The insula in nicotine use disorder: Functional neuroimaging and implications for neuromodulation

•Animal models and human literature suggests the insula is necessary in maintaining nicotine use disorders.•During acute nicotine withdrawal, the insula arbitrates bottom-up versus top-down saliency mechanisms to guide behavior – either to pursue smoking or to avoid relapse – and this arbitration is associated with craving and the nicotine withdrawal syndrome.•Recent studies have shown that the insula is a saturable node of information processing, such that different insular functions compete for limited resources – this saturability explains how craving during withdrawal can overload insular processing to the exclusion of other functions, such as saliency and network homeostasis.•Standard-of-care treatments for nicotine use disorder have limited efficacy.•Neuromodulation of the insula has potential to improve abstinence success rates amongst smokers. Insula dysfunction contributes to nicotine use disorders. Yet, much remains unknown about how insular functions promote nicotine use. We review current models of brain networks in smoking and propose an extension to those models that emphasizes the role of the insula in craving. During acute withdrawal, the insula provides the sensation of craving to the cerebrum and is thought to negotiate craving sensations with cognitive control to guide behavior – either to smoke or abstain. Recent studies have shown that insula processing is saturable, such that different insular functions compete for limited resources. We propose that this saturability explains how craving during withdrawal can overload insular processing to the exclusion of other functions, such as saliency and network homeostasis. A novel signal flow model illustrates how limited insular capacity leads to breakdown of normal function. Finally, we discuss suitability of insula as a neuromodulation target to promote cessation. Given the limited efficacy of standard-of-care treatments for nicotine use disorder, insular neuromodulation offers an innovative, potentially therapeutic target for improving smoking cessation.