Hedy Kober - US grants

Abstract/Project Summary: Project #3 In addicted individuals, exposure to conditioned drug cues (e.g., paraphernalia) elicits craving: the desire to use drugs1. Craving is increasingly recognized as an important contributory factor in addiction in general, and in cigarette smoking in particular2-7. Indeed, it has been shown to predict smoking and relapse following abstinence8-16, suggesting that treatments to mitigate the effects of cue-induced craving are needed17. Consistently, skills training in regulation of craving (a form of cognitive control) is an important feature of many interventions7, 18-22, including cognitive-behavioral therapy23, 24 and mindfulness-based treatments25, 26. Craving and its regulation have distinct neurobiological mechanisms. The neural correlates of craving include the ventral striatum and ventromedial prefrontal cortex27-29. We developed the Regulation of Craving (ROC) task30-35 to investigate the neural mechanisms associated with the regulation of craving. In this task, nicotine-dependent smokers are exposed to smoking-related stimuli. In one condition they experience craving, and in another (the regulation condition), they are instructed to use a strategy to modulate their craving for cigarettes31. Research has shown that self-reported craving and craving-related neural activity are significantly reduced during the regulation condition32, 34, 36. However, the exact neural mechanisms by which regulation operates depend on the strategy used. Specifically, regulation of craving with cognitive strategies depends on activation in prefrontal regions, typically associated with cognitive control, such as dorsolateral and ventrolateral prefrontal cortex32, 36-38. However, regulation with mindfulness strategies does not involve PFC34. We propose that brief training in regulation of craving may increase the efficacy of smoking cessation treatments, but that training in cognitive vs. mindfulness-based strategies may operate via different psychological and neural mechanisms. We propose to test the efficacy of such training by randomizing 126 cigarette smokers to the following conditions: 1) brief training in cognitive regulation of craving + standard treatment, 2) mindfulness-based training + standard treatment, and 3) standard treatment (no training). Training will be delivered in 4x1 hour computerized sessions over four weeks, with an 8-week follow-up. We will evaluate the effects of training on craving and regulation of craving measured by self-report and functional magnetic resonance imaging during the ROC task administered pre- and post- treatment, as well as smoking. This project promises to advance our psychological and neurobiological understanding of craving and its regulation, how these processes change during specific types of training, and how they relate to actual smoking behaviors. Results from this study hold potential to allow neurobiologically-targeted adaptation of current treatments, with an aim of discovering potentially precise biological predictions of treatment outcomes.

? DESCRIPTION (provided by applicant): Craving and the ability to regulate it are increasingly recognized for having key roles in the maintenance of addictions including nicotine dependence, and the prevention of relapse. To investigate these important processes, we developed the Regulation of Craving (ROC) task1-5. In this task, nicotine- dependent smokers are exposed to smoking-related stimuli. In the craving condition, they are instructed to think of the pleasant feelings associated with smoking, which results in cigarette craving. Then, in the regulation condition, they are instructed to use a cognitive strategy to regulate their craving for cigarettes (e.g., `think of the negative consequences associated with smoking')1. We used the ROC task and functional magnetic resonance imaging (fMRI) to demonstrate that self-reported craving is significantly reduced during the regulation condition, and that this depends on recruitment of regions in prefrontal cortex associated with cognitive control, such as dorsolateral prefrontal cortex2, 6. We have also shown that recruitment of these brain regions, in turn, modulates activity in subcortical regions that underlie craving, such as the ventral striatum2, 3, 7. Stress s another key factor contributing to drug use in general and smoking in particular8. A leading hypothesis is that stress contributes to smoking and relapse by potentiating craving and neural activity in brain regions associated with craving (including ventral striatum)9-11. However, recent research suggests that stress can also impair prefrontal function12. Thus, it is possible that stress may lead to drug use via two distinct routes: by (1) potentiating craving and neural activity in craving-related regions (as shown with other addictions), and also (2) compromising the regulation of craving via decrements to prefrontal function. To test our novel model and evaluate these alternative hypotheses we will administer the ROC task to 84 nicotine-dependent smokers, and 84 matched healthy controls during a 90-minute fMRI session. We will use threat of electric shock, which is known to induce acute stress on half of the trials. Then, we will compare (a) self-report and (b) neural activity between craving and regulation conditions, in a 2x2x2 factorial design: 2 ROC conditions (Craving vs. Regulation) x 2 Stress conditions (Threat of Shock vs. Safe from Shock) x 2 Stimulus types (Cigarettes vs. Appetitive Food control). To establish the clinical relevance of our findings, we will assess the contribution of each effect (Stress on Craving vs. on Regulation) to smoking severity. Finally, we will preliminarily explore gender and individual differences in stress, craving, and the regulation of craving, as evidence suggests they may moderate effects of stress and craving, with implications for smoking cessation. This project promises to advance our neurobiological understanding of stress, craving, and the regulation of craving, as well as their interaction and contribution to smoking. I turn, this would provide both a new theoretical framework to understand extant data on stress and substance use, and also adapt current treatments to specifically address the effects of stress of craving and its regulation.

Abstract The experience of drug craving is known to increase drug use1-6 and relapse after treatment7-16. Specifically, drug-related stimuli are known to elicit cue-induced craving, as well as physiological and neural responses, called cue reactivity, which have all been directly linked to drug use and relapse across addictions17-35, including gambling36-39. To date, hundreds of studies investigated neural cue-reactivity; however, there is little consensus in findings, due to significant variation in methods, drug types, cue types, and analysis procedures. Further, prior meta-analyses used suboptimal methods and inclusion criteria, and were underpowered40-44. In Aim 1, we propose to use state-of-the-art meta-analytic methods45-47 to summarize findings from ~120 published imaging studies, representing >3000 participants during neural cue reactivity/cue- induced craving (and 3x larger than any prior meta-analysis). Following our prior meta-analytic work in other domains48-61, we will use optimized inclusion criteria and correction methods, and account for multiple methodological differences in studies across substances (e.g., cigarettes, alcohol, cocaine, cannabis) and gambling, a behavioral addiction. Further, we will test for differences across drug types (e.g., cigarettes vs. alcohol) and different cue-types (e.g., pictures vs. video) to resolve several open questions in the field (e.g., role of insula in cigarette craving vs. drug craving in general62, 63; pre-scan abstinence64, 65). In Aim 2, we will go beyond meta-analysis to address an urgent need in addiction research66: development of predictive biomarkers67-69, which are stable indicators of biological processes. Biomarkers have been developed in other areas of medicine70, and we have recently done this in pain71, negative emotion72-74, and empathy74. To do this, we will combine the meta-analytic results obtained in Aim 1 with person-level fMRI data from our lab (of cue-induced craving75-79) using machine learning models, to establish a multivariate pattern of neural activity that can predict craving self-report from neural activity ? a predictive neuromarker for craving. Given the associations between neural cue reactivity, craving, and drug use outcome, a multivariate neuromarker could provide a powerful neural predictor of outcomes66, 67. Thus, in Aim 3, we will validate this neuromarker on data from two ongoing clinical trials of N=128 cigarette smokers and N=150 cocaine users collected at Yale's Psychotherapy Development Center (P50 DA09241; Center PI: Carroll; Project PI: Kober). Here, the neuromarker will be used on pre-treatment fMRI cue-reactivity data to predict both self-reported craving and long-term clinical outcomes (e.g., cocaine abstinence). The validated neuromarker will provide well-defined brain targets that can then be used to test the efficacy of interventions to reduce craving and drug use, such as pharmacotherapies, brain stimulation, or cognitive training, and to monitor patient progress in both research and clinical settings. !

Abstract/Project Summary Craving and the ability to regulate it are increasingly recognized for having key roles in the maintenance of addictions (including nicotine dependence), and in the prevention of relapse. To investigate these important processes, we developed the Regulation of Craving (ROC) task1-5. In this task, nicotine-dependent smokers are exposed to smoking-related stimuli. In the craving condition, they are instructed to think of the pleasant feelings associated with smoking, which results in cigarette craving. Then, in the regulation condition, they are instructed to use a cognitive strategy to regulate their craving for cigarettes (e.g., `think of the negative consequences associated with smoking')1. We used the ROC task and functional magnetic resonance imaging (fMRI) to demonstrate that self-reported craving is significantly reduced during the regulation condition, and that this depends on recruitment of regions in prefrontal cortex associated with cognitive control, such as dorsolateral prefrontal cortex2, 6. We have also shown that recruitment of these brain regions, in turn, modulates activity in subcortical regions that underlie craving, such as the ventral striatum2, 3, 7. Stress is another key factor contributing to drug use in general and smoking in particular8. A leading hypothesis is that stress contributes to smoking and relapse by potentiating craving and neural activity in brain regions associated with craving (including ventral striatum)9-11. However, recent research suggests that stress can also impair prefrontal function12. Thus, it is possible that stress may lead to drug use via two distinct routes: by (1) potentiating craving and neural activity in craving-related regions (as shown with other addictions), and also by (2) compromising the regulation of craving via decrements to prefrontal function. To test our novel model and evaluate these alternative hypotheses, we will administer the ROC task to 84 nicotine-dependent smokers and 84 matched healthy controls in a 90-minute fMRI session. We will use threat of electric shock, which is known to induce acute stress, on half the trials. We will compare (a) self-report and (b) neural activity between craving and regulation conditions, in a 2x2x2 design: 2 ROC conditions (Craving vs. Regulation) x 2 Stress conditions (Threat of Shock vs. Safe from Shock) x 2 Stimuli (Cigarettes vs. Appetitive Food control). Exponential inter-trial intervals will ensure proper separation of neural events13, 14. To increase clinical impact we will assess the contribution of each effect (Stress on Craving vs. Regulation) to smoking severity. Finally, we will explore gender and individual differences in stress, craving, and the regulation of craving, as they may moderate effects of stress, with implications for smoking cessation. This project promises to advance our neurobiological understanding of stress, craving, and the regulation of craving, as well as their interaction and contribution to smoking. In turn, this would provide both a new theoretical framework to understand extant data on stress and substance use, and also adapt current treatments to specifically address the effects of stress on craving and its regulation.

Abstract/Summary Attention-Deficit/Hyperactivity Disorder (ADHD) affects 11% of children and leads to adverse outcomes[1,2]. These include impaired psychosocial, educational, and neuropsychological development, lower achievement levels across domains, and distress, often continuing into adulthood[3?7]. Medications, while often effective in reducing certain ADHD symptoms, have many disadvantages, including misuse and side effects[8?15]. Behavioral interventions do not have these adverse effects, but they are not as effective[9,10]. Mindfulness has been the subject of increasing academic and clinical attention[16]. In recent years, it has been studied in adult populations for a variety of medical and psychiatric conditions, and it is known to be effective across disorders, including ADHD[17?34]. Moreover, we and others have shown that it improves attention and emotion regulation, and alters resting state brain activity and connectivity[35,36]. However, investigations in children and adolescents are far less common[37?40]. To our knowledge, mindfulness as an intervention for ADHD in elementary school children has not been systematically and rigorously studied. We propose to evaluate the feasibility and acceptability of Mindfulness-Based ADHD Treatment for Children (MBAT-C), a novel neuroscience-informed intervention for elementary school children, in an underserved area. MBAT-C is designed for children at precisely the age when ADHD-relevant neurocognitive systems are developing and clinical symptoms begin to appear. There is reason to believe that this innovative treatment will succeed in treating ADHD, given the overlap between neuroscientific mechanisms by which mindfulness exerts its effects and the neurobiology of ADHD[41?44]. Proposed mechanisms of mindfulness include modulation of subsystems of attention, suggesting that a treatment program that targets the attention regulation capacities impaired in elementary school children with ADHD may be efficacious. Forty-five children from Southwest Community Health Center in Bridgeport, CT will be recruited to participate in this randomized- controlled feasibility trial that will compare MBAT-C and medication. Aim 1 is to finalize the MBAT-C manual. Aim 2 is to evaluate the feasibility of MBAT-C on indices of recruitment, randomization, attendance, medication adherence, participation, retention, homework completion, acceptance, and teacher fidelity. Aim 3 is to preliminarily evaluate (within group) pre-, post-, and follow-up measures of ADHD severity, behavior, attention, executive function, working memory, and mindfulness. In accordance with the National Center for Complementary and Integrative Medicine?s framework for developing mind and body interventions, data from this feasibility study will be used in subsequent mechanism- based, multi-site feasibility, and multi-site efficacy studies that will be funded by R61/R33, U01, UG3/UH3+U24 grants, respectively, as well as a K23 training grant. The ultimate goal is to develop a non-pharmacologic intervention for children with ADHD with the efficacy of pharmacotherapy, but without its side effects.

Project Summary/Abstract Major Depressive Disorder (MDD) is a prevalent and debilitating psychiatric illness. Having a mother with MDD is a significant risk factor for MDD. A central process implicated in MDD transmission is emotion dysregulation, which results from a combination of irregular emotional reactions and maladaptive emotion regulation (ER; the ability to alter one?s emotional experience and expression in an adaptive way). Prior studies have shown that ? in response to negative stimuli ? adolescents with familial MDD risk display increased activation in brain regions associated with negative affect (NA; e.g., amygdala), and decreased activity in regions related to cognitive control (e.g., dorsolateral prefrontal cortex [dlPFC]). In response to positive stimuli, at-risk adolescents show blunted response in regions related to reward processing (e.g., ventral striatum) and increased activation in regions related to cognitive control. Together, these findings support the idea that emotion dysregulation is a risk factor for MDD. Conversely, adaptive ER may serve as a protective factor. Thus, emotion dysregulation is an important target for research and intervention. Prior imaging studies, however, suffer from low ecological validity. The present study will address this limitation in two ways. First, we will focus on interpersonal context, which is central to MDD risk. The few studies that used social stimuli examined only responses to peer feedback, despite the evidence that parental feedback is crucial in MDD. The present study will be the first to examine neural responses to both maternal and peer feedback using functional magnetic resonance imaging (fMRI). Second, we will complement fMRI with experience sampling methods (ESM), a highly ecologically valid procedure that involves monitoring individuals in daily life. Thus, the proposed study will uniquely shed light on the associations between neural responses to maternal and peer feedback and everyday experiences. We will recruit 60 never-disordered children (aged 9-13) of mothers with (high-risk) or without (low-risk) past MDD. Participants will complete an fMRI task assessing responses to peer and maternal feedback. Then, we will use ESM for 21 days to assess their emotional reactivity and regulation in response to interpersonal events. We hypothesize that (1) those at high (vs. low) risk will respond to criticism with greater activation in brain regions related to NA and less activation in regions related to cognitive control, whereas in response to praise, they will show less activation in brain regions related to reward circuitry and increased activity in regions related to cognitive control. (2) In response to everyday negative events, high-risk adolescents will experience more NA and use more maladaptive ER and less adaptive ER; in response to positive events, high-risk adolescents will experience less positive affect (PA) and use more maladaptive ER and less adaptive ER. (3) Neural responses to feedback will predict NA, PA, ER, and depressive symptoms in everyday life, and will (4) moderate within-person associations between interpersonal events and affect. (5) Gender will be used as an exploratory moderator across analyses.

Abstract/Project Summary Heavy drinking in young adults (YA) is prevalent, and associated with serious negative consequences including mortality and risk for alcohol use disorders (AUD)1-7. However, existing interventions have shown modest efficacy8-14, and innovative interventions are needed. YA interventions have potential for broad impact if they are brief, computerized (especially web-based), and target core neurocognitive mechanisms underlying heavy drinking14,15. Two such mechanisms are craving and regulation of craving. Defined in DSM-5 as ?a strong desire?16, craving is prospectively associated with and predicts drinking (e.g.,17- 25, including in YAs (e.g.,26-29). Importantly, alcohol-associated cues increase craving30; such cue-induced craving is also prospectively associated with and predicts drinking(e.g.,31-35), including in YA32,33,36,37. These data implicate cue-induced craving as a core mechanism underlying drinking38. Consistently, skills training in regulation of craving is an important feature of many interventions39-44, including cognitive-behavioral therapy (CBT)45 and mindfulness-based treatments (MBT)46,47. Further, regulation of craving directly relates to reductions in craving and drinking, and better treatment outcomes(e.g.,34,41,42,48-52), including in YA53. These data implicate regulation of craving as a core mechanism underlying change in drinking/abstinence54. We developed the Regulation of Craving (ROC) task to investigate cognitive, affective, and neural mechanisms associated with craving and its regulation across substances55-61. In one study, alcohol drinkers were exposed to alcohol images60. On craving trials, they experienced cue-induced craving and exhibited neural activity in regions including ventral striatum and ventromedial prefrontal cortex62-64. On regulation trials they used a treatment-based strategy to modulate their craving. We found that self-reported craving and craving-related neural activity were significantly reduced during regulation60. However, across studies we found that the neural mechanisms by which regulation operates depend on the strategy used. Specifically, regulation with CBT strategies (e.g., ?think of the negative consequences of drinking?) depends on the PFC56,60,65 while regulation with MBT strategies (e.g., ?notice and accept craving without judgment?) does not57,66,67. Based on this, we developed two brief, web-based, mechanism-focused interventions: CBT-based and MBT-based Regulation of Craving Training (ROC-T)58,68,69, in which participants repeatedly practice regulating craving in the presence of alcohol images. We propose to evaluate the efficacy of ROC-T and its mechanisms by randomizing 177 YA heavy drinkers to 4x45 minute sessions of (1) CBT-ROC-T, (2) MBT- ROC-T, or (3) CONTROL (no strategy). Alcohol use will be measured via Timeline Followback70 for 10 weeks as well as a wearable transdermal sensor71,72. Pre- and post-training, we will evaluate cognitive, affective, and neural mechanisms underlying ROC-T using the ROC task and fMRI. The current project has the potential to significantly advance mechanism-targeted interventions for heavy drinking, AUD, and other addictive disorders.