David Marcus - US grants

[unreadable] DESCRIPTION (provided by applicant): ADHD is a common childhood disorder, affecting roughly 7% of school-aged children. Children diagnosed with ADHD are at risk for academic underachievement, peer rejection, elevated family discord, serious conduct problems, and substance abuse. Although ADHD is one of the most studied childhood disorders, research on its latent structure is in its infancy. One primary question to be explored regarding the latent structure is whether ADHD exists on a continuum or whether it is a unique/discrete condition The long-range goal is to refine the characterization of the phenotypal nature of ADHD. The objective of this application is to determine the latent structure of ADHD using indicators drawn from the NICHD Study of Early Child Care and Youth Development. These indicators will be analyzed using both Paul Meehl's taxometric procedures and factor mixture modeling (FMM). The taxometric analyses will yield dimensional or taxonic (i.e., categorical) results, whereas the FMM analyses can also model various combined structures (e.g., dimensions nested within categories, qualtitatively distinct subtypes). The first specific aim of the study will be to determine the latent structure of ADHD through taxometric and FMM analyses. The second specific aim will be to examine the relations between ADHD and such associated variables as conduct problems, reading difficulties, negative affect, and child-rearing environment, which will help to establish concurrent validity for the latent structure of ADHD. The central hypothesis is that the latent structure of ADHD is primarily unidimensional (i.e., exists on a continuum with quantifiable differences between individuals in the population). Ultimately, determining the latent structure of ADHD will (a) help to refine the diagnostic criteria for ADHD, (b) aid with the development of more sensitive ADHD assessment instruments, (c) have important implications for understanding the etiology of ADHD, and (d) contribute to the development of optimal treatments for children with ADHD. ADHD is a common childhood disorder that is associated with a variety of negative outcomes including academic underacheivement and substance abuse. The proposed study will help determine whether ADHD exists on a continuum or is a discrete disorder, and these findings will have implications for the understanding, diagnosis, and treatment of this condition. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION: Project Summary State of the art diagnostic assessment procedures for externalizing disorders of childhood (i.e., ADHD and the disruptive behavior disorders) rely on reports from multiple informants (e.g., parents and teachers), often using multiple measures of the same construct, raising the challenge of how to interpret discrepant scores. Researchers and clinicians often use idiosyncratic decision rules for weighing the various reports, which is inconsistent with the recent attention and emphasis on evidence based assessment (EBA). By quantifying the degree of measurement consistency across types of raters, Generalizability Theory (GT) can provide an empirical basis for interpreting the results from multiple informants. Therefore, a GT study of the measurement of externalizing disorders can make a significant contribution toward the goal of EBA. The long- range goal is to maximize the measurement consistency of childhood externalizing disorders. The objective of this application is to quantify the degree of measurement error associated with parent and teacher ratings of childhood externalizing disorders using data for a community sample from the NICHD Study of Early Child Care and Youth Development (SECCYD) and for an archived clinical sample from The University of Alabama at Birmingham. These data are ideal, because they allow for multiple facets of measurement error that can be quantified by GT analyses. The first specific aim of this study is to partition the error variance in reports of externalizing symptoms across items, rater type, and grade (i.e., measurement occasion), as well as the interactions among these three facets. The second specific aim is to generate reliability estimates (Generalizability and Dependability coefficients) that incorporate all relevant sources of error. The third specific aim is to determine the generalizability of the various sources of information about these externalizing symptoms. All analyses will be conducted simultaneously for both ADHD and ODD behaviors in a multivariate analysis. Analyses will be replicated (for only one measurement occasion) with a clinical sample. The rationale for the study is that partitioning the error variance due to items, rater type, and grade will (a) determine which externalizing disorder (ADHD or ODD) are most reliably assessed by which informants, at which times, and thus (b) contribute to the further development of evidence based assessment. PUBLIC HEALTH RELEVANCE: Childhood externalizing disorders are linked to negative consequences and thus accurate assessment and diagnosis is critical. One of the major challenges of such an assessment is resolving how to interpret discrepant scores from different sources. The proposed study will help determine the best way to integrate assessment data from multiple sources for use in the diagnosis of externalizing disorders, which will contribute to the further development of evidence based assessment.

PROJECT SUMMARY Stress exposure is ubiquitous risk factor for the development of negative emotional states and neuropsychiatric disorders such as anxiety, depression, and post-traumatic stress disorder (PTSD). However, a causal link between stress-induced neuropathologies and resultant pathological behavioral states remains elusive. There is significant evidence to suggest that stress induces a wide variety of morphological and neurochemical adaptions in the prelimbic component of the medial prefrontal cortex (plPFC), a key nodal structure that is highly implicated in the top down regulation of emotional behavior. Indeed, susceptibility to the depressive effects of traumatic stress exposure is correlated with synaptic potentiation within this region. Interestingly, the anxiolytic effects of cannabinoid compounds are primarily mediated by activation of CB1 receptors on glutamatergic axon terminals within the mPFC. Stress itself dynamically alters endocannabinoid (eCB) signaling within the mPFC, as stress exposure induces a dramatic increase in levels of the EC ligand 2- AG in the mPFC, which is purported to represent an adaptive coping response that buffers against the negative physiological effects induced by stress exposure. However, it is completely unknown what neural pathways are modulated by eCBs to elicit this buffering effect on stress-induced behavioral pathologies. In our studies, we are looking at the projections to the plPFC from the Basolateral Amygdala (BLA), a brain region that has been highly implicated in the pathophysiology of affective disorders and PTSD. The BLA sends glutamatergic projections to the plPFC, and also receives reciprocal glutamatergic input from the plPFC. Using optogenetic projection targeting techniques combined with retrograde labeling of plPFC cells, we gain both specificity of input to the plPFC but also specificity of output of plPFC cells projecting to the BLA. In order to understand the role that eCB signaling plays in buffering against stress induced psychopathologies in the BLA- plPFC circuit, we have developed a behavioral model that separates mice into stress-susceptible and stress- resilient groups. The current proposal will aim to answer two critical open questions: Does eCB signaling in the BLA-plPFC circuit represent a resiliency factor that blunts stress-induced behavioral pathology? Can we experimentally induce stress susceptibility by impairing eCB signaling within BLA-plPFC reciprocal circuits? Using state of the art viral mediated gene transfer approaches and conditional gene knockout animals, we aim to understand the role of eCB signaling within the BLA-plPFC circuits in conferring resiliency to stress. These experiments represent the first investigation of eCB signaling in a reciprocal glutamatergic circuit. This will enhance are understanding of the pathophysiology of anxiety and mood disorders, as well as reveal a putative target for the anxiolytic effects of cannabinoid agonists. This proposal also constitutes a rigorous technical training plan, in which I will learn and refine skills related to stereotaxic surgery, whole-cell electrophysiology, immunohistochemistry, and animal behavior.