2015 — 2018 |
Macnamara, Annmarie Eileen |
K23Activity Code Description: To provide support for the career development of investigators who have made a commitment of focus their research endeavors on patient-oriented research. This mechanism provides support for a 3 year minimum up to 5 year period of supervised study and research for clinically trained professionals who have the potential to develop into productive, clinical investigators. |
Brain-Behavior Markers of Negative Affectivity, Comorbidity in Anxiety Disorders @ University of Illinois At Chicago
? DESCRIPTION (provided by applicant): Anxiety disorders (ADs) may be more similar than different in terms of neural dysfunction. Examining phenotypic variability that is independent of specific diagnoses may help explicate fundamental biobehavioral substrates of psychopathology in the ADs, leading to improved classification and treatment. For instance, comorbidity in the ADs is common and is known to relate to severity and measures of emotional reactivity such as self-reported negative affectivity (NA), yet evidence of its underlying neurobiology is scarce. The primary goal of this K23 is to provide the candidate with training in brain (functional magnetic resonance imaging, fMRI) and behavior (eyeblink startle) measures of negative emotion processing, in order to launch the candidate's career as an independent clinical neuroscientist with expertise in the multi-level, neurobiological, dimensional analysis of emotional dysfunction in anxiety. The proposal has three components: 1) a mentorship team with complementary expertise, 2) didactics to fill gaps in the candidate's previous education and 3) hands-on experience critical to the candidate's growth. The research plan tests the utility of a dimensional transdiagnostic approach in linking neural and behavioral measures of dysregulated negative emotion processing to clinically relevant anxiety burden characterized by comorbidity load and self-reported NA. Participants in the proposed project will comprise 75 adults with a 'simple' phobia (specific phobia or performance-only social anxiety) recruited to fill 3 comorbidity load cells: 1) n = 25 with no comorbidity; 2) n = 25 with 1 other anxiety or depressive (AnxDep) disorder; and 3) n = 25 with 2 or more other AnxDep disorders, all compared to psychiatrically healthy controls (HCs, n = 25). This K23 leverages the recruitment infrastructure of mentor Phan's NIH-funded R01 (MH101497 [08/2013- 07/2017]) study, but is distinct practically (different tasks and scan sessions) and scientifically. Participants will undergo simultaneous fMRI and electromyographic (EMG) startle recording during: a) anticipation of; and b) response to aversive stimuli. Consonant with candidate's training goals in fMRI affective neuroscience and task design, startle methodology and their clinical application to dimensional constructs relevant to ADs, the project's aims are to: 1) examine the relationship between brain measures of negative emotion processing, comorbidity load and NA; 2) examine the relationship between behavioral (startle) measures of negative emotion processing, comorbidity load and NA; and 3) examine the interrelationships between brain and behavioral measures of negative emotion processing in relation to comorbidity load and NA. Comorbidity load, a marker of disease burden, may aid understanding of dimensional and categorical internalizing psychopathology. Through completion of this project and the coordinated training plan, the candidate will build upon her prior expertise in event-related potentials (ERPs) and anxiety to emerge as a multi-modal, neurobiological expert using complementary, layered methodologies (brain and peripheral psychophysiology) to close gaps between neurobiology and clinical profiles, in order to improve diagnosis and guide new treatments.
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0.958 |
2021 |
Macnamara, Annmarie Eileen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Harm-a: a Neurobiological Predictor of Comorbidity and Stress Reactivity in Anxiety Disorders
PROJECT SUMMARY Comorbidity in the anxiety disorders is common and strongly associated with poor outcomes, lower rates of remission, increased disability and higher rates of relapse. Yet despite its clinical relevance, clinicians are unsure how to treat comorbid anxiety patients, in part because it is unknown whether comorbid cases are marked by distinct pathophysiology, or whether they should simply be conceptualized as the 'sum of their parts' (i.e., multiple, separate clinical entities). Characterizing comorbid individuals as having multiple, independent, disease processes occludes understanding of synergistic, pathophysiological processes that may uniquely characterize highly comorbid patients. The current project focuses on a neural profile that corresponds to increased comorbidity load across the anxiety disorders and is routed in aberrant brain connectivity. This neural profile is comprised of increased alarm (heightened amygdala) and reduced motivated attention (attenuated late positive potential, LPP; an EEG measure of elaborated stimulus processing) to negative images, and is referred to as HARM-A (Heightened Alarm, Reduced Motivated Attention). Controlling for separate effects of alarm and motivated attention, preliminary data suggest that higher HARM-A is associated with (a) greater internalizing psychopathology; (b) higher rates of past comorbidity (controlling for current comorbidity) and (c) increased dysphoria 12-24 months later (controlling for baseline dysphoria). Those with higher HARM-A also showed aberrant connectivity between key nodes involved in threat detection and appraisal (amygdala-anterior cingulate cortex), as well as a stronger link between stress and negative affect. Therefore, HARM-A might underlie the worse outcome in comorbid anxiety cases, and may do so by increasing risk for negative affect generation following stressful events. The current project extends this preliminary work by examining negative emotion processing in 180 individuals, recruited to insure dimensionality on current and past internalizing symptoms. Participants will undergo 3 multi-level assessments (fMRI, EEG, clinical interview, self-report measures) over 24 months; at each assessment, participants will also complete 10 days of experience sampling assessments of stressful events and negative affect. The project will test a bidirectional model of HARM-A, in which HARM-A predicts increased future comorbidity load and higher scores on latent, transdiagnostic, internalizing psychopathology, which will in turn predict increased HARM-A (i.e., a mutually reinforcing ?spiral?). It will also assess the neurocircuitry that supports higher HARM-A and will use experience sampling data to test whether HARM-A predicts stronger linkage between stress exposure and subsequent negative affect. Finding that HARM-A is prospectively and reciprocally associated with worse internalizing psychopathology, delineating its neurocircuitry and elucidating its role in the linkage between stressors and negative affect would deliver a mechanistic explanation for greater disease burden in comorbid anxiety and provide a path forward for more etiologically tractable understanding of anxiety-related disorders, and for the development of targeted treatments.
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0.958 |