The Oregon ADHD-1000: A new longitudinal data resource enriched for clinical cases and multiple levels of analysis.

The fields of developmental psychopathology, developmental neuroscience, and behavioral genetics are increasingly moving toward a data sharing model to improve reproducibility, robustness, and generalizability of findings. This approach is particularly critical for understanding attention-deficit/hyperactivity disorder (ADHD), which has unique public health importance given its early onset, high prevalence, individual variability, and causal association with co-occurring and later developing problems. A further priority concerns multi-disciplinary/multi-method datasets that can span different units of analysis. Here, we describe a public dataset using a case-control design for ADHD that includes: multi-method, multi-measure, multi-informant, multi-trait data, and multi-clinician evaluation and phenotyping. It spans > 12 years of annual follow-up with a lag longitudinal design allowing age-based analyses spanning age 7-19 + years with a full age range from 7 to 21. Measures span genetic and epigenetic (DNA methylation) array data; EEG, functional and structural MRI neuroimaging; and psychophysiological, psychosocial, clinical and functional outcomes data. The resource also benefits from an autism spectrum disorder add-on cohort and a cross sectional case-control ADHD cohort from a different geographical region for replication and generalizability. Datasets allowing for integration from genes to nervous system to behavior represent the "next generation" of researchable cohorts for ADHD and developmental psychopathology.

Longitudinal network model of the co-development of temperament, executive functioning, and psychopathology symptoms in youth with and without ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) is a common, chronic, and impairing disorder, yet presentations of ADHD and clinical course are highly heterogeneous. Despite substantial research efforts, both (a) the secondary co-occurrence of ADHD and complicating additional clinical problems and (b) the developmental pathways leading toward or away from recovery through adolescence remain poorly understood. Resolving these requires accounting for transactional influences of a large number of features across development. Here, we applied a longitudinal cross-lagged panel network model to a multimodal, multilevel dataset in a well-characterized sample of 488 children (nADHD=296) to test Research Domain Criteria initiative-inspired hypotheses about transdiagnostic risk. Network features included DSM symptoms, trait-based ratings of emotional functioning (temperament), and performance-based measures of cognition. Results confirmed that ADHD symptom domains, temperamental Irritability, and Working Memory are independent transdiagnostic risk factors for psychopathology based on their direct associations with other features across time. ADHD symptoms and working memory each had direct, independent associations with depression. Results also demonstrated tightly linked co-development of ADHD symptoms and temperamental Irritability, consistent with the possibility that this type of anger dysregulation is a core feature that is co-expressed as part of the ADHD phenotype for some children.

Increased Maternal Prenatal Adiposity, Inflammation, and Lower Omega-3 Fatty Acid Levels Influence Child Negative Affect.

OBJECTIVE: Increased maternal adiposity during pregnancy is associated with offspring risk for psychiatric disorders. Inflammation secondary to adiposity is believed to be an important mechanism through which this effect occurs. Although increased adiposity introduces risk, not all children of overweight mothers develop these problems. Gestational factors that modify this risk are not well-understood. If maternal increased adiposity exerts its effects on offspring outcomes by increasing inflammation in the gestational environment, then anti-inflammatory inputs such as omega-3 fatty acids may be one protective factor. The goal of this study was to investigate whether maternal pre-pregnancy body mass index (BMI) and omega-3 fatty acid levels independently and/or interactively predicted offspring infant negative affect, an early life marker of risk for psychopathology. METHODS: Data came from a prospective study of women recruited during pregnancy and their 6 month old infants (N = 62; 40% female). Maternal pre-pregnancy BMI was pulled from medical charts and third trimester omega-3 fatty acid concentrations were assessed in plasma. Child negative affect was assessed using observer- and maternal-ratings at 6 months of age. Maternal inflammation was indexed by third trimester plasma levels of interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1. RESULTS: Maternal pre-pregnancy BMI was associated with increased infant negative affect whereas eicosapentaenoic acid was associated with less infant negative affect. Maternal omega-3 fatty acid levels moderated the effect of BMI on infant negative affect, such that omega-3 fatty acids buffered children against the negative consequences of increased adiposity. Supporting the role of maternal inflammation in these associations, maternal BMI and omega-3 fatty acid levels interacted to predict maternal third trimester inflammation. Further, maternal inflammation was associated with increased infant negative affect. CONCLUSION: Results suggest that omega-3 supplementation during pregnancy may protect against offspring behavioral risk associated with increased maternal adiposity.

Maternal prenatal depression predicts infant negative affect via maternal inflammatory cytokine levels.

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.

Early identification of ADHD risk via infant temperament and emotion regulation: a pilot study.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is theorized to have temperamental precursors early in life. These are difficult to identify because many core features of ADHD, such as breakdowns in executive function and self-control, involve psychological and neural systems that are too immature to reliably show dysfunction in early life. ADHD also involves emotional dysregulation, and these temperamental features appear earlier as well. Here, we report a first attempt to utilize indices of emotional regulation to identify ADHD-related liability in infancy. METHODS: Fifty women were recruited in the 2nd trimester of pregnancy, with overselection for high parental ADHD symptoms. Measures of maternal body mass index, nutrition, substance use, stress, and mood were examined during pregnancy as potential confounds. Offspring were evaluated at 6 months of age using LABTAB procedures designed to elicit fear, anger, and regulatory behavior. Mothers completed the Infant Behavior Questionnaire about their child's temperament. RESULTS: After control for associated covariates, including maternal depression and prenatal stress, family history of ADHD was associated with measures of anger/irritability, including infant negative vocalizations during the arm restraint task (p = .004), and maternal ratings of infant distress to limitations (p = .036). In the regulation domain, familial ADHD was associated with less parent-oriented attention seeking during the still face procedure (p < .001), but this was not echoed in the maternal ratings of recovery from distress. CONCLUSIONS: Affective response at 6 months of age may identify infants with familial history of ADHD, providing an early indicator of ADHD liability. These preliminary results provide a foundation for further studies and will be amplified by enlarging this cohort and following participants longitudinally to evaluate ADHD outcomes.

Maternal high fat diet consumption during the perinatal period programs offspring behavior.

The environment that a developing offspring experiences during the perinatal period is markedly influenced by maternal health and diet composition. Evidence from both epidemiological studies and animal models indicates that maternal diet and metabolic status play a critical role in programming the neural circuitry that regulates behavior, resulting in long-term consequences for offspring behavior. Maternal diet and metabolic state influence the behavior of offspring directly by impacting the intrauterine environment and indirectly by modulating maternal behavior. The mechanisms by which maternal diet and metabolic profile shape the perinatal environment remain largely unknown, but recent research has found that increases in inflammatory cytokines, nutrients (glucose and fatty acids), and hormones (insulin and leptin) affect the environment of the developing offspring. Offspring exposed to maternal obesity and high fat diet consumption during development are more susceptible to developing mental health and behavioral disorders such as anxiety, depression, attention deficit hyperactivity disorder, and autism spectrum disorders. Recent evidence suggests that this increased risk for behavioral disorders is driven by modifications in the development of neural pathways involved in behavioral regulation. In particular, research indicates that the development of the serotonergic system is impacted by exposure to maternal obesity and high fat diet consumption, and this disruption may underlie many of the behavioral disturbances observed in these offspring. Given the high rates of obesity and high fat diet consumption in pregnant women, it is vital to examine the influence that maternal nutrition and metabolic profile have on the developing offspring.

Unraveling the mechanisms responsible for the comorbidity between metabolic syndrome and mental health disorders.

The increased prevalence and high comorbidity of metabolic syndrome (MetS) and mental health disorders (MHDs) have prompted investigation into the potential contributing mechanisms. There is a bidirectional association between MetS and MHDs including schizophrenia, bipolar disorder, depression, anxiety, attention-deficit/hyperactivity disorder, and autism spectrum disorders. Medication side effects and social repercussions are contributing environmental factors, but there are a number of shared underlying neurological and physiological mechanisms that explain the high comorbidity between these two disorders. Inflammation is a state shared by both disorders, and it contributes to disruptions of neuroregulatory systems (including the serotonergic, dopaminergic, and neuropeptide Y systems) as well as dysregulation of the hypothalamic-pituitary-adrenal axis. MetS in pregnant women also exposes the developing fetal brain to inflammatory factors that predispose the offspring to MetS and psychopathologies. Due to the shared nature of these conditions, treatment should address aspects of both mental health and metabolic disorders. Additionally, interventions that can interrupt the transfer of increased risk of the disorders to the next generation need to be developed. © 2013 S. Karger AG, Basel.

The Impact of Maternal High-Fat Diet Consumption on Neural Development and Behavior of Offspring.

Maternal diet and metabolic state are important factors in determining the environment experienced during perinatal development. Epidemiological studies and evidence from animal models provide evidence that a mother's diet and metabolic condition are important in programming the neural circuitry that regulates behavior, resulting in a persistent impact on the offspring's behavior. Potential mechanisms by which maternal diet and metabolic profile influence the perinatal environment include placental dysfunction and increases in circulating factors such as inflammatory cytokines, nutrients (glucose and fatty acids) and hormones (insulin and leptin). Maternal obesity and high-fat diet (HFD) consumption exposure during development have been observed to increase the risk of developing serious mental health and behavioral disorders including anxiety, depression, attention deficit hyperactivity disorder and autism spectrum disorder. The increased risk of developing these behavioral disorders is postulated to be due to perturbations in the development of neural pathways that regulate behavior, including the serotonergic, dopaminergic and melanocortinergic systems. It is critical to examine the influence that a mother's nutrition and metabolic profile have on the developing offspring considering the current and alarmingly high prevalence of obesity and HFD consumption in pregnant women.