Objective: How best to capture heterogeneity in attention-deficit/hyperactivity disorder (ADHD) using biomarkers has been elusive. This study evaluated whether emotion reactivity and regulation ...provide a means to achieve this. Method: Participants were classified into three groups: children with ADHD plus low prosocial behavior (hypothesized to be high in callous/unemotional traits; n = 21); children with ADHD with age-appropriate prosocial behavior (n = 54); and typically developing children (n = 75). Children completed a task with four conditions: negative induction, negative suppression, positive induction, and positive suppression of affect. The task required children to view an emotion-laden film clip, while either facially mimicking (induction) or masking (suppression) the emotion of the main character. Parasympathetic and sympathetic nervous system activity were assessed via respiratory sinus arrhythmia (RSA) and cardiac pre-ejection period (PEP), respectively. Symptoms of anxiety, conduct, and oppositional defiant disorders were treated as covariates. Results: The ADHD-typical-prosocial group displayed atypically elevated parasympathetic reactivity (emotion dysregulation) during positive induction, along with increased sympathetic activity (elevated arousal) across conditions. In contrast, the ADHD-low-prosocial group displayed reduced parasympathetic reactivity and reduced sympathetic activity (low emotional arousal) across baseline and task conditions. Thus, both ADHD groups had altered patterns of autonomic functioning, but in two distinct forms. Conclusion: Although ADHD is heterogeneous clinically, results suggest that ADHD is also heterogeneous with regard to physiological indices of emotion and regulation. Future studies of emotion, regulation, and ADHD should take this into account. Further study of physiological responding in ADHD may yield clinically and etiologically distinct domains or groups. (Contains 2 figures and 3 tables.)
Psychopathology emerges from the dynamic interplay of physiological and mental processes and ecological context. It can be seen as a failure of recursive, homeostatic processes to achieve adaptive ...re-equilibrium. This general statement can be actualized with consideration of polygenic liability, early exposures, and multiunit (multi-"level") analysis of the psychological action and the associated physiological and neural operations, all in the context of the developmental exposome. This article begins by identifying key principles and clarifying key terms necessary to mental disorder theory. It then ventures a sketch of a model that highlights epigenetic dynamics and proposes a common pathways hypothesis toward psychopathology. An epigenetic perspective elevates the importance of developmental context and adaptive systems, particularly in early life, while opening the door to new mechanistic discovery. The key proposal is that a finite number of homeostatic biological and psychological mechanisms are shared across most risky environments (and possibly many genetic liabilities) for psychopathology. Perturbation of these mediating mechanisms leads to development of psychopathology. A focus on dynamic changes in these homeostatic mechanisms across multiple units of analysis and time points can render the problem of explaining psychopathology tractable. Key questions include the mapping of recursive processes over time, at adequate density, as mental disorders unfold across development.
General Scientific Summary
Mental disorders develop in the midst of complex processes. A focus on causal mechanism can benefit from a focus on regulatory processes and on common pathways of effect across multiple risks and conditions.
•Maternal prenatal depression was associated with greater infant negative affect.•The effect was specific to infant sadness, a risk factor for internalizing problems.•This association was mediated by ...increased 3rd trimester maternal cytokines.•This is the first human study to report such mediation by maternal inflammation.
Maternal depressive symptoms during pregnancy are associated with risk for offspring emotional and behavioral problems, but the mechanisms by which this association occurs are not known. Infant elevated negative affect (increased crying, irritability, fearfulness, etc.) is a key risk factor for future psychopathology, so understanding its determinants has prevention and early intervention potential. An understudied yet promising hypothesis is that maternal mood affects infant mood via maternal prenatal inflammatory mechanisms, but this has not been prospectively examined in humans. Using data from a pilot study of women followed from the second trimester of pregnancy through six months postpartum (N = 68) our goal was to initiate a prospective study as to whether maternal inflammatory cytokines mediate the association between maternal depressive symptoms and infant offspring negative affect. The study sample was designed to examine a broad range of likely self-regulation and mood-regulation problems in offspring; to that end we over-selected women with a family history or their own history of elevated symptoms of attention-deficit/hyperactivity disorder. Results supported the hypothesis: maternal pro-inflammatory cytokines during the third trimester (indexed using a latent variable that included plasma interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 concentrations as indicators) mediated the effect, such that higher maternal depressive symptoms were associated with higher maternal inflammation, and this mediated the effect on maternal report of infant negative affect (controlling for maternal affect during the infant period). This is the first human study to demonstrate that maternal inflammatory cytokines mediate the association between prenatal depression and infant outcomes, and the first to demonstrate a biological mechanism through which depressive symptoms impact infant temperament.
IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are believed to partially share genetic factors and biological influences. As the number of children ...with these diagnoses rises, so does the number of younger siblings at presumed risk for ADHD and ASD; reliable recurrence risk estimates within and across diagnoses may aid screening and early detection efforts and enhance understanding of potential shared causes. OBJECTIVE: To examine within-diagnosis sibling recurrence risk and sibling cross-aggregation of ADHD and ASD among later-born siblings of children with either disorder. DESIGN, SETTING, AND PARTICIPANTS: Using data extracted from medical records of 2 large health care systems in the United States, estimates of recurrence risk and cross-aggregation in later-born siblings of children with ADHD or ASD were compared with later-born siblings of children without these diagnoses. One data set included children seen between January 1, 1995, and December 31, 2013; the other included children born between January 1, 1998, and May 17, 2010. Participants included 15 175 later-born siblings of children with ADHD, ASD, and no known diagnosis. The study was conducted from October 2, 2017, to August 14, 2018. MAIN OUTCOMES AND MEASURES: Diagnoses of ASD or ADHD in the later-born sibling, ascertained from medical records, were the primary outcomes of interest; moderators included sex, gestational age, and maternal age. RESULTS: A total of 15 175 later-born siblings were classified by familial risk status based on the older child’s diagnostic status: ADHD risk (n = 730; male 51.92%), ASD risk (n = 158; male 48.10%), and no known risk (n = 14 287; male 50.73%). Compared with later-born siblings of children without ADHD or ASD, later-born siblings of children with ASD were more likely to be diagnosed with ASD (odds ratio OR, 30.38; 95% CI, 17.73-52.06) or ADHD in the absence of ASD (OR, 3.70; 95% CI, 1.67-8.21). Compared with later-born siblings of children without a diagnosis, later-born siblings of children with ADHD were more likely to be diagnosed with ADHD (OR, 13.05; 95% CI, 9.86-17.27) or ASD in the absence of ADHD (OR, 4.35; 95% CI, 2.43-7.79). CONCLUSIONS AND RELEVANCE: Later-born siblings of children with ASD or ADHD appear to be at elevated risk for the same disorder, but also of being diagnosed with the other disorder. These findings provide further support for shared familial mechanisms underlying ASD and ADHD, which may be useful for genetic and prospective developmental studies. Later-born siblings of children with ADHD or ASD should be monitored for both conditions.
Background
Clinical course in attention‐deficit/hyperactivity disorder (ADHD) is highly heterogeneous with respect to both core symptoms and associated features and impairment. Onset of comorbid ...anxiety and mood disorders during later childhood and adolescence is one critical aspect of divergent outcomes in ADHD. Characterizing heterogeneity in onset of anxiety and depression and identifying prospective predictors of these divergent courses may facilitate early identification of the children most at risk.
Methods
A total of 849 children recruited for a case–control study of ADHD development, aged 7–12 years at baseline, completed up to six annual waves of comprehensive clinical and cognitive assessment, including multi‐informant behavior ratings, parent semi‐structured clinical diagnostic interviews, and measures of executive function (EF). Latent class growth curve analyses (LCGAs) characterized patterns of anxiety and depression over time. Trajectories were predicted from baseline parent‐rated child temperament, lab‐measured child EF, coded parental criticism, and child‐reported self‐blame for inter‐parental conflict.
Results
Latent class growth curve analyses separately identified three trajectories for anxiety and three for depression: persistently high, persistently low, and increasing. Temperamental fear/sadness and irritability were independent predictors that interacted with family characteristics. Baseline parental criticism and self‐blame for inter‐parental conflict exerted influence but only in the context of low temperamental risk. Better baseline child working memory was associated with delayed onset of depression.
Conclusions
The interaction of baseline child emotional features with EF or family environment predicted divergent courses of both anxiety and depression from middle‐childhood to mid‐adolescence. Results suggest modifiable risk factors associated with prospective differences in long‐term outcomes.
Background: Prenatal problems are among theorized etiologies for child disruptive behavior problems. A key question concerns whether etiological contributors are shared across the broad range of ...disruptive psychopathology or are partially or largely distinct. Method: We examined prenatal smoking exposure and low birth weight as risk factors for attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) in a population-based longitudinal design from ages 6 to 17 years. Multiple informants were used, with emphasis on parent and teacher report for ADHD, parent-and self-report interview for ODD, and self-report interview for CD, in keeping with evidence about the most valid sources of information for these respective syndromes. Results: The association of prenatal smoking exposure with ADHD was highly confounded by family variables. In contrast, low birth weight independently predicted ADHD, even with family variables statistically controlled. The opposite pattern appeared for ODD and CD. Prenatal smoking exposure but not low birth weight predicted ODD independent of potential confounding variables. Prenatal smoking exposure also predicted CD. The effect on CD was via its effect on ODD. Conclusion: Prenatal smoking exposure may contribute to ODD and via that route to later CD, but does not have a specific association with ADHD in this sample. Findings have implications for distinct etiological contributors to these often comorbid aspects of the disruptive behavior domain. (Contains 4 tables.)
This review evaluates the diagnostic criteria for three of the most common disorders for which children and adolescents are referred for mental health treatment: attention deficit hyperactivity ...disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD). Although research supports the validity and clinical utility of these disorders, several issues are highlighted that could enhance the current diagnostic criteria. For ADHD, defining the core features of the disorder and its fit with other disorders, enhancing the validity of the criteria through the lifespan, considering alternative ways to form subtypes of the disorder, and modifying the age-of-onset criterion are discussed relative to the current diagnostic criteria. For ODD, eliminating the exclusionary criteria of CD, recognizing important symptom domains within the disorder, and using the cross-situational pervasiveness of the disorder as an index of severity are highlighted as important issues for improving classification. Finally, for CD, enhancing the current subtypes related to age of onset and integrating callous-unemotional traits into the diagnostic criteria are identified as key issues for improving classification.
The domains of self-regulation, self-control, executive function, inattention, and impulsivity cut across broad swathes of normal and abnormal development. Attention-deficit/hyperactivity disorder is ...a common syndrome that encompasses a portion of these domains. In the past 25 years research on attention-deficit/hyperactivity disorder has been characterized by dramatic advances in genetic, neural, and neuropsychological description of the syndrome as well as clarification of its multidimensional phenotypic structure. The limited clinical applicability of these research findings poses the primary challenge for the next generation. It is likely that clinical breakthroughs will require further refinement in describing heterogeneity or clinical/biological subgroups, renewed focus on the environment in the form of etiological events as well as psychosocial contexts of development, and integration of both with biological understanding.
Significance Noninvasive brain imaging holds great promise for expanding our capabilities of treating human neurologic and psychiatric disorders. However, key limitations exist in human-only studies, ...and the ability to use animal models would greatly advance our understanding of human brain function. Mice offer sophisticated genetic and molecular methodology, but correlating these data to functional brain imaging in the mouse brain has remained a major hurdle. This study is the first, to our knowledge, to use whole-brain functional imaging to show large-scale functional architecture with structural correlates in the mouse. Perhaps more important is the finding of conservation in brain topology and default network among rodents and primates, thereby clearing the way for a bridge measurement between human and mouse models.
Noninvasive functional imaging holds great promise for serving as a translational bridge between human and animal models of various neurological and psychiatric disorders. However, despite a depth of knowledge of the cellular and molecular underpinnings of atypical processes in mouse models, little is known about the large-scale functional architecture measured by functional brain imaging, limiting translation to human conditions. Here, we provide a robust processing pipeline to generate high-resolution, whole-brain resting-state functional connectivity MRI (rs-fcMRI) images in the mouse. Using a mesoscale structural connectome (i.e., an anterograde tracer mapping of axonal projections across the mouse CNS), we show that rs-fcMRI in the mouse has strong structural underpinnings, validating our procedures. We next directly show that large-scale network properties previously identified in primates are present in rodents, although they differ in several ways. Last, we examine the existence of the so-called default mode network (DMN)—a distributed functional brain system identified in primates as being highly important for social cognition and overall brain function and atypically functionally connected across a multitude of disorders. We show the presence of a potential DMN in the mouse brain both structurally and functionally. Together, these studies confirm the presence of basic network properties and functional networks of high translational importance in structural and functional systems in the mouse brain. This work clears the way for an important bridge measurement between human and rodent models, enabling us to make stronger conclusions about how regionally specific cellular and molecular manipulations in mice relate back to humans.
Clinical investigations of many neuropsychiatric disorders rely on the assumption that diagnostic categories and typical control samples each have within-group homogeneity. However, research using ...human neuroimaging has revealed that much heterogeneity exists across individuals in both clinical and control samples. This reality necessitates that researchers identify and organize the potentially varied patterns of brain physiology. We introduce an analytical approach for arriving at subgroups of individuals based entirely on their brain physiology. The method begins with Group Iterative Multiple Model Estimation (GIMME) to assess individual directed functional connectivity maps. GIMME is one of the only methods to date that can recover both the direction and presence of directed functional connectivity maps in heterogeneous data, making it an ideal place to start since it addresses the problem of heterogeneity. Individuals are then grouped based on similarities in their connectivity patterns using a modularity approach for community detection. Monte Carlo simulations demonstrate that using GIMME in combination with the modularity algorithm works exceptionally well--on average over 97% of simulated individuals are placed in the accurate subgroup with no prior information on functional architecture or group identity. Having demonstrated reliability, we examine resting-state data of fronto-parietal regions drawn from a sample (N = 80) of typically developing and attention-deficit/hyperactivity disorder (ADHD) -diagnosed children. Here, we find 5 subgroups. Two subgroups were predominantly comprised of ADHD, suggesting that more than one biological marker exists that can be used to identify children with ADHD based from their brain physiology. Empirical evidence presented here supports notions that heterogeneity exists in brain physiology within ADHD and control samples. This type of information gained from the approach presented here can assist in better characterizing patients in terms of outcomes, optimal treatment strategies, potential gene-environment interactions, and the use of biological phenomenon to assist with mental health.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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