Developing Three New Pathophysiologically Based Measures of Nicotine Dependence: A Dissertation

BACKGROUND: Of the 22 known measures of nicotine dependence (ND), none capture the overall disease severity of physical dependence alone. Instead, they capture constructs related to dependence, such as perceived risk, psychological addiction, smoker motivations, or smoking related behaviors, but none of the measures include only physical withdrawal symptoms to capture physical dependence on nicotine. AIM: To develop a range of nicotine dependence measures that capture physical dependence on nicotine. METHODS: The final measures were developed in a cross-sectional study conducted in three phases: 1) candidate item development through literature review and cognitive interviews, 2) developing and pre-testing the survey, and 3) survey administration and psychometric evaluation to validate three distinct measures. The final survey was conducted at four health clinics and three high schools. Psychometric tests used to select the final measure items included inter-item correlations, sensitivity analyses done by subgroup, item-total correlations, convergent validity tests, and confirmatory factor analysis. The final measures were evaluated using confirmatory factor analysis (CFA), internal reliability, total score distributions, and convergent validity correlations. Relative validity analyses were also conducted using a ratio of F-Statistics to compare the ability of each new measure to differentiate dependent smokers as compared previous measures. RESULTS: The final sample included 275 smokers ranging from 14 to 76 years old (mean=30.9, SD=16.2), who smoked an average of 11.5 cigarettes per day (range=0-50, SD=9.4). The sample was 86.5% white and 57.5% male. The three new measures developed included: 1) the 4-item Withdrawal-Induced Craving Scale (WICS) used to capture severity of craving, the most common physical withdrawal symptom; 2) the 12- item Nicotine Withdrawal Symptom Checklist (NWSC), which measures both overall disease severity and the severity of a comprehensive list of individual physical withdrawal symptoms including withdrawal-induced craving, anger, anxiety, depression, headache, insomnia, loss of focus, restlessness, and stress; and 3) the 6-item brief NWSC (NWSC-b), a short measure which only captures overall disease severity. All of the new measures exhibited a unidimensional factor structure loading highly on a single factor (thought to be physical dependence). They also correlated highly (over 0.6) and significantly (p\u3c0.001) to a battery of convergent validity indices including four widely used nicotine dependence measures: Hooked on Nicotine Checklist (HONC), the Autonomy Over Tobacco Scale (AUTOS), the Fagerström Test for Nicotine Dependence (FTND), and self-rated addiction. CONCLUSION: The WICS, NWSC, and NWSC-b provide three distinct validated tools that can be used by researchers, clinicians, and educators to track the progression of physical dependence on nicotine across a range of smoking behaviors and histories

Short Measures Of Tobacco Dependence Optimized For Biological Research

Biological research requires valid and reliable measures of the biologically-based aspects of dependence. Traditional dependence measures focus on behaviors (e.g., patterns of use), that can be constrained by sociocultural factors such as cost and restrictions on smoking.When dependence measures reflect non-biological factors, they are less suitable for biological research.We will present new data concerning several tobacco dependence measures that assess only biologically-based symptoms. The Levels of Physical Dependence (PD) is a 3-item instrument that assesses how subjects experience the urge to smoke that is triggered by withdrawal. It provides a quantitative measure of a person’s progression along 4 levels of PD. As all tobacco users progress through the 4 levels of PD in the same sequence, biological events associated with level 2 must precede events associated with level 3. This measure provides a unique and valuable time perspective to the interpretation of data. The Hooked on Nicotine Checklist assesses 10 symptoms of dependence. It’s excellent sensitivity and reliability allowed it to demonstrate a nearly perfect correlation (r=-.96) with changes in neural density that accompany the progression of PD. The Latency to Withdrawal (LTW) is a single item subjective measure of the length of time a person can forgo the use of tobacco before experiencing a withdrawal-triggered urge to smoke. Valid values for the LTW vary from minutes to weeks. The LTW is an important biological factor to consider in studying withdrawal and cue-induced craving. By focusing on the subjective symptoms of dependence rather than the behaviors prompted by those symptoms, the measures discussed here are all universal measures, that is, they are valid for all forms of tobacco use and with tobacco users of all ages

What Aspect of Dependence Does the Fagerström Test for Nicotine Dependence Measure?

Although the Fagerström Test for Nicotine Dependence (FTND) and the Heaviness of Smoking Index (HSI) are widely used, there is a uncertainty regarding what is measured by these scales. We examined associations between these instruments and items assessing different aspects of dependence. Adult current smokers ( , mean age 33.3 years, 61.9% female) completed a web-based survey comprised of items related to demographics and smoking behavior plus (1) the FTND and HSI; (2) the Autonomy over Tobacco Scale (AUTOS) with subscales measuring Withdrawal, Psychological Dependence, and Cue-Induced Cravings; (3) 6 questions tapping smokers’ wanting, craving, or needing experiences in response to withdrawal and the latency to each experience during abstinence; (4) 3 items concerning how smokers prepare to cope with periods of abstinence. In regression analyses the Withdrawal subscale of the AUTOS was the strongest predictor of FTND and HSI scores, followed by taking precautions not to run out of cigarettes or smoking extra to prepare for abstinence. The FTND and its six items, including the HSI, consistently showed the strongest correlations with withdrawal, suggesting that the behaviors described by the items of the FTND are primarily indicative of a difficulty maintaining abstinence because of withdrawal symptoms

Three Measures of Tobacco Dependence Independently Predict Changes in Neural Structure

Studies have demonstrated moderate correlations between fractional anisotropy (FA, a measure of white matter organization), and Fagerström Test for Nicotine Dependence (FTND) scores in various white matter brain structures (r=-.52 to -.64). FA increases with smoking in adolescents, but in adult smokers FA declines with the progression of physical dependence. We examined correlations between FA and 3 measures of tobacco dependence: the FTND, Levels of Physical Dependence (PD), and the Hooked on Nicotine Checklist (HONC). The latter 2 measures assess only symptoms rather than behaviors, based on an assumption that a direct assessment of subjective symptoms will better reflect underlying biological conditions than behaviors that might be constrained by sociocultural factors.We compared white matter FA in 8 smokers and 10 nonsmokers and plotted the location of maximal correlation between FA and each dependence measure. FA trended higher in smokers than nonsmokers in the anterior cingulum bundle (ACb) (p=0.05). Among smokers, plots of the maximal correlation for all 3 measures fell within a circumscribed area of the left ACb, showing excellent concordance of results across measures. The maximal correlation with FA was r= -.78 for the FTND, -.85 for Levels of PD, and -.96 for the HONC (

Progressive levels of physical dependence to tobacco coincide with changes in the anterior cingulum bundle microstructure

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 Fagerstrom Test for Nicotine Dependence (FTND). RESULTS: Among smokers, FA in the left anterior cingulate bundle (ACb) correlated negatively with the Level of PD (r = -0.68, p = 0.02) and HONC scores (r = -0.65, p = 0.03), but the correlation for the FTND did not reach statistical significance (r = -49, p = 0.12). With advancing Levels of PD, the density of streamlines between the ACb and precuneus increased (r = -0.67, p\u3c0.05) and those between the ACb and white matter projecting to the superior-frontal cortex (r = -0.86, 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

The development and expression of physical nicotine dependence corresponds to structural and functional alterations in the anterior cingulate-precuneus pathway

INTRODUCTION: Perturbations in neural function provoked by a drug are thought to induce neural adaptations, which, in the absence of the drug, give rise to withdrawal symptoms. Previously published structural data from this study indicated that the progressive development of physical dependence is associated with increasing density of white matter tracts between the anterior cingulum bundle and the precuneus. METHODS: Using functional magnetic resonance imaging, we compared 11 smokers after 11 h of abstinence from nicotine and after satiation, with 10 nonsmoking controls, using independent component analysis for brain network comparisons as well as a whole brain resting-state functional connectivity analysis using the anterior cingulate cortex as a seed. RESULTS: Independent component analysis demonstrated increased functional connectivity in brain networks such as the default mode network associated with the withdrawal state in multiple brain regions. In seed-based analysis, smokers in the withdrawal state showed stronger functional connectivity than nonsmoking controls between the anterior cingulate cortex and the precuneus, caudate, putamen, and frontal cortex (P \u3c 0.05). Among smokers, compared to the satiated state, nicotine withdrawal was associated with increased connectivity between the anterior cingulate cortex and the precuneus, insula, orbital frontal gyrus, superior frontal gyrus, posterior cingulate cortex, superior temporal, and inferior temporal lobe (P \u3c 0.02). The intensity of withdrawal-induced craving correlated with the strength of connectivity between the anterior cingulate cortex and the precuneus, insula, caudate, putamen, middle cingulate gyrus, and precentral gyrus (r = 0.60-0.76; P \u3c 0.05). CONCLUSIONS: In concordance with our previous report that structural neural connectivity between the anterior cingulate area and the precuneus increased in proportion to the progression of physical dependence, resting-state functional connectivity in this pathway increases during nicotine withdrawal in correlation with the intensity of withdrawal-induced craving. These findings suggest that smoking triggers structural and functional neural adaptations in the brain that support withdrawal-induced craving

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma

Purpose To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. Method Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. Results 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/ s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). Conclusions Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

Funder: NIHR Cambridge Biomedical Research CentreFunder: Addenbrooke’s Charitable TrustFunder: National Institute for Health Research (NIHR)Funder: Mark Foundation For Cancer ResearchFunder: Cambridge Commonwealth, European and International TrustFunder: Cancer Research UKFunder: Cambridge Clinical Trials UnitFunder: Cancer Research UK Cambridge CentreFunder: Engineering and Physical Sciences Research Council Cancer Imaging Centre in Cambridge and ManchesterFunder: Cambridge Experimental Cancer Medicine CentrePURPOSE: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. METHOD: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. RESULTS: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). CONCLUSIONS: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS. TRIAL REGISTRATION: EudraCtNo: 2005-004502-82