Challenges in researching the immune pathways between early life adversity and psychopathology

AbstractExposure to childhood adversity is a critical risk factor for the development of psychopathology. A growing field of research examines how exposure to childhood adversity is translated into biological risk for psychopathology through alterations in immune system functioning, most notably heightened levels of inflammation biomarkers. Though our knowledge about how childhood adversity can instantiate biological risk for psychopathology is growing, there remain many challenges and gaps in the field to understand how inflammation from childhood adversity contributes to psychopathology. This paper reviews research on the inflammatory outcomes arising from childhood adversity and presents four major challenges that future research must address: (a) the measurement of childhood adversity, (b) the measurement of inflammation, (c) the identification of mediators between childhood adversity and inflammation, and (d) the identification of moderators of inflammatory outcomes following childhood adversity. We discuss synergies and inconsistencies in the literature to summarize the current understanding of the association between childhood adversity, a proinflammatory phenotype, and the biological risk for psychopathology. We discuss the clinical implications of the inflammatory links between childhood adversity and psychopathology, including possibilities for intervention. Finally, this review conclude by delineates future directions for research, including issues of how best to detect, prevent, and understand these “hidden wounds” of childhood adversity.

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Hair glucocorticoids are associated with childhood adversity, depressive symptoms and reduced global and lobar grey matter in Generation Scotland

Translational Psychiatry ◽

10.1038/s41398-021-01644-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Claire Green ◽

Aleks Stolicyn ◽

Mathew A. Harris ◽

Xueyi Shen ◽

Liana Romaniuk ◽

...

Keyword(s):

Hpa Axis ◽

Life Stress ◽

Early Life ◽

Childhood Adversity ◽

Later Life ◽

Early Life Adversity ◽

Brain Volumes ◽

Stable Measure ◽

Regional Brain ◽

Generation Scotland

AbstractHypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (βrange = −0.057 to −0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; βrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (β = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: β = −0.059, P = 0.043; nucleus accumbens: β = −0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.

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Targeting Parenting Quality to Reduce Early Life Adversity Impacts on Lifespan Cardiometabolic Risk

Frontiers in Psychology ◽

10.3389/fpsyg.2021.678946 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maria E. Bleil ◽

Susan J. Spieker ◽

Cathryn Booth-LaForce

Keyword(s):

Health Outcomes ◽

Early Life ◽

Cardiometabolic Risk ◽

Intervention Studies ◽

Cardiometabolic Disease ◽

Future Research ◽

Cardiometabolic Health ◽

Early Life Adversity ◽

Parenting Quality ◽

Family Based

Mounting evidence that early life adversity (ELA) exposures confer risk for cardiometabolic disease over the lifespan motivated this narrative review to examine parenting quality as a potential intervention target to reduce ELA exposures or mitigate their impact as a way of reducing or preventing cardiometabolic disease. We describe findings from the limited number of family-based intervention studies in ELA-exposed children that have tested parenting impacts on cardiometabolic health outcomes. We then describe the implications of this work and make recommendations for future research that will move this field forward.

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Association of BDNF Val66Met Polymorphism and Brain BDNF levels with Major Depression and Suicide

10.1101/233304 ◽

2017 ◽

Author(s):

Mariam M. Youssef ◽

Mark D. Underwood ◽

Yung-Yu Huang ◽

Shu-chi Hsiung ◽

Yan Liu ◽

...

Keyword(s):

Major Depression ◽

Early Life ◽

Childhood Adversity ◽

Anterior Cingulate ◽

Bdnf Expression ◽

Early Life Adversity ◽

Val66met Polymorphism ◽

Protein Levels ◽

Dorsolateral Prefrontal ◽

Bdnf Val66met Polymorphism

ABSTRACTBrain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depressive disorder (MDD) and suicide. Both are partly caused by early life adversity (ELA) and ELA reduces both BDNF protein and gene expression. This study examines the association of BDNF Val66Met polymorphism and brain BDNF levels with depression and suicide. We hypothesized that both MDD and ELA would be associated with the Met allele and lower brain BDNF levels. Such an association would be consistent with low BDNF mediating the effect of ELA on adulthood suicide and MDD. BDNF Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 non-suicides. Additionally, BDNF protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9; BA9), anterior cingulate cortex (ACC; BA24), caudal brainstem and rostral brainstem. The relationships between these measures and major depression, death by suicide and reported childhood adversity were examined. Depressed subjects had an excess of the Met allele and lower BDNF levels in ACC and caudal brainstem compared with non-depressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower BDNF levels in ACC were found in subjects who had been exposed to early life adversity and/or died by suicide compared to nonsuicide decedents and no reported childhood adversity. This study provides further evidence for low BDNF in major depression related to the BDNF met risk allele. Future studies should seek to determine how altered BDNF expression contributes to MDD and suicide.

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Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psycho-Social Stress

10.20944/preprints202104.0024.v1 ◽

2021 ◽

Author(s):

Sara B. Fernandes ◽

Neha D. Patil ◽

Sophie B. Meriaux ◽

Maud Theresine ◽

Fleur A.D. Leenen ◽

...

Keyword(s):

Immune System ◽

Immune Responses ◽

Nk Cells ◽

Early Life ◽

Social Stress ◽

Maternal Separation ◽

Economic Status ◽

Childhood Adversity ◽

Early Life Adversity ◽

Human Situation

Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD), the closest animal model available to the human situation, is known to similarly induce long lasting behavioural effects, to cause changes in the HPA axis and to have an impact in the immune system. Even though the immune responses to potential pathogens after early stress have been somehow documented, the mechanisms by which they occur are still not fully understood. Here, we have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells’ profile and response to target cell lines are significantly changed after childhood adversity. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. Altogether, these results lead us to conclude that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.

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Corticolimbic Circuit Structure Moderates an Association Between Early Life Stress and Later Trait Anxiety

10.1101/581926 ◽

2019 ◽

Author(s):

M. Justin Kim ◽

Madeline J. Farber ◽

Annchen R. Knodt ◽

Ahmad R. Hariri

Keyword(s):

Trait Anxiety ◽

Life Stress ◽

Early Life ◽

Emotional Reactivity ◽

Early Life Stress ◽

Childhood Adversity ◽

Structural Features ◽

Individual Variability ◽

Future Research ◽

Wide Range

AbstractChildhood adversity is associated with a wide range of negative behavioral and neurodevelopmental consequences. However, individuals vary substantially in their sensitivity to such adversity. Here, we examined how individual variability in structural features of the corticolimbic circuit, which plays a key role in emotional reactivity, moderates the association between childhood adversity and later trait anxiety in 798 young adult university students. Consistent with prior research, higher self-reported childhood adversity was significantly associated with higher self-reported trait anxiety. However, this association was attenuated in participants with higher microstructural integrity of the uncinate fasciculus and greater thickness of the orbitofrontal cortex. These structural properties of the corticolimbic circuit may capture a neural profile of relative resiliency to early life stress, especially against the negative effects of childhood adversity on later trait anxiety. More generally, our findings highlight the potential utility in the simultaneous consideration of qualitatively different brain structural measures in explaining complex behavioral associations in future research.

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Actor–Partner Effects of Childhood Disadvantage on Later Life Subjective Well-Being Among Individuals in Coresidential Unions

The Journals of Gerontology Series B ◽

10.1093/geronb/gbz150 ◽

2019 ◽

Vol 75 (6) ◽

pp. 1275-1285 ◽

Cited By ~ 1

Author(s):

Jack Lam

Keyword(s):

Early Life ◽

Male Partner ◽

Childhood Adversity ◽

Later Life ◽

Well Being ◽

Future Research ◽

Subjective Well Being ◽

Childhood Health ◽

Self Rated Health ◽

Childhood Disadvantage

Abstract Objectives Prior research on cumulative disadvantage has primarily focused on individuals’ own childhood adversity for their later-life outcomes. Nevertheless, partner’s childhood disadvantage may also shape respondent’s later-life well-being. Methods Drawing on a household-level dataset, I examine respondent’s own childhood adversity as well as their partner’s childhood adversity (poor childhood health, parental divorce, or father’s long-term unemployment) on respondent’s subjective well-being, at aged 50 and older. Results Findings from the actor-partner interdependence model (APIM) show poor childhood health of the male partner as associated with worse mental health and self-rated health of the female partner in later life. For both outcome measures, the partner effects were attenuated after adjusting for the female partner’s report of perceived social support. For self-rated health, adjusting for variation in the presence of a chronic illness and household income also attenuated the association. Discussion Partnered individuals are nested within a specific context, whereby stress and implications of early life disadvantage may be conceptualized at the couple-level. Future research that assesses how early life experiences of individuals may have implications for family members’ later-life well-being may be valuable.

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Childhood trajectories of anxiousness and disruptiveness explain the association between early-life adversity and attempted suicide

Psychological Medicine ◽

10.1017/s0033291712000438 ◽

2012 ◽

Vol 42 (11) ◽

pp. 2373-2382 ◽

Cited By ~ 24

Author(s):

B. Wanner ◽

F. Vitaro ◽

R. E. Tremblay ◽

G. Turecki

Keyword(s):

Mental Disorders ◽

Suicidal Behavior ◽

Early Life ◽

Suicide Attempts ◽

Childhood Adversity ◽

Externalizing Disorders ◽

Mediating Effect ◽

Early Life Adversity ◽

History Of ◽

Axis I

BackgroundSuicidal behavior is frequently associated with a history of childhood abuse yet it remains unclear precisely how early life adversity may increase suicide risk later in life. As such, our aim was to examine whether lifetime trajectories of disruptiveness and anxiousness trait dysregulation explain the association between childhood adversity and suicidal behavior; and moreover, to test the potential modifying effects of mental disorders on these associations.MethodA sample of 1776 individuals from a prospective school-based cohort followed longitudinally for over 22 years was investigated. We tested the influence of disruptiveness and anxiousness trajectories from age 6 to 12 years on the association between childhood adversity (i.e. sexual and physical abuse) and history of suicide attempts (SA) using logistic regression models. Both adolescent externalizing and internalizing Axis I disorders and gender were tested as potential modifiers of these associations.ResultsFour distinct longitudinal trajectories were identified for both disruptiveness and anxiousness. The high disruptiveness trajectory accounted for the association between childhood adversity and SA, but only for females. The high anxiousness trajectory also explained the association between adversity and SA; however, in this case it was not sex but mental disorders that influenced the potency of the mediating effect. More specifically, anxiousness fully explained the effect of adversity on SA in the presence of externalizing disorders, whereas in the absence of these disorders, this effect was significantly attenuated.ConclusionsThis study provides evidence that both disruptiveness and anxiousness play an important role in explaining the relationship between childhood adversity and SA.

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Differential Alterations in Resting State Functional Connectivity Associated with Depressive Symptoms and Early Life Adversity

Brain Sciences ◽

10.3390/brainsci11050591 ◽

2021 ◽

Vol 11 (5) ◽

pp. 591

Author(s):

Eleonora Fadel ◽

Heinz Boeker ◽

Matti Gaertner ◽

Andre Richter ◽

Birgit Kleim ◽

...

Keyword(s):

Depressive Symptoms ◽

Functional Connectivity ◽

Childhood Abuse ◽

Resting State ◽

Early Life ◽

Clinical Symptoms ◽

Future Research ◽

Resting State Functional Connectivity ◽

Early Life Adversity ◽

Depression Subtypes

Depression and early life adversity (ELA) are associated with aberrant resting state functional connectivity (FC) of the default mode (DMN), salience (SN), and central executive networks (CEN). However, the specific and differential associations of depression and ELA with FC of these networks remain unclear. Applying a dimensional approach, here we analyzed associations of FC between major nodes of the DMN, SN, and CEN with severity of depressive symptoms and ELA defined as childhood abuse and neglect in a sample of 83 healthy and depressed subjects. Depressive symptoms were linked to increased FC within the SN and decreased FC of the SN with the DMN and CEN. Childhood abuse was associated with increased FC within the SN, whereas childhood neglect was associated with decreased FC within the SN and increased FC between the SN and the DMN. Our study thus provides evidence for differential associations of depressive symptoms and ELA with resting state FC and contributes to a clarification of previously contradictory findings. Specific FC abnormalities may underlie specific cognitive and emotional impairments. Future research should link specific clinical symptoms resulting from ELA to FC patterns thereby characterizing depression subtypes with specific neurobiological signatures.

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Early Life Adversity and Adult Biological Risk Profiles

Psychosomatic Medicine ◽

10.1097/psy.0000000000000147 ◽

2015 ◽

Vol 77 (2) ◽

pp. 176-185 ◽

Cited By ~ 61

Author(s):

Esther M. Friedman ◽

Arun S. Karlamangla ◽

Tara L. Gruenewald ◽

Brandon Koretz ◽

Teresa E. Seeman

Keyword(s):

Early Life ◽

Risk Profiles ◽

Early Life Adversity ◽

Biological Risk

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827Early life influences on timing of menarche in racial/ethnic minority and immigrant women

International Journal of Epidemiology ◽

10.1093/ije/dyab168.039 ◽

2021 ◽

Vol 50 (Supplement_1) ◽

Author(s):

Ayana April-Sanders ◽

Parisa Tehranifar ◽

Erica Lee Argov ◽

Shakira Suglia ◽

Jasmine McDonald

Keyword(s):

Ethnic Minority ◽

Mentally Ill ◽

Early Life ◽

Childhood Adversity ◽

Reproductive Development ◽

Age At Menarche ◽

Early Life Adversity ◽

Early Menarche ◽

History Of ◽

Racial Ethnic

Abstract Background Early life adversity and infections may theoretically affect the timing and effort of reproductive development. We examined associations of childhood adversity and exposure to tonsillitis with age at menarche in women age 40-64 years. Methods A multi-ethnic cohort of 394 women reported on exposure to parental maltreatment and maladjustment during childhood (<18 years) and on any diagnosis of tonsillitis, an infection primarily acquired in early life and adolescence. We used linear and logistic regression models to examine the associations of cumulative/specific childhood adversity experience(s) and history of tonsillitis with average age at menarche and early onset of menarche (<12 years of age). Results The average age at menarche was 12.6 years, and was significantly lower for women who lived with a mentally ill caregiver (M = 12.4 (95% CI: 11.7-13.0)) and those with a history of tonsillitis (M = 12.6 (95% CI: 12.0-13.2)). In adjusted multivariable models, living with a mentally ill caretaker (RR = 1.5, 95% CI: 1.0-2.1) and a having a history of tonsillitis (RR = 1.7, 95% CI: 1.3-2.4) were associated with increased risk of early menarche compared with women without these exposures. Cumulative and other specific adversities were not statistically associated with early menarche. Conclusions These findings support growing evidence that early life experiences may influence reproductive development. Key messages Early life adversity related to living with mentally ill caretakers and a history of tonsillitis is associated with earlier menarche in racial/ethnic minority and immigrant women.

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