Early-life adversity and neurological disease: age-old questions and novel answers.

Neurological illnesses, including cognitive impairment, memory decline and dementia, affect over 50 million people worldwide, imposing a substantial burden on individuals and society. These disorders arise from a combination of genetic, environmental and experiential factors, with the latter two factors having the greatest impact during sensitive periods in development. In this Review, we focus on the contribution of adverse early-life experiences to aberrant brain maturation, which might underlie vulnerability to cognitive brain disorders. Specifically, we draw on recent robust discoveries from diverse disciplines, encompassing human studies and experimental models. These discoveries suggest that early-life adversity, especially in the perinatal period, influences the maturation of brain circuits involved in cognition. Importantly, new findings suggest that fragmented and unpredictable environmental and parental signals comprise a novel potent type of adversity, which contributes to subsequent vulnerabilities to cognitive illnesses via mechanisms involving disordered maturation of brain 'wiring'

Exposure to Prenatal Maternal Distress and Infant White Matter Neurodevelopment

The prenatal period represents a critical time for brain growth and development. These rapid neurological advances render the fetus susceptible to various influences with life-long implications for mental health. Maternal distress signals are a dominant early life influence, contributing to birth outcomes and risk for offspring psychopathology. This prospective longitudinal study evaluated the association between prenatal maternal distress and infant white matter microstructure. Participants included a racially and socioeconomically diverse sample of 85 mother–infant dyads. Prenatal distress was assessed at 17 and 29 weeks’ gestational age (GA). Infant structural data were collected via diffusion tensor imaging (DTI) at 42–45 weeks’ postconceptional age. Findings demonstrated that higher prenatal maternal distress at 29 weeks’ GA was associated with increased fractional anisotropy, b = .283, t(64) = 2.319, p = .024, and with increased axial diffusivity, b = .254, t(64) = 2.067, p = .043, within the right anterior cingulate white matter tract. No other significant associations were found with prenatal distress exposure and tract fractional anisotropy or axial diffusivity at 29 weeks’ GA, or earlier in gestation

Brain white matter development, associations to maternal perinatal psychological distress and emotional attention at the age of 5 years

Development of the brain white matter (WM) is highly plastic, and myelination continues from the second trimester into early adulthood which predisposes the brain to effects of both adverse and supporting factors during early life. Maternal perinatal psychological distress is acknowledged as an important contributor to the offspring’s development. Furthermore, sex is known to affect the WM microstructure as well as the emergence of psychopathologies. Understanding the normal variation of microstructure in the developing brain WM is a prerequisite for recognizing alterations inflicted by early adversity that have possible long-term programming effects on behavioral and socio-emotional outcomes. This study aimed to 1) investigate the incidence, risk factors and consequences of incidental findings in brain magnetic resonance imaging of infants; 2) optimize data acquisition parameters and pre-processing pipeline of diffusion tensor imaging (DTI) protocol applied with children; 3) describe the normal microstructural features of WM in infants and 5-year-old children; 4) investigate the associations between WM integrity and exposure to maternal perinatal psychological distress; 5) explore the associations of WM integrity and child’s emotional attention. Vacuum assistance and vaginal birth were observed to increase the risk for subdural hemorrhages (incidence 6.9%) with no effects on early neurological development. In 5-year-olds, higher WM integrity in widespread regions was observed in girls, and we found marked asymmetry in the WM, resembling patterns previously shown in adults. Maternal perinatal psychological distress showed sexand timing-specific associations with WM integrity: prenatal symptoms predicting higher integrity in boys and postnatal symptoms lower integrity in girls. Maternal postpartum anxiety increased girls’ vigilance toward fearful faces, which was also associated with reduced WM integrity. The results imply that maternal psychological distress affects WM development with effects especially on girls. Collectively, these studies provide fundamental insight for future studies addressing the mediating mechanisms and longer-term effects between the observed associations.Aivojen valkean aineen kehitys, äidin raskauden ympärillä esiintyvän psykologisen stressin vaikutus ja tunneperäinen huomion kohdentaminen 5-vuotiailla Aivojen valkean aineen kehitys jatkuu toiselta raskauskolmannekselta varhaiseen aikuisuuteen, mikä altistaa sen muovautuvuutensa vuoksi sekä epäsuotuisten että tukevien tekijöiden vaikutukselle varhaisen elämän aikana. Äidin raskauden ympärillä esiintyvä psykologinen stressi on tunnettu jälkeläisten kehitykseen vaikuttava tekijä. Lisäksi sukupuoli vaikuttaa valkean aineen rakenteeseen ja psykiatristen häiriöiden ilmaantuvuuteen. Kehittyvien aivojen rakenteen normaalivaihtelun ymmärtäminen on oleellista, jotta voidaan tunnistaa aikaisten vastoinkäymisten aiheuttamia muutoksia sekä niiden mahdollisia pitkäaikaisia ohjelmoivia vaikutuksia käytökseen ja tunnepohjaisiin toimintoihin. Tämän väitöskirjan tavoitteena oli 1) raportoida vastasyntyneiden aivojen magneettikuvien sattumalöydösten esiintyvyyttä, riskitekijöitä ja neurologisia seurauksia; 2) optimoida lasten diffuusiotensorikuvantamisaineiston keräämistä ja esikäsittelyä; 3) tarkastella 5-vuotiaiden valkean aineen normaalipiirteitä; 4) tutkia äidin raskauden ympärillä esiintyvän psykologisen stressin vaikutusta jälkeläisten valkean aineen rakenteeseen; ja 5) selvittää valkean aineen yhteyksiä lapsen tunnepohjaiseen huomion kohdentamiseen silmänliikemittausten avulla. Imukuppiavustus ja alatiesynnytys lisäsivät sattumalöydöksinä havaittujen kovakalvonalaisten vuotojen (6.9 %) riskiä, mutta eivät vaikuttaneet varhaiseen neurologiseen kehitykseen. 5-vuotiaiden tyttöjen valkean aineen integriteetti oli laajaalaisesti korkeampi poikiin verrattuna, ja epäsymmetrisyys vastasi aiemmin aikuisilla havaittua rakennetta. Äidin psykologinen stressi liittyi jälkeläisten valkean aineen integriteettiin sukupuoli- ja ajankohtariippuvaisesti: pojilla raskaudenaikainen altistus lisäsi valkean aineen integriteettiä, kun taas tytöillä raskaudenjälkeinen altistus vähensi sitä. Äidin raskauden jälkeinen ahdistus lisäsi tyttöjen tarkkaavaisuutta pelokkaisiin ilmeisiin, joka liittyi myös alentuneeseen valkean aineen integriteettiin. Aiempia tutkimustuloksia tukien äidin psykologisen stressin havaittiin muovaavan valkean aineen kehitystä etenkin tytöillä, ja tämä luo pohjaa mekanismien ja kausaliteetin tarkastelulle myös tulevissa tutkimuksissa

Frontal-limbic brain processes in healthy individuals : environmental, epigenetic and behavioral correlates

Des altérations au niveau du cerveau ont été observées dans le circuit fronto-limbique (incluant le cortex préfrontal, le cortex cingulaire antérieur, hippocampe et amygdale), densément innervé avec la sérotonine, chez les individus souffrant de troubles affectifs. La relation entre les processus fronto-limbiques et le bien-être émotionnel peut être influencée par la génétique et l’environnement, ainsi que par leur interaction (GxE). Toutefois, les mécanismes spécifiques sous-tendant cette relation ne sont pas connus à ce jour. Un mécanisme physiologique sous-jacent l’effet GxE sur l’expression des gènes est la méthylation de l’ADN. Le but de cette thèse était, donc, d'étudier les effets environnementaux sur et la pertinence de la méthylation de l'ADN pour les processus fronto-limbiques chez des individus en bonne santé. Dans la première étude, l'association entre l'humeur au quotidien (évaluée à l’aide de la méthode de journal quotidien) et les processus cérébraux a été étudiée. Dans la deuxième étude, l'association entre la méthylation périphérique du gène du transporteur de la sérotonine [SLC6A4] (liée au fonctionnement émotionnel), provenant de différents tissus, et les processus cérébraux a été étudiée. Dans la troisième étude, nous avons examiné si l'association entre la méthylation périphérique du gène SLC6A4 et les processus cérébraux était indépendante de la variation génétique (en utilisant un échantillon de jumeaux homozygotes). Sommairement, l'humeur négative et positive était positivement associée à la connectivité fonctionnelle au repos entre le cortex cingulaire postérieur et antérieur. La méthylation du gène SLC6A4 était positivement associée au volume cortical préfrontal lorsqu'elle était dérivée du sang, de la salive et des cellules buccales. La méthylation du gène SLC6A4 dérivée des cellules buccales était également positivement associée au volume cortical antérieur cingulaire et à la connectivité fonctionnelle au repos entre les régions pariétales et le cortex cingulaire antérieur. Aussi, la méthylation périphérique du gène SLC6A4 était positivement associée à l'activité corticale orbitofrontale ainsi qu'à la connectivité fonctionnelle entre l’amygdale, le cortex orbitofrontal et le cortex cingulaire antérieur en réponse à des stimuli émotionnels négatifs, indépendamment de la séquence d'ADN des individus. Dans l'ensemble, les résultats actuels pourraient indiquer que la fonction et la structure cérébrale dans les régions fronto-limbiques, particulièrement dans le cortex cingulaire antérieur et préfrontal, sont positivement associées à l'humeur dans la vie quotidienne et à la méthylation périphérique du gène SLC6A4 chez des individus en bonne santé. En outre, la relation entre ces processus fronto-limbiques et la méthylation périphérique du gène SLC6A4 serait largement sous influence de l’environnement. Aussi, les résultats actuels suggèrent que les cellules buccales constitueraient un tissu préférable pour étudier la méthylation du gène SLC6A4 et les processus neuraux apparentés. Des études supplémentaires sont nécessaires pour valider ces résultats auprès de populations cliniques ou chez les individus exposés à des conditions environnementales différentes.Neural alterations have been observed in the frontal-limbic circuitry (including the prefrontal cortex, the anterior cingulate cortex, the hippocampus and the amygdala), densely innervated with serotonin, in the individuals with affective disorders. Relationship between the frontal-limbic processes and emotional well-being is affected by the genetics and the environment as well as by their interaction (GxE). Yet, the specific mechanisms are not known to this day. The aim of the present thesis was to study the environmental effects on and the relevance of DNA methylation (a physiological mechanism underpinning the GxE influences on gene expression) for the frontal-limbic brain processes in healthy individuals. In the first study, association between the daily-life mood (assessed using a daily diary method) and the brain processes was studied. In the second study, association between the peripheral DNA methylation in the serotonin transporter [SLC6A4] gene (linked to emotional functioning), derived from different tissues, and the brain processes was examined. In the third study, we examined whether the association between the peripheral SLC6A4 gene methylation and the brain processes was independent of the genetic variation (using a monozygotic twin sample). Briefly, daily-life negative and positive mood was positively associated with the resting-state functional connectivity between posterior and anterior cingulate cortices. The SLC6A4 gene methylation was positively associated with the prefrontal cortical volume when derived from blood, saliva and buccal cells; buccal-derived SLC6A4 gene methylation was also found to be positively associated with the anterior cingulate cortical volume and the resting-state functional connectivity between parietal areas and the anterior cingulate cortex. The peripheral SLC6A4 gene methylation was also positively associated with the orbitofrontal cortical activity as well as with the functional connectivity between the amygdala, the orbitofrontal and the anterior cingulate cortices in response to negative emotional stimuli, regardless of individuals’ DNA sequence. Overall, current findings might indicate that brain function and structure in the frontal-limbic regions, particularly in the anterior cingulate and the prefrontal cortices, are positively associated with the daily-life mood and the peripheral SLC6A4 gene methylation in healthy individuals. Additionally, the relationship between these frontal-limbic processes and peripheral SLC6A4 gene methylation appear to be largely driven by the environmental influences. Also, current results suggest that buccal cells may be a suitable peripheral tissue for studying the SLC6A4 gene methylation and its related neural processes. Future studies are necessary to validate these results in the clinical population as well as in the individuals exposed to differential environmental conditions

Becoming dad: Exploring the neurobiology of the transition into fatherhood

Item does not contain fulltextVrije Universiteit Amsterdam, 22 juni 2021Promotores : Bakermans-Kranenburg, M.J., Schuengel, C. Co-promotor : Riem, M.M.E.177 p

Early-Life Adversities and Neurocognitive Outcomes:An Epidemiological Study

This thesis is the compilation of studies that assessed stress and adversity using different approaches, and investigated the relation between adversities and early‑life stress with subsequent neurocognitive outcomes in the general population. This thesis also includes studies that addressed the role of protective factors, and the interplay between adversity and multiple protective factors in relation to brain morphology. Data from the population‑based Generation R Study, and the high‑risk Mannheim Study of Children at Risk were used in the studies presented here

Lead and crime: an ecological study between lead contaminated topsoil and violent crime.

Lead is a known neurotoxicant. Human exposure to lead comes primarily through environmental exposures, including remnant lead paint, lead contaminated topsoil and lead contaminated water. Prenatal and early life lead exposure has been associated with numerous neurocognitive and neuropsychiatric disorders. This dissertation presents findings from an ecological study which evaluated the geospatial association between topsoil lead content and the incidence of FBI designated violent crime in Jefferson County, Kentucky. A total of 412 topsoil samples were collected along roadways (n=300) and from Louisville Metro Parks (n=112). Jefferson County crime data was obtained from the Louisville Metro Police Department – Crime Information Center. Shared areas of higher than expected rates of FBI designated violent crime was designated as the Study Area. Three Control Areaswere established based upon their low to expected rates of violent crime. The Control Areas were located northeast, southeast and southwest of the Study Area. Spatial Error Model was used to compare topsoil lead content between the Study Areaand the threeControl Areas. A Bayesian sparse spatial generalized linear mixed model (SGLMM) was used to evaluate the geospatial association between violent crime and topsoil lead content while controlling for eight pertinent census-tract-level covariates. Spatial Error Model results showed that the Study Areahad an approximate 8-fold increase in topsoil lead content compared to the referent Control Area. Unadjusted SGLMM, found that every 100-unit increase in topsoil lead content was associated with a 62 percent increased risk for violent crime events per census tract (RR=1.62, 95% CI:1.59, 1.64). The full SGLMM, which controlled for eight census-tract-level covariates, found that every 100-unit increase in topsoil lead content was associated with a 5 percent increased risk for violent crime events per census tract (RR=1.05, 95% CI: 1.03, 1.08). The results of this study are based upon an ecological study and should be interpreted with caution. However, these findings provide a rationale for the design of future studies aimed at exploring the relationship between lead poisoning and subsequent criminality

Adverse mental health and educational outcomes in offspring of parents with mental health problems

This thesis investigated the risk of psychiatric disorders and symptoms and adverse educational outcomes in offspring of parents with mental health problems. The data for this thesis came from both primary (longitudinal birth cohort data) and secondary (published studies). Findings suggested that, after adjusting for potential confounders, parental mental health problems were associated with increased risk of a wide range of mental health problems in the offspring during childhood, adolescence, and young adulthood