A cross-sectional study of the association between exposure to violence, intelligence, and executive function in Brazilian youths.

We carried out an exploratory study of the association between exposure to violence, intelligence, and executive functions in Brazilian preadolescents. The study included 56 participants (31 males) aged 8 to 14 years old (mean = 11.3, SD = 1.0). We administered neuropsychological tests to evaluate executive functions and the Juvenile Victimization Questionnaire (JVQ) to evaluate exposure to violence. We used the following neuropsychological instruments: Wechsler Abbreviated Scale of Intelligence (WASI), Stroop Color-Word Interference task, digits subtest of the Wechsler Intelligence Scale for Children, and an N-back task. We generated a composite score from neuropsychological test scores and investigated the association of that score, and individual test scores, with exposure to violence and socioeconomic status (SES). Results suggest, first, that exposure to violence is associated with a 0.5-point lower intelligence quotient score for every reported victimization event in the Juvenile Victimization Questionnaire. Results also show that the digits backward subtest scores showed a significant negative correlation with exposure to violence (JVQ; rho = -0.29, p < 0.05); both analyses were adjusted for the level of schooling of parents or guardians, which was also found to be significantly associated with lower intelligence quotient scores. We discuss results in the light of the existing literature on the effects of exposure to violence on adolescent development, and the amounting evidence that suggests an association of exposure to violence, and of victimization, with tests that evaluate constructs of executive functions. The study struggled with low compliance from participants, and we underscore the challenges of carrying out empirical studies aimed at better understanding the development of underrepresented youths, such as those from Central and Latin America.

Caregiving of children with Down syndrome: impact on quality of life, stress, mental and oral health.

AIM: Parental caregivers of children with Down Syndrome (DS) have a greater burden of daily activities that may affect their health. The aim of this exploratory study was to evaluate the impact of caregiving of children with Down syndrome on parenting quality of life, stress, mental and oral health. METHODS: Fifty-four parental caregivers of children with DS and 51 parents of children without physical or mental disabilities participated of this study. All participants were clinically examined to evaluate the presence of dental caries, gingival conditions and answered a sociodemographic questionnaire. Depression, anxiety, quality of life and coping strategies were assessed using specific instruments. Hair cortisol level was assessed as biological marker of chronic stress. RESULTS: Psychological and quality of life parameters were similar between the groups of caregivers (p > .05). Caregivers of children with DS were older (48.6 vs. 41.5, p < .001), had longer caregiving period (> 10 vs < 10 years, p = .003), presented higher gingival bleeding index (6.1 vs. 4.7, p = .014) and higher cortisol levels (55.9 vs. 38.4, p = .07) as compared with parents of children without disabilities. Sociodemographic data has no influence on cortisol levels (p > .05). CONCLUSIONS: These findings suggest that the caregiving of children with DS has an impact on parenting oral health and stress.

Oxytocin Receptor Exon III Methylation in the Umbilical Cord Blood of Newborns With Prenatal Exposure to Crack Cocaine.

BACKGROUND: Prenatal cocaine exposure (PCE) is associated with behavioral, cognitive, and social consequences in children that might persist into later development. However, there are still few data concerning epigenetic mechanisms associated with the effects of gestational cocaine exposure, particularly in human newborns. AIMS: We investigated the effects of PCE on DNA methylation patterns of the Oxytocin Receptor (OXTR) gene in the umbilical cord blood (UCB). The relationship between UCB DNA methylation levels and the severity of the mother's cocaine use during pregnancy was also evaluated. METHODS: In this cross-sectional study, 28 UCB samples of newborns with a history of crack cocaine exposure in utero and 30 UCB samples of non-exposed newborns (NEC) were compared for DNA methylation levels at two genomic loci located in exon III of the OXTR gene (OXTR1 and OXTR2) through pyrosequencing. Maternal psychopathology was investigated using the Mini International Neuropsychiatric Interview, and substance use characteristics and addiction severity were assessed using the Smoking and Substance Involvement Screening Test (ASSIST). RESULTS: No differences between newborns with a history of PCE and NEC were observed in OXTR1 or OXTR2 DNA methylation levels. However, regression analyses showed that maternal addiction severity for crack cocaine use predicted OXTR1 DNA methylation in newborns. CONCLUSION: These data suggest that OXTR methylation levels in the UCB of children are affected by the severity of maternal crack cocaine usage. Larger studies are likely to detect specific changes in DNA methylation relevant to the consequences of PCE.

Hair cortisol levels and mental health problems in children and adolescents exposed to victimization.

Youths who experience multiple forms of victimization are at a heightened risk for psychopathology across the lifespan. The hypothalamic-pituitary-adrenal (HPA) axis is a key target for the investigation of neurobiological changes induced by chronic stress and violence exposure. The measurement of hair cortisol concentration allows the investigation of long-term HPA activity and its association with victimization. The present study investigated the impact of exposure to polyvictimization in Latin-American children and adolescents on hair cortisol levels. We investigated association among cortisol, mental health problems and victimization. The study included 83 youths (mean age 10.84 years-old) from southern Brazil. We assessed self-reported victimization scores (Juvenile Victimization Questionnaire - JVQ-R2), mental health problems (Child Behavior Checklist - CBCL/6-18), and hair cortisol concentrations for the previous 30 days. The results showed an association between exposure to multiple forms of victimization and higher concentrations of hair cortisol; the results also showed that cortisol levels and mental health problems were associated with the severity of polyvictimization. These findings suggest that preadolescent victimization is associated with hyperactivation of HPA axis and with increased risk of mental health issues.

An fMRI study of inhibitory control and the effects of exposure to violence in Latin-American early adolescents: alterations in frontoparietal activation and performance.

We used functional magnetic resonance to investigate the effects of exposure to violence on early adolescent brain function in an inhibitory control task. We investigated the association among scores on self-reported exposure to violence, performance and brain activation. Thirty-seven early adolescents (ages 10-14) from a Latin-American urban region participated in the study. Results showed that recent and chronic exposure to violence was associated with less activation of a network of frontal regions, including the anterior cingulate gyrus and the superior frontal cortex; recent exposure to violence was also associated with less activation of the superior parietal lobe. Results also showed that less activation correlated with more prominent deterioration in the performance in the inhibitory control task (increased latency with time). The findings suggest that early adolescence exposure to violence is associated with differences in activation of a neural network commonly associated with executive function and control. The results underscore the urgency of addressing exposure to violence in adolescence, a period of high susceptibility to the environment, and are discussed in the light of the evidence of the effects of violence on adolescent brain function. Executive function training may be a candidate for targeted cognitive interventions aimed at mitigating these effects.

Hair cortisol concentration, cognitive, behavioral, and motor impairment in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that is characterized by the demyelinated inflammatory processes that occur within the central nervous system. Hypothalamus-pituitary-adrenal axis (HPA axis) dysfunctions have been associated with the triggering or increase in MS symptoms. We thus aimed at evaluating motor and behavioral functions, planning skills, processing speed, and their relationship with stress through measuring hair cortisol concentration from patients with MS. The sample was composed of 40 volunteers that were clinically diagnosed with MS, along with 33 healthy adults. Evaluations included: Clinical Evaluation Form, Mini-Mental State Exam, Hamilton Depression Rating Scale, Multiple Sclerosis Functional Composite Measure, Expanded Disability Status Scale, Berg Balance Scale, Perceived Stress Scale, Zoo Map task, and a hair sample to analyze cortisol levels in the last 30 days. MS patients showed highly elevated hair cortisol levels in comparison to the control group (p = 0.048). All groups presented some degree of depressive and anxiety symptoms, aside from considerable perceived stress levels. The MS group presented deficits in gait, balance, manual skills and processing speed, and this was particularly so in individuals with moderate impairments when compared to control group (p < 0.001). Individuals with MS spent less time planning on ZooMap1 (p = 0.024) and made more mistakes (p < 0.001). No correlation was found between hair cortisol and the symptoms we assessed. However, depressive symptoms and anxiety were related to perceived stress, and higher hair cortisol suggests a change in levels in the HPA axis in MS. Nevertheless, future studies will be necessary to further understand how basal hair cortisol is related to MS symptoms.

Subjective and physiological stress measurement in a multiple sclerosis sample and the relation with executive functions performance.

In multiple sclerosis (MS), hypothalamic-pituitary-adrenal (HPA) axis functioning may be dysregulated due to the high cortisol levels involved in the disease activity. HPA axis dysregulation can affect cognitive performance, including executive functions. This study aimed to evaluate hair cortisol concentration and perceived stress as well as verify the association with the performance of executive function in both individuals diagnosed with MS and control individuals. Hair cortisol concentration and perceived stress were evaluated and their association with the performance of healthy individuals (n = 33) and those with MS (n = 64), most of them with remitting-relapsing multiple sclerosis (RRMS) assessed using the Expanded Disability Status Scale (EDSS). Instruments that were employed to measure perceived stress and health aspects included the Behavioral Assessment Dysexecutive Syndrome, Wisconsin Card Sorting Test, Stroop Test, and Perceived Stress Scale. No significant statistical difference was found in the comparison of means among the groups; however, an association was found when using statistical correlation tests between cortisol and cognitive performance in the clinical group (r = 0.31, p = 0.10). Further, an absence of correlations with perceived stress measure was noted. It was possible to observe interaction between group factors and low level of cortisol and problem-solving/cognitive flexibility in the MS group. The results indicated that stress measures used in the present study seem to influence the performance of inhibitory control and problem-solving/cognitive flexibility, the latter with low levels of cortisol in individuals with MS. We suggest studies that examine different measures of physiological stress and characteristics of the disease such as more time of stress.

Violence and Latin-American preadolescents: A study of social brain function and cortisol levels.

The present study investigated exposure to violence and its association with brain function and hair cortisol concentrations in Latin-American preadolescents. Self-reported victimization scores (JVQ-R2), brain imaging (fMRI) indices for a social cognition task (the 'eyes test'), and hair cortisol concentrations were investigated, for the first time, in this population. The eyes test is based on two conditions: attributing mental state or sex to pictures of pairs of eyes (Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001). The results showed an association among higher victimization scores and (a) less activation of posterior temporoparietal right-hemisphere areas, in the mental state condition only (including right temporal sulcus and fusiform gyrus); (b) higher functional connectivity indices for the Amygdala and Right Fusiform Gyrus (RFFG) pair of brain regions, also in the mental state condition only; (c) higher hair cortisol concentrations. The results suggest more exposure to violence is associated with significant differences in brain function and connectivity. A putative mechanism of less activation in posterior right-hemisphere regions and of synchronized Amygdala: RFFG time series was identified in the mental state condition only. The results also suggest measurable effects of exposure to violence in hair cortisol concentrations, which contribute to the reliability of self-reported scores by young adolescents. The findings are discussed in light of the effects of exposure to violence on brain function and on social-cognitive development in the adolescent brain. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=qHcXq7Y9PBk.

Maternal separation induces hippocampal changes in cadherin-1 (CDH-1) mRNA and recognition memory impairment in adolescent mice.

In rodents, disruption of mother-infant attachment induced by maternal separation (MS) is associated with recognition memory impairment and long-term neurobiological consequences. Particularly stress-induced modifications have been associated to disruption of cadherin (CDH) adhesion function, which plays an important role in remodeling of neuronal connection and synaptic plasticity. This study investigated the sex-dependent effect of MS on recognition memory and mRNA levels of classical type I and type II CDH and the related ß -catenin (ß -Cat) in the hippocampus and prefrontal cortex of late adolescent mice. We provided evidence that the BALB/c mice exposed to MS present deficit in recognition memory, especially females. Postnatal MS induced higher hippocampal CDH-2 and CDH-8 mRNA levels, as well as an upregulation of CDH-1 in the prefrontal cortex in both males and females. MS-reared female mice presented lower CDH-1 mRNA levels in the hippocampus. In addition, hippocampal CDH-1 mRNA levels were positively correlated with recognition memory performance in females. MS-reared male mice exhibited higher ß -Cat mRNA levels in the hippocampus. Considering sex-specific effects on CDH mRNA levels, it has been demonstrated mRNA changes in CDH-1, ß -Cat, and CDH-6 in the hippocampus, as well as CDH-1, CDH-8 and CDH-11 in the prefrontal cortex. Overall, these findings suggest a complex interplay among MS, CDH mRNA expression, and sex differences in the PFC and hippocampus of adolescent mice.

Running during adolescence rescues a maternal separation-induced memory impairment in female mice: Potential role of differential exon-specific BDNF expression.

Exposure to early life stress has been associated with memory impairments related to changes in brain-derived neurotrophic factor (BDNF) signaling. However, the potential impact of physical exercise to reverse these effects of maternal separation has been under investigated. Mice were subjected to maternal separation during the first 2 weeks of life and then exposed to a 3-week running protocol during adolescence. The spontaneous object recognition task was performed during adolescence followed by analysis of hippocampal expression of exons I, IV, and IX of the BDNF gene. As expected, maternal separation impaired recognition memory and this effect was reversed by exercise. In addition, running increased BDNF exon I expression, but decreased expression of BDNF exon IV in all groups, while exon IX expression increased only in MS animals exposed to exercise. Our data suggest that memory deficits can be attenuated by exercise and specific transcripts of the BDNF gene are dynamically regulated following both MS and exercise.

Increased cocaine-induced conditioned place preference during periadolescence in maternally separated male BALB/c mice: the role of cortical BDNF, microRNA-212, and MeCP2.

RATIONALE: Early life stress is a major risk factor for cocaine addiction; however, the underlying molecular mechanisms remain relatively unexplored. MicroRNA-212 (miR-212) and methyl CpG binding protein 2 (MeCP2) have recently emerged as key regulators of brain-derived neurotrophic factor (BDNF) signaling during the acquisition and maintenance of cocaine-seeking behaviors. OBJECTIVES: We therefore investigated the effect of maternal separation (MS) on cocaine-induced conditioned place preference (CPP) during periadolescence and how this influences miR-212, Mecp2, and Bdnf expressions in the prefrontal cortex. METHODS: Male BALB/c mice subjected to MS (3 h/day) from postnatal day 2 to 15 or normal animal facility rearing (AFR) were tested for CPP at postnatal day 45, or not exposed to experimental manipulations (drug-naïve animals). Cultured primary cortical neurons were used to determine miR-212 expression changes following depolarization by KCL treatment. RESULTS: MS increased cocaine-induced CPP and decreased Bdnf exon IV expression, which correlated with higher CPP scores in such animals. An experience-dependent decrease in miR-212 expression was observed following CPP test. This effect was mimicked in primary cortical neurons in vitro, under activity-dependent conditions. In contrast, increased Mecp2 expression was found after CPP test, suggesting an opposing relationship between miR-212 and Mecp2 expression following cocaine place preference acquisition. However, these effects were not present in mice exposed to MS. CONCLUSIONS: Together, our results suggest that early life stress can enhance the motivational salience for cocaine-paired cues during periadolescence, and that altered expression of miR-212, Mecp2, and Bdnf in the prefrontal cortex is involved in this process.

Crack cocaine addiction, early life stress and accelerated cellular aging among women.

BACKGROUND: Early life stress (ELS) and addiction are related to age-related diseases and telomere shortening. However, the role of telomere length (TL) in crack cocaine addiction remains unknown. The purpose of this study was to investigate the TL in a sample of crack cocaine dependent-women who reported an ELS history and in a community-based sample of elderly women as a reference group for senescence. METHODS: This study included treatment seeking crack cocaine dependents women (n=127) and elderly women without a psychiatric diagnosis (ELD, n=49). The crack cocaine sample was divided in two groups according to their Childhood Trauma Questionnaire (CTQ) scores: presence of history of childhood abuse and neglect (CRACK-ELS) and absence of ELS history (CRACK). TL was assessed by T/S ratio obtained from peripheral blood DNA using quantitative PCR assay. RESULTS: CRACK and CRACK-ELS subjects exhibited shortened TL in comparison to the ELD group, despite their younger age. Among crack cocaine sample, CRACK-ELS group had significantly shorter telomeres than the CRACK group. Correlation analysis within crack cocaine group indicated that TL was negatively correlated with emotional abuse scores. CONCLUSIONS: These results support previous findings associating telomere shortening with both ELS and drug addiction. This study suggests new evidence of a distinct biological phenotype for drug-dependent women with ELS. The results support the biological senescence hypothesis underpinning ELS experience.

An overview of maternal separation effects on behavioural outcomes in mice: Evidence from a four-stage methodological systematic review.

Early life stress (ELS) developmental effects have been widely studied by preclinical researchers. Despite the growing body of evidence from ELS models, such as the maternal separation paradigm, the reported results have marked inconsistencies. The maternal separation model has several methodological pitfalls that could influence the reliability of its results. Here, we critically review 94 mice studies that addressed the effects of maternal separation on behavioural outcomes. We also discuss methodological issues related to the heterogeneity of separation protocols and the quality of reporting methods. Our findings indicate a lack of consistency in maternal separation effects: major studies of behavioural and biological phenotypes failed to find significant deleterious effects. Furthermore, we identified several specific variations in separation methodological procedures. These methodological variations could contribute to the inconsistency of maternal separation effects by producing different degrees of stress exposure in maternal separation-reared pups. These methodological problems, together with insufficient reporting, might lead to inaccurate and unreliable effect estimates in maternal separation studies.

Brain-Derived Neurotrophic Factor and Delayed Verbal Recall in Crack/Cocaine Dependents.

BACKGROUND/AIMS: Considering the role of brain-derived neurotrophic factor (BDNF) in memory processes and its peripheral response during the detoxification of cocaine, the aim of this study was to investigate whether plasma BDNF levels could be related to memory performance in women with crack/cocaine dependence. METHODS: Twenty-five abstinent female crack/cocaine users (CCD) and 25 unmedicated healthy women (HW), carefully matched for age and years of formal education, were assessed regarding memory performance. Logical Memory was used to assess the immediate verbal recall (IVR), delayed verbal recall (DVR) and memory retention. Plasma BDNF levels were measured by Elisa immunoassay. Beck Depression Inventory was used to assess the severity of depressive symptoms, and the Cocaine Selective Severity Assessment the severity of cocaine abstinence symptoms. RESULTS: The CCD group had lower DVR scores and higher plasma BDNF levels when compared to HW group. In addition, a linear regression model showed that BDNF levels predicted DVR scores within CCD group independently of depressive symptoms (R = 0.51; R(2) = 0.26; t(22) = 4.025, p = 0.03). CONCLUSION: Despite higher plasma BDNF levels, crack users exhibited memory impairments when compared to healthy women. Specifically, peripheral BDNF levels predicted better cognitive performance only within individuals who already had cognitive impairment.

Cocaine reverses the changes in GABAA subunits and in glutamic acid decarboxylase isoenzymes mRNA expression induced by neonatal 6-hydroxydopamine.

Attention-deficit/hyperactivity disorder is related to altered functions in the dopaminergic and GABAergic pathways of cortical and subcortical brain areas The hyperactivity of attention-deficit/hyperactivity disorder is commonly modelled in rats after neonatal lesion with 6-hydroxydopamine (6-OHDA), and amphetamines are effective in reducing hyperactivity in this animal model. Our objectives were to evaluate whether cocaine reverses the motor hyperactivity of 6-OHDA-lesioned rats and to verify cocaine effects in altered mRNA expression of alpha2, alpha4, beta1 and beta2-GABAA subunits and GAD isoenzymes in the prefrontal cortex, hippocampus and striatum of 6-OHDA-lesioned rats. On PND4, 6-OHDA-lesioned or sham rats received 6-OHDA (100 microg intracisternal) or vehicle. Cocaine solution (0.1 mg/ml/day) was offered when adult for 23 days, using the two-bottle choice procedure. The subjects were evaluated in an open-field on the last day of cocaine treatment. 6-OHDA-lesioned rats showed increased locomotion and this hyperactivity was reversed during cocaine self-administration. 6-OHDA lesion caused an increase in the mRNA expression of GABAA subunits in specific brain areas and GAD isoenzymes in the hippocampus and striatum. Increased GAD65 and decreased GAD67 mRNA expression were also shown in the prefrontal cortex. Cocaine self-administration attenuated the effects of 6-OHDA lesions on the mRNA expression of alpha2-GABAA and beta2-GABAA subunits in the prefrontal cortex, reversed the mRNA expression of alpha2-GABAA subunits in the striatum and of alpha4-GABAA subunits in the prefrontal cortex and in the hippocampus, and reversed the mRNA expression of GAD65 and GAD67 in the brain areas studied. Our findings suggest that cocaine reverses some mRNA changes of GABAA subunits and GAD isoenzymes in reward circuits and the behavioural hyperactivity caused by 6-OHDA lesion.