The Neurobiological and Neurocognitive Consequences of Chronic Cigarette Smoking

The primary goals of this project are two-fold: 1) to elucidate the neurobiological and neurocognitive consequences of chronic cigarette smoking, and their interrelationships, and 2) to provide a platform for my transition into an independent neuroimaging scientist. Tobacco smoking, greater than 98% in the form of cigarettes, is the leading preventable cause of mortality and morbidity worldwide. Among the approximately 64.5 million active smokers in the USA, smoking-related disease results in approximately 440,000 preventable annual deaths, with the greatest mortality increasingly emergent among economically disadvantaged groups. The multiple adverse health consequences and morbidity associated with cigarette smoking are well known. However, the effects of chronic smoking on human brain neurobiology and neurocognition are not well understood, as research efforts in this area are limited in number, scope, and generalizability.

The central hypothesis of this proposal is that active chronic cigarette smoking is associated with abnormalities in brain neurochemistry, tissue volume, and tissue perfusion, which are related to neurocognitive dysfunction. There is increasing evidence that chronic cigarette smoking adversely affects neurobiology and neurocognition. However, the full scope, magnitude, and association of the neurobiological and neurocognitive effects of chronic smoking are unclear as: (a) previous neuroimaging research has been restricted to a few studies of brain morphology, metabolites and blood flow, which targeted only neocortical and subcortical GM; regional WM was not examined. Assessment of the cerebral WM is vital to better understand the structural and biochemical correlates of the neurocognitive reported in chronic smokers (b) previous neurocognitive studies assessed a limited number of functional domains, employed measures not commonly used in clinical practice or research, and several studies included participants with medical comorbidies that may have influenced the findings; and (c) previous research of the effects of chronic cigarette smoking on the human brain acquired either neurobiological or neurocognitive data. At the time of this grant submission, no published research has concurrently evaluated both the neurobiological and neurocognitive consequences of chronic cigarette smoking, and their inter-relationships. Therefore, it is unknown if the reported neuroimaging abnormalities in chronic smokers are of functional significance.

To address the major gaps in knowledge regarding the extent and magnitude of the neurobiological and functional consequences of cigarette chronic smoking, this proposal will combine state-of-the-art standard and high-field multi-modality MR studies, with comprehensive neurocognitive testing, to concurrently assess both the neurobiological and neurocognitive consequences of chronic cigarette smoking in community dwelling non-clinical volunteers. This will be accomplished by comparing chronic smoking and non-smoking participants on: (a) 1.5 Tesla MR measures of regional brain volumes, metabolite markers of regional neuronal viability (i.e., N-acetylaspartate), cell membrane synthesis/turnover (choline-containing compounds) (b) 4.0 Tesla regional brain perfusion (i.e., blood flow); and neocortical levels of glutamate (Glu) and γ-aminobutyric acid (GABA), which are both implicated in the development and maintenance of dependence on nicotine and other substances of abuse; and (c) a comprehensive neurocognitive battery assessing domains of functioning reported to be adversely affected by chronic smoking. Importantly, the relationships between MR-derived neurobiological measures and comprehensive neurocognitive assessment will be examined.

The following primary hypotheses will be tested:

  1. Chronic smokers, relative to non-smokers, show abnormalities in: a) regional neocortical gray and white matter volumes; b) regional neocortical gray and white matter metabolite concentrations of N-acetylaspartate and choline-containing compounds; c) frontal and parietal gray matter perfusion; d) the neurocognitive domains of cognitive efficiency, executive skills, learning and memory, information processing speed, working memory, and postural stability.
  2. In chronic smokers, greater abnormalities in regional brain metabolite concentrations, brain volumes and perfusion are associated with poorer neurocognitive function.
  3. In chronic smokers, greater smoking severity is related to poorer neurocognition and lower concentrations of N-acetylaspartate and choline-containing compounds in neocortical gray matter and white matter.

The proposed research spans the gap between basic science and every-day-function in humans. It will identify neurobiological markers of smoking-induced brain injury and will elucidate general biological mechanisms associated with the neurocognitive dysfunction recently reported in chronic smokers. Such translational neuroscience research is of considerable import as studies focusing on both the neurobiological and neurocognitive consequences of chronic smoking in non-clinical populations were non-existent at the time of this application. Overall, the proposed research will significantly advance our current knowledge of the effects of chronic smoking on both human neurobiology and neurocognition, and their inter-relationships. From a wider perspective, the proposed research will generate much needed public health information for the USA and abroad regarding the effects of chronic smoking on the integrity of human brain neurobiology and function.