Mustafa al'Absi, Ph.D. - US grants

Abstinence from cigarette smoking is associated with negative affect symptoms, such as anxiety, irritability, depression and craving. These symptoms present a major obstacle in cessation, and they are intensified under acute stressful situations. Mechanisms responsible for the stress- induced exacerbation of withdrawal symptoms are not known. Without specific knowledge of the biobehavioral mechanisms responsible for the effects of stress in smoking, targeted efforts to stress-precipitated smoking will remain limited. The long-term goal of this research is to determine how psychobiological responses to behavioral stress influence smoking behavior. The specific goal of this project is to evaluate cortisol responses to behavioral stress and to assess the extent to which smoking abstinence alters these responses in dependent cigarette smokers. Smokers and non-smokers will participate in two counter-balanced laboratory sessions conducted on two separate days (rest session and stress session). Smokers will be randomly assigned to one of two conditions: abstinence from smoking for 24 hours prior to each lab session or ad libitum smoking. During the laboratory stress session, behavioral stress will be modeled by work on an extended, interpersonally demanding stress (public-speaking) with an emphasis on social evaluation. Salivatory cortisol and self-report measures of withdrawal symptoms will be obtained during the two laboratory sessions and during the 24-hour period prior to each session. During lab sessions, we will also monitor heart rate, systolic and diastolic blood pressure, and measure stroke volume using impedance cardiography. Calculated valuables will include cardiac output, systemic vascular resistance, and rate-pressure product. The project will include men and women, and will explore gender differences in responses to abstinence from nicotine and to behavioral stress. Ultimately this work should lead to a better understanding of the biobehavioral mechanisms responsible for the increased desire to smoke under stressful situations, and to development of more effective intervention techniques for smoking cessation and relapse prevention.

DESCRIPTION: (Applicant's Description) Cigarette smoking is the leading preventable cause of cancer and cardiovascular diseases. Although the decades have witnessed accelerated efforts to develop effective smoking cessation strategies, the long-term success rates have been disappointing. The majority of smokers relapse within two weeks of a cessation attempt, and little is known about the nature of this early relapse. Smoking cessation is associated with negative affect symptoms. These symptoms are intensified in stressful situations, possibly accelerating the progression towards a full relapse. Mechanisms responsible for this stress effect are not known. Without specific knowledge of the stress-related biobehavioral changes, targeted efforts to reduce smoking and relapse will remain limited. The long-term goal of this research is to determine the psycho biological mechanisms responsible for smoking relapse. The specific goal of this project is to evaluate hormonal changes during early abstinence and in response to behavioral stress, and to assess the extent to which these changes predict early relapse. Our central hypothesis is that exaggerated responses to behavioral stress predict a shorter time to relapse. This hypothesis is based on the well-established observation that stressful events, characterized by negative emotions, are associated with rises in adrenocorticotropic hormone (ACTH) and cortisol concentrations. It is also based on the observation that environmental stressors increase the risk for smoking relapse. We will specifically determine the extent to which basal cortisol activity during early smoking abstinence predicts relapse, examine endocrine and cardiovascular responses to stress as predictors of smoking relapse, and evaluate gender differences in psycho biological changes during smoking abstinence and in response to behavioral stress. This research focuses on the pituitary-adrenocortical axis, an important stress-related biological system recently implicated in addiction. We will integrate hormonal, autonomic and psychological indices to gain an accurate profile of the stress response patterning among smokers and use this information in a prospective fashion to predict relapse in men and women. The results will provide a base of knowledge concerning psycho biological changes associated with quitting and risk for relapse. This information will facilitate efforts towards improving methods to identify and assist individuals at high risk for relapse. Reducing relapse rates will contribute significantly towards reducing smoking and its harmful effects.

DESCRIPTION (provided by applicant): Tobacco addiction is the leading preventable cause of cancer and cardiovascular diseases. Although the last two decades have witnessed accelerated efforts to develop effective smoking cessation strategies, the long-term success rates have been disappointing. The majority of smokers relapse within two weeks of a cessation attempt. Stress is one of the most commonly reported precipitants of smoking relapse. Mechanisms responsible for the stress-precipitated relapse are not known. Without specific knowledge of the stress-related psychobiological changes in smokers, targeted efforts to reduce smoking relapse will remain limited. The long-term goal of our research is to determine the psychobiological mechanisms responsible for smoking relapse. The specific goal of this project is to determine the extent to which changes in the pituitaryadrenocortical activity during early abstinence and in response to acute stress predict relapse in smokers attempting to quit. Our central hypothesis is that exaggerated adrenocorticotropic hormone (ACTH) and cortisol changes during early abstinence, as measured during ambulatory monitoring and in response to stress, predict time to relapse. This hypothesis is based on our previous studies and on the observation that psychosocial stressors increase the risk for smoking relapse. The proposed study will include ambulatory measurement of diurnal cortisol levels and awakening rise in cortisol during 24 hours while participants are still smoking at their normal rates (baseline), and during the period of 24-48 hours of abstinence. The study will also include measurement of plasma ACTH, cortisol, blood pressure, and withdrawal symptoms during two laboratory stress sessions (during ad libitum smoking and after 48 hours of abstinence). During each session participants will perform three stressful challenges (public speaking, math, and cold pressor). This research focuses on the hypothalamic-pituitary-adrenocortical axis, an important biological system recently implicated in addiction. The research integrates hormonal, hemodynamic, and psychological indices to determine stress response patterning among smokers during this critical period of a quit attempt, and uses this information in a prospective fashion to identify specific biobehavioral markers of relapse over a 12-month period. An important goal for this research is to determine differences in psychobiological changes between men and women, and establish the extent to which these differences predict relapse. The results will be important in the development of optimal diagnostic and intervention strategies for smokers interested in cessation and at high risk for relapse. Reducing relapse rates will contribute significantly towards decreasing tobacco use and its devastating effects.

stress; pain threshold; opioid receptor; hormone regulation /control mechanism; receptor binding; gender difference; hormone metabolism; naltrexone; cortisol; blood pressure; adrenocorticotropic hormone; endorphins; clinical research; human subject; blood chemistry;

DESCRIPTION (provided by applicant): A dramatic escalation in the prevalence of tobacco use and addiction in developing countries has been documented, increasing the threat of grave consequences for health and for sustainable economic development in these countries. In order to slow this epidemic, it is important to identify psychosocial and biochemical factors that promote and maintain this addiction, and to subsequently develop effective methods to address it. The situation in Yemen and in neighboring countries is particularly grim and complicated by the concurrent use of khat, a psychostimulant drug widely used by both men and women. Yemen is a low-income country with unique strategic characteristics, being centrally located within a group of culturally and linguistically similar countries in need of efforts to reduce tobacco use. The long-term goal of this proposal is to develop a multidisciplinary research program focusing on biobehavioral mechanisms of tobacco addiction and the concurrent use of khat in Yemen. The specific goal of this FIRCA proposal is to determine hormonal, hemodynamic, and mood changes during rest and in response to acute behavioral stressors among dependent tobacco users and non-users who are or are not regular khat users. The design will include 4 groups: tobacco and khat users, tobacco users only, khat users only, and those who do not use either drug. Measures will be collected in two counterbalanced sessions conducted on two separate days, after abstinence or ad libitum tobacco use. Ambulatory cortisol and self-report measures of withdrawal symptoms will also be obtained during the 24-hour period prior to each session. We will include men and women, and will, therefore, examine gender differences in responses to psychological stress among tobacco and khat users. The project will represent a first stage towards developing a sustainable research program that will focus on understanding and combating tobacco addiction and concurrent use of khat in Yemen and the surrounding region. The results will improve our basic understanding of concurrent addictions and subsequently help us develop effective methods for prevention and treatment of these addictions. This work is also relevant to research focusing on concurrent addictive behaviors in other countries. Successful efforts to reduce the tobacco epidemic and to reduce concurrent use of other substances will have a significant positive impact on global health and security.

ACTH; ACTH (1-39); Abstinence; Adrenocorticotropic Hormone; Adrenocorticotropin; Biological; Blood Plasma; Blood Pressure; CRISP; Computer Retrieval of Information on Scientific Projects Database; Corticotropin; Corticotropin (1-39); Development; Diagnostic; Funding; Goals; Grant; Hormonal; Hour; Hypophysis; Hypophysis Cerebri; Hypothalamic structure; Hypothalamus; Institution; Intervention; Intervention Strategies; Investigators; Laboratories; Measurement; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Pituitary; Participant; Pituitary; Pituitary Gland; Plasma; Public Speaking; Rate; Relapse; Research; Research Personnel; Research Resources; Researchers; Resources; Reticuloendothelial System, Serum, Plasma; Risk; Serum, Plasma; Smoker; Smoking; Source; Speaking, Public; Stress; System; System, LOINC Axis 4; Tobacco Consumption; Tobacco use; United States National Institutes of Health; Withdrawal Symptom; acute stress; addiction; hypothalamic; interest; interventional strategy; psychobiologic; psychobiological; response

DESCRIPTION (provided by applicant): We plan to establish a multidisciplinary research and training program focusing on khat, a psychostimulant plant widely used in Africa and the Middle East associated with significant neurobehavioral and health effects. We will use this exploratory/developmental grant to achieve two primary goals. The first is to develop collaborative relationships and provide needed capacity-building resources that will include a series of research training workshops, establishing an Institutional Review Board, conducting relevant training on ethical standards of research, and organizing semi-annual meetings to develop future programmatic research. The second goal is to complete preliminary research to determine cognitive, affective, and biobehavioral consequences of long-term khat use. Khat users and nonusers will be compared on their performance on tests of response inhibition, attention, concentration, memory, and hormonal and cardiovascular responses to acute stress. We will include two samples of khat users, those who use khat alone and those who use khat and tobacco together. The purpose will be to examine the influence of the concurrent use of both substances. The program will take advantage of a unique population and setting by conducting this work in Yemen. The design of the preliminary research is geared towards maximizing the potential for advancing khat-related research in this and surrounding countries, and will facilitate later development of research that will guide efforts to develop methods to reduce the harm caused by khat and tobacco use. The combination of measures of the stress response and cognitive functioning will provide novel information on the impact of khat use on important behavioral and neurobiological functions. We have assembled a multidisciplinary, international team with distinguished records and experience in all relevant topics. Both the training and research arms of the program will emphasize this breadth of expertise. This program will form a core part of our conceptualization of future research initiatives to further identify neurobehavioral effects of khat an concurrent tobacco use and develop means for effective intervention strategies. PUBLIC HEALTH RELEVANCE: This program addresses the growing use of khat and its harmful effects on health in many countries in Africa and the Middle East and among immigrant communities in Western Europe and North America. The program will advance our knowledge of the short and long-term effects of khat use and help guide efforts to develop future research programs related to prevention and treatment of khat and tobacco use. Combating this problem will have significant benefits on the health conditions in many countries in the world. The program will also be significant in fostering scientific and research capacity-building efforts in Yemen.

DESCRIPTION (provided by applicant): Our research to date has demonstrated that cigarette smokers exhibit enhanced basal hypothalamic-pituitary-adrenocortical (HPA) activity and attenuated cortisol responses to multiple stress procedures. Our particularly important finding has been that this altered stress response predicts early smoking relapse. It is well-established that the endogenous opioid system plays a critical role in HPA regulation and that both systems are involved in regulating mood and reinforcing effects of drug use. The extent to which altered HPA response in smokers is due to disrupted endogenous opioid regulation is unknown and is the focus of the proposed research. Preliminary findings on the effects of opioid blockade on HPA stress response indicate that diminished opioid tone may be one potentially important mechanism. The extent to which these opioid-HPA alterations are modified by smoking abstinence and the extent to which they exacerbate symptoms associated with abstinence will be elucidated by this research. We have also demonstrated sex differences with respect to relapse predictors. The proposed research will examine and clarify sex differences in hormonal response patterns during an opioid blockade challenge and in response to stress in dependent female and male smokers. In combination, the findings to date and the potential discovery of an important pathway for stress effects on smoking point to the importance of delineating the opioid-HPA interactions. Confirmation of dysregulated endogenous opioid tone in abstinent smokers and in response to stress will set the stage for refined investigations to develop biobehavioral markers of nicotine dependence, stress-related craving, and relapse. PUBLIC HEALTH RELEVANCE: Tobacco addiction/dependence is the leading preventable cause of cancer and cardiovascular diseases. Stress is widely cited as a reason for continued smoking and for relapse in those attempting to achieve long term abstinence. The proposed research extends our program to identify biobehavioral mechanisms and determinants of stress effects on smoking. This will set the stage for research to determine relapse vulnerability markers. In turn, this will provide unique opportunities for prediction and development of targeted interventions.

DESCRIPTION (provided by applicant): Converging evidence indicates that concern about weight gain after abstinence increases reluctance to attempt smoking cessation, and that post-cessation weight gain is associated with smoking relapse. Chronic smoking causes numerous neurobiological changes, and smoking abstinence is associated with changes in appetite. Elucidating biobehavioral mechanisms associated with these effects of abstinence is critical in identifying those at high risk for weight gain and for planning appropriate treatment contingencies. The long-term goal of our research is to delineate the interactions of neurobiological mechanisms responsible for appetite regulation and tobacco addiction. The specific goal of this project is to determine the extent to which levels of appetite-regulating peptides (i.e., leptin, ghrelin, GLP-1, neuropeptide Y, and orexin) measured during smoking and during the early phase of abstinence predict subsequent changes in appetite, dietary intake, weight, and relapse during smoking cessation. We will also examine the extent to which abstinence-induced blunted adrenocortical and cardiovascular responses to stress predict changes in appetite, dietary intake, weight, and relapse over the first three months of a cessation attempt. This application is a continuation of our focused program investigating the role of stress in smoking relapse while taking into account that the effects of stress do not operate in vacuum, and that there is a need to clearly identify interactions of stress effects with other motivational and mood states. We have completed studies identifying specific psychobiological patterns of the stress response sensitive to individual and situational factors in smokers and non-smokers. We recently completed a series of studies that examined changes in hypothalamic-pituitary- adrenocortical responses to stress following short-term smoking abstinence and evaluated the extent to which these changes predict early relapse. The composite work and literature have provided relevant directions to guide the development of the proposed program. PUBLIC HEALTH RELEVANCE: Tobacco addiction/dependence is the leading preventable cause of cancer and cardiovascular diseases. Evidence indicates that weight gain occurring after smoking abstinence increases reluctance to attempt smoking cessation, especially among women. There is also evidence that post-cessation weight gain is associated with smoking relapse. We plan to determine the extent to which changes in appetite-related peptides and stress response during early abstinence predict subsequent weight gain and smoking relapse. Gaining a better understanding of these factors will be essential in designing interventions to address weight gain and stress effects during cessation, and to subsequently reduce smoking relapse rates. Reducing smoking relapse will have a direct public health impact in reducing the burden of smoking-related diseases.

The collaborative research project (IIS-1231754, Santosh Kumar, University of Memphis; IIS-1231525, Mustafa al'Absi, University of Minnesota Twin Cities; IIS-1231577, Emre Ertin, Ohio State University) is developing and evaluating a mobile sensor called EasySense that can provide continuous physiological monitoring without skin contact in the field environments using radio frequency (RF) probes. This approach addresses the problem of physiological monitoring today that requires skin contacts such as electrodes for ECG, and hence cannot scale to widespread monitoring of patients and healthy adults for years. The key challenge is to develop high-resolution sensing on low-power mobile platforms that can separate out the weak motion signals of heart and lung, from the gross motion of the body and the sensor. The project is developing theory and design for a compressive ultrawideband (UWB) RF sensor that achieves two orders of magnitude reduction in the required sampling rate to make it feasible to realize in a low-power mobile form factor. EasySense employs dynamic compressive sensing algorithms to improve the quality of sensing through temporal integration of information and employs interference subspace cancelation methods to cancel out motion artifacts using data obtained from accelerometers and gyroscopes. The project is implementing all the needed hardware, firmware, embedded software on the sensor node for sampling, processing, and wireless communication, and mobile phone software for data collection, storage, and visualization. EasySense is evaluated against traditional physiological sensors via lab and field studies on human subjects involving stress and exercise protocols.

By realizing contactless sensing of physiology in the field environment, EasySense will enable long-term physiological monitoring at large-scale that is essential for determining potential causes and early biomarkers of fatal diseases of slow accumulation such as cancer and cardiovascular diseases. In addition to being used widely in health research and practice, EasySense can be used for hands-on demonstration in health education. Information on the project, developed hardware and software design files and code relating to the testbed infrastructure will be accessible in open source form via the project web site (http://www.easysense.org).

Abstract Smoking cessation interventions (pharmacological and behavioral) and policy actions have reduced overall smoking rates. However, there remain significant populations for whom success rates are lower than predicted, most notably smokers who use other substances and those with psychiatric disorders. Cannabis, the most prevalent illicit drug in the U.S. and among tobacco users, may increase risk for relapse to cigarette smoking. Stress is one of the most commonly reported precipitants of smoking and relapse for both tobacco and cannabis users. Systems involved in the stress response, including the hypothalamic-pituitary-adrenocortical (HPA), endocannabinoid, and sympathetic systems, play a critical role in regulating mood and the reinforcing effects of drug use. Research from our current and previous funding periods has shown that cigarette smokers exhibit: 1) enhanced basal HPA activity; 2) blunted cortisol response to multiple stressors; 3) disrupted opioid regulation of the stress response; 4) association of attenuated stress response and early smoking relapse; and 5) sex differences in patterns of predictors of relapse-- men exhibit consistent hormonal prediction, while women show consistent withdrawal symptoms predictive of smoking relapse. It is not known whether the altered stress response observed in smokers is further exacerbated by cannabis co-use. How these systems are modified by withdrawal and influence risk for relapse is also unknown. Research to elucidate sex differences in these factors is particularly lacking. We propose to elucidate stress-related psychobiological mechanisms associated with concurrent cannabis use that impede successful smoking cessation and which, when identified, can be used as metrics to identify and tailor interventions. We will therefore conduct this research to: 1) Define the impact of concurrent cannabis use on the psychobiological mechanisms of the stress response in smokers who are interested in quitting but still smoking ad libitum, 2) determine the impact of abstinence from cannabis use, in conjunction with abstinence from cigarette smoking, on stress response in smokers who are interested in tobacco cessation, 3) examine the extent to which stress response during ad libitum smoking and during abstinence from tobacco, or from tobacco and cannabis, predict affective disturbance and smoking relapse over three months, and 4) identify sex differences in diurnal patterns and the stress response during ad libitum smoking and withdrawal in smokers and co-users, and establish the extent to which these differences predict relapse. The proposed work will build on our previous research to set the stage for interventions that involve a personalized medicine approach to predicting smoking relapse. This will enable the development and testing of targeted, sex-specific, just-in-time interventions to address the impact of stress and co-use of cannabis on smoking cessation.

Summary Stress is one of the most commonly reported triggers of smoking relapse. It increases frequency of smoking among chronic smokers and accelerates progression towards full relapse among abstinent smokers. This relapse risk is particularly high in the presence of other negative affective states, including anxiety, irritability, depression, and craving, especially in women. Our previous research has demonstrated altered hypothalamic-pituitary-adrenocortical (HPA) axis and endogenous opioid system (EOS) regulation of the stress response in smokers. We found that 1) smokers exhibit enhanced basal HPA activity, 2) they exhibit decreased cortisol responses to multiple acute stress procedures, and 3) early smoking relapse can be predicted by attenuated adrenocorticotropin (ACTH) and cortisol responses to stress. Recent results using an opioid blockade challenge demonstrate blunted opioid regulation of the HPA stress response in smokers relative to nonsmokers; and smoking appears to acutely normalize opioid regulation of the stress response. The clinical significance of altered opioid regulation of the stress response has not been tested in the clinical context of smoking cessation and relapse. Building on previous findings, we plan in this new study to take a novel approach in addiction relapse research by identifying indices of risk for relapse using opioid- HPA stress response patterns. Our hypothesis is that smokers who exhibit blunted HPA stress response to opioid blockade are more likely to relapse early in their cessation attempt. Blunted opioid regulation contributes to inefficient stress response and may exacerbate stress effects on craving and withdrawal symptoms. We will establish the link between altered endogenous opioid regulation of the HPA stress response, withdrawal symptoms, and craving during smoking cessation. We will develop a model to predict early smoking relapse using HPA responses to stress and HPA responses to endogenous opioid blockade. Finally, we will examine sex differences in the HPA response to stress, in the HPA response to opioid blockade, and in predictors of relapse. This research represents a step forward in translating established preclinical neurobiological models of addiction and stress. It is grounded in theory, builds on important preliminary results, and uses rigorous and reproducible procedures. Demonstrating the utility of an opioid challenge in predicting relapse is a novel direction in addiction relapse research that will enable indexing two important stress biological pathways, providing both a novel mechanism of long-term effects of tobacco addiction and a marker of treatment outcome and relapse probability. This will facilitate future efforts targeting those susceptible to effects of stress on their risk for relapse with new or existing behavioral and pharmacological treatments. Reducing relapse rates will reduce tobacco use and its devastating health effects.