Early Adverse Experiences Research Articles

Early Childhood Adverse Experiences, Inferior Frontal Gyrus Connectivity, and the Trajectory of Externalizing Psychopathology

Early adverse childhood experiences (ACEs) have been linked to the development of both internalizing and externalizing psychopathology. In our prior work, we found that ACEs predicted reductions in the volume of the inferior frontal gyrus (IFG), a brain region important for impulse control and emotion regulation. Here we tested the hypothesis that ACEs might influence child behavioral outcomes through an impact on IFG functional connectivity, which may influence impulsive or risk-taking behavior. We examined the effects of prospectively assessed ACEs on IFG connectivity in childhood, and their relationship to the trajectory of subsequent psychopathology from late school age and early adolescence, using data from an 11-year longitudinal study of children starting in preschool that included 3 waves of resting state functional connectivity across childhood and early adolescence. ACEs predicted functional connectivity of both left and right IFG. Multi-level modeling of symptoms across 3 waves of assessments indicated that more ACEs predicted both internalizing and externalizing symptoms. However, altered IFG connectivity specifically predicted greater externalizing symptoms over time in middle childhood and early adolescence, as compared to internalizing symptoms. Longitudinal modeling indicating that the relationships between externalizing and functional connectivity were maintained across 3 waves of functional connectivity assessment. These findings underscore the relationship of ACEs to later psychopathology, and suggest that connectivity of the IFG, a region known to play an important role in impulse control and emotion regulation, may play a key role in the risk trajectory of ACEs to externalizing problems. However, further work is needed to understand whether these relationships reflect a direct effect of ACEs or whether ACEs are a marker for other environmental or genetic factors that may also influence brain development and behavior.

Early postnatal development of electrophysiological and histological properties of sensory sural nerves in male rats that were maternally deprived and artificially reared: Role of tactile stimulation.

Early adverse experiences disrupt brain development and behavior, but little is known about how such experiences impact on the development of the peripheral nervous system. Recently, we found alterations in the electrophysiological and histological characteristics of the sensory sural (SU) nerve in maternally deprived, artificially reared (AR) adult male rats, as compared with maternally reared (MR) control rats. In the present study, our aim was to characterize the ontogeny of these alterations. Thus, male pups of four postnatal days (PND) were (1) AR group, (2) AR and received daily tactile stimulation to the body and anogenital region (AR-Tactile group); or (3) reared by their mother (MR group). At PND 7, 14, or 21, electrophysiological properties and histological characteristics of the SU nerves were assessed. At PND 7, the electrophysiological properties and most histological parameters of the SU nerve did not differ among MR, AR, and AR-Tactile groups. By contrast, at PND 14 and/or 21, the SU nerve of AR rats showed a lower CAP amplitude and area, and a significant reduction in myelin area and myelin thickness, which were accompanied by a reduction in axon area (day 21 only) compared to the nerves of MR rats. Tactile stimulation (AR-Tactile group) partially prevented most of these alterations. These results suggest that sensory cues from the mother and/or littermates during the first 7-14 PND are relevant for the proper development and function of the adult SU nerve. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 351-362, 2018.

Early Adverse Caregiving Experiences and Preschoolers' Current Attachment Affect Brain Responses during Facial Familiarity Processing: An ERP Study.

When being placed into more benign environments like foster care, children from adverse rearing backgrounds are capable of forming attachment relationships to new caregivers within the first year of placement, while certain problematic social behaviors appear to be more persistent. Assuming that early averse experiences shape neural circuits underlying social behavior, neurophysiological studies on individual differences in early social-information processing have great informative value. More precisely, ERP studies have repeatedly shown face processing to be sensitive to experience especially regarding the caregiving background. However, studies on effects of early adverse caregiving experiences are restricted to children with a history of institutionalization. Also, no study has investigated effects of attachment security as a marker of the quality of the caregiver-child relationship. Thus, the current study asks how adverse caregiving experiences and attachment security to (new) caregivers affect early- and mid-latency ERPs sensitive to facial familiarity processing. Therefore, pre-school aged foster children during their second year within the foster home were compared to an age matched control group. Attachment was assessed using the AQS and neurophysiological data was collected during a passive viewing task presenting (foster) mother and stranger faces. Foster children were comparable to the control group with regard to attachment security. On a neurophysiological level, however, the foster group showed dampened N170 amplitudes for both face types. In both foster and control children, dampened N170 amplitudes were also found for stranger as compared to (foster) mother faces, and, for insecurely attached children as compared to securely attached children. This neural pattern may be viewed as a result of poorer social interactions earlier in life. Still, there was no effect on P1 amplitudes. Indicating heightened attentional processing, Nc amplitude responses to stranger faces were found to be enhanced in foster as compared to control children. Also, insecurely attached children allocated more attentional resources for the neural processing of mother faces. The study further confirms that early brain development is highly sensitive to the quality of caregiving. The findings are also relevant from a developmental perspective as miswiring of neural circuits may possibly play a critical role in children's psycho-social adjustment.

Telomere Length in Preterm Infants: A Promising Biomarker of Early Adversity and Care in the Neonatal Intensive Care Unit?

Preterm infants present an immature neurobehavioral profile at birth, even in absence of severe brain injuries and perinatal complications. As such, they require a long-lasting hospitalization in the Neonatal Intensive Care Unit (NICU), which is thought to grant at-risk newborns’ survival, but still entails a number of physical, painful, and socio-emotional stressors. Hence, preterm birth and NICU stay represent an early adverse experience, which has been linked to detrimental consequences for neurological, neuro-endocrinal, behavioral, and socio-emotional development, as well as to disease later in life. Recent advances in the behavioral epigenetic field are helping us to unveil the potential mechanisms through which early NICU-related stress may lead to negative developmental outcomes. From this perspective, telomere regulation might be a key programming mechanism. Telomeres are the terminal portion of chromosomes and are known to get shorter with age. Moreover, telomere length (TL) is affected by the exposure to stress during early development. As such, TL might be an innovative biomarker of early adverse exposures in young infants and children. Unfortunately, there is paucity of studies investigating TL in populations of preterm infants and its association with known NICU-related stressors remains unexplored. In the present paper, the potential relevance of TL for research and clinical work with preterm infants will be underlined in the light of recent contributions linking progressive telomere shortening and early exposure to adverse experiences and stressful environments in humans. Finally, insights will be provided to guide clinically relevant translational research on TL in the field of VPT birth and NICU stay.

Maternal separation induces long-term effects on monoamines and brain-derived neurotrophic factor levels on the frontal cortex, amygdala, and hippocampus: differential effects after a stress challenge.

The maternal separation (MS) paradigm is a well-known animal model that resembles the stress of early adverse life experiences and produces structural and functional abnormalities when animals are adults. The present study analyzed the effect of MS, in adult mice, on brain-derived neurotrophic factor (BDNF), serotonin (5-HT), and dopamine (DA) levels, and the turnover rate in the hippocampus, frontal cortex, and amygdala, and brain regions that are associated with emotion. Also, the effects of MS in depression-like responses in adult mice were studied. The results showed that MS from postnatal day 8-21 induces depression-like behaviors. In MS mice, the three brain areas showed differential responses in 5-HT, DA, and BDNF concentrations both in basal levels and when animals were challenged with an acute stressor in adulthood. Specifically, under basal conditions, MS increased monoamine and BDNF levels in the hippocampus and amygdala, but decreased these levels in the frontal cortex. In MS, but not in control mice, the amygdala responded to the stress challenge, whereas the frontal cortex showed no response. Finally, the hippocampus showed increased 5-HT and DA activity, but not increased BDNF after the stress challenge in MS mice. The present results support the theory of the hypofunctionality of the frontal cortex and hyperactivity of mesolimbic areas in depression-like conditions.

HPA axis dysregulation in adult adoptees twenty years after severe institutional deprivation in childhood

Hypothalamic–pituitary–adrenal (HPA) axis function is disrupted in institutionally-deprived children – reduced morning cortisol, flattened diurnal slope and blunted reactivity persist even after successful adoption into positive family environments. Here we test whether such effects persist into adulthood. Cortisol release across the day (sampled at awakening, 30 and 45min later, and at four points across the day) was investigated in young adult adoptees who had lived in severe deprivation for up to 43 months in early childhood in Ceaușescu’s Romanian orphanages and a comparison group of non-deprived UK adoptees (Total N=57; mean age=24±0.9years). The mediating role of cortisol levels on adult mental health was examined using data from standardized clinical assessments. Cortisol profiles were disrupted in the Romanian adoptees who experienced more than 6 months deprivation marked by a striking absence of the cortisol awakening response (CAR) and a significantly flatter cortisol curve until 1h 15min after awakening. Whereas institutional deprivation was associated with both cortisol secretion and emergence of emotional problems in young adulthood, path analysis revealed no evidence for a mediating role of CAR disruption in the sub-sample studied here. The results are in line with findings of HPA axis hypo-functionality following early adverse experience and provide strong evidence for long-term programming effects of HPA axis function through experience of institutional deprivation.

Adult Attachment Style and Suicidality.

There is evidence in the literature that adverse early attachment experiences and subsequent attachment insecurities during adulthood would lead to pessimism, low self-esteem, hopelessness and, ultimately, to suicide risk. This paper aims to review finding on the link between attachment style and suicidality. We searched the literature using the database of the U.S. National Center for Biotechnology Information (NCBI)-MedLine/Pubmed system from January 1992 until December 2016. We started with 1992 because, as far as we know, there are no published studies exploring the relationship between suicide and insecure attachment before that year. We considered reports published on the relationship between attachment style and suicidality. We applied several combinations of the following search terms: attachment, adult attachment style and suicidality, suicide, suicidal ideation, suicidal behavior or suicidal thoughts, and suicide attempts. We selected only English language studies. Research suggests that insecure attachment style, mostly anxious, and unresolved traumas are associated with an increased suicide risk. Few studies prospectively examined clinical course, comorbid psychiatric disorders, familial suicidality or other psychosocial factors. Further research is needed to highlight the nature of the link between attachment and suicidality. The presence of suicidal ideation and attempts might be a consequence of an underlying interaction between the emergence of psychiatrics symptoms, and the long-lasting presence of inadequate patterns of attachment. Within this context, Separation Anxiety Disorder, categorized in the DSM-5 as a condition not confined to childhood but as an anxiety disorder that may occur through the entire lifespan, might be the a key for the comprehension of this link. From a neurobiological point of view, the role of oxytocin remains unclear.

Social, Familial and Psychological Risk Factors for Endocrine, Nutritional and Metabolic Disorders in Childhood and Early Adulthood: a Birth Cohort Study Using the Danish Registry System

Research studies have identified associations between a range of social, familial and psychological risk factor and physical health. However, there are many methodological limitations in such studies (e.g. self-reported health status, retrospective recall of adverse events, and lack of control for possible heritability effects). The current study seeks to assess the effect of a range of social and psychosocial risk factors on a diagnosis of any endocrine, nutritional, and metabolic (ENM) disorders (ICD-10 E00–99) using linked Danish registry data from a large birth cohort. Data linkage. A national birth cohort of the Danish population born in 1984 was used in the current study (n = 54,458). Psychosocial risk factors including parental history of diagnosis of an ENM disorder, advanced parental age, gender, urban dwelling, economic deprivation, family dissolution and childhood adversity (child in care) were used to predict any ENM diagnosis. Bivariate associations showed that all variables, except advanced paternal age, were significantly associated with ENM diagnosis. When the variables were entered into a multivariate binary logistic regression analysis childhood adversity (child in care) was the strongest predictor of diagnosis (OR = 2.36) followed by maternal diagnosis of an endocrine disorder (OR = 1.74) and advanced maternal age (OR = 1.69). Results suggest that childhood adversity is the dominant factor in the prediction of an ENM diagnosis. The current study extends the literature conducted on adult populations by demonstrating that early adverse experiences are associated with poor or poorer health outcomes in young adulthood.

Social Learning Requires Plasticity Enhanced by Fluoxetine Through Prefrontal Bdnf-TrkB Signaling to Limit Aggression Induced by Post-Weaning Social Isolation.

Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression again escalated in a novel environment. We demonstrate that when re-socialization was combined with the antidepressant fluoxetine, which has been shown to reactivate juvenile-like state of plasticity, escalated aggression was greatly attenuated, while neither treatment alone was effective. Early isolation induced a permanent, re-socialization-resistant reduction in Bdnf expression in the amygdala and the infralimbic cortex. Only the combined treatment of fluoxetine and re-socialization was able to recover Bdnf expression via epigenetic regulation. Moreover, the behavior improvement after the combined treatment was dependent on TrkB activity. Combined treatment specifically strengthened the input from the ventral hippocampus to the mPFC, suggesting that this pathway is an important mediator of the beneficial behavioral effects of the combined psychosocial and pharmacological treatment of abnormal aggression. Our findings suggest that synergy between pharmacological induction of plasticity and psychosocial rehabilitation could enhance the efficacy of therapies for pathological aggression.

A Social Learning Perspective on Childhood Trauma and Same-Sex Intimate Partner Violence

The family violence and childhood trauma literature has suggested that early adverse experiences create risk factors for intimate partner violence (IPV). Thus, this study used a sample of lesbian, gay, and bisexual (LGB) college students (N = 266) to explore differences among childhood trauma, same-sex IPV, and IPV acceptance. The authors used survey methodology and multivariate analysis of variance. Results indicated that LGB individuals reporting childhood trauma also reported higher rates of IPV, suggesting implications for research and practice.

Infant titi monkey behavior in the open field test and the effect of early adversity.

The open field test is commonly used to measure anxiety-related behavior and exploration in rodents. Here, we used it as a standardized novel environment in which to evaluate the behavioral response of infant titi monkeys (Callicebus cupreus), to determine the effect of presence of individual family members, and to assess how adverse early experience alters infant behavior. Infants were tested in the open field for 5 days at ages 4 and 6 months in four successive 5 min trials on each day. A transport cage, which was situated on one side of the open field, was either empty (non-social control) or contained the father, mother, or sibling. Infant locomotor, vocalization, and exploratory behavior were quantified. Results indicated that age, sex, social condition, and early experience all had significant effects on infant behavior. Specifically, infants were generally more exploratory at 6 months and male infants were more exploratory than females. Infants distinguished between social and non-social conditions but made few behavioral distinctions between the attachment figure and other individuals. Infants which had adverse early life experience demonstrated greater emotional and physical independence, suggesting that early adversity led to resiliency in the novel environment.

The Stress Acceleration Hypothesis of Nightmares.

Adverse childhood experiences can deleteriously affect future physical and mental health, increasing risk for many illnesses, including psychiatric problems, sleep disorders, and, according to the present hypothesis, idiopathic nightmares. Much like post-traumatic nightmares, which are triggered by trauma and lead to recurrent emotional dreaming about the trauma, idiopathic nightmares are hypothesized to originate in early adverse experiences that lead in later life to the expression of early memories and emotions in dream content. Accordingly, the objectives of this paper are to (1) review existing literature on sleep, dreaming and nightmares in relation to early adverse experiences, drawing upon both empirical studies of dreaming and nightmares and books and chapters by recognized nightmare experts and (2) propose a new approach to explaining nightmares that is based upon the Stress Acceleration Hypothesis of mental illness. The latter stipulates that susceptibility to mental illness is increased by adversity occurring during a developmentally sensitive window for emotional maturation—the infantile amnesia period—that ends around age 3½. Early adversity accelerates the neural and behavioral maturation of emotional systems governing the expression, learning, and extinction of fear memories and may afford short-term adaptive value. But it also engenders long-term dysfunctional consequences including an increased risk for nightmares. Two mechanisms are proposed: (1) disruption of infantile amnesia allows normally forgotten early childhood memories to influence later emotions, cognitions and behavior, including the common expression of threats in nightmares; (2) alterations of normal emotion regulation processes of both waking and sleep lead to increased fear sensitivity and less effective fear extinction. These changes influence an affect network previously hypothesized to regulate fear extinction during REM sleep, disruption of which leads to nightmares. This network consists of a fear circuit that includes amygdala, hippocampus, and medial prefrontal cortex and whose substantial overlap with the stress acceleration findings allows the latter to be incorporated into a wider, more developmentally coherent framework.

Psychologically informed environments for homeless people: resident and staff experiences

PurposeMany homeless people have significant levels of early adverse experiences and consequent mental health difficulties. The purpose of this paper is to examine the experiences of residents and staff living and working in a psychologically informed environment (PIE), a new model of hostel for homeless people which aims to update and make more flexible the principles of the therapeutic community, thereby meeting the psychological and emotional needs of residents.Design/methodology/approachSemi-structured interviews were carried out with nine residents, ten staff and five psychotherapists at two PIE hostels in London. The data were analysed using thematic analysis with a phenomenological epistemological approach.FindingsAnalysis generated 18 themes for residents and staff combined, organised into five domains: what makes a home, resident needs, managing relationships, reflective practice and theory vs practice of PIEs. The study suggests that PIEs broadly meet their aim in providing a different type of environment from standard hostels. Efforts to build relationships with residents are particularly prioritised. This work can be challenging for staff and reflective practice groups provide a supportive forum. There are limits to the extent to which the theoretical PIE can be put into practice in the current political and economic climate.Originality/valueThis is one of the first qualitative studies of PIEs. It provides perspectives on their theoretical background as well as how they operate and are experienced in practice. It may be informative to services intending to establish a PIE and to commissioners in assessing appropriate resources.

Mating strategies and experience of early adversity in female patients with borderline personality disorder: Insights from life history theory

Borderline personality disorder (BPD) is a psychiatric condition which severely affects psychological well-being. Etiological explanations of BPD include the experience of early adversity, but how this impacts on risk-taking and impulsivity in relation to sexuality and mating has remained elusive. Here, we tested the hypothesis that people with BPD adopt a “fast” life history strategy which impacts their mate choice and sexual behavior.Sixty female patients with BPD and 45 controls were given 3 hypothetical vignettes depicting a “Predictably Safe”, an “Unpredictably Safe-Risky”, and a “Predictably Risky” life conditions, requiring the participant to put herself imaginatively into the described situation. Participants also completed questionnaires about their psychosexual development, depressiveness, and childhood experiences.Patients with BPD were significantly more likely to expect less parental investment from their hypothetical partners in the predictably safe condition, and to consent to sexual affairs at an earlier age than controls. Correlation analyses suggest that subjective depressiveness, childhood trauma, rearing style of patients' parents, and actual psychosexual development impacted on mate choice in the hypothetical scenarios. In addition, findings may also corroborate ideas of nonrandom mating in patients with BPD, which may be taken into consideration when interpersonal difficulties with romantic partners are dealt with in psychotherapy.

M122. Impact of Childhood Trauma on Educational Achievement in Young People at Clinical High Risk of Psychosis

Abstract Several studies reported that childhood trauma is associated with the emergence of psychosis as well as with several cognitive deficits including impaired memory, attention and emotion discrimination (Varese et al 2013; Kraan et al 2015). However, little is known about the impact of early adverse experiences on educational achievement in people at clinical high risk (CHR) of developing psychosis. This study examines the relationship between specific types of childhood trauma and academic achievements in CHR. Ninety-six CHR participants were recruited after consecutive referrals to the Outreach and Support in South London early intervention team and 39 healthy comparisons (HC) were recruited from the same area. The Childhood Trauma Questionnaire (CTQ) was used to examine type and severity of childhood trauma and a semi-structured interview was used to collect data on educational achievement. Data was analyzed using multiple linear regressions and multinomial logistic regression on years and level of education with primary predictors CTQ scales and potential confounders age, gender and IQ. Compared to HC, CHR reached a significantly lower level of education ( < .001) and spent significantly fewer years in education ( = .002). 65.6% CHR and 23.1% HC experienced some form of childhood abuse or neglect. The amount of childhood trauma experienced was significantly associated to number of years of education, regardless of the diagnosis ( = −0.042; = .014). Physical neglect in CHR was significantly associated to years of education completed ( = −0.320; = .002). Interactions between age and physical neglect ( = .022), age and physical abuse ( < .001) and gender and physical abuse ( = .003) predicted the level of education in CHR. These results suggest that young individuals at high risk of psychosis are particularly vulnerable to the effects of trauma on educational achievements. Early intervention services should aim at developing specific interventional programmes that can support completion or return to education paying particular attention to those individuals who have experienced childhood trauma.

Child Maltreatment Typologies and Intimate Partner Violence: Findings From a Danish National Study of Young Adults

The association between exposure to childhood maltreatment and subsequent intimate partner violence (IPV) has been well documented. Recently, there has been increased attention to IPV in adolescence and young adulthood, with studies demonstrating that IPV peaks in young adulthood. Data were collected from a Danish national study conducted by The Danish National Centre for Social Research in 2008 and 2009. A sample of 4,718 young adults (aged 24) was randomly selected using the total birth cohort of children born in 1984. Structured interviews were conducted with 2,980 participants equating to a response rate of 63%. Childhood maltreatment including emotional, sexual, and multiple abuse experiences and being female and a young parent were used to test the association with experiencing IPV victimization. Bivariate associations showed that all variables were significantly associated with experiencing IPV. When the variables were entered into a multivariate binary logistic regression analysis, being female indicated the strongest association (odds ratio [OR] = 13.96), followed by experiencing childhood sexual abuse (OR = 10.90) and experiencing multiple types of abuse (OR = 6.49). Results suggest that among the child maltreatment typologies, sexual abuse is the dominant factor associated with IPV. The current study extends the literature conducted on a young adult population by demonstrating that early adverse experiences and being female and a parent are associated with IPV in young adulthood. These findings suggest prevention programs should be targeted in early adolescence to support young people to establish and maintain positive and healthy relationships that promote safe conflict resolution strategies.

Consequences of early adverse rearing experience(EARE) on development: insights from non-human primate studies.

Early rearing experiences are important in one's whole life, whereas early adverse rearing experience (EARE) is usually related to various physical and mental disorders in later life. Although there were many studies on human and animals, regarding the effect of EARE on brain development, neuroendocrine systems, as well as the consequential mental disorders and behavioral abnormalities, the underlying mechanisms remain unclear. Due to the close genetic relationship and similarity in social organizations with humans, non-human primate (NHP) studies were performed for over 60 years. Various EARE models were developed to disrupt the early normal interactions between infants and mothers or peers. Those studies provided important insights of EARE induced effects on the physiological and behavioral systems of NHPs across life span, such as social behaviors (including disturbance behavior, social deficiency, sexual behavior, etc), learning and memory ability, brain structural and functional developments (including influences on neurons and glia cells, neuroendocrine systems, e.g., hypothalamic-pituitary-adrenal (HPA) axis, etc). In this review, the effects of EARE and the underlying epigenetic mechanisms were comprehensively summarized and the possibility of rehabilitation was discussed.

Neurobiological Programming of Early Life Stress: Functional Development of Amygdala-Prefrontal Circuitry and Vulnerability for Stress-Related Psychopathology.

Early adverse experiences are associated with heighted vulnerability for stress-related psychopathology across the lifespan. While extensive work has investigated the effects of early adversity on neurobiology in adulthood, developmental approaches can provide further insight on the neurobiological mechanisms that link early experiences and long-term mental health outcomes. In the current review, we discuss the role of emotion regulation circuitry implicated in stress-related psychopathology from a developmental and transdiagnostic perspective. We highlight converging evidence suggesting that multiple forms of early adverse experiences impact the functional development of amygdala-prefrontal circuitry. Next, we discuss how adversity-induced alterations in amygdala-prefrontal development are associated with symptoms of emotion dysregulation and psychopathology. Additionally, we discuss potential mechanisms through which protective factors may buffer the effects of early adversity on amygdala-prefrontal development to confer more adaptive long-term outcomes. Finally, we consider limitations of the existing literature and make suggestions for future longitudinal and translational research that can better elucidate the mechanisms linking early adversity, neurobiology, and emotional phenotypes. Together, these findings may provide further insight into the neuro-developmental mechanisms underlying the emergence of adversity-related emotional disorders and facilitate the development of targeted interventions that can ameliorate risk for psychopathology in youth exposed to early life stress.

Effects of early life adverse experiences on the brain: implications from maternal separation.

Effects of early life adverse experiences on the brain: implications from maternal separation.

Tumor necrosis factor-alpha expression in peripheral blood mononuclear cells correlates with early childhood social interaction in autism spectrum disorder

Autism spectrum disorder is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Elevated blood levels of pro-inflammatory cytokines have been reported in subjects with autism spectrum disorder. On the other hand, early childhood adverse experience also increases blood levels of these cytokines. Since social experience of children with autism spectrum disorder is generally unlike to typically developing children, we hypothesized that social interaction during childhood contribute to pro-inflammatory cytokine expression in subjects with autism spectrum disorder. We compared revised Autism Diagnostic Interview scores and expression levels of pro-inflammatory cytokines in peripheral blood mononuclear cells of subjects with autism spectrum disorder (n = 30). The score of domain A on the revised Autism Diagnostic Interview, indicating social interaction impairment in early childhood, was negatively correlated with tumor necrosis factor-α mRNA expression level in peripheral blood mononuclear cells but not interleukin-1β or -6. Consistently, tumor necrosis factor-α mRNA expression was markedly low in subjects with autism spectrum disorder compared to typically developing children who presumably experienced the regular levels of social interaction. These findings suggest that the low blood levels of tumor necrosis factor-α mRNA in subjects with autism spectrum disorder might be due to impaired social interaction in early childhood.