Brett Froeliger, Ph.D. - US grants

DESCRIPTION (provided by applicant): Cigarette smoking remains the number one preventable cause of premature death in the U.S. In spite of these avoidable consequences, an estimated 60-90% of smokers motivated to attempt to quit relapse within the first year of their attempt. Research suggests that two of the primary reasons smokers relapse is 1) to attenuate stress and/or reduce negative affect and 2) to enhance or restore cognition. Therefore, understanding the neurobiological basis of smoking abstinence on affective and cognitive processes may provide new and valuable insights into the nature and treatment of tobacco addiction. The overarching objective of this proposal is to identify functional neuroanatomical correlates of changes in emotional and executive brain function during smoking abstinence, and to relate these changes to clinically relevant variables. We will measure changes in performance and regional blood oxygenation levels using fMRI while smokers and non-smokers complete a task designed to assess the effects of emotional stimuli on the detection of novel visual targets. In smokers, we will examine the effects of current drug state on the interaction between emotional processing and novelty detection by scanning participants 1) after smoking their regular number and brand of cigarettes (satiated condition) and 2) after 24 hr abstinence (deprived condition). Doing so will provide an assessment of how withdrawal modulates the neural substrates of emotion information processing. Data from non-smokers will allow us to compare brain activity during emotional information processing in normal healthy individuals with brain activity in smokers. We hypothesize that deprived smokers, when presented with negative emotional distractors will exhibit increased fMRI signal relative to smoking satiety in brain regions underlying 1) visual information processing (extrastriate cortex), 2) attention (e.g., anterior cingulate cortex), 3) evaluation of emotional information (e.g., posterior cingulate cortex), and 4) limbic/reward areas (e.g., amygdala). We further hypothesize that negative emotional distractors will disrupt processing of subsequent novel visual targets. The magnitude of this disruption will be greatest among deprived smokers, suggesting that withdrawal leads to greater interference of executive functioning by competing emotional processes. The results of this study will enhance our understanding of the neurobiological basis of tobacco withdrawal, inform treatment development, and generate additional hypotheses and research plans. PUBLIC HEALTH RELEVANCE: The results of this study will enhance our understanding of the neurobiological basis of tobacco withdrawal, inform treatment development, and generate additional hypotheses and research plans.

DESCRIPTION (provided by applicant): Smoking and affective function are closely intertwined and considerable research suggests that dysregulated affect is a primary factor in the maintenance of, and relapse to smoking. Smokers frequently cite withdrawal-induced negative affect (NA) as a primary factor for re-initiating smoking (i.e. smoking lapse). This is significant given that lapses are one of the best predictors of full-blown relapse. Smokers with major depressive disorder (MDD) smoke at significantly higher rates, report greater NA during abstinence and are at greater risk for relapse than non-depressed (ND) individuals. Although considerable work has been conducted to characterize the association between dysregulated affect and smoking among MDD and ND individuals, little work has focused on the neural bases of this association, and to our knowledge, no reported work has focused on the effects of smoking and depression on the ability to regulate affective processes (i.e. emotion regulation [ER]). Recently, we have demonstrated that smoking abstinence disrupts emotional function via its impact on frontal executive function. Moreover, this modulation appears to be greater among smokers with elevated depressive symptoms. Whereas those data provide novel insights into the role of withdrawal on emotional reactivity, they fail to inform the neural basis of smoking-depression comorbidity and their interactive effects on the proactive regulation of emotion. Identifying smoking-depression effects on ER is critical for understanding self-regulation failure in the context of addiction and mental illness. In addition, though increased NA precipitates smoking relapse, associations between ER and smoking relapse remain unknown. Therefore, the goal of this application is to use affective neuroscience to investigate the effects of smoking and depression on ER, and their interaction with smoking behavior. Our overarching hypothesis is that smoking abstinence will disrupt ER via its impact on frontal executive function and that depression will worsen the effects. Furthermore, we hypothesize that ER failure will be associated with smoking lapse behavior as modeled in the laboratory. Dependent smokers (n=60) with and without MDD will be scanned during an ER task on two occasions: smoking as usual, and 24hrs abstinent. A nonsmoker control group with and without MDD will also be scanned on two occasions. On a separate visit, NS and ABS smokers will receive a monetary reinforcement to perform the ER task, and for smokers, resist the opportunity to smoke ad lib. The proposed research is significant as it will shed new light on the neural mechanisms that govern associations between depression and smoking. Despite known and costly associations between these factors, little is known regarding their co-occurrence and such information will provide a foundation for the development of novel and more effective interventions. For instance, support for our hypotheses will guide the rationale development of targeted interventions for disrupted emotional information processing in smokers using neural stimulation (rTMS), behavioral (CBT) and/or pharmacologic techniques.

? DESCRIPTION (provided by applicant): Nicotine addiction is a manifold process that involves dysregulated executive control, reward processing and negative affect. Preclinical models reveal that self-administration of nicotine produces an imbalance in corticostriatal glutamate transmission that mediates cue-induced reinstatement to nicotine seeking. Prior research suggests that N-acetylcysteine (NAC), a modified cysteine chain that regulates glial glutamate and normalizes cocaine-induced synaptic plasticity, may attenuate perceived smoking reward and smoking behavior. Crucially however, our preclinical data suggests NAC may be most effective under conditions of abstinence as a relapse prevention aid. Thus, pairing a smoking cessation medication (Varenicline: VRN) that promotes abstinence, with a relapse prevention aid (NAC), may produce greater cessation outcomes than either treatment alone. The overarching goal of this proposal is to use clinical and preclinical neuroscience to investigate limbic-striatal and corticostriatal circuits involved in nicotine addiction and determine the valueof VRN+NAC for normalizing circuitry function and treating nicotine addiction. Smokers interested in quitting will be randomized to one of four placebo (PBO) controlled conditions to examine the individual and combined effects of VRN and NAC over 4-weeks. Following 1-week of treatment, participants will be contingently reinforced for 3 days of smoking abstinence and undergo an fMRI scan. Participants will be followed over the next 3-weeks of treatment and clinically relevant behaviors will be assessed. Relations between fMRI measures and clinical variable will be explored. In our analog preclinical studies that use the same treatment groups as the clinical studies, we will employ an optogenetic strategy to examine the efficacy of VRN+NAC at inhibiting synaptic plasticity in prelimbic (PL) and basolateral amygdala (BLA) inputs to the nucleus accumbens produced during cue-induced nicotine seeking.

PROJECT SUMMARY - Overall The personal, social and criminal consequences of opioid and cocaine abuse are enormous problems in North America. This is most tragically seen in rising morbidity due to heroin, prescription opioids and fentanyl overdose in the USA. Addiction to drugs typically cycles between three phases, active drug use, withdrawal from drug use and relapse to drug use. A point in the cycle of addiction where pharmacological intervention can be particularly beneficial is to interfere with the overwhelming motivation by addicts to relapse to drug use, even after extended periods of abstinence when acute withdrawal symptoms have dissipated. However, the enduring state of relapse vulnerability arises from interdependent brain adaptations produced during all three phases of addiction. Thus, in order to develop biological rationales for treating relapse, it is necessary to understand not only the neurobiology of relapse itself, but to determine which changes produced by drug administration and drug withdrawal contribute to the final enduring state of relapse vulnerability. The overarching goal of the Center for Opioid and Cocaine Addiction (COCA) is to create and maintain mechanisms of scientific synergy that will facilitate discovering the neuropathologies that underpin the enduring and uncontrollable drive to seek opioids and cocaine, and thereby advance biological rationales needed to efficiently generate pharmacotherapies that inhibit drug relapse. This goal will be achieved through a bidirectional translational strategy that involves 3 Cores and 4 research Projects. In addition to the Administrative and Pilot Cores, the Animal & Validation Core makes available transgenic rodents that have been trained to self-administer heroin or cocaine, and have been instrumented with intracranial cannulae, fiber optics or GRIN lens. This Core will also validate all viral reagents and transgenic animals shared by the COCA Cores and Projects. The 4 Projects range from determining the epigenetic substrates of long- lasting drug-induced alterations to understanding the molecular and brain circuit mechanisms of cue-induced drug seeking in rodents and humans. The Projects are designed to be highly integrated and form a bidirectional translation strategy for providing biological rationales for new therapeutic approaches to relapse prevention.

ABSTRACT Tobacco use disorder (TUD), like other drugs of abuse, is associated with deficits in prefrontal mediated inhibitory control (IC)?the ability to stop pre-potent behavioral responding. We recently reported findings showing that IC task-based functional connectivity (tbFC) between the right inferior frontal gyrus (r.IFG) and thalamus (corticothalamic circuit) mediated the association between successful inhibition and smoking lapse / relapse vulnerability in the laboratory and in a smoking cessation study. Preliminary data from our laboratory shows that using intermittent theta burst stimulation (iTBS)?which induces long-term potentiation and putatively strengthens network activity?to the r.IFG significantly improves inhibitory control task performance among individuals with TUD. The goal of this proposal is to examine the mechanistic underpinnings of the effects of TBS on corticothalamic mediated inhibitory control and smoking and evaluate whether modulating corticothalamic tbFC translates to improved inhibitory control and reducing smoking lapse/relapse among individuals with TUD.

ABSTRACT Nicotine addiction is a manifold process involving dysregulated brain circuitry subserving reward and motivation (i.e. corticostriatal). Despite extant cross-species models in the literature, there is a gap in the human literature concerning the role of corticostriatal pathways that regulate appetitive processes, whether cognitive training may restructure circuitry function, and whether neuroplasticity in self-regulatory mechanisms alter appetitive behaviors, in particular cigarette smoking. Preliminary data from our laboratory provide initial support for our published model positing that cognitive control training via Mindfulness Oriented Recovery Enhancement (MORE), to enhance valuation of non-drug related reward relative to drug reward may remediate maladaptive appetitive behaviors, craving, and affective deficits by restructuring reward processing. The goal of this proposal is to examine the effects of MORE on corticostriatal mediated regulation of appetitive responding and smoking. Smokers (N=100) will be randomized to 4-weeks of MORE or CBT, undergo fMRI pre/post training, complete a laboratory-based smoking relapse analog task, and be followed for 2-weeks to assess relations between neural function, lab behavior and real-world smoking.

ABSTRACT Tobacco use disorder (TUD), like other drugs of abuse, is associated with deficits in prefrontal mediated inhibitory control (IC)?the ability to stop pre-potent behavioral responding. We recently reported findings showing that IC task-based functional connectivity (tbFC) between the right inferior frontal gyrus (r.IFG) and thalamus (corticothalamic circuit) mediated the association between successful inhibition and smoking lapse / relapse vulnerability in the laboratory and in a smoking cessation study. Preliminary data from our laboratory shows that using intermittent theta burst stimulation (iTBS)?which induces long-term potentiation and putatively strengthens network activity?to the r.IFG significantly improves inhibitory control task performance among individuals with TUD. The goal of this proposal is to examine the mechanistic underpinnings of the effects of TBS on corticothalamic mediated inhibitory control and smoking and evaluate whether modulating corticothalamic tbFC translates to improved inhibitory control and reducing smoking lapse/relapse among individuals with TUD.