Michael R. Koenigs, Ph.D. - US grants

DESCRIPTION (provided by applicant): A key step in the development of more effective treatments for mood and anxiety disorders is to identify the brain circuits critically involved in the regulation of emotion. A predominant neurobiological model of emotion regulation, supported by animal and functional imaging data, is that ventromedial prefrontal cortex (vmPFC) mediates the regulation of negative affect through top-down inhibition of the amygdala. A corollary prediction of this model is that the loss of vmPFC function would result in disinhibition of the amygdala, and consequently greater negative affect. However, the candidate's preliminary studies of brain-injured humans demonstrate that focal damage to vmPFC actually reduces the experience of negative emotion. These preliminary data raise important follow-up questions about the role of vmPFC in regulating negative emotion in humans. The immediate overall aim of the research and training plan is to test whether vmPFC is indeed critically involved in the regulation of negative emotion through inhibition of the amygdala. In four studies of brain-injured humans, the candidate will examine how vmPFC damage affects 1) the cortisol response to psychosocial stress, 2) the acquisition and extinction of conditioned fear responses, as measured with skin conductance and startle reflex, 3) the structural integrity of white matter pathways between PFC and amygdala, as measured with diffusion tensor imaging (DTI) and 4) the functional activation of the amygdala in response to emotional facial expressions, as measured with fMRI. Results from these studies will help illuminate the role of vmPFC in the regulation of emotion. Through completion of these projects and other training activities, the candidate will acquire expertise in DTI, fMRI, and several physiological measures related to emotion. Learning these experimental techniques will allow the candidate to significantly advance the methods used to study brain lesion patients, and establish a framework for innovative long-term research into the neural substrates of emotional processing. The proposed program of training and research will be conducted at the University of Wisconsin-Madison, which is a leading institution in the neuroscientific study of emotion, featuring state-of-the art neuroimaging facilities and distinguished faculty. PUBLIC HEALTH RELEVANCE: Depression and anxiety disorders afflict millions of Americans, yet the standard treatments, such as antidepressant drugs and counseling, have had limited success. A better understanding of the brain circuits underlying human emotion is an important step in developing more effective treatments. The proposed research will provide new information about how the brain functions to regulate negative emotion.

DESCRIPTION (provided by applicant): A key step in advancing psychiatric medicine is to more fully elucidate the neural circuits responsible for specific domains of function that are commonly disrupted in mental disorders. Clarification of these circuit- function relationships will facilitate the development of pathophysiologically-based diagnostic and treatment strategies. The ventromedial sector of prefrontal cortex (vmPFC) is a crucial brain area in this regard. Abnormalities in vmPFC function and structure have been identified in virtually all mood and anxiety disorders, suggesting that vmPFC underlies some critical domain (or domains) of affective function that cut across traditional diagnostic categories. Yet the precise mechanisms by which vmPFC contributes to affective psychopathology remain unclear. The predominant neural circuitry model proposes that vmPFC regulates negative affect via top-down inhibition of brain areas involved in processing negative emotion-particularly the amygdala and insula-and that the pathologically elevated levels of negative affect characterizing mood and anxiety disorders result from a defect in this vmPFC-mediated inhibition of amygdala and insula activity. Three distinct mechanisms of vmPFC action have been proposed: (1) regulation of amygdala and insula activity in response to emotionally aversive stimuli, (2) regulation of amygdala and insula activity during the anticipation of emotionally aversive stimuli, and (3) regulation of amygdala activity during the extinction of conditioned fear. To date, empirical support for this model has largely been derived from two sources: animal fear conditioning studies (which cannot address the uniquely human psychological processes related to negative affect) and human fMRI studies of normal or psychiatric patient populations (which cannot address whether vmPFC dysfunction actually causes dysregulated amygdala or insula activity). Using an innovative approach-fMRI in neurological patients with discrete vmPFC lesions-this study will be the first to determine whether vmPFC is in fact necessary for regulating the activity of the amygdala and insula during affective processing in humans. We will examine amygdala and insula activity during each of the three fundamental aspects of affective processing described above, corresponding to three Specific Aims. Furthermore, in order to directly test the clinical relevance of this novel approach, each aim will also include a group of anxiety disorder patients. The direct comparison of fMRI results between vmPFC lesion patients and anxiety disorder patients will definitively establish whether the predominant theory-which holds that pathological levels of negative affect result from elevated amygdala and insula activity due to deficient top-down regulation by vmPFC-is indeed a viable neuropsychological model for mood and anxiety disorders. The study results will thus fill a major knowledge gap regarding the psychological and neurobiological mechanisms by which vmPFC modulates negative affect in humans, and significantly advance a program of research aimed at identifying neural circuit-level substrates of specific domains of affective function that are relevant to mental illness.

PROJECT SUMMARY The pernicious link between substance abuse and criminal behavior imposes major costs to society, totaling billions of dollars in the U.S. annually. There is a critical need for more effective interventions to counteract the high rates of relapse and recidivism in alcohol and substance abusing criminal offenders. Periods of offender incarceration provide a unique opportunity to develop and deploy such interventions. Progress in intervention development could be achieved by targeting specific cognitive and affective vulnerabilities that are common among substance abusing criminal offenders. Preliminary studies suggest that meditative or mindfulness interventions may confer significant psychological and behavioral benefits to inmates. However, the mechanisms and extent of intervention efficacy are unclear, as these previous studies have been beset by a number of methodological limitations. Moreover, to date no study has examined the neurobiological mechanisms that relate to treatment success in this population. NIAAA has recently made a program call to address these issues (PA-15-299). Here we answer this program call and propose to undertake a rigorous and comprehensive longitudinal study of mindfulness treatment of alcohol and substance use disorders among female inmates. This project will randomly assign over 400 female inmates to a mindfulness or relapse prevention training course, and both will be compared against a no treatment control. The mindfulness intervention will be tailored to address two key neuropsychological deficits in alcohol abusing criminal offenders: impulsivity and craving. We will test hypotheses about the neural changes over time with treatment to elucidate mechanisms of change. We will obtain estimates of ?real-world? efficacy of the intervention by collecting outcome measures in prison (conduct reports) and following release (alcohol use relapse and antisocial behavior). This project takes advantage of a unique, longstanding partnership between the research team and the states of New Mexico and Wisconsin Correction Departments that allows collection of comprehensive assessment data from inmates during incarceration, including brain imaging data with a mobile MRI scanner, as well as access to post-release outcomes and relapse data. Completion of these aims is a critical step for implementing and evaluating a promising mindfulness intervention for this high-risk population. The proposed research will also begin to elucidate the psychological and neurobiological mechanisms of the treatment. These results will thus significantly advance a program of research seeking to translate the growing knowledge of neuropsychological deficits into more targeted and effective treatments for alcohol and substance abuse problems in criminal offenders.

PROJECT SUMMARY Prisons and jails are the de facto largest providers of mental health services in the U.S. The failure to effectively treat mental illness in this setting is associated with a host of dire outcomes: higher rates of suicide; higher rates of victimization for rape and other forms of abuse; higher rates of rules infractions and solitary confinement; and higher rates of recidivism and re-arrest after release. Thus, there is a critical need for more effective mental health treatment strategies for incarcerated individuals. There is a particular need for more targeted therapeutic approaches for individuals with post-traumatic stress disorder (PTSD). The prevalence of trauma history and PTSD are markedly higher in jail and prison populations than in the general population. In fact, the prevalence of PTSD among inmates exceeds that of military combat veterans. Despite the pressing need for PTSD treatment within the jail and prison population, there is virtually no research examining the effectiveness of empirically-supported therapies for PTSD in incarcerated individuals. Cognitive Processing Therapy (CPT) is a promising PTSD treatment for the prison setting, primarily due to its cost- and time- effectiveness in the manualized group format. In studies of non-incarcerated individuals, CPT has been found to be more effective than waitlist control and equivalent to Prolonged Exposure. Yet, there has never been a study of CPT among adult prison inmates. This R34 project will lay the groundwork for a sustained research effort to dramatically improve the treatment of PTSD in our nation's prisons. This pilot study will cover the initial project development stages: (1) Establish the feasibility of group CPT delivery in male and female prisons; (2) Obtain preliminary effectiveness estimates for reducing PTSD symptom severity; and (3) Identify putative psychological mechanisms of symptom change through pre-, mid-, and post-intervention assessments. Through a unique partnership with the State of Wisconsin Department of Corrections, we will collect and analyze data for both male and female prison inmates. Completion of these aims is a requisite initial step to implement and evaluate a promising PTSD intervention in this severely underserved and costly population. By demonstrating the feasibility and effectiveness of empirically-supported group psychotherapy in the prison setting, this program of research could ultimately help radically improve the treatment of psychiatric illness among prison inmates.