Psychological characteristics and emotional difficulties underlying school refusal in adolescents using functional near-infrared spectroscopy.

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.

Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice.

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.

Prevalence, increase and predictors of family violence during the COVID-19 pandemic, using modern machine learning approaches.

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.

A resting state fMRI study of major depressive disorder with and without anxiety.

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.

The promiscuity of the oxytocin-vasopressin systems and their involvement in autism spectrum disorder.

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.

Fluoxetine as an anti-inflammatory therapy in SARS-CoV-2 infection.

Hyperinflammatory response caused by infections such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) increases organ failure, intensive care unit admission, and mortality. Cytokine storm in patients 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-kappaB) and its downstream target gene interleukin 6 (IL6) which interacts with IL6 receptor (IL6R) and the IL6 signal transduction protein (IL6ST or gp130) to regulate intracellular inflammatory pathways. 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 IL6ST and NF-kappaB Subunit 1 (NFKB1) in fluoxetine's ability to act as a potential therapy for hyperinflammatory states such as asthma, sepsis, and COVID-19.

Effects of Oxytocin on Emotion Recognition in Schizophrenia: A Randomized Double-Blind Pilot Study.

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.

The neural correlates of paternal consoling behavior and frustration in response to infant crying.

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.

Oxytocin's anti-inflammatory and proimmune functions in COVID-19: a transcriptomic signature-based approach.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic, infecting over 16 million people worldwide with a significant mortality rate. However, there is no current Food and Drug Administration-approved drug that treats coronavirus disease 2019 (COVID-19). Damage to T lymphocytes along with the cytokine storm are important factors that lead to exacerbation of clinical cases. Here, we are proposing intravenous oxytocin (OXT) as a candidate for adjunctive therapy for COVID-19. OXT has anti-inflammatory and proimmune adaptive functions. Using the Library of Integrated Network-Based Cellular Signatures (LINCS), we used the transcriptomic signature for carbetocin, an OXT agonist, and compared it to gene knockdown signatures of inflammatory (such as interleukin IL-1ß and IL-6) and proimmune markers (including T cell and macrophage cell markers like CD40 and ARG1). We found that carbetocin's transcriptomic signature has a pattern of concordance with inflammation and immune marker knockdown signatures that are consistent with reduction of inflammation and promotion and sustaining of immune response. This suggests that carbetocin may have potent effects in modulating inflammation, attenuating T cell inhibition, and enhancing T cell activation. Our results also suggest that carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19.

Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity.

The role of oxytocin in social cognition has attracted tremendous interest in social neuroscience and psychiatry. Some studies have reported improvement in social symptoms following oxytocin treatment in autism spectrum disorders (ASD), while others point to endogenous factors influencing its efficiency and to mixed results in terms of long-term clinical benefits. Epigenetic modification to the oxytocin receptor gene (OXTR) in ASD could be an informative biomarker of treatment efficacy. Yet, little is known about the relationship between OXTR methylation, clinical severity, and brain function in ASD. Here, we investigated the relationship between OXTR methylation, ASD diagnosis (in N = 35 ASD and N = 64 neurotypical group), measures of social responsiveness, and resting-state functional connectivity (rsFC) between areas involved in social cognition and reward processing (in a subset of ASD, N = 30). Adults with ASD showed higher OXTR methylation levels in the intron 1 area compared with neurotypical subjects. This hypermethylation was related to clinical symptoms and to a hypoconnectivity between cortico-cortical areas involved in theory of mind. Methylation at a CpG site in the exon 1 area was positively related to social responsiveness deficits in ASD and to a hyperconnectivity between striatal and cortical brain areas. Taken together, these findings provide initial evidence for OXTR hypermethylation in the intron area as a potential biomarker for adults with ASD with less severe developmental communication deficits, but with impairments in theory of mind and self-awareness. Also, OXTR methylation in the exon 1 area could be a potential biomarker of sociability sensitive to life experiences.

The Role of Amygdala in Patients With Euthymic Bipolar Disorder During Resting State.

The current study aims to explore the functional changes of the amygdala in patients with euthymic Bipolar Disorder (BD) using resting state fMRI (rs-fMRI). Twenty-one euthymic patients with bipolar disorder and 28 healthy controls participated in this study. Two of the euthymic patients with BD and three of the healthy controls were excluded due to excessive head motion. We found that patients with euthymia (38.79 ± 12.03) show higher fALFF (fractional Amplitude of low-frequency fluctuation) value of the amygdala (t = 2.076, P = 0.044), and lower functional connectivity between the amygdala and supplementary motor area (p < 0.01, GRF corrected) than healthy controls (33.40 ± 8.21). However, euthymic patients did not show a differential activity in ReHo (Regional Homogeneity) and gray matter of the amygdala region as compared to healthy controls. Thus, despite the absence of clinical symptoms in euthymic patients with BD, the amygdala functional activity and its connectivity to other brain regions remain altered. Further investigation of negative emotions and social functioning in euthymic patients with BD are needed and can help pave the way for a better understanding of BD psychopathology.

RDoC-based categorization of amygdala functions and its implications in autism.

Confusion endures as to the exact role of the amygdala in relation to autism. To help resolve this we turned to the NIMH's Research Domain Criteria (RDoC) which provides a classification schema that identifies different categories of behaviors that can turn pathologic in mental health disorders, e.g. autism. While RDoC incorporates all the known neurobiological substrates for each domain, this review will focus primarily on the amygdala. We first consider the amygdala from an anatomical, historical, and developmental perspective. Next, we examine the different domains and constructs of RDoC that the amygdala is involved in: Negative Valence Systems, Positive Valence Systems, Cognitive Systems, Social Processes, and Arousal and Regulatory Systems. Then the evidence for a dysfunctional amygdala in autism is presented with a focus on alterations in development, prenatal valproic acid exposure as a model for ASD, and changes in the oxytocin system therein. Finally, a synthesis of RDoC, the amygdala, and autism is offered, emphasizing the task of disambiguation and suggestions for future research.

A Precision Medicine Approach to Oxytocin Trials.

In this chapter, we introduce a new area of social pharmacology that encompasses the study of the role of neuromodulators in modulating a wide range of social behaviors and brain function, with the interplay of genetic and epigenetic factors. There are increasing evidences for the role of the neuropeptide oxytocin in modulating a wide range of social behaviors, in reducing anxiety, and in impacting the social brain network. Oxytocin also promotes social functions in patients with neuropsychiatric disorders, such as autism and reduces anxiety and fear in anxiety disorders. In this chapter, we will emphasize the importance of integrating basic research and clinical human research in determining optimal strategies for drug discoveries for social dysfunctions and anxiety disorders. We will highlight the significance of adopting a precision medicine approach to optimize targeted treatments with oxytocin in neuropsychiatry. Oxytocin effects on social behavior and brain function can vary from one individual to another based on external factors, such as heterogeneity in autism phenotype, childhood experiences, personality, attachment style, and oxytocin receptor polymorphisms. Hence, targeted therapies for subgroups of patients can help alleviating some of the core symptoms and lead to a better future for these patients and their families.

Brief Report: Relationship Between ADOS-2, Module 4 Calibrated Severity Scores (CSS) and Social and Non-Social Standardized Assessment Measures in Adult Males with Autism Spectrum Disorder (ASD).

The ADOS-2 Modules 1-3 now include a standardized calibrated severity score (CSS) from 1 to 10 based on the overall total raw score. Subsequent research published CSS for Module 4 (Hus, Lord, Journal of Autism and Developmental Disorders 44(8):1996-2012, 2014); however more research is needed to examine the psychometric properties of this CSS. Forty males with ASD completed an assessment battery consisting of ADOS-2 Module 4 and other clinical measures assessing core ASD symptomology and comorbidity. Pearson correlation analyses found that CSS did not correlate with measures that assessed core social deficits of ASD or general psychiatric co-morbidity, but CSS did correlate negatively with intellectual quotient. These findings provide information on the limitations and relevance of CSS to be taken into account in future clinical evaluations of ASD.

Adaptive coding of the value of social cues with oxytocin, an fMRI study in autism spectrum disorder.

The neuropeptide oxytocin (OT) is one of the major targets of research in neuroscience, with respect to social functioning. Oxytocin promotes social skills and improves the quality of face processing in individuals with social dysfunctions such as autism spectrum disorder (ASD). Although one of OT's key functions is to promote social behavior during dynamic social interactions, the neural correlates of this function remain unknown. Here, we combined acute intranasal OT (IN-OT) administration (24 IU) and fMRI with an interactive ball game and a face-matching task in individuals with ASD (N = 20). We found that IN-OT selectively enhanced the brain activity of early visual areas in response to faces as compared to non-social stimuli. OT inhalation modulated the BOLD activity of amygdala and hippocampus in a context-dependent manner. Interestingly, IN-OT intake enhanced the activity of mid-orbitofrontal cortex in response to a fair partner, and insula region in response to an unfair partner. These OT-induced neural responses were accompanied by behavioral improvements in terms of allocating appropriate feelings of trust toward different partners' profiles. Our findings suggest that OT impacts the brain activity of key areas implicated in attention and emotion regulation in an adaptive manner, based on the value of social cues.

Oxytocin's fingerprint in personality traits and regional brain volume.

Oxytocin has a fundamental role in social behavior. In humans, supporting evidence shows that oxytocin enhances people's ability to trust or affiliate with others. A key question is whether differences in plasma oxytocin concentration in humans are related to people's differences in their social traits of personality and if such differences are reflected in the structural organization of brain areas responsive to the action of this hormone. We examined the correlation between oxytocin plasma levels and personality traits in 30 healthy subjects, tested with the Inventory revised neuroticism-extroversion-openness personality inventory (NEO-PI-R). By using the voxel-based morphometry technique, we also investigated changes in gray matter volume as a function of the plasma oxytocin level and NEO-PI-R scores. A positive correlation was found between plasma oxytocin and extraversion scores, a dimension that captures social affiliative tendencies. Moreover, we found an inverse correlation between plasma oxytocin and the volume of the right amygdala and the right hippocampus, 2 brain areas implicated in fear and anxiety. Finally, we showed that the amygdala-hippocampal complex correlate negatively with extraversion scores. Our findings provide evidence for a neural mechanism linking physiological oxytocin's variability and structural variation of brain regions relevant for emotion regulation to individual differences in affiliative personality traits.