Karmen K. Yoder - US grants

[unreadable] DESCRIPTION (provided by applicant): Alcoholism is a serious disorder that is extremely difficult to treat. Understanding the neurochemistry of alcoholism will ultimately result in more effective treatment strategies. Recent research has indicated that the neurotransmitter dopamine (DA) codes prediction errors (the difference between expectation and outcome) regarding reward delivery. Prediction error signaling may be involved in the development of alcoholism and also may determine how well treatment-seeking alcoholics can maintain abstinence. The quantitation of the relationship between dopaminergic prediction error signals and alcohol consumption may provide investigators with a useful biomarker for future alcohol research on the interfaces between neurochemistry, cognition, and alcohol addiction. The long-term goal of this work is to increase our understanding of how DA is involved in the development and maintenance of alcoholism. The primary objective of this proposal is to compare the striatal dopaminergic prediction error signal among populations that differ in level of alcohol consumption, and to determine whether nontreatment-seeking alcoholics have different DA prediction error signals across addictive stimuli (i.e., alcohol versus caffeine). We will test the following hypotheses: (1) Compared to social drinkers, nontreatment-seeking alcoholics will have a greater decrease in DA in response to alcohol-related negative prediction error (alcohol administration expected but not delivered), and (2) In nontreatment-seeking alcoholics, alcohol-related prediction error will provoke a greater decrease in DA levels than caffeine-related prediction error. Changes in striatal DA levels will be detected using PET scanning and [11C]raclopride, a DA D2 receptor ligand that is sensitive to changes in endogenous dopamine levels. Twenty social drinkers and twenty nontreatment- seeking alcoholics will receive an IV infusion of either caffeine or alcohol on Day 1. On Day 2, subjects will be scanned during a baseline state and again during a negative prediction error state corresponding to the infusion they received on Day 1 (either caffeine or alcohol is expected, but not delivered). Quantitation of changes in DA levels as a function of prediction error will be achieved by calculating the change in D2 receptor availability during the prediction error scan relative to the baseline scan. The knowledge to be gained from the extension of this work will significantly advance the field of alcohol research by providing novel and important information about how DA prediction error signals are related to alcohol consumption. The neurotransmitter dopamine provides signals that indicate when an outcome does not meet expectation (prediction error). Characterizing the role of dopamine prediction error signal in social drinkers and nontreatment-seeking alcoholics will provide new and important information about the neurochemical processes involved in alcoholism. The knowledge to be gained from this proposal will set the stage for future studies which will use dopamine prediction error signal as a biomarker to investigate (1) why some, but not all, risky drinkers progress to full blown alcoholism, (2) why some alcoholic individuals are incapable of maintaining abstinence, and (3) if this biomarker can be used to predict to which treatment an individual alcoholic is likely to respond. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Fibromyalgia is a debilitating chronic pain disorder that affects 2% of the population. Many drugs used to treat fibromyalgia are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms of fibromyalgia. The long-range goal of our neuroimaging research is to better understand the neurochemistry of fibromyalgia and how alterations in neurotransmission and neuroinflammation relate to treatment efficacy and patient outcome. The objective of this application is to ascertain how the dopamine system in fibromyalgia subjects differs from that of a healthy control population. The central hypothesis is that fibromyalgia patients have a higher dopaminergic tone and a less responsive dopaminergic system relative to normal control subjects, and that these abnormalities are related to the high pain sensitivity and cognitive dysfunction in fibromyalgia. The proposed work will utilize PET and [18F]fallypride (FAL) and standard tracer kinetic modeling methods to study the dopamine system in fibromyalgia. Ten healthy control subjects and ten fibromyalgia subjects will undergo two FAL PET scans, one during a resting (baseline) state, and one during a n-back working memory task. Baseline D2 receptor availability and task-induced change in D2 availability (indicative of dopamine release) will be determined for several brain areas, including prefrontal cortex, insula, anterior cingulate, amygdala, hippocampus, thalamus, and striatal subdivisions (limbic, associative, sensorimotor). Subjects will also undergo pressure/pain threshold testing. Specific Aim 1 of this study will determine if fibromyalgia subjects have a higher basal central dopaminergic tone relative to control subjects, and determine if dopaminergic tone is related to pain sensitivity. Specific Aim 2 will determine if dopamine release induced by a working memory task is reduced in fibromyalgia patients relative to controls, and determine if task-induced DA release is related to task performance. The rationale for this study is that the information gained about the dopamine system in fibromyalgia ultimately will result in selectively targeted non-addictive pharmacotherapies that will be efficacious in treating both the pain and cognitive problems inherent to this disorder. PUBLIC HEALTH RELEVANCE: Studying the dopamine system in fibromyalgia is directly relevant to public health, as it will ultimately reduce use of highly addictive drugs for pain management. Understanding the neurochemistry of pain will lead to better strategies for treatment of pain, including the development of sophisticated non-addictive therapies. We also expect that the results of this study will contribute to the development of neuroimaging protocols that will be used to tailor treatment regimens for patients, based on individual neurochemical patterns.

DESCRIPTION (provided by applicant): The exact eurobiological factors [that drive problem drinking and contribute to relapse to hazardous drinking] remain unidentified. Understanding the neurochemistry that underlies [alcoholism and relapse] will ultimately result in more effective treatment strategies. Recent research has indicated that the neurotransmitter dopamine (DA) is involved in attributing salience to rewards: reward salience may determine how much an individual pays attention to a reward and how much an individual "wants" a reward. Several theories of addiction suggest that abnormally high "salience" attribution to alcohol [is a key factor in development of hazardous drinking, and may place an important role in explaining why some recovering alcoholics relapse.] [The DA salience signal response to rewards may prove to be a useful tool for development of therapeutic interventions and prediction of treatment response.] We propose that alterations in salience attribution are related to the development of alcoholism, and that DA responses to alcohol reward are indicative of salience attribution. The long-term goal of this work is increase our understanding of how DA is involved in the [unconscious processes that lead to chronic and excessive alcohol consumption]. The primary objective of this proposal is to compare the striatal DA responses to [predicted and unpredicted IV alcohol administration between nontreatment-seeking alcoholics (NTS) and social drinkers (SD). The central hypothesis of this proposal is that NTS subjects have abnormal salience attribution to alcohol that is mediated by striatal DA.] We will test the following specific hypotheses: [(1) NTS subjects will have increases in DA in response to expected IV alcohol but SD will not;(2) Unexpected (highly salient) IV alcohol administration will result in a greater magnitude of DA release in NTS compared to SD;(3) Unexpected caffeine administration will result in increases in DA in SD, but not NTS. Additionally, the dataset we collect will permit testing of a fourth, secondary hypothesis, which is to determine whether alcohol and smoking have an additive effect on deficits in striatal D2 receptor availability.] Changes in striatal DA levels will be detected using PET scanning and [11C]raclopride, a DA D2/D3 receptor ligand that is sensitive to changes in endogenous dopamine levels. Sixty social drinkers and sixty nontreatment- seeking alcoholics will each receive two PET scans. One scan will be acquired during a baseline state, the other during [either (i) an expected IV alcohol infusion to a target breath alcohol concentration of 80 mg%, (ii) an unexpected IV alcohol infusion, or (iii) an unexpected IV caffeine infusion.] Quantitation of changes in DA levels will be achieved by calculating the change in D2/D3 receptor availability from the [challenge] scan relative to the baseline scan. The knowledge to be gained from the extension of this work will significantly advance the field of alcohol research by providing novel and important information about how striatal DA signaling is related to hazardous alcohol consumption. PUBLIC HEALTH RELEVANCE: The neurotransmitter dopamine [is involved in communicating the importance of rewarding stimuli.] Characterizing the role of dopamine responses to alcohol reward in social drinkers and nontreatment-seeking alcoholics will provide new and important information about the neurochemical processes involved in alcoholism. The knowledge to be gained from this proposal will set the stage for future studies which will use dopamine responses to reward to investigate [(1) if effective treatments for alcoholism modulate the DA salience response, (2) if the DA salience response can be used to identify alcoholic individuals who are likely to respond to treatment and individuals who are likely to relapse, and (3) if the DA salience response can be used to provide personalized treatment plans for alcoholism in order to maximize clinical response.

DESCRIPTION (provided by applicant): Even after decades of careful research, neuroscientists still do not fully understand the neurobiological mechanisms that lead to alcoholism and relapse drinking. Recent advances in neuroimaging technologies have revealed the existence of resting state brain networks that mediate various aspects of cognitive and behavioral functions. However, very little is known about the function of these networks in alcoholism. Of particular interest is the cortical salience network (CSN), which detects internal states such as alcohol intoxication. The CSN, which is anchored by the insula and the anterior cingulate gyrus (ACC), plays a key role in assigning emotional attributes and salience to internal stimuli, and integrates this information to influence behavioral output. Additionally, the insula and ACC are innervated by dopamine (DA), a neurotransmitter heavily implicated in alcoholism and other addictions. We propose that aberrant functioning of the CSN during alcohol intoxication may underlie the development of alcohol use disorders, tolerance, and loss-of-control drinking. The functional and neurochemical signatures of the CSN may prove to be useful tools for development of therapeutic strategies and prediction of treatment response. The long-term goal of this work is to understand the relationships among the CSN, cortical DA, alcohol intoxication, and hazardous drinking behavior. The primary objective of this R21 pilot proposal is to begin a systematic characterization of the CSN with respect to functional connectivity and dopamine D2/D3 receptors. The central hypothesis is that the cortical salience network functions differently in social drinkers (SD) and nontreatment-seeking alcoholics (NTS). The primary endpoints of this study are: (i) functional connectivity of the cortical salience network (fcCSN), as assessed by fMRI and the blood-oxygenation-level-dependent signal, and (ii) relative DA tone, as indexed by DA D2/D3 receptor availability via PET and [18F]fallypride (FAL). We will test the following specific hypotheses: (1) fcCSN will be increased in NTS compared to SD; (2) alcohol intoxication affects fcCSN differently in NTS and SD; (3) insular and ACC D2/D3 receptor availability are related to fcCSN, and these relationships are altered in NTS; (4) alcohol intoxication increases DA levels in the insula and ACC. Ten SD and ten NTS subjects will receive two sets of resting-state MRI and FAL PET scans. One set of scans will be acquired during a baseline state; the other set will be acquired during alcohol intoxication maintained by an IV alcohol infusion at a target breath alcohol concentration of 80mg%. Independent components analysis will be used to quantify fcCSN. Reference region graphical analysis methods will be used to estimate FAL binding potential (BP). Changes in DA levels between alcohol and baseline will be inferred from changes in FAL BP between conditions. The knowledge to be gained from the extension of this work will significantly advance the field of alcohol research by providing novel and important information about how the cortical salience network is related to hazardous alcohol consumption.

Abstract The negative health consequences of cigarette smoking (CS) are indisputable: extensive heart and lung damage and significant risk for multiple types of cancer. Similarly, the addictive properties of CS are also well- documented. Epidemiological studies have repeatedly shown that cigarette addiction is highly comorbid with alcohol and other substance use disorders (AUD, SUD). Discussions of these data typically center around concern for the serious peripheral health consequences of smoking and/or risk for relapse for AUD/SUD. While these are worthy topics of inquiry, the current state of the literature has failed to address several critical points: first, while smoking rates are decreasing in the general U.S. population, they remain high in AUD/SUD. Second, while we know that the toxic compounds in combustible tobacco products are highly likely to induce brain damage, we do not yet have an understanding of putative dose-response functions of smoking history and current CS status on markers of neural damage. Third, it is not known how lifetime CS exposure interacts with other addictions at the level of brain structure and biochemistry to produce behavior: this could be key for discovering how the cycle of comorbid addictions is perpetuated, and thus is crucial for advancing treatment and predicting outcomes. Recently, a wealth of neuroimaging studies have emerged that have examined brain structure in chronic smokers. However, the majority of these studies looked at single outcome variables, only considered cigarette addiction, and did not design the studies from a perspective of a brain damage hypothesis. What are missing is information derived from comprehensive, multi-modal studies that attempt to understand the caustic effects of CS on the brain, and data that inform us of how CS exposure may compound effects of and complicate outcomes in CS comorbid with AUD/SUD. Lack of such knowledge is an important, clinically relevant problem, as it prevents us from developing targeted, mechanism-driven therapies designed to promote both smoking cessation and alcohol/drug abstinence, and to mitigate or repair brain damage from CS. We propose to address this critical knowledge gap by applying state-of-the art neuroimaging technologies to determine how the lifetime dose response function of CS exerts negative consequences on the brain in AUD. We will conduct parallel studies at the Indiana University School of Medicine and Stanford. Both sites will recruit the following samples: never-smoking controls, currently-smoking controls, never-smoking AUD, former-smoking AUD, and currently-smoking AUD. All AUD subjects will be nontreatment-seeking and active drinkers. We will test the effects of lifetime CS exposure on brain metabolites (Aim 1), white matter tract integrity (Aim 2), and brain network function (Aim 3). Exploratory Aim 4 will develop a predictively valid model of the relative contributions of CS-mediated brain damage on neurocognition and drinking behaviors. The dual-site design maximizes the power of the study by sampling two geographically distinct populations, and has a built-in replication component that is crucial, but often not realized in human neuroimaging studies.