Discussion
anxious mood, hyper-reactivity, anxiety
STAGGERING, EMA
Tobacco smoking imposes a staggering burden on global public health [Acute abstinence had robust consequences for subjective responses to the threat-anticipation paradigm, amplifying the intensity of threat-evoked fear and anxiety (Clinical, observational (e.g. EMA), experimental, and animal behavioral data suggest that withdrawal-related negative affect and heightened stressor reactivity are key triggers of lapses during nicotine cessation attempts [Work in rodents suggests that the pervasive increases in anxiety (tonic) and heightened surges of stressor-evoked distress (reactive) that often accompany periods of abstinence in nicotine-dependent humans reflect hyper-reactivity to threat in the EAc [How should we interpret this apparent failure of translation? One possibility is that the mechanistic insights gleaned from animal models of nicotine dependence are fundamentally correct, but conventional fMRI approaches—which rely on bulk changes in regional blood oxygenation—are insufficiently sensitive to underlying alterations in EAc molecular signaling and neuronal function [Another possibility is that our results represent a genuine translation failure; that the neurobiological mechanisms identified in rodents are sound, but that shock-probe burying and other instrumental defensive behaviors are a suboptimal means of modeling the subjective feelings of anxiety and distress that are central to withdrawal and relapse among abstinent human smokers (“wrong” animal assay). We are not the first commentators to raise this concern [A final possibility is that we simply lack the power to detect modest abstinence-induced changes in EAc threat reactivity. As detailed in the Method, our study was powered to detect medium-to-large effects (Cohen’s While not the primary aim of the present project, our neuroimaging findings also shed light on the neurobiology of fear and anxiety. Since the time of Freud, the distinction between certain (‘fear’) and uncertain (‘anxiety’) danger has been a key feature of neuropsychiatric models of emotion—including the National Institute of Mental Health’s influential Research Domain Criteria (RDoC) framework—but the architecture of the underlying neural systems has remained contentious [Our results also have implications for on-going debates about the functional architecture of the EAc [Tobacco smoking is a leading preventable cause of morbidity and mortality, and converging lines of evidence underscore the relevance of abstinence-induced anxiety and negative reinforcement mechanisms to the maintenance and treatment of nicotine use. Our experimental results reinforce and extend claims—made largely made on the basis of observational data—that acute nicotine abstinence triggers persistent increases in anxious mood and potentiates subjective stressor reactivity. Our neuroimaging results demonstrate that the impact of acute abstinence on EAc threat reactivity is negligible in humans, raising questions about the translational relevance of popular animal and human experimental models of addiction. A key challenge for the future will be to establish coordinated cross-species models of anxiety and addiction (bi-directional translation). A comprehensive multidimensional approach, well-established threat-anticipation task, and best-practice approaches to data acquisition, processing, and analysis enhance confidence in the robustness and translational relevance of our results. These observations provide a novel framework for conceptualizing anxious withdrawal symptoms and negative reinforcement mechanisms and for accelerating the development of more effective treatment strategies for nicotine dependence.