Progressive Levels of Physical Dependence to Tobacco Coincide with Changes in the Anterior Cingulum Bundle Microstructure

et al. (2013) Progressive Levels of Physical Dependence to Tobacco Coincide with Changes in the Anterior Cingulum Bundle Microstructure. PLoS ONE 8(7): e67837. doi:10.1371/journal.pone.0067837 Progressive Levels of Physical Dependence to Tobacco Coincide with Changes in the Anterior Cingulum Bundle Microstructure Wei Huang 0 Joseph R. DiFranza 0 David N. Kennedy 0 Nanyin Zhang 0 Douglas Ziedonis 0 Sanouri Ursprung 0 Jean A. King 0 Xiang Yang Zhang, Baylor College of Medicine, United States of America 0 1 Center for Comparative NeuroImaging, Department of Psychiatry, University of Massachusetts Medical School , Worcester , Massachusetts, United States of America, 2 Department of Family Medicine and Community Health, University of Massachusetts Medical School , Worcester , Massachusetts, United States of America, 3 Department of Psychiatry, University of Massachusetts Medical School , Worcester, Massachusetts , United States of America Background: The tobacco withdrawal syndrome indicates the development of neurophysiologic dependence. Clinical evidence indicates that neurophysiologic dependence develops through a set sequence of symptom presentation that can be assessed with a new 3-item survey measure of wanting, craving, and needing tobacco, the Level of Physical Dependence (PD). This study sought to determine if advancing neurophysiologic dependence as measured by the Level of PD correlates with characteristics of white matter structure measured by Fractional Anisotropy (FA). Methods: Diffusion-MRI based FA and diffusion tensor imaging probabilistic tractography were used to evaluate 11 smokers and 10 nonsmokers. FA was also examined in relation to two additional measures of dependence severity, the Hooked on Nicotine Checklist (HONC), and the Fagerstro m Test for Nicotine Dependence (FTND). Results: Among smokers, FA in the left anterior cingulate bundle (ACb) correlated negatively with the Level of PD (r = 20.68, p = 0.02) and HONC scores (r = 20.65, p = 0.03), but the correlation for the FTND did not reach statistical significance (r = 249, p = 0.12). With advancing Levels of PD, the density of streamlines between the ACb and precuneus increased (r = 20.67, p,0.05) and those between the ACb and white matter projecting to the superior-frontal cortex (r = 20.86, p = 0.0006) decreased significantly. Conclusions: The correlations between neural structure and both the clinical Level of PD survey measure and the HONC suggest that the Level of PD and the HONC may reflect the microstructural integrity of white matter, as influenced by tobacco abuse. Given that the Level of PD is measuring a sequence of symptoms of neurophysiologic dependence that develops over time, the correlation between the Level of PD and neural structure suggests that these features might represent neuroplastic changes that develop over time to support the development of neurophysiologic dependence. - Funding: This work was funded by National Institutes of Health grant 1 R03 DA024217. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Dr. Nanyin Zhang, who is a co-author of this manuscript, is a PLOS ONE editorial board memeber. However this does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. Imaging studies have found differences in brain structure between smokers and nonsmokers [1,2,3,4,5,6]. Fractional anisotropy (FA) is a measure of the microstructural order in white matter. High values of FA indicate uniformly ordered structure in the imaged voxel; as more heterogeneity of structural orientation occurs, the FA decreases. Previous studies have used diffusion tensor imaging (DTI) to examine FA as related to smoking. Smokers tend to have higher FA than nonsmokers [5,6,7,8]. The generally higher FA seen in smokers may reflect an increase in FA that follows the initiation of smoking, but prolonged smoking appears to reverse this effect with a progressive decline in FA with increasing pack-years of smoking [6,7]. FA has correlated with Fagerstro m Test for Nicotine Dependence (FTND) scores in some studies [6,9], but not others [5,10,11]. Hudkins et al [6]. reported that FA in the anterior cingulum bundle (ACb) correlated inversely with FTND scores (r = 20.64). Zhang et al. reported a negative correlation (r = 20.52) between FA and FTND score in prefrontal white matter, but only in highly dependent smokers [9]. In a small study, Paul et al. reported a non-significant negative correlation (r = 20.58) between FA and FTND in the corpus callosum [5]. In each of these cross-sectional studies, there was the possibility that differences between smokers and nonsmokers, or between smokers with different FTND scores, might reflect conditions that predated the onset of smoking. A stronger argument for a causal connection between structure and dependence could be made if changes in structure were shown to parallel the development of dependence. Table 1. The Level of Physical Dependence measure. The Level of Physical Dependence Measure If I go too long without smoking, the first thing I will notice is a mild desire to smoke that I can ignore. If I go too long without smoking, the desire for a cigarette becomes so strong that it is hard to ignore and it interrupts my thinking. If I go too long without smoking, I just cant function right, and I know I will have to smoke just to feel normal again. This item describes me Neurophysiologic dependence is an important feature of tobacco addiction. In smokers who do not have neurophysiologic dependence, abstinence does not trigger a desire to smoke. However, in smokers who have neurophysiologic dependence, abstinence always triggers an urge to smoke. The quality and intensity of the strongest abstinence-induced urges to smoke differs between smokers and is reflected in the terms wanting, craving, and needing [12,13,14]. Clinical studies indicate that neurophysiologic dependence always develops through the same sequence: level 0 no abstinence-induced urges to smoke, level 1- wanting, level 2- craving, and level 3- needing (Table 1) [12,14,15,16]. The observation that neurophysiologic dependence progresses through an identical sequence of 4 levels in all smokers has important theoretical implications because it implies that the alterations in the brain that underlie neurophysiologic dependence also develop in sequence in all smokers. If this is true, it might be possible to correlate the clinical symptoms of advancing neurophysiologic dependence with changes in brain structure to identify structures that are involved with neurophysiologic dependence. To enable this approach, a 3-item self-report survey measure, the Levels of Physical Dependence (PD), was developed (Table 1). The Levels of PD assesses how far neurophysiologic dependence has progressed by assessing the qualitative severity of withdrawal symptoms experienc (...truncated)