The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors.

Conduct Disorder (CD) is an impairing psychiatric disorder of childhood and adolescence characterized by aggressive and dissocial behavior. Environmental factors such as maternal smoking during pregnancy, socio-economic status, trauma, or early life stress are associated with CD. Although the number of females with CD is rising in Western societies, CD is under-researched in female cohorts. We aimed at exploring the epigenetic signature of females with CD and its relation to psychosocial and environmental risk factors. We performed HpaII sensitive genome-wide methylation sequencing of 49 CD girls and 50 matched typically developing controls and linear regression models to identify differentially methylated CpG loci (tags) and regions. Significant tags and regions were mapped to the respective genes and tested for enrichment in pathways and brain developmental processes. Finally, epigenetic signatures were tested as mediators for CD-associated risk factors. We identified a 12% increased methylation 5' of the neurite modulator SLITRK5 (FDR = 0.0046) in cases within a glucocorticoid receptor binding site. Functionally, methylation positively correlated with gene expression in lymphoblastoid cell lines. At systems-level, genes (uncorr. P < 0.01) were associated with development of neurons, neurite outgrowth or neuronal developmental processes. At gene expression level, the associated gene-networks are activated perinatally and during early childhood in neocortical regions, thalamus and striatum, and expressed in amygdala and hippocampus. Specifically, the epigenetic signatures of the gene network activated in the thalamus during early childhood correlated with the effect of parental education on CD status possibly mediating its protective effect. The differential methylation patterns identified in females with CD are likely to affect genes that are expressed in brain regions previously indicated in CD. We provide suggestive evidence that protective effects are likely mediated by epigenetic mechanisms impairing specific brain developmental networks and therefore exerting a long-term effect on neural functions in CD. Our results are exploratory and thus, further replication is needed.

Reconsidering the role of sex hormones in psychopathy development: Estrogen and psychopathy among male justice-involved youth.

Prominent theory suggests that factor one psychopathic traits may develop from increased input from hormones in the hypothalamic pituitary gonadal axis (HPG; i.e., testosterone) and decreased input from the hypothalamic pituitary adrenal axis (HPA; i.e., cortisol). Although there are extensive findings connecting low cortisol to psychopathy, less support has emerged for high levels of testosterone. This study examined whether incorporating the HPG hormone, estradiol, into this model would reveal relationships in line with theory: high levels of estradiol and testosterone in combination with low levels of cortisol would inform psychopathic traits. Baseline and reactive hormone levels were measured and compared to Psychopathy Checklist-Youth Version (PCL-YV) interviews among 66 male justice-involved youth (M age = 15.73) in a Southeastern juvenile detention center. The primary findings of this study were relationships between interacting HPA and HPG axis hormones with facet one and facet two psychopathic traits. Specifically, psychopathy total scores, interpersonal traits, and affective traits related to estradiol and testosterone reactivity, in that psychopathy scores were more likely with decreases in hormone reactivity (i.e., change in hormone level) following a stressor. Moreover, affective traits related to reactivity in all three hormones. These findings support inclusion of estradiol in neurobiological models of psychopathy and consideration of the individual components of psychopathy. This study adds to the growing body of research supporting interactions between variations in functioning of the HPA and HPG axes in relation to psychopathy.

Saliva oxytocin, cortisol, and testosterone levels in adolescent boys with autism spectrum disorder, oppositional defiant disorder/conduct disorder and typically developing individuals.

The aim of the current study was to compare levels of oxytocin, cortisol, and testosterone in adolescents with either autism spectrum disorder (ASD), or oppositional defiant disorder (ODD)/conduct disorder (CD), and in typically developing individuals (TDI), and relate hormone levels to severity and subtype of aggression and callous-unemotional (CU) traits. Saliva concentrations of oxytocin, cortisol, and testosterone were assessed in 114 male participants (N = 49 ASD, N = 37 ODD/CD, N = 28 TDI,) aged 12-19 years (M = 15.4 years, SD = 1.9). The ASD and the ODD/CD groups had significantly lower levels of oxytocin than the TDI group, and the ODD/CD group had significantly higher levels of testosterone than the ASD group. There were no group effects on cortisol levels. Group differences remained for oxytocin after correcting for the influence of CU traits, but were not significant after controlling for aggression. Results for testosterone became non-significant after correction for either CU traits or aggression. Across groups, higher levels of CU traits were related to higher levels of cortisol and testosterone, however, proactive and reactive aggression were unrelated to all three hormonal levels. The current findings show that, regardless of cognitive ability or comorbid disorders, the diagnostic groups (ASD, ODD/CD) differ from each other by their hormonal levels, with the ASD group characterized by relative low level of oxytocin, and the ODD/CD group by a relative low level of oxytocin and high level of testosterone. These group effects were partly driven by differences in CU traits between the groups.

Parenting and Cortisol in Infancy Interactively Predict Conduct Problems and Callous-Unemotional Behaviors in Childhood.

This study examines observed maternal sensitivity, harsh-intrusion, and mental-state talk in infancy as predictors of conduct problems (CP) and callous-unemotional (CU) behaviors in middle childhood, as well as the extent to which infants' resting cortisol and cortisol reactivity moderate these associations. Using data from the Family Life Project (n = 1,292), results indicate that maternal sensitivity at 6 months predicts fewer CP at first grade, but only for infants who demonstrate high levels of cortisol reactivity. Maternal harsh intrusion predicts fewer empathic-prosocial behaviors, a component of CU behaviors, but only for infants who demonstrate high resting cortisol. Findings are discussed in the context of diathesis-stress and differential susceptibility models.

Intranasal oxytocin administration promotes emotional contagion and reduces aggression in a mouse model of callousness.

Deficits in empathy, the ability to share an emotion of another individual, constitute a hallmark of several psychopathological conditions, including conduct disorder. The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional traits confers specific risk for adult psychopathy. In the present study, we relied on a recently devised experimental model of conduct disorder in mice to test the potential efficacy of intranasal oxytocin administration. Two subgroups of BALB/cJ male mice exhibiting opposite profiles in emotional contagion (i.e. socially transmitted adoption of another's emotional states) underwent a series of tests mapping onto reactive aggression, information processing, perseverative behaviour, punishment-related emotional memory, physiological arousal and hormonal stress reactivity, with or without intranasal oxytocin administration (5.0 or 20.0 µg/kg). Collectively, our data indicate that a trait of markedly reduced emotional contagion is associated with a behavioural syndrome of sensorimotor gating deficits, impaired emotional memory, increased aggression and stereotyped behaviours, dysregulations in the circadian rhythms of activity and body temperature and dampened physiological reactivity to external stressors. Moreover, in the absence of changes in oxytocin receptor density in the neural network involved in empathy-like behaviour, we showed that oxytocin administration normalised emotional contagion, aggression and behavioural stereotypies, thereby ameliorating the phenotype of mice characterised by deficient empathy-like behaviour. Besides, oxytocin led to a lower, more prolonged neuroendocrine response of the HPA-axis to stress in all mice. Ultimately, current data support the notion that oxytocin may constitute a valid therapeutic approach in disturbances characterised by abnormal aggression and excess callousness.

Hair and Salivary Testosterone, Hair Cortisol, and Externalizing Behaviors in Adolescents.

Although testosterone is associated with aggression in the popular imagination, previous research on the links between testosterone and human aggression has been inconsistent. This inconsistency might be because testosterone's effects on aggression depend on other moderators. In a large adolescent sample ( N = 984, of whom 460 provided hair samples), we examined associations between aggression and salivary testosterone, hair testosterone, and hair cortisol. Callous-unemotional traits, parental monitoring, and peer environment were examined as potential moderators of hormone-behavior associations. Salivary testosterone was not associated with aggression. Hair testosterone significantly predicted increased aggression, particularly at low levels of hair cortisol (i.e., Testosterone × Cortisol interaction). This study is the first to examine the relationship between hair hormones and externalizing behaviors and adds to the growing literature that indicates that androgenic effects on human behavior are contingent on aspects of the broader endocrine environment-in particular, levels of cortisol.

The reliability, concurrent validity and association with salivary oxytocin of the self-report version of the Inventory of Callous-Unemotional Traits in adolescents with conduct disorder.

The present study evaluated the self-report version of the Inventory of Callous-Unemotional Traits (ICU-SR) in terms of reliability, concurrent validity, and correlation with salivary oxytocin levels, a potential biomarker of CU traits. 67 socially at-risk male adolescents (mean 16.2 years) completed the ICU-SR, ICU teacher-version (ICU-TR), Strengths and Difficulties Questionnaire, and their medical files were coded for previous antisocial acts using Brown-Goodwin Lifetime Aggression Scale. Salivary samples were assayed for oxytocin. The reliability of ICU-SR was lower (α = 0.71) than ICU-TR (α = 0.86). ICU-SR mean score was significantly lower than ICU-TR (M = 25.29, SD = 8.02; M = 33.14, SD = 9.47). ICU-TR but not ICU-SR, significantly correlated with history of antisocial acts (r = 0.40). Two-way analysis of variance showed a significant effect of conduct disorder and oxytocin on ICU-TR but not ICU-SR [F(1,59) = 6.53; F(1,59) = 6.08], and a significant interaction only for ICU-TR [F(1,59) = 2.89]. Subjective self-reports of CU traits may be less reliable and valid than teachers' reports.

Abnormal serotonin transporter availability in the brains of adults with conduct disorder.

BACKGROUND/PURPOSE: The aims of the current study were to determine whether patients with conduct disorder (CD) showed an abnormal availability of serotonin reuptake transporter (SERT), and if their hyperkinetic symptoms, impulsivity, and quality of life were correlated with the availability of SERT. METHODS: We recruited 14 drug-naïve patients with CD and eight age-matched healthy controls (HCs). The adult attention-deficit/hyperactivity disorder (ADHD) self-report scale (ASRS), Barrett impulsivity scale (BIS), and the World Health Organization quality of life-brief version (WHOQOL-BREF) scale were administered. Positron emission tomography (PET) of the brain with 4-[18F]-ADAM was arranged for SERT imaging. RESULTS: SERT availability was significantly reduced in the striatum and midbrain of patients with CD. Quality of life and inattention symptoms were also significantly correlated with the availability of SERT in the prefrontal cortex. CONCLUSION: The study suggested that a reduction in the availability of SERT might be associated with CD and could potentially predict poor quality of life or symptoms of inattention for these patients. The implications of our results might be limited to individuals with CD; a future study with a larger sample to validate our preliminary results is warranted.

The role of anxiety in cortisol stress response and cortisol recovery in boys with oppositional defiant disorder/conduct disorder.

Children with antisocial and aggressive behaviors have been found to show abnormal neurobiological responses to stress, specifically impaired cortisol stress reactivity. The role of individual characteristics, such as comorbid anxiety, in the stress response is far less studied. Furthermore, this study extended previous studies in that not only baseline and reactivity to a psychosocial stressor were examined, but also recovery from a stressor. These three phases of cortisol could be impacted differentially in boys with oppositional defiant disorder/conduct disorder (ODD/CD) with (+ANX) and without anxiety (-ANX). The results revealed that cortisol patterns in response to psychosocial stress were different for boys with ODD/CD+ANX (n=32), ODD/CD-ANX (n=22) and non-clinical controls (NC) (n=34), with age range of 7.8-12.9 years. The ODD/CD-ANX group showed lower overall cortisol levels than the NC group. When considering the three phases of cortisol separately, the ODD/CD-ANX group had lower baseline cortisol levels relative to the other groups, whereas the ODD/CD+ANX showed an impaired cortisol recovery response. Within those with ODD/CD, callous-unemotional traits were predictive of high baseline cortisol levels. Also, anxiety predicted high baseline and recovery cortisol levels, whereas a high number of CD symptoms predicted reduced cortisol stress reactivity. These results clearly indicate that comorbid anxiety is an important factor in explaining differences in stress response profiles in boys with ODD/CD; although boys with CD/ODD are generally characterized by an impaired cortisol stress response, we found that those with comorbid anxiety showed impaired cortisol recovery, whereas those without anxiety showed reduced baseline cortisol levels.

Intervención sobre la conducta: prevención, anticipación y límites / No disponible

Uno de los factores que más dificultan la integración de los niños con síndrome de Down en centros escolares ordinarios y que preocupa especialmente a padres y profesionales, es la presencia de conductas disruptivas o inadecuadas. Con ellas rompen la dinámica de las clases, retrasan el aprendizaje y producen tensión en profesores y compañeros. Por eso es esencial fomentar un comportamiento adecuado a la edad, para que tengan éxito en sus interacciones sociales, en la familia, en el entorno cercano y en el colegio. Un estudio riguroso de los posibles antecedentes que están provocando el comportamiento del niño nos proporcionará valiosas ideas para realizar una intervención efectiva

Disruptive behaviors of individuals with Down syndrome may appear in several environments: at home, at school and other social settings. They may become a challenge for parents and professionals because they disrupt the normal dynamics in the family and the classroom, delay the learning progression and become a focus of anxiety to peers and caregivers. Early educative strategies should be applied from infancy into adulthood, so that the each individual might learn coherent and social interactions in an acceptable environment. On the face of a disruptive behavior, it is most important to search for all possible preceding events and circumstances which might trigger that behavior

Greater fear reactivity and psychophysiological hyperactivity among infants with later conduct problems and callous-unemotional traits.

BACKGROUND: Approximately one third of children who meet criteria for conduct problems (CP) are also characterized by elevated callous-unemotional (CU) traits. This subgroup is at elevated risk for more pervasive and extreme levels of later antisocial behavior and has been characterized by a fearlessness temperament and blunted stress psychophysiology at older ages. The objective of this study was to examine group differences in fear reactivity and stress psychophysiology in infancy among children classified as having CP with CU (CP + CU), CP without CU (CP only), or no CP in later childhood. METHODS: A birth cohort study (n = 1,292) was followed longitudinally from birth through first grade. Behavioral fear, baseline heart period (HP) and respiratory sinus arrhythmia (RSA), and pretask, 20-min posttask, and 40-min posttask salivary cortisol were assessed at 6 and 15 months of age around a fear challenge task. CP and CU were assessed by maternal report at first grade and children were classified into CP and CU groups if they scored in the upper 10(th) percentile of these ratings. RESULTS: No group differences were observed in children at 6 months of age. However, at 15 months of age children with later CP + CU displayed greater high-intensity fear behavior, higher pretask and overall cortisol levels, and lower levels of HP and RSA compared to children with CP only and children with no CP. CONCLUSIONS: The discrepancy between the biobehavioral correlates of conduct problems with callous-unemotional traits in infancy and those reported from studies of older children and adults suggests that the etiology of this behavioral phenotype may be more complex than a simple genetic maturation model.

Socially explosive minds: the triple imbalance hypothesis of reactive aggression.

The psychobiological basis of reactive aggression, a condition characterized by uncontrolled outbursts of socially violent behavior, is unclear. Nonetheless, several theoretical models have been proposed that may have complementary views about the psychobiological mechanisms involved. In this review, we attempt to unite these models and theorize further on the basis of recent data from psychological and neuroscientific research to propose a comprehensive neuro-evolutionary framework: The Triple Imbalance Hypothesis (TIH) of reactive aggression. According to this model, reactive aggression is essentially subcortically motivated by an imbalance in the levels of the steroid hormones cortisol and testosterone (Subcortical Imbalance Hypothesis). This imbalance not only sets a primal predisposition for social aggression, but also down-regulates cortical-subcortical communication (Cortical-Subcortical Imbalance Hypothesis), hence diminishing control by cortical regions that regulate socially aggressive inclinations. However, these bottom-up hormonally mediated imbalances can drive both instrumental and reactive social aggression. The TIH suggests that reactive aggression is differentiated from proactive aggression by low brain serotonergic function and that reactive aggression is associated with left-sided frontal brain asymmetry (Cortical Imbalance Hypothesis), especially observed when the individual is socially threatened or provoked. This triple biobehavioral imbalance mirrors an evolutionary relapse into violently aggressive motivational drives that are adaptive among many reptilian and mammalian species, but may have become socially maladaptive in modern humans.

Disorder-specific inferior prefrontal hypofunction in boys with pure attention-deficit/hyperactivity disorder compared to boys with pure conduct disorder during cognitive flexibility.

BACKGROUND: Problems with cognitive flexibility have been observed in patients with attention deficit hyperactivity disorder (ADHD) and in patients with conduct disorder (CD), characterized by the violation of societal rules and the rights of others. Functional magnetic resonance imaging (fMRI) of cognitive switching, however, has only been investigated in patients with ADHD, including comorbidity with CD, finding frontostriatal and temporoparietal underactivation. This study investigates disorder-specific functional abnormalities during cognitive flexibility between medication-naïve children and adolescents with noncomorbid CD and those with noncomorbid ADHD compared to healthy controls. METHODS: Event-related fMRI was used to compare brain activation of 14 boys with noncomorbid, childhood-onset CD, 14 boys with noncomorbid ADHD, and 20 healthy comparison boys during a visual-spatial Switch task. RESULTS: Behaviorally, children with ADHD compared to children with CD had significantly slower reaction times to switch compared to repeat trials. The fMRI comparison showed that the patients with ADHD compared to both controls and patients with CD showed underactivation in right and left inferior prefrontal cortex. No disorder-specific brain underactivation was observed in patients with CD. Only when compared with controls alone, the disruptive behavior group showed reduced activation in bilateral temporoparietal and occipital brain regions. CONCLUSIONS: The findings extend previous evidence for disorder-specific underactivation in patients with ADHD compared to patients with CD in inferior prefrontal cortex during tasks of inhibitory control to the domain of cognitive flexibility. Inferior prefrontal underactivation thus appears to be a disorder-specific neurofunctional biomarker for ADHD when compared with patients with CD.

Cortisol and alpha amylase reactivity and timing of puberty: vulnerabilities for antisocial behaviour in young adolescents.

The theoretical framework proposed that cortisol and saliva alpha amylase (sAA) reactivitiy are vulnerabilities for antisocial behaviour. These indices of hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medulary (SAM) components of the stress system, respectively, were considered vulnerabilities that also interact with the putative stressful transition of timing of puberty to predispose adolescents toward antisocial behaviour. The sample consisted of 8- to-13-year-old boys and girls (N=135) and a parent. For boys, timing of puberty moderated the association between cortisol and sAA reactivity and antisocial behaviour. Higher cortisol reactivity in later timing boys was related to a composite index of antisocial behaviour and rule-breaking behaviour problems. In contrast, lower sAA reactivity and earlier timing of puberty in boys was related to rule breaking and conduct disorder symptoms. The interaction between timing of puberty and HPA or SAM regulation and timing of puberty in boys suggests that reproductive, neuroendocrine mechanisms may be involved in the extensively documented adverse consequences of off-time pubertal development.

Cortisol awakening response in healthy children and children with ADHD: impact of comorbid disorders and psychosocial risk factors.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common child psychiatric disorders. Previous studies have reported a blunted cortisol response to challenging situations and a decreased cortisol awakening response (CAR) in children with ADHD. As ADHD often is comorbid with oppositional defiant disorder (ODD), conduct disorder (CD), or anxiety disorder (AnxD), and changes in hypothalamic-pituitary-adrenal (HPA) axis activity have also been reported for these disorders, the present study aimed to compare the CAR in children with ADHD with and without comorbid disorders. Data on the CAR were obtained in 128 children with ADHD (aged 6-13 years) and in 96 control children (aged 6-12 years). Children with ADHD+ODD showed an attenuated CAR (area under the curve, AUC) compared to children with ADHD without ODD/CD and control children. Findings point towards either disinhibition or pervasive underarousal in children with ADHD+ODD, and seem to be specific for children with ADHD+ODD, as the attenuated CAR-AUC was not observed in children with ADHD without comorbid disorders or children with ADHD+CD or ADHD+AnxD. In addition, current adverse parenting conditions, family conflicts, and acute life events were associated with mean increase in CAR, emphasizing the role of psychosocial risk factors in mediating HPA axis activity in children with ADHD.

Cortisol diurnal rhythm and stress reactivity in male adolescents with early-onset or adolescence-onset conduct disorder.

BACKGROUND: Previous studies have reported lower basal cortisol levels and reduced cortisol responses to stress in children and adolescents with conduct disorder (CD). It is not known whether these findings are specific to early-onset CD. This study investigated basal and stress-induced cortisol secretion in male participants with early-onset and adolescence-onset forms of CD. METHODS: Forty-two participants with early-onset CD, 28 with adolescence-onset CD, and 95 control subjects participated in the study. They collected saliva across the day to assess their cortisol awakening response and diurnal rhythm. Subsequently, salivary cortisol was measured before, during, and after a psychosocial stress procedure designed to elicit frustration. Cardiovascular activity and subjective mood states were also assessed during stress exposure. RESULTS: There were no group differences in morning cortisol levels or the size of the cortisol awakening response. Basal cortisol levels in the evening and at 11 am during the laboratory visit were higher in both CD subgroups relative to control subjects. In contrast, cortisol and cardiovascular responses to psychosocial stress were reduced in both CD subgroups compared with control subjects. All groups reported similar increases in negative mood states during stress. CONCLUSIONS: Our findings suggest that group differences in cortisol secretion are most pronounced during stress exposure, when participants with CD show cortisol hyporeactivity compared with control subjects. There was no evidence for reduced basal cortisol secretion in participants with CD, but rather increased secretion at specific time points. The results do not support developmentally sensitive differences in cortisol secretion between CD subtypes.

Criterios de derivación a la atención especializada / Criteria of referral to specialized care

No disponible

No disponible

The relation between salivary cortisol, callous-unemotional traits, and conduct problems in an adolescent non-referred sample.

BACKGROUND: Previous research has suggested that adult psychopathic behavior and child callous-unemotional (CU) traits are uniquely related to low emotional reactivity. Salivary cortisol is a promising biological measure of emotional reactivity that has been relatively overlooked in research on CU traits and antisocial behavior. The current study examined for gender differences in the relation between resting salivary cortisol levels and CU traits in a non-referred adolescent sample. Salivary testosterone levels were assessed to provide discriminant validity for cortisol analyses and were not expected to bear a relation to CU traits. METHOD: An extreme groups strategy was used to recruit 108 adolescents (53 male, 55 female) from a larger screening sample who exhibited various combinations of low and high scores on parent-report measures of CU traits and conduct problems. Resting saliva samples were assayed for cortisol and testosterone levels using a radioimmunoassay procedure. RESULTS: Consistent with prediction, male participants exhibiting elevated CU traits were uniquely characterized by low cortisol levels relative to male comparison groups (p<.05). Testosterone levels did not differentiate groups and no hormone effects were found for female participants. CONCLUSIONS: The current findings build upon recent research in suggesting that low cortisol may be a biological marker for male CU traits.

Salivary cortisol and aggression in a population-based longitudinal study of adolescent males.

Chronic antisocial behaviour in youth has been associated with cortisol, a measure of stress reactivity. However, some studies have found low cortisol levels, while others have found elevated cortisol levels. The present study compared variously defined aggressive subgroups for differences in salivary cortisol. A population-based sample of boys was followed longitudinally from childhood to adolescence. Assessments of different forms of antisocial behaviour were obtained from various informants at several points in time, and cortisol was collected at age 13. Higher cortisol levels were found in boys with conduct disorder (CD) than in boys without CD. In addition, boys with an aggressive form of CD had higher cortisol levels than boys who showed a covert form of CD. Furthermore, reactive aggression was strongly correlated with elevated cortisol. Adolescent boys with chronic reactive aggression and those who scored high on aggressive CD symptoms seem to have a more active hypothalamic-pituitary-adrenal system.

Cortisol levels and conduct disorder in adolescent mothers.

OBJECTIVE: To examine the association between cortisol levels and conduct disorder (CD) in adolescent mothers. Past research has shown that low levels of cortisol were associated with CD, particularly with its aggressive symptoms. The authors tested the hypothesis that adolescent mothers with CD would show lower levels of salivary cortisol compared to mothers without CD at 4 and 9 months postpartum. METHOD: Midmorning salivary cortisol levels were measured in 228 adolescent mothers (age at delivery 16.9 +/- 1 years [mean +/- SD]) during a laboratory visit at 4 and 9 months postpartum. CD was diagnosed during pregnancy according to the CD subsection on the criteria for antisocial personality disorder (DSM-III-R). RESULTS: Results did not confirm the hypothesis. Lower cortisol levels were not significantly associated with a CD diagnosis, the number of CD symptoms, or aggressive symptoms. CONCLUSIONS: Despite valid measures and strong statistical power, this study failed to find an association between cortisol levels and CD in a sample of adolescent mothers. The results may have been influenced by the fact that participants were 4 and 9 months postpartum and by comparisons of mothers with CD to mothers living in stressful circumstances.