Jon-Kar Zubieta - US grants

We propose to test the hypothesis that patients diagnosed with Bipolar Disorder have increased monoaminergic synaptic densities, by using Positron Emission Tomography and the non-selective monoamine vesicle marker [11]C-dihydrotetrabenazine (labeling dopamine, norepinephrine and serotonin terminals). In this project we will utilize stringent selection criteria, recruiting only patients with Bipolar Disorder Type I who have a family history of this illness, but are currently asymptomatic. Results obtained in these patients will be compared with age- and sex-matched healthy controls. Confirmation of differences in monoamine synaptic density between patients and control subjects would represent a significant advance in our understanding of this illness, and has relevance for the diagnosis, treatment and ultimately, the outcome and health care costs associated with the treatment of patients diagnosed with Bipolar Disorder.

Epidemiological and experimental evidence points to sex differences in the responses to antinociceptive pharmacological agents, the experience of pain, and the prevalence of certain chronic pain conditions, such as temporomandibular disorders (TMD). It has been suggested that these reflect the presence of sex-differences in brain neurochemical systems involved in pain perception and control, and that these may also be hormone-sensitive. The application of functional imaging techniques allows the direct examination of neuronal networks and neurochemical systems involved in the human experience of pain. The overall goal of the proposed research is the description and understanding of relevant aspects of the gender-specific neurobiology that occurs as the human undergoes tonic pain. The current proposal focuses on the opioid system, and specifically the mu opioid receptors, since these sites mediate many of the actions of exogenously administered antinociceptive drugs, as well as stress- and nociception-induced analgesia. Preliminary data using PET demonstrate that regions involved in the modulation of pain, such as the anterior cingulate cortex, prefrontal cortex, amygdala, thalamus and midbrain, show sex-differences in the concentration of mu opioid receptors. Additional findings reveal that the function of these receptors is subject to modulation by circulating estradiol, making this receptor site a logical candidate for the investigation of pain mechanisms and their differences between the sexes. This proposal takes advantage of state-of-the-art brain imaging technology for the quantification of mu opioid receptor sites in the human brain. It combines PET with a validated model of temporomandibular pain to examine the involvement of the mu opioid receptors in the regulation of tonic pain. A randomized, double blind, repeated measures crossover design will be employed to investigate the effect of tonic experimental pain on the opioid function of healthy subjects. The in vivo availability of 4 opioid receptors, as measured in living human subjects with PET and the selective radiotracer [11C]carfentanil will be quantified under baseline, placebo and tonic pain conditions. Baseline regional receptor levels, and receptor occupancy resulting from the administration of control and algesic substances into the masseter muscle, will be quantified. Regional binding and receptor occupancy will be related to psychophysical aspects of pain in men and women. These studies will show for the first time the function of the mu opioid receptor and the endogenous opioid system as the human undergoes pain. It will also examine the effect of sex and the involvement of various brain regions on sensory and affective components of pain.

DESCRIPTION (provided by applicant): Experimental evidence points to placebo responses that can potentially enhance, as well as confound, the therapeutic benefit of active conditions. Perhaps the area in which the effects of placebos have been best described at pharmacological and behavioral levels is that involving experimental and clinical pain. Expectation of analgesia during placebo administration activates endogenous opioid neurotransmitter systems, in turn regulating sensory and affective qualities of pain. However, at the present time the neuronal and neurochemical networks where placebo-associated sensory, emotional and cognitive appraisals are translated into neurobiological effects are unknown. The endogenous opioid system is known to suppress stress responses and pain through the activation of mu-opioid receptors. Recent data from our laboratory has demonstrated that this regulation takes place at multiple brain levels, including cortical and subcortical regions involved in the integration of sensory, emotional and cognitive information (anterior cingulate, prefrontal cortex, insular cortex, thalamus, nucleus accumbens, amygdala). This information, together with that arising from biobehavioral studies suggests that/mu-opioid mechanisms impacting integrative-motivational brain networks may be mediating the "mind-body" interactions typically associated with placebo responses. In this regard, preliminary data is presented demonstrating the susceptibility of this neurotransmitter system to modulation by cognitive-emotional appraisals, including the expectation of a pain stressor. The present proposal seeks to examine the effects of a placebo intervention with expectation of analgesia on/mu-opioid neurotransmission, directly in human subjects with PET and molecular imaging techniques. Placebo responses are to be studied in healthy male and female volunteers during non-painful (saline control) and painful (sustained pain-stress challenge) conditions. We further control for factors known to influence the function of/mu-opioid networks: anticipatory stress responses, age, gender, and the female gonadal steroid environment. Knowledge of the circuits and mechanisms engaged in the production of placebo analgesia opens the possibility of designing scientifically-based methods to hamess those effects. Furthermore, examination of factors that regulate these placebo-activated neurotransmitter responses will greatly clarify the overall neurobiology underlying interindividual variations in the responses to placebos, as well as pain and other stressful conditions, ultimately leading to the optimization of medical and psychological interventions.

DESCRIPTION (provided by applicant): A distributed network of regions, both cortical (e.g., prefrontal cortex, anterior cingulate cortex, insular cortex) and subcortical (e.g., amygdala, thalamus, ventral striatum), increase their synaptic activity during the presentation of emotional stimuli or the experience of emotional states. Functional and structural changes in some of these regions have also been implicated in the pathophysiology of mood disorders (e.g., Major Depression). By comparison, relatively little information has been acquired on the neurotransmitter systems involved in the regulation of emotional and mood states in humans, and by extension, in Borderline Personality Disorder (BPD). There are suggestions that the endogenous opioid system (EOS) may have physiological relevance to some BPD symptoms such as stress-related analgesia, dissociative behavior, and self-injurious activity. Recent work from our laboratory has also implicated the EOS in affective regulation during the experience of negative emotional states, as well as in response to stressors. The EOS may therefore interface sensory-related symptoms of BPD with abnormalities in affective regulation present in this disorder. The utilization of radiotracers labeling specific receptor sites and appropriate kinetic models allows the examination of neurotransmitter release in response to experimental challenges. Employing these techniques, we have demonstrated the involvement of mu-opioid-receptor mediated opioid neurotransmission in the regulation of stress and affective responses, as well as sex and genetic influences on these phenomena. The present proposal extends this work to BPD patient volunteers and age- and sex-matched healthy controls. The additional influence of chronic stress on interindividual variations in these responses is also introduced. Secondary analyses will be performed to preliminarily examine the contribution of met158val COMT genotypes to these interindividual variations. The psychophysiological consequences of these genotypic and endophenotypic influences will then be examined using both objective (e.g., HPA axis measures) and subjective measures (e.g., ratings of pain, affective states, mood). The results obtained in these studies will provide a foundation for a systems-level understanding of neurochemical and behavioral responses to a stressor in BPD, and the circuits and regulatory mechanisms critically involved in this disorder. This information is critical for the understanding of the biological mechanisms underlying the symptomatology of BPD, and to guide future research and treatment interventions in this common but poorly understood illness.

DESCRIPTION (provided by applicant): Experimental evidence points to important interindividual and sex differences in responses to drugs of abuse, stressors, and in the function of neurotransmitter systems thought to mediate those responses. Genetic variations may account for a significant proportion of that variance, possibly modifying the subsequent risk for the development of substance abuse in humans. Understanding the mechanisms linking relevant genotypic variants with behavioral phenotypes requires a systems-level approach that includes the study of intermediary brain responses. In other words, we cannot ignore that the pathway from genetics to behavior is through the brain. These intermediary endophenotypes include neurotransmitter systems directly regulated by the genotypes, as well as downstream modulatory influences. The present proposal focuses on a common functional single nucleotide polymorphism known to directly influence dopamine neurotransmission and which has been implicated in modifying responses to stress and substances of abuse. Preliminary data is presented demonstrating the differential activation of downstream, regulatory mu-opioid system responses to a pain-stress challenge as a function of this genotypic variant, resulting in significant interindividual differences in physical and psychological responses in humans. The present proposal seeks to confirm and extend these findings in a sample of healthy human volunteers selected on the basis of genotype. We are to examine the functional responses of D2 dopaminergic and mu-opioid neurotransmission with positron emission tomography and neurochemical imaging with specific radiotracers and validated quantification models. Measurements will be performed during control conditions and during an experimental challenge (moderate levels of steady sustained pain, utilized here a model of physical and psychological stress) known to activate those neurotransmitter systems. The individual phenotypic responses to this challenge will then be associated with the presence of specific genotypes and with the function of neurotransmitter systems directly and indirectly regulated by them. Linking genotypic determinants, endophenotypic neurotransmitter responses (dopaminergic and opioid neurotransmission) and their phenotypic expression provides a unique, systems-level understanding of human physiological processes. Such an understanding is essential for the elucidation of the multiple neurobiological factors involved in the individual responses to stress and the action of drugs of abuse, known to confer varying levels of risk for the development of substance abuse disorders.

human therapy evaluation; serotonin receptor; mental disorder chemotherapy; major depression; antidepressants; glucocorticoids; neurotransmitters; patient oriented research; human subject; clinical research;

serotonin receptor; major depression; serotonin; neural transmission; human therapy evaluation; psychopharmacology; stress; mental disorder chemotherapy; glucocorticoids; hormone regulation /control mechanism; neurotransmitters; antidepressants; patient oriented research; human subject; clinical research; positron emission tomography;

[unreadable] DESCRIPTION (provided by applicant): Experimental evidence points to important interindividual and sex differences in responses to drugs of abuse, stressors, and in the function of neurotransmitter systems thought to mediate those responses. Specifically, variations in the function or responses of dopaminergic (DA) and opioid systems are known to be centrally implicated in the development of opiate abuse and dependence. Recent data from our laboratory and others using PET and selective radiotracers targeting mu-opioid and DA-D2 receptors has also shown that these neurotransmitter systems are involved in the responses and regulation of pain. Data in healthy subjects demonstrates opposing effects of these neurotransmitters, with DA-D2 neurotransmission enhancing, and mu-opioid suppressing, pain reporting and pain sensitivity measures. A modulation of DA-D2 receptors (increases) and mu-opioid receptors (reduced) has been shown in clinical chronic pain samples, further associated with higher levels of pain reporting and pain sensitivity. In response to RFA-DA-06-005, the present application builds on that initial data to examine the effects of chronic pain and opioid administration on the function of these neurotransmitter systems. It is proposed to study a well-charaterized sample of patients diagnosed with chronic lumbar pain either treated or not with opiates and an age- and sex- matched sample of healthy controls. We are to examine the effect of chronic pain and opiate treatment on baseline levels of mu-opioid and DA-D2 receptors in vivo. In addition, we propose to utilize a pain challenge mimicking a flair in the pain signal to determine the involvement of DA and mu-opioid release on behavioral responses to variations in pain in these three samples. These neurochemical measures will then be related to individual differences in prospectively rated pain, analgesic requirements, subjective effects of cumulative doses of the prototypical mu-opioid agonist fentanyl, and rates of discounting in a opiate and monetary delay discounting paradigm. We are not proposing to study patients known to misuse or abuse opiates, or dependent on opiates, as concurrent abuse or dependence would confound the effects of chronic pain and therapeutic opiate administration. However, these initial studies will provide with valuable information in humans, linking the function of opioid and DA neurotransmission with factors and constructs known to confer an elevated risk for the subsequent development of opioid misuse and abuse (e.g., pain variability, distress in responses to variations in pain, impulsive choice and rewarding responses to acute opiate administration). [unreadable] [unreadable] [unreadable]

Project Summary Abstract This proposal aims to study the application of functional magnetic resonance imaging in real time (rtfMRI) as an operant training feedback mechanism for treating substance use disorders. Recent data suggest that individuals can reduce activity in some brain regions (e.g. anterior cingulate cortex, anterior insula, auditory cortex when they are presented with information about activation in that brain region. Experimental and clinical pain have been reduced with rtfMRI signal feedback from the rostral anterior cingulate in a manner proportional to reductions in the blood oxygenation level dependent (BOLD) signal from that region. These regions overlap with those involved in the effets of substances of abuse and the development of substance use disorders (SUDs). The initial information opens the possibility of applying neurofeedback to improve treatment outcomes in patient samples. The present application seeks to expand the investigation of these processes and validate their applicability to substance dependent volunteers. In initial studies we will examine the capacity of nicotine dependent volunteers to reduce their craving for cigarettes. This substance was selected for its high retention rates and prevalence and public health burden in the general population, but it is expected that future studies would explore other forms of addiction (e.g. cocaine, opiates). Our multidisciplinary team proposes to advance current knowledge in this area by: (1) using data not from a single brain region, but from networks involved in nicotine craving and dependence, thereby accounting for inter- individual differences in brain regional activation patterns during nicotine craving; (2) developing a quantifiable method by using arterial spin labeling (ASL); and (3) determining the influence of individual expectations on these processes (e.g. assessing the degree to which these effects are attributable to placebo-related responding). The developmental and experimental elements of this proposal will lead to new avenues for treatment that would be readily generalizable to other forms of drug addiction besides nicotine, and potentially impacting on the outcomes of the substantial numbers of individuals seeking substance abuse treatment.

DESCRIPTION (provided by applicant): High levels of comorbidity have been observed between nicotine dependence and persistent pain conditions. There are also suggestions that nicotine dependence may complicate the presentation and outcomes of patients experiencing persistent pain, already a condition that is both difficult to treat and can be self- perpetuating. Experimental evidence shows that nicotine has effects on pain regulatory mechanisms. The effects of the interaction between nicotine dependence and chronic pain are however poorly understood at both neurobiological and phenotypic levels, particularly in humans. The present proposal is concerned with individual variations in the function of neurochemical mechanisms implicated in the pathophysiology of both chronic pain and nicotine dependence and how they impact on the individual characteristics of both disorders. It is proposed to examine the function of endogenous opioid and dopamine neurotransmission, systems involved in the reinforcing effects of nicotine in the CNS, but also known to be dysregulated in chronic pain conditions. We propose to first characterize the effects of nicotine dependence on the responses of dopamine and opioid systems to sustained experimental pain, by comparing them to those of non-smoker controls. Neurobiological responses will then be related to pain psychophysics and measures related to nicotine dependence (e.g., craving). Similar studies and analyses are proposed in samples of chronic low back pain patients, nicotine dependent or non-smokers. We will employ the selective radiotracers [11C]carfentanil and [11C]raclopride and positron emission tomography for the non-invasive quantification of dopamine D2/3 and 5- opioid receptors. Baseline, pain expectation and pain responses will be quantified and examined against psychophysical characteristics across the four matched volunteer groups proposed: non-smoker and nicotine dependent controls, chronic low back pain non-smokers and nicotine dependent. At the completion of these studies we will be able to determine how nicotine dependence modifies pain responses in humans, and how pain, both clinical and experimental, modifies neurobiological and phenotypic elements of this addiction (e.g., craving). In addition, the interaction between an existing persistent painful condition and nicotine dependence will be examined at the neural function level and related to the individual clinical and experimental pain experience and measures of nicotine dependence. Both nicotine dependence and chronic pain are self- perpetuating conditions with high comorbidity. The studies proposed will clarify their points of interaction at neurobiological and psychophysical levels, providing much needed information for the understanding of individual variations in patient presentation and clinical courses. This information would ultimately guide individualized treatment strategies by providing a neurobiological framework for their development.

DESCRIPTION (provided by applicant): The onset of sex bias in the expression of depressive illness after the onset of puberty, as well as anecdotal studies suggesting an association between mood and cyclic gonadal steroid changes suggest that gonadal axis hormones may modulate the onset and course of depression. Hormones of the hypothalamic pituitary adrenal (HPA) axis have been demonstrated to affect the hypothalamic pituitary gonadal axis, particularly the secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus. Our previous studies on reproductive axis in pre- menopausal women with major depression found lower estradiol in the follicular phase. In addition, we found suggestions of decreased LH amplitude, mean levels and half-life during the follicular phase in depressed women, but we had inadequate power (n=12) to demonstrate significant differences. Finally, it appeared that several of these abnormalities were related to mean cortisol levels. We seek to confirm these findings in a larger group of depressed women studied during the first 10 days of the menstrual cycle along with age and menstrual cycle day matched control women. We will also examine the links between these abnormalities and mean cortisol. Furthermore, neuroimaging data, post-mortem suicide data and treatment data support a role for serotonin in the etiology of depression. Gender differences in the serotonin systems have been demonstrated in humans and estradiol has been shown to influence these systems in animal studies. Our underlying model is that both estradiol and cortisol modulate 5HT1a binding and thereby influence susceptibility to depression in women. To test this model, we propose to: 1) evaluate HPG hormones as well as cortisol in drug free depressed patients and matched controls;2) examine the effects of estradiol supplementation on 5HT1a binding in the raphe, hippocampus and cortex in normal women as measured by [11C]-WAY100635 and 3) conduct correlational analyses on the relationship between estradiol, cortisol and 5HT1a BP binding in the raphe, hippocampus and cortex in normal women and women with MDD. PUBLIC HEALTH RELEVANCE: Women are more likely to suffer from depression, and at times when estrogen levels are low or falling, such as puberty, following childbirth and in the transition to menopause, depression rates increase. These findings suggest that estrogen affects mood. This project will evaluate whether women with depression show low estrogen levels and if the changes in estrogen are accompanied by changes in serotonin binding in the brains of women with major depression

DESCRIPTION (provided by applicant): A substantial body of evidence implicates the endogenous opioid system, and the mu opioid receptor (MOR) in particular, in the reinforcing effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the mu opioid receptor gene (OPRM1 Asp40) is associated with the ability to quit smoking, as well as nicotine reward and withdrawal symptoms. However, the precise mechanism through which this SNP influences nicotine dependence remains unresolved. In this R21 application, we propose a translational cross-species approach to elucidate the functional significance of the OPRM1 Asp40 variant in the neurobiology of nicotine dependence. Toward this end, we have developed a knock-in mouse that possesses the mouse equivalent of the Asp40 in the Oprm1 gene (Asp38), and we provide compelling preliminary evidence for functional significance. Understanding whether this variant alters MOR binding in response to nicotine in mice and in human smokers will improve our understanding of genotype by nicotine interactions, and will provide a critical first step toward elucidating the neurobehavioral mechanisms through which this SNP alters smoking behavior. The proposed mice experiments will: 1) determine if the mouse Asp38 alters basal or nicotine-stimulated changes in MOR binding and signaling throughout the brain using [3H]carfentanil and autoradiography;and 2) evaluate the effect of the Asp38 variant on behavioral responses to nicotine using conditioned place preference and nicotine-primed re-instatement paradigms. The human experiment will use [11C]carfentanil PET imaging to assess the effects of intravenous (IV) nicotine versus saline (within-subject) on MOR binding potential in 24 chronic smokers genotyped prospectively and stratified by OPRM1 genotype. These experiments will establish a translational cross-species model for functional characterization of genetic variants, and will elucidate the neurobiology of nicotine dependence, a significant public health problem. PUBLIC HEALTH RELEVANCE: The proposed experiments in mice and humans will help us understand the mechanisms by which a specific gene variant (OPRM1 A118G) is associated with nicotine dependence.

DESCRIPTION (provided by applicant): The present proposal is concerned with the prediction of individual placebo responses in clinical samples. Here we part from the usual view of placebos as inert control states. On the contrary, it is hypothesized that placebo administration triggers a cascade of events activating endogenous mechanisms that promote homeostasis. This leads to the proposal that a substantial proportion of the variance in placebo responding in CNS trials can be explained by the functional variation of specific neurobiological circuits and mechanisms. We focus on the prediction of placebo effects in patients diagnosed with Major Depressive Episode (MDE), unmedicated at the time of the study. This illness was selected because of its high frequency and chronicity in the general population, but also one that presents with high placebo responses in controlled trials. Half of the subjects will also present with a diagnosis of nicotine dependence, which is expected to reduce placebo responses rates, but also affect the underlying neurobiology, increasing the generalizability of the findings. Non-problem alcohol use will be permitted and entered as a covariate in the analyses. A 3-step process is proposed. Studies using positron emission tomograph will determine the placebo-induced activation of neurotransmitter systems through to be involved in both the pathophysiology of MDE and the effects of expectations. Functional magnetic resonance imaging will be employed to determine the proportion of the variance in placebo effects explained by the function of reward, decision-making and "motivation" regions. Individual variations in neurotransmitter systems and circuits involved will then be modeled by a combination of neuropsychological tests and the presence of common genetic polymorphisms regulating those regional networks. This proposal therefore addresses the predictability of the placebo effect and its underlying neurobiology. The capacity to utilize internal resources to change clinical conditions (as opposed to traditional therapies that are given or applied to the patient with little individual control) represents both a shift in paradigm and a source of "noise" in clinical trials. As such, the results of the studies proposed have the potential for lasting impact in the practice of medicine at large. Placebo effects are a common occurrence in clinical trials. Recent data has shown that those may be caused by the effect that expectations have on specific brain mechanisms. Those brain mechanisms may then change the clinical state of the patients. This proposal examines these mechanisms in Major Depression with and without substance use to determine their predictability and application in clinical trials. The NIDA/NIMH/NINDS EUREKA applications were reviewed differently from more traditional NIH grant mechanisms. Specifically, the review process consisted of two phases. During the first (i.e., electronic) phase a selected panel of reviewers were given the following guidelines by which to assess the applications. They were asked to determine whether they: Strongly Agree, Moderately Agree, Neither Agree nor Disagree, Moderately Disagree, or Strongly Disagree with these descriptions. Their ratings and any additional comments are below. These initial ratings also provided the basis for the review panel to determine whether an application would be discussed during an in person meeting. Because of the very stringent review criteria and limited pool of funds set aside for this program, the review panel chose only to discuss applications that garnered the most enthusiasm. The Resume and Summary of the Discussion above summarizes opinions of the in person meeting and forms the basis of the final score. Significance: This study addresses an important problem and the outcome of the proposed studies will drive the field. The potential impact of the proposed research is exceptional, in terms of the magnitude of the impact and the size of the community affected. Innovation: The project is highly original and exceptionally innovative and seriously challenges existing paradigms or clinical practice. The project addresses a major barrier to progress in the field or it develops or employs exceptionally novel concepts, approaches, methodologies, tools, or technologies. Approach: The logic of the approach is sufficiently compelling despite the lack of experimental detail. The conceptual (or clinical) framework, design, methods, and analyses are adequately developed, well integrated and reasoned, and are appropriate for the aims of the project. The applicant acknowledges potential problem areas and considers alternative tactics. The information in the timeline inspires confidence that the PI will be able to document progress in each year of the award and either complete the project or demonstrate conclusively that it cannot be completed, despite good-faith efforts, during the term of the award. The requested duration of the award is appropriate for the proposed research. Investigators: The PD/PI(s) and other key personnel are appropriately trained and well-suited to carry out this work. Past achievements of the PI(s) suggest that the investigator(s) is/are exceptionally innovative and likely to make paradigm-shifting, high-impact discoveries. If the PI does not have a history of doing exceptionally innovative, high-impact research, the logic of the experimental plan suggests that there is at least some likelihood of success. The project is high priority for the PI(s), as indicated by the person-months of effort that the PI(s) will devote to it. For applications designating multiple PDs/PIs, the leadership plan, including the designated roles and responsibilities, governance, and organizational structure, are consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs. Environment: The scientific environment(s), in which the work will be performed, contributes to the probability of success. The proposed studies benefit from unique features of the scientific environment, subject populations, or employ useful collaborative arrangements. There is evidence of institutional support.

DESCRIPTION (provided by applicant): Placebo responses represent a substantial source of noise in clinical trials. Examination of inter-individual differences in the function of placebo responsive mechanisms, and potential surrogates (biomarkers) would help inform the sources of variability in clinical studies in an objective, mechanistic fashion. The formation of biologica placebo effects also represents a resiliency mechanism, uncovered by the cognitive emotional integration of the expectations created by the treating environment. As such, delineation of these processes would point to biological targets that have not been contemplated in traditional drug or treatment development. Endogenous opioid mechanisms have been centrally implicated in the formation of placebo analgesic effects for more than three-decades, but their function has not been systematically studied in clinical samples. This application examines the integrity of the endogenous opioid system in a sample of patients diagnosed with fibromyalgia (FM), a persistent pain syndrome with moderate placebo responses. We will utilize positron emission tomography (PET) and a selective ¿-opioid receptor radiotracer to acquire objective molecular measures known to be associated with the formation of placebo analgesic effects in clinical and experimental samples. Measures of ¿-opioid receptor (¿OR) availability at baseline and the activation of this neurotransmitter system in response to a releasing challenge (intravenous placebo with expectation of analgesia) will be examined against treatment response measures in what effectively represents a within- subject, randomized, cross-over trial of placebo pills wit and without expectations of activity. We will utilize non-deceptive consent methodology, following current ethical recommendations and consistent with ongoing studies in our laboratory. It is proposed that baseline ¿OR availability in vivo and the capacity to activate this neurotransmitter system in the context of positive expectations of improvement experimentally created during scanning and by the administration of placebo during the trial, will be associated with treatment response in FM patients. In the spirit of clinical applicability, these mechanistic, molecular imaging studies of predictors of treatment response in FM will be complemented by the examination of simpler biomarkers. The selected markers have been found associated with endogenous opioid system function, and their predictive value, alone and in combination, will be examined as potential predictors of so-called non-specific treatment responses. This proposal assembles a comprehensive team of clinicians and scientists with specialized and complementary expertise, and substantial track records in molecular imaging, chronic pain, FM and clinical trials that is uniquely positioned to manage and complete the studies proposed. It addresses a severe health problem, chronic pain, and a substantial source of variability in clinical studies, biological placebo effects, which has not been systematically studied at a mechanistic level in clinical samples. The data acquired will also point to novel treatment targets not addressed in traditional drug discovery strategies.

? DESCRIPTION (provided by applicant): In science, profound changes in paradigm have emerged when previously unexplained phenomena, typically disregarded as noise or measurement error, are explained by a new theoretical structure. If a comparable phenomenon could be found in clinical medicine, an unexplained source of variance, it would be the so-called placebo effect. It should be noted that placebo effects have a different meaning for clinical trials and for neurobiologists. In the former case, they are considered non-specific, and contributing to the variability, noise, in treatment responses. This effect is particularly prominent in Major Depressive Disorder (MDD), a chronic and disabling illness that nevertheless presents with ? 30-50% responses attributable to placebo. For the neurobiologists, however, there is now uncontroversial evidence that the cognitive-emotional integrative processes that take place in the context of positive expectations associated with a potential therapeutic intervention, induce changes in brain function and neurochemistry that are associated with symptom improvement and illness recovery. In that context, true neurobiological placebo responses represent potential mechanisms of resiliency and treatment response, as well as new treatment target opportunities, as will be described in this application and backed by convincing preliminary data. This application proposes to examine non-specific and specific neurobiological contributions to treatment response, objectively explaining variance by studying the function of a neurotransmitter system linked with the regulation of stress, affect and mood, but also placebo responses, the endogenous opioid system and µ-opioid receptors. We are to determine interindividual variations in the function of µ-opioid receptor-mediated neurotransmission in patients diagnosed with moderate-severe MDD and the effect of placebo and active antidepressant administrations on these mechanisms. The data acquired will determine neurobiological factors that are associated with symptom improvement across non-specific and drug-specific conditions. Contributing variables that would explain variability in these mechanisms, specifically genetic variation, biomarkers and personality trait variation will be examined and pooled to develop markers of treatment response and orient novel approaches to the conduct of clinical trials. Some of these markers, specifically those linked to functional genetic polymorphisms would also direct the examination of novel treatment approaches not currently contemplated in drug target screening.

Chronic pain is typically managed with extended use of opioid analgesics, despite an absence of data on their long-term efficacy and clear evidence of significant health risks. Prolonged opioid use dysregulates the endogenous opioid system, disrupting hedonic homeostasis in the brain and resulting in hyperalgesia, stress reactivity, and reward insensitivity ? factors that exacerbate chronic pain and increase risk for opioid misuse. Thus, chronic pain patients receiving extended opioid therapy suffer from impaired regulation of aversive (e.g., pain) and appetitive experience (e.g., pleasure), dual processes subserved by opioid-mediated, hedonic regulatory mechanisms. However, according to a 2015 NIH systematic review, there are no interventions with proven efficacy for improving outcomes among chronic pain patients on long-term opioid therapy. Extant therapies may have limited efficacy because they fail to directly target the neural circuits of hedonic regulation. In contrast, meditation-based interventions, which have been conceptualized as means of self-regulating hedonic function, may hold promise for addressing this public health concern. The overarching aim of this proposal is to determine the capacity of a novel meditation intervention, Mindfulness-Oriented Recovery Enhancement (MORE), to restore endogenous opioid system function as measured with PET and a selective ?-opioid radiotracer. In the R61, we will compare the effects of MORE to a support group (SG) control on measures of endogenous opioid system function during sustained muscle pain, and will use fMRI and behavioral measures to assess whether changes in opioid function are associated with improved regulation of appetitive (reward) and aversive (pain) experience among chronic non-neuropathic back pain patients (CNBP). In the R33, we will further validate the opioid functional mechanism by examining the A118G allele of the ?-opioid receptor gene (which has been linked to low ?-opioid function, hyperalgesia, and insensitivity to opioid analgesia) as a moderator of MORE?s effects on the endogenous opioid system, fMRI measures of natural reward responsiveness, and clinical outcomes ? including pain and opioid use. Furthermore, to refine our understanding of how the intervention modulates these neural mechanisms, the R33 will assess the dose of meditation skill practice as a predictor of changes in endogenous opioid function and clinical correlates. This multi-PI proposal unites expertise in meditation-based interventions with expertise in neurogenetics and the use of PET and fMRI to probe the neurobiological mechanisms of pain and affective experience, and builds upon a program of prior research which provided preliminary efficacy data on the MORE intervention and standardized its delivery via manualization of the treatment and development of fidelity measures. By elucidating a key mechanism of this meditation-based intervention, the proposed translational research will enable rapid optimization of MORE for Stage III clinical trial implementation and dissemination, allowing us to provide a timely solution to this public health problem of escalating significance.

PROJECT ABSTRACT The scope of the current opioid crisis necessitates a broad-based health system response to addiction that extends beyond the specialty addiction care system. There is a critical need to expand research infrastructure to develop, test, and implement new clinical interventions and evidence-based opioid use disorder (OUD) treatment into diverse clinical settings. We propose the University of Utah?s (UofU) Greater Intermountain Node (GIN) to expand the existing NIH NIDA Clinical Trial Network?s (CTN) infrastructure by developing and testing innovative OUD interventions, expanding the settings for CTN research, and bringing new research acumen to the CTN. The GIN brings expertise in three spheres of OUD research: 1) non-addiction health care settings, 2) large health systems of care, and 3) implementation science. GIN?s sphere of non-addiction specialty care settings research will enable the CTN to continue and further establish these settings for OUD research by leveraging environments where GIN faculty are conducting ongoing research, for example, in primary care, obstetrical, and community pharmacies. GIN?s sphere of health systems of care research will enable the CTN access to Utah?s comprehensive, linked health/social service system databases and the Veterans Health Administration integrated data system in addition to bringing extensive experience in data science and informatics. GIN?s sphere of implementation science will allow CTN to promote and support implementation research proposals, expertise, and environments with a focus on studying/improving implementation of medication treatment for OUD, OUD identification and treatment in rural clinical settings, and improving provider knowledge, attitudes, and clinical behaviors toward patients with OUD. Advancing the work of these targeted spheres will enable the GIN to successfully achieve the following Specific Aims (SA): SA1: Enhance CTN?s ability to conduct research in primary care and non-addiction care settings (e.g. primary care, inpatient, pharmacy); SA2: Enhance CTN?s ability to conduct research within integrated systems of care with ?big data? resources (Utah population-level databases, VA); and SA3: Enhance CTN?s ability to conduct implementation science research to rapidly and effectively integrate and disseminate evidence-based addiction care into diverse non-addiction and health system targets. The GIN?s interdisciplinary leadership team has a proven track record in addiction investigative scholarship. We will leverage a robust institutional commitment and infrastructure, institutional centers focused on addiction-related research, and training programs with strong regional and national connections to clinicians, educators, and community stakeholders.