulcus and Sensorimotor Network; or ACC/Insula with visual cortex, Posterior Cingulate Cortex and visual cortex. The second subtype NADR (Neurocognitive and Affect Dysregulation with Resistance to Change) was characterized by higher DNA methylation of OXTR , hyperconnectivity between default mode network, reward areas and inferior frontal and fusiform networks. NADR has more cognitive difficulties and higher ADI-R scores as well as higher Neuroticism, higher personal distress, higher rigidity and lower openness. In a mixed model analysis, we found that IN-OXT in a dose dependent manner impacted NASA subtype by modulating rsFC between PCC and cerebellum and between Brainstem/Cerebellum and Parietal cortex to probably enhance social cognition and to reduce negative valence in this subtype.

Social learning is the process of acquiring social skills, new information, or associating negative or positive valence to a context through the observation of others and through direct social interaction with others. Neurodevelopmental disorders such as autism spectrum disorder show deficits in social salience and reciprocal affective responses. Social learning implicates the basolateral amygdala (BLA), anterior cingulate cortex (ACC), and anterior insula (AI). The lateral habenula (LHb), a brain area renowned for its role in negative reinforcement learning, has not been yet extensively studied in the domain of social learning. We developed a fear conditioning by proxy paradigm called ‘social transmission of negative valence’ (STNV) and tested prairie voles on the task. Observers experienced negative social conditioning through a proxy cage mate that served as the demonstrator during retrieval of a cued fear memory. Observers went through a social memory recall session 24 h after observation. We measured observers’ freezing time, self-grooming, rearing, and ultrasonic vocalizations emitted as signs of distress. We also quantified immediate early gene translation as a proxy for neural activity using c-Fos immunochemistry 80 min after observing demonstrators going through memory recall. Socially-conditioned observers that were exposed to the fear-conditioned demonstrators displayed increased freezing time, self-grooming, and rearing during social recall sessions compared to control observers. They also displayed higher ultrasonic vocalization frequency compared to controls. Socially-conditioned observers showed increased c-Fos expression in the LHb, BLA, ACC and AI compared to controls. The c-Fos findings are correlational and additional experiments involving chemo- or optogenetic inhibition or excitation of LHb neurons in observers are necessary for causality confirmation. We found that the LHb is co-activated with other key areas during social learning in prairie voles. These findings extend the traditional view of the LHb as an area involved in negative reinforcement learning and position it as a critical area for social affect. This offers a fresh perspective on the neural mechanisms of social affect and opens a new line of inquiry into brain dysfunction of social salience in neurodevelopmental disorders.

Intranasal oxytocin (IN-OXT) has shown some promises in rescuing social deficits in autism spectrum disorder (ASD) as well as some inconsistencies in long-term trials. We conducted a target engagement study to study the precise effects of different doses of IN-OXT on brain resting-state functional connectivity (rsFC) in ASD. We examined the effects of varying doses of IN-OXT (0 IU, 8 IU, 24 IU, 48 IU) on rsFC in a double-blind, placebo-controlled, within-subject design in 30 male adults with ASD and 17 neurotypical controls (NT) receiving placebo. Random forest analysis was used to classify individuals as ASD or NT. Shapely Additive explanations values were calculated to rank brain functional networks by level of contribution to ASD deficits and to evaluate IN-OXT dose effects. The model predicted ASD diagnosis with an AUC of 94%. Hypoconnectivity between salience/empathy and visual networks, and hyperconnectivity between reward and sensorimotor networks and theory of mind networks were among the strongest predictors of ASD deficits. IN-OXT had a dose-dependent effect on rescuing both deficits described above. Overall, 48 IU dose was more effective, and 24 IU dose was more effective in those who have lower DNA OXT receptor methylation and lower severity of clinical symptoms. Higher doses of OXT might be necessary to enhance empathic responses, and ASD individuals with less support needs and with a preserved OXT system might benefit most from OXT treatment. Applying machine learning approaches in OXT research can provide data-driven unbiased results that can inform future clinical trials.

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

Neurodevelopmental disorders (NDDs) are a widespread and growing public health challenge, affecting as many as 17% of children in the United States. Recent epidemiological studies have implicated ambient exposure to pyrethroid pesticides during pregnancy in the risk for NDDs in the unborn child. Using a litter-based, independent discovery-replication cohort design, we exposed mouse dams orally during pregnancy and lactation to the Environmental Protection Agency's reference pyrethroid, deltamethrin, at 3 mg/kg, a concentration well below the benchmark dose used for regulatory guidance. The resulting offspring were tested using behavioral and molecular methods targeting behavioral phenotypes relevant to autism and NDD, as well as changes to the striatal dopamine system. Low-dose developmental exposure to the pyrethroid deltamethrin (DPE) decreased pup vocalizations, increased repetitive behaviors, and impaired both fear conditioning and operant conditioning. Compared with control mice, DPE mice had greater total striatal dopamine, dopamine metabolites, and stimulated dopamine release, but no difference in vesicular dopamine capacity or protein markers of dopamine vesicles. Dopamine transporter protein levels were increased in DPE mice, but not temporal dopamine reuptake. Striatal medium spiny neurons showed changes in electrophysiological properties consistent with a compensatory decrease in neuronal excitability. Combined with previous findings, these results implicate DPE as a direct cause of an NDD-relevant behavioral phenotype and striatal dopamine dysfunction in mice and implicate the cytosolic compartment as the location of excess striatal dopamine.

Background This study aims to explore the psychological characteristics, related emotional problems and potential NIR brain function mechanism of adolescents who refuse to attend school. Methods The study included 38 adolescents (12–18 years old) who were not attending school and 35 healthy controls (12–18 years old) who are attending school regularly. Participants completed (1) general demographics, (2) Eysenck Personality Questionnaire (EPQ), (3) Zung Self-Rating Depression Scale (SDS), (4) Zung Self-Rating Anxiety Scale (SAS), and (5) Symptom Checklist-90 (SCL-90). In addition to the clinical tests, participants completed functional near-infrared spectroscopy (fNIRS). Mental health, personality, and emotional state were evaluated in both groups to explore the differences and to understand the underlying mechanisms of school refusal during adolescence. Results Adolescents who did not attend school had higher neuroticism scores on the Eysenck Personality Questionnaire than healthy controls ( p(FDR) < 0.001), introversion and concealment scores were lower than those of healthy controls ( p(FDR) < 0.001), there was no significant difference in psychoticism scores between groups. SDS, SAS, SCL-90 scores and factor scores were higher than those of healthy control group ( p(FDR) < 0.001), NIR functional brain imaging was different from healthy control group in the 12 and 27 channels ( p(FDR) = 0.030, p(FDR) = 0.018), and no difference was found in the remaining channels ( p(FDR) > 0.05). There were statistically significant differences in age and gender between the adolescents who refused school and the control group ( p(FDR) < 0.001). Conclusion School refusal adolescents are relatively introverted and sensitive and need more attention in daily life. Although the adolescents’ emotional problems did not reach the diagnostic criteria of depressive disorder and anxiety disorder, their scores were still higher than those of the control group, suggesting that we should pay more attention to their emotional problems in order to better help them return to school. Using fNIRS, it was found that abnormalities in frontal lobe regions in adolescents with school refusal behaviors, which would contribute to early diagnosis and timely intervention of school refusal behaviors.

BACKGROUND:The neurobiology of the Major depressive disorder (MDD) with anxiety is still unclear. The present study aimed to explore the brain correlates of MDD with and without anxiety in men and women during resting-state fMRI.METHODS:Two hundred and fifty-four patients with MDD (MDD with anxiety, N = 152) and MDD without anxiety, N = 102) and 228 healthy controls (HCs) participated in this study. We compared the fALFF(fractional amplitude of low-frequency fluctuations) and ReHo(regional homogeneity) of ACC(anterior cingulate cortex) and insula among these three groups. We also compared gender difference between MDD with anxiety and MDD without anxiety.RESULTS:We found that the fALFF values within the ACC and insula were significantly lower in MDD with anxiety compared to without anxiety and HCs. However, we did not find differences in ReHo values among the three groups. In women, we found significant differences in fALFF values between MDD with and without anxiety. These differences were not observed in men.CONCLUSIONS:It is possible that MDD with anxiety show less spontaneous BOLD-fMRI signal intensity within the ACC and insula compared to MDD without anxiety, especially in women. The fALFF within the ACC and insula can be a potential biomarker for severe MDD phenotype.

Background We are facing an ongoing pandemic of coronavirus disease 2019 (COVID-19), which is causing detrimental effects on mental health, including disturbing consequences on child maltreatment and intimate partner violence. Methods We sought to identify predictors of child maltreatment and intimate partner violence from 380 participants (mean age 36.67 ± 10.61, 63.2% male; Time 3: June 2020) using modern machine learning analysis (random forest and SHAP values). We predicted that COVID-related factors (such as days in lockdown), parents’ psychological distress during the pandemic (anxiety, depression), their personality traits, and their intimate partner relationship will be key contributors to child maltreatment. We also examined if there is an increase in family violence during the pandemic by using an additional cohort at two time points (Time 1: March 2020, N = 434; mean age 35.67 ± 9.85, 41.69% male; and Time 2: April 2020, N = 515; mean age 35.3 ± 9.5, 34.33%). Results Feature importance analysis revealed that parents’ affective empathy, psychological well-being, outdoor activities with children as well as a reduction in physical fights between partners are strong predictors of a reduced risk of child maltreatment. We also found a significant increase in physical punishment (Time 3: 66.26%) toward children, as well as in physical (Time 3: 36.24%) and verbal fights (Time 3: 41.08%) among partners between different times. Conclusion Using modernized predictive algorithms, we present a spectrum of features that can have influential weight on prediction of child maltreatment. Increasing awareness about family violence consequences and promoting parenting programs centered around mental health are imperative.

Abstract Background Schizophrenia (SCZ) is a neurodevelopmental disorder that leads to poor social function. Oxytocin (OXT), a neuropeptide involved in social cognition, is a potential therapeutic agent for alleviating social dysfunction. Therefore, we investigated the effects of intranasal oxytocin (IN-OXT) on emotional processes in experimental interactive social contexts in individuals with SCZ. Methods In a male-only parallel randomized placebo-controlled double-blind trial, we investigated the effects of IN-OXT (24 IU) on visual fixation on pictures of faces and emotion recognition in an interactive ball-tossing game that probed processing of social and nonsocial stimuli. Results Intranasal oxytocin enhanced the recognition of emotions during an emotion-based ball-tossing game. This improvement was specific to the game that included social cue processing. Intranasal oxytocin did not affect eye gaze duration or gaze dwell time on faces in these patients. Conclusions An acute low dose of IN-OXT had a modest effect on social cue processing and was limited to emotion recognition. Higher doses and long-term trials targeting emotional processing in SCZ may lead to improved social function.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is characterized by deficits in social interaction and communication. Oxytocin is a key modulator of social behavior. Acute administration of intranasal oxytocin (IN-OT) enhances social functioning in autism. Here, we conducted a dose-dependent study with IN-OT to examine target engagement for this treatment on the brain activity of adults with ASD.

Oxytocin and vasopressin systems have been studied separately in autism spectrum disorder (ASD). Here, we provide evidence from an evolutionary and neuroscience perspective about the shared mechanisms and the common roles in regulating social behaviors. We first discuss findings on the evolutionary history of oxytocin and vasopressin ligands and receptors that highlight their common origin and clarify the evolutionary background of the crosstalk between them. Second, we conducted a comprehensive review of the increasing evidence for the role of both neuropeptides in regulating social behaviors. Third, we reviewed the growing evidence on the associations between the oxytocin/vasopressin systems and ASD, which includes oxytocin and vasopressin dysfunction in animal models of autism and in human patients, and the impact of treatments targeting the oxytocin or the vasopressin systems in children and in adults. Here, we highlight the potential of targeting the oxytocin/vasopressin systems to improve social deficits observed in ASD and the need for further investigations on how to transfer these research innovations into clinical applications.

Hyperinflammatory response caused by infections such as Severe Acute Respiratory SyndromeCoronavirus 2 (SARS-CoV-2) increase organ failure, intensive care unit admission, and mortality. Cytokine storm inpatients with Coronavirus Disease 2019(COVID-19) drives this pattern of poor clinical outcomes and is dependent upon the activity of the transcription factor complex nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB) and its downstream target gene interleukin 6 (IL6). In this study, we compare transcriptomic signatures from a variety of drug-treated or genetically suppressed (i.e.knockdown) cell lines in order to identify a mechanism by which antidepressants such as fluoxetine demonstrate non-serotonergic anti-inflammatory effects. Our results demonstrate a critical role for the IL6 signal transduction protein(IL6ST or gp130) in fluoxetine’s ability to act as a potential therapy for hyperinflammatory states such as asthma and sepsis.

Human fathers often form strong attachments to their infants that contribute to positive developmental outcomes. However, fathers are also the most common perpetrators of infant abuse, and infant crying is a known trigger. Research on parental brain responses to infant crying have typically employed passive listening paradigms. However, parents usually engage with crying infants. Therefore, we examined the neural responses of 20 new fathers to infant cries both while passively listening, and while actively attempting to console the infant by selecting soothing strategies in a video game format. Compared with passive listening, active responding robustly activated brain regions involved in movement, empathy and approach motivation, and deactivated regions involved in stress and anxiety. Fathers reporting more frustration had less activation in basal forebrain areas and in brain areas involved with emotion regulation (e.g., prefrontal cortex and the supplementary motor area). Successful consolation of infant crying activated regions involved in both action-outcome learning and parental caregiving (anterior and posterior cingulate cortex). Overall, results suggest that active responding to infant cries amplifies activation in many brain areas typically activated during passive listening. Additionally, paternal frustration during active responding may involve a combination of low approach motivation and low engagement of emotion regulation.