Acute nicotine abstinence amplifies subjective withdrawal symptoms and threat-evoked fear and anxiety, but not extended amygdala reactivity

Abstract

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)—including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis—but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

Adolescent social anxiety is associated with diminished discrimination of anticipated threat and safety in the bed nucleus of the stria terminalis

“…EPI volumes acquired before the first trial and following the final trial were unmodeled and contributed to the baseline estimate. Consistent with prior work using shock-reinforced variants of the countdown task in adults ( Grogans et al, accepted in principle ; Hur et al, 2022 ; Hur et al, 2020 ; Kim et al, 2023 ), additional nuisance variates included estimates of volume-to-volume displacement, motion (6 parameters, 0- and 1-volume lagged), cerebrospinal fluid (CSF) signal, instantaneous pulse and respiration rates, and ICA-derived nuisance signals (e.g. brain edge, CSF edge, global motion, white matter) ( Pruim et al, 2015 ).…”

“…Consistent with prior work by our group, task-related Ce and BST activation was quantified using well-established, anatomically defined ROIs and spatially unsmoothed fMRI data ( Grogans et al, accepted in principle ; Hur et al, 2018 ; Kim et al, 2023 ) ( Figure 1 ). The derivation of the Ce ROI is detailed in Tillman et al ( Tillman et al, 2018 ).…”

“…Normalized EPI data were resampled (2 mm 3 ) using fifth-order b-splines. To maximize anatomical resolution, no additional spatial filters were applied, consistent with recent recommendations ( Tillman et al, 2018 ) and other work by our group ( Grogans et al, accepted in principle ; Kim et al, 2023 ). Hypothesis testing focused on anatomically defined ROIs (see below).…”

“…Methods are similar to those described in other recent reports by our group ( Grogans et al, accepted in principle ; Hur et al, 2018 ; Hur et al, 2022 ; Hur et al, 2020 ; Kim et al, 2023 ). T1-weighted images were inhomogeneity corrected using N4 ( Tustison et al, 2010 ) and denoised using ANTS ( Avants et al, 2011 ).…”

“…Building on prior work in adults ( Grogans et al, accepted in principle ; Hur et al, 2022 ; Hur et al, 2020 ; Kim et al, 2023 ), the MSTC paradigm takes the form of a 2 ( Valence: Social Threat/Safety) × 2 ( Temporal Certainty: Uncertain/Certain) × 2 ( Phase: Anticipation/Presentation) repeated-measures, randomized event-related design ( Figure 1 ). On Certain Social Threat trials, participants saw a descending stream of integers (‘count-down’) for 18 s. To maximize distress, the anticipation period always culminated with the presentation of a multi-modal social threat (1.8 s) encompassing a photograph of an angry young-adult face and an audio clip of a hostile verbal remark (e.g., “No one wants you here” ).…”