Neurobiological Mechanisms of Risk for Psychopathology in Adolescents Exposed to Childhood Adversity

Childhood adversity (CA) exerts a deleterious toll on mental health, contributing to population-wide disparities in educational attainment, economic productivity and responsible citizenship (Shonkoff et al., 2012). The past decade has witnessed a burgeoning interest in how exposure to adversity affects neurobiological development, thereby representing one pathway through which these experiences become developmentally embedded. However, our knowledge of these intervening processes currently remains limited. This dissertation examines neurobiological mechanisms linking childhood adversity with adolescent psychopathology, a critical step for developing effective prevention and intervention efforts supporting at-risk youth. In Study 1, I explore the differential impact of threat (exposures that involve traumatic risks to the safety of the child, as with abuse) and deprivation (exposures that involve the absence of expected environmental inputs, as with neglect or poverty) on physiological reactivity to stress and psychopathology. Although both threat and deprivation were associated with greater psychopathology, only threat exposures were mediated by changes in physiological reactivity. These findings underscore the importance of distinguishing between different forms of confounded adversities, and highlight the potential value of targeting interventions based on disorder etiology. In Study 2, I use a longitudinal design to identify whether neural structure mediates the association between childhood maltreatment and psychiatric disorders. Maltreatment was associated with reduced cortical thickness in prefrontal and temporal cortex, and these differences prospectively predicted psychopathology two years later. Identifying pre-clinical, transdiagnostic indicators of vulnerability is likely to have important ramifications for the field of preventative psychiatry, facilitating intervention efforts. Finally, in Study 3, I explore whether adolescents’ inhibitory control of threatening stimuli is moderated by maltreatment exposure. Participants completed a Go/No-Go task, a standard measure of inhibitory control, for stimuli that had previously been paired with an aversive sound (CS+) and those that had not (CS-). Contrary to hypotheses, inhibitory control was not impaired for the CS+ compared to the CS-, and this effect did not differ by maltreatment exposure. However, maltreated adolescents’ inhibitory control for the CS+ predicted anti-social behavior symptoms. Further research is needed to examine the conditions for which learned threat compromises cognitive functioning in maltreated youth

Dimensions of Adversity, Physiological Reactivity, and Externalizing Psychopathology in Adolescence: Deprivation and Threat

Dysregulation of autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis function is a putative intermediate phenotype linking childhood adversity (CA) with later psychopathology. However, associations of CAs with ANS and HPA-axis function vary widely across studies. Here, we test a novel conceptual model discriminating between distinct forms of CA (deprivation and threat) and examine their independent associations with physiological reactivity and psychopathology

Childhood abuse and reduced cortical thickness in brain regions involved in emotional processing

Alterations in gray matter development represent a potential pathway through which childhood abuse is associated with psychopathology. Several prior studies find reduced volume and thickness of prefrontal (PFC) and temporal cortex regions in abused compared to non-abused adolescents, although most prior research is based on adults and volume-based measures. The current study tests the hypothesis that child abuse, independent of parental education, predicts reduced cortical thickness in prefrontal and temporal cortices as well as reduced gray mater volume (GMV) in subcortical regions during adolescence

Neurobehavioral Markers of Resilience to Depression amongst Adolescent Exposed to Child Abuse

Childhood maltreatment is strongly associated with depression, which is characterized by reduced reactivity to reward. Identifying factors that mitigate risk for depression in maltreated children is important for understanding etiological links between maltreatment and depression as well as improving early intervention and prevention. We examine whether high reward reactivity at behavioral and neurobiological levels is a marker of resilience to depressive symptomology in adolescence following childhood maltreatment. A sample of 59 adolescents (21 with a history of maltreatment; Mean Age = 16.95 years, SD = 1.44) completed an fMRI task involving passive viewing of emotional stimuli. BOLD signal changes to positive relative to neutral images were extracted in basal ganglia regions of interest. Participants also completed a behavioral reward-processing task outside the scanner. Depression symptoms were assessed at the time of the MRI and again 2 years later. Greater reward reactivity across behavioral and neurobiological measures moderated the association of maltreatment with baseline depression. Specifically, faster reaction time (RT) to cues paired with monetary reward relative to those unpaired with reward and greater BOLD signal in the left pallidum was associated with lower depression symptoms in maltreated youth. Longitudinally, greater BOLD signal in the left putamen moderated change in depression scores over time, such that higher levels of reward response were associated with lower increases in depression over time among maltreated youths. Reactivity to monetary reward and positive social images, at both behavioral and neurobiological levels, is a potential marker of resilience to depression among adolescents exposed to maltreatment. These findings add to a growing body of work highlighting individual differences in reactivity to reward as a core neurodevelopmental mechanism in the etiology of depression

Entropy in the Classical and Quantum Polymer Black Hole Models

We investigate the entropy counting for black hole horizons in loop quantum gravity (LQG). We argue that the space of 3d closed polyhedra is the classical counterpart of the space of SU(2) intertwiners at the quantum level. Then computing the entropy for the boundary horizon amounts to calculating the density of polyhedra or the number of intertwiners at fixed total area. Following the previous work arXiv:1011.5628, we dub these the classical and quantum polymer models for isolated horizons in LQG. We provide exact micro-canonical calculations for both models and we show that the classical counting of polyhedra accounts for most of the features of the intertwiner counting (leading order entropy and log-correction), thus providing us with a simpler model to further investigate correlations and dynamics. To illustrate this, we also produce an exact formula for the dimension of the intertwiner space as a density of "almost-closed polyhedra".Comment: 24 page

Sensitive periods for the effect of child maltreatment on psychopathology symptoms in adolescence

Introduction: Child maltreatment is among the strongest risk factors for mental disorders. However, little is known about whether there are ages when children may be especially vulnerable to its effects. We sought to identify potential sensitive periods when exposure to the 2 most common types of maltreatment (neglect and harsh physical discipline) had a particularly detrimental effect on youth mental health. Methods: Data came from the Future of Families and Child Wellbeing Study (FFCWS), a birth cohort oversampled from “fragile families” (n=3,474). Maltreatment was assessed at 3, 5, and 9 years using an adapted version of the Parent-Child Conflict Tactics Scales (CTS-PC). Using least angle regression, we examined the relationship between repeated measures of exposure to maltreatment on psychopathology symptoms at age 15 (Child Behavior Checklist; CBCL/6-18). For comparison, we evaluated the strength of evidence to support the existence of sensitive periods in relation to an accumulation of risk model. Results: We identified sensitive periods for harsh physical discipline, whereby psychopathology symptom scores were highest among girls exposed at age 9 (r2=0.67 internalizing symptoms; r2=1% externalizing) and among boys exposed at age 5 (r2=0.41%). However, for neglect, the accumulation of risk model explained more variability in psychopathology symptoms for both boys and girls. Conclusion: Child maltreatment may have differential effects based on the child’s sex, type of exposure, and the age it occurs. These findings provide additional evidence for clinicians assessing the benefits and drawbacks of screening efforts and point towards mechanisms driving increased vulnerability to psychopathology

What life course theoretical models best explain the relationship between exposure to childhood adversity and psychopathology symptoms: Recency, accumulation, or sensitive periods?

Copyright © Cambridge University Press 2018Â. Background Although childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship.Methods Prospective data came from the Avon Longitudinal Study of Parents and Children (n = 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association.Results Recency was the best fitting theoretical model for the effect of physical/sexual abuse (girls r2 = 2.35%; boys r2 = 1.68%). Both recency (girls r2 = 1.55%) and accumulation (boys r2 = 1.71%) were the best fitting models for caregiver physical/emotional abuse. Sensitive period models were chosen alone (parent legal problems in boys r2 = 0.29%) and with accumulation (financial stress in girls r2 = 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22-1.18).Conclusions Child psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity

Root traits and arbuscular mycorrhiza on perennial grasses exposed to defoliation after a controlled burning

Plant competition for soil resources is common in semiarid rangelands. Plants have various, alternative mechanisms to deal with soil resource acquisition. They include (1) length, weight and proliferation of roots, (2) root length density, and (3) root colonization by arbuscular mycorrhiza. In rangelands of Argentina, plants are exposed to herbivory after natural fires. As a result, knowledge on how these disturbances impact root traits is important for outlining guidelines focused on rangeland management and improvement. Our aim was to analyze the effects of defoliation after a controlled burning on root traits (1) to (3) on two preferred (Poa ligularis and Nassella tenuis) and one unpreferred (Amelichloa ambigua) perennial grasses. Applied treatments did not affect neither root length nor percentage colonization by arbucular mycorrhiza. The smaller diameter and greater root length found in P. ligularis might contribute to explain its lower root mycorrhizal colonization in comparison to A. ambigua and N. tenuis, respectively. The greatest root length and weight, on P. ligularis will contribute to explain the already known greater competitive ability in this than in the other two study species. Our results suggest that defoliating P. ligularis after fire would not compromise its competitive ability, thus contributing to rangeland management.En pastizales semiáridos, la competencia por los recursos subterráneos es una de las principales formas de competencia entre plantas. Las plantas poseen varios mecanismos alternativos para la adquisición de los recursos del suelo. Éstos incluyen (1) la longitud, peso y proliferación radical, (2) la densidad de longitud de raíces y (3) la colonización del sistema radical por hongos micorrízicos arbusculares. En los pastizales de Argentina las plantas están expuestas a herbivoría luego de fuegos naturales. En consecuencia, resulta crucial conocer cómo impactan dichos disturbios sobre los atributos radicales, con el objeto de emplearlos como herramientas de manejo para hacer un uso sustentable de estos ecosistemas. El objetivo del estudio fue analizar el efecto de la defoliación luego de una quema controlada sobre los parámetros subterráneos mencionados (1 a 3), en dos especies deseables (Poa ligularis y Nassella tenuis) y una indeseable (Amelichloa ambigua). Los tratamientos aplicados no afectaron la longitud radical ni la colonización por hongos micorrízicos arbusculares. El menor diámetro y la mayor longitud radical de P. ligularis, contribuyeron a explicar la menor colonización radical de esta especie respecto de A. ambigua y N. tenuis, respectivamente. Los resultados encontrados sugieren que la defoliación de P. ligularis luego de una quema controlada no comprometería la habilidad competitiva de esta especie, contribuyendo al mejoramiento de los pastizales.Artículo publicado en Phyton, International Journal of Experimental Botany (2018) 87: 51-5

The NAMPT inhibitor FK866 reverts the damage in spinal cord injury

<p>Abstract</p> <p>Background</p> <p>Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting.</p> <p>Methods</p> <p>We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI.</p> <p>Results</p> <p>Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-α, IL-1β, PAR, NAMPT, Bax, MPO activity, NF-κB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-α, IL-1β, Bax expression and NF-κB activity.</p> <p>We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866.</p> <p>Conclusions</p> <p>Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.</p