Alexander J. Shackman - US grants

? DESCRIPTION (provided by applicant): Anxiety disorders and depression are common, costly, and often difficult to treat, underscoring the need to understand the biological mechanisms that confer elevated risk. Individuals with a neurotic-anxious (NA) disposition are particularly vulnerable to these debilitating emotional disorders during late adolescence and early adulthood. NA is a trait-like phenotype that is evident early in life, stable over time, heritable, and characterized by sustained levels of heightened anxiety in contexts where threat is uncertain, ambiguous, or remote. Although NA is among the most robust phenotypic risk markers for anxiety and depression, it remains unclear why individuals with elevated NA are more likely to experience emotional disorders. Recent work by our group and others suggests the hypothesis that elevated risk reflects alterations in the activity and functional connectivity f the brain networks supporting sustained anxiety. In particular, this work highlights the contributions of the bed nucleus of the stria terminalis (BNST) and cortical regions, such as the anterior insula (AI). Building on our productive track record of fMRI and ecological momentary assessment (EMA) research, our goal is to understand the contribution of sustained-anxiety circuitry to the development, intensification, and recurrence of clinically-significant internalizig symptoms using an innovative combination of advanced fMRI analytic techniques and longitudinal assessments of daily experience and clinical symptom dimensions. We will use well-established NA assays to phenotype >5,000 racially-diverse 18-19 year olds and enroll the full spectrum of phenotypic risk (without gaps), over-sampling those at greatest risk (120 high, 60 medium, 60 low NA; half female). At enrollment, fMRI will be used to probe brain networks involved in sustained as well as transient anxiety. Using EMA, daily experience will be intensively sampled at 0, 6, 24, and 30 months, enabling an unprecedented longitudinal assessment of mood, function, and pathology-promoting behaviors and affording the first opportunity to explore the real-world significance of NA-related intermediate phenotypes. Diagnoses, dimensional symptoms, and life stress will be assessed via gold-standard interview techniques at 0, 15, and 30 months. These data would enable us to: (1) discover the neural bases of phenotypic risk and develop risk (NA) biomarkers, (2) understand the contribution of the BNST, AI, amygdala, and other anxiety- sensitive circuitry to the future progression of stress-sensitive, clinically-significant internalizing symptoms and diagnoses, and (3) understand the contribution of sustained-anxiety circuitry to the emergence of pathology- promoting feelings and behaviors in daily life. These objectives are closely aligned with the NIMH Strategic Objectives and RDoC initiative. This project would provide a potentially transformative opportunity to identify the distributed neural networks most relevant to transdiagnostic risk and most predictive of internalizing symptoms, inform our understanding of etiology, and guide the development of novel translational models and more precise intervention strategies.

Nearly 50 million Americans smoke tobacco and smoking is the leading cause of premature death and disability in the US. Although the transition from tobacco use to nicotine dependence is associated with enduring changes in multiple motivational mechanisms, most neurobiological research has focused on reward- related systems. Very little attention has been devoted to understanding the brain circuits involved in withdrawal-related negative affect in humans. This is unfortunate?heightened anxiety is a hallmark of nicotine deprivation in both rodents and humans and there is compelling evidence that this evolutionarily-conserved feature of withdrawal powerfully motivates nicotine dependence and relapse. Mechanistic work in rodents and imaging work by our group suggests the hypothesis that withdrawal-potentiated anxiety reflects alterations in a neural circuit encompassing the bed nucleus of the stria terminalis (BNST), anterior insula (AI), and mid- cingulate cortex (MCC). But the relevance of this circuitry to withdrawal in humans is unexplored and remains unknown. Leveraging our team's unique multi-disciplinary expertise, the goal of this proposal is to use an innovative combination of advanced fMRI analytic techniques and mobile phone-based ecological momentary assessment (EMA) to understand, for the first time, the relevance of anxiety-related brain circuits to chronic tobacco use and acute nicotine withdrawal in abstinent smokers. fMRI will be used to assay anxiety-related activation and functional connectivity in well matched groups of 24-hour abstinent and non-abstinent tobacco smokers (n=36/group; half female). EMA will be used to assay stressor exposure, negative affect, smoking urge/craving, alcohol/substance use, and smoking for 14 days (5x/day), including the 24-hour period of withdrawal immediately prior to the fMRI session. These data would enable us to systematically understand the relevance of anxiety-related brain circuits to: (1) acute nicotine withdrawal and (2) clinically-relevant features of mood and behavior in the real world. These objectives are closely aligned with the NIDA Strategic Plan. Addressing the first objective would afford an unprecedented opportunity to examine the translational relevance of prominent neurobiological models of addiction, guide the development of bidirectional translational models of nicotine dependence, identify new biological targets at the circuit level, and inform the develop of novel cessation aids. Addressing the second objective would refine our understanding of etiology, provide new targets for behavioral therapy, and inform the development of mobile phone-based interventions. Understanding the role of anxiety-related brain circuits in withdrawal is critical for efforts aimed at reducing the tremendous suffering and economic burden caused by tobacco dependence.

Paranoid ideation?the mistaken belief that intentional harm is likely to occur?spans a continuum, from mild suspicion to persecutory delusions. Among patients with schizophrenia and other psychosis disorders, elevated levels of paranoia are common, debilitating, and challenging to treat. The cues (public environments, strangers) and processes (anxiety) that promote paranoia have grown increasingly clear, but the brain bases of these pathways are unknown, thwarting the development of mechanistic models and, ultimately, the development of more effective or tolerable biological interventions. Leveraging our team?s unique multidisciplinary expertise and productive track record of NIH-sponsored research, this project will use an innovative combination of paranoia assessments, advanced neuroimaging techniques, and smartphone-based experience sampling to clarify the factors governing paranoia. We will enroll the full spectrum of paranoia without gaps or discontinuities?including psychosis patients with frank persecutory delusions and matched community controls. These data will allow us to rigorously examine the hypothesized contribution of brain circuits responsible for triggering anxiety and evaluating the threat potential of everyday social cues, such as faces. Integrating neuroimaging measures with experience-sampling data will enable us to extend these insights to the real world?a key step to establishing therapeutic relevance?for the first time. It has become increasingly clear that categorical psychiatric diagnoses (e.g. schizophrenia) present significant barriers to understanding pathophysiology. Our focus on dimensional measures of paranoia overcomes many of these barriers and dovetails with the National Institute of Mental Health?s Strategic Objectives and Research Domain Criteria (RDoC) initiative. This work would provide a potentially transformative opportunity to test and refine theory, deepen our understanding of etiology, guide the development of new translational models, discover new treatment targets, and provide an integrative biopsychosocial framework for unifying research across investigators, approaches, and scholarly guilds.