101238455 International Journal of Environmental Research and Public Health 1661-7827 1660-4601 Molecular Diversity Preservation International (MDPI) 10.3390/ijerph7103760 ijerph-07-03760 Article Chronic Cigarette Smoking: Implications for Neurocognition and Brain Neurobiology DurazzoTimothy C.12* MeyerhoffDieter J.12 NixonSara Jo34 Department of Radiology and Biomedical Imaging, University of California, 505 Parnassus Avenue, M-391, San Francisco, CA 94143, USA Center for Imaging of Neurodegenerative Diseases, San Francisco VA Medical Center, 4150 Clement St., San Francisco, CA 94121, USA; E-Mail: dieter.meyerhoff@ucsf.edu (D.J.M.) Department of Psychiatry, University of Florida, P.O. Box 100256, Gainesville, FL 32611, USA; E-Mail: sjnixon@ufl.edu (S.J.N) Department of Psychology, University of Florida, P.O. Box 112250, Gainesville, FL 32611, USA Author to whom correspondence should be addressed; E-Mail: timothy.durazzo@ucsf.edu; Tel.: +1-415-221-4810 Ext. 4157; Fax: +1-415-668-2864. 10 2010 21 10 2010 7 10 3760 3791 9 9 2010 29 9 2010 9 10 2010 © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. 2010

This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

Compared to the substantial volume of research on the general health consequences associated with chronic smoking, little research has been specifically devoted to the investigation of its effects on human neurobiology and neurocognition. This review summarizes the peer-reviewed literature on the neurocognitive and neurobiological implications of chronic cigarette smoking in cohorts that were not seeking treatment for substance use or psychiatric disorders. Studies that specifically assessed the neurocognitive or neurobiological (with emphasis on computed tomography and magnetic resonance-based neuroimaging studies) consequences of chronic smoking are highlighted. Chronic cigarette smoking appears to be associated with deficiencies in executive functions, cognitive flexibility, general intellectual abilities, learning and/or memory processing speed, and working memory. Chronic smoking is related to global brain atrophy and to structural and biochemical abnormalities in anterior frontal regions, subcortical nuclei and commissural white matter. Chronic smoking may also be associated with an increased risk for various forms of neurodegenerative diseases. The existing literature is limited by inconsistent accounting for potentially confounding biomedical and psychiatric conditions, focus on cross-sectional studies with middle aged and older adults and the absence of studies concurrently assessing neurocognitive, neurobiological and genetic factors in the same cohort. Consequently, the mechanisms promoting the neurocognitive and neurobiological abnormalities reported in chronic smokers are unclear. Longitudinal studies are needed to determine if the smoking-related neurobiological and neurocognitive abnormalities increase over time and/or show recovery with sustained smoking cessation.

 chronic cigarette smoking neurocognition neurobiology neuroimaging genetics Introduction

Approximately 2 billion people worldwide use tobacco products, mostly in the form of cigarettes, with tobacco smoking-related diseases resulting in 4 million deaths per year [1]. Among the approximately 64.5 million active smokers in the USA, smoking-related disease results in approximately 440,000 preventable annual deaths [2]. The enormous healthcare expenditures and mortality associated with chronic cigarette smoking results in an estimated $92 billion annual productivity loss in the US. Internationally, the greatest smoking related mortality is increasingly apparent among economically disadvantaged groups, which, in the US includes a disproportionate number of ethnic minorities and those with psychiatric and substance use disorders [3,4]. An extensive body of research thoroughly describes the deleterious effects of chronic cigarette smoking on human cardiac and pulmonary function, peripheral vascular systems as well as its carcinogenic properties [5–8]. Recent research indicates chronic cigarette smoking is associated with increased risk for numerous biomedical conditions that may directly or indirectly compromise brain neurobiology and neurocognition [9–12]. However, compared to the substantial volume of research on the cardiovascular, pulmonary and cancer-related health consequences associated with chronic smoking, surprisingly little research has been specifically devoted to the investigation of its effects on human neurocognition and brain neurobiology.

This review summarizes the peer-reviewed literature on the neurocognitive and neurobiological repercussions of chronic cigarette smoking in cohorts and population-based samples that were not specifically seeking treatment for substance use or psychiatric disorders. Prospective or retrospective studies that expressly assessed the neurocognitive or neurobiological consequences of chronic smoking are targeted. Research employing proton magnetic resonance-based studies of brain morphology and metabolites that specifically evaluated the neurobiological consequences of chronic smoking are emphasized. In this review, non-smoking control groups are referred to as NSC and individuals comprising these groups generally were indicated to be never smokers or consumed less than 100 cigarettes over lifetime. NSC were equivalent in age to smoking cohorts unless otherwise specified. The research reviewed was generally conducted with individuals in one of three age ranges: 18–30, 40–59 and 60–90. Individuals 18–30 years of age are referred to as “young adults”, 40–59 as “middle-aged adults” and 60–90 years of age as “older adults”. In studies where the participants do not conform to the above defined age groups, specific age ranges are provided. For reviews on the effects of chronic smoking on brain neurobiology and function in alcohol and substance use disorders see [13–15]. Please refer to [16–20] for thorough reviews on the acute effects of nicotine administration and nicotine withdrawal on brain neurobiology and neurocognition (although not the focus of this review, these topics are briefly addressed in Section 4). For inclusive reviews on functional MRI and nuclear imaging findings in chronic smokers see [21,22].

 Neurocognitive Consequences of Chronic Cigarette Smoking (see <xref ref-type="table" rid="t1-ijerph-07-03760">Table 1</xref>)

The vast majority of research investigating the neurocognitive consequences of chronic cigarette smoking is cross-sectional in design and focused primarily on middle-aged and older adults. In the sole study of adolescents, daily smokers (mean age = 17 ± 1) showed deficits in accuracy of working memory relative to NSC, with individuals who began smoking at a younger age demonstrating greater impairment than those who began smoking at a later age [23]. In the few studies with young adults, smokers were inferior to NSC on measures of sustained attention and impulse control [24], auditory-verbal memory, oral arithmetic, and receptive and expressive vocabulary [25], information processing speed [26] and general intelligence [27]. On an experimental behavioral measure of risk-taking (Balloon Analogue Risk Task [28]), young adults smokers demonstrated higher levels of risk-taking [29]. In cross-sectional studies specifically comparing NSC to middle-aged and/or older adult smokers, poorer performance in smokers was reported for auditory-verbal learning and/or memory [30–34], working memory [26,35,36], executive functions [33,37,38], general intellectual abilities [39], visual search speed [40], processing speed and cognitive flexibility [30–32,38,41,42] and global cognitive function (e.g., brief mental status examinations such as the MMSE) [41]. In a middle-aged cohort of combined current and former smokers, any history of smoking was associated with increased risk for abnormal auditory-verbal memory [43]. Some studies observed the performance of former smokers fell between that of current smokers and NSC in young [25], middle-aged and older adults [31,35,39]. Other studies found no differences between former smokers and NSC [25,30]. The inconsistencies among these studies may be related to the substantial variety of measures used across studies to evaluate the domain of functioning in question as well as inconsistency in the magnitude of neurocognitive dysfunction in the smoking study cohort.

In cross-sectional population-based studies with community-dwelling older adults, where smoking status (i.e., current smoker, past smoker, never smoker) was used as a prospective or retrospective predictor, current smoking [44–46] and any history of smoking [47] were associated with poorer performances on measures of global cognitive function. Any previous smoking history (with variable lengths of smoking cessation) was associated with poorer cognitive flexibility [45], and impaired general cognitive function [44] or, conversely, decreased risk of global cognitive impairment [46]. Chronic smoking in older adults has also been associated with a diminished ability to execute some activities of daily living [48] and compromised postural stability [49].

Longitudinal research with non-demented, population-based samples found that current cigarette smokers demonstrated an abnormal rate of decline on indices of reasoning [43] and auditory-verbal memory [40] in middle aged adults, and abnormal decline on measures of global cognitive function [47,50–53] and auditory-verbal memory in older adults [54].

Sex effects in neurocognition among smokers have also been addressed in some studies. Edelstein et al. [34] found no differences between older adult male smokers and male NSC on measures of global cognitive functioning, set-shifting, semantic fluency and auditory-verbal and visuospatial learning and memory, while older adult female smokers demonstrated poorer global cognitive functioning and auditory-verbal memory than female NSC. Jacobsen and colleagues [23] reported that male adolescent smokers performed more poorly than did female smokers on measures of selective and divided attention. Similarly, Razani and colleagues [37] observed that sex was a significant predictor of non-verbal abstraction in currently smoking older adults, however, no interactions were reported among sex, smoking status or smoking severity. Other studies, however, have found no sex effects on neurocognition in middle aged and older adults [32,33,39].

The level and chronicity of smoking, as reflected in the number of cigarettes smoked per day, duration of smoking over lifetime, and/or dose-duration (i.e., pack-years) were inversely related to various domains of neurocognition in adults across a wide age range [25,30,32,45,52,55,56]. Several reports indicate chronic smoking is associated with increased risk for various forms of dementia, in particular Alzheimer’s Disease and vascular dementia [57–61]. This risk may be modulated through the apolipoprotein E ɛ4 (ApoE4) genotype, a known genetic risk for the development of Alzheimer’s Disease [52,54]. Interestingly, some studies have reported that risk for development of Alzheimer’s Disease was greater in smokers who were not ApoE4 carriers [52,54,58,59].

Several studies, smoking status (i.e., smoker or non-smoker) or measures of smoking consumption (e.g., pack years), showed weak or no relationships to specific neurocognitive functions (e.g., measures of learning and memory, mental arithmetic, verbal fluency, processing speed), global neurocognitive function (e.g., MMSE) and neurocognitive decline in young and middle aged adults [62,63] and in large community-based samples consisting of middle-aged and older adults [64–70].

 Neurobiological Consequences of Chronic Cigarette Smoking (See <xref ref-type="table" rid="t2-ijerph-07-03760">Table 2</xref>)

The specific neurobiological factors underlying the reported smoking-related cognitive deficits are not established. However, there are a few of computed tomography (CT) and magnetic resonance (MR)-based studies that suggest the reported neurocognitive deficiencies in smokers may be, in part, mediated by abnormalities in brain morphology, perfusion and/or neurochemistry. The majority of these studies are cross-sectional in design.

Brain Morphology

Computed tomography (CT) studies with cohorts ranging from middle-aged to older adults report that chronic smoking is associated with an abnormal increase of global brain atrophy with advancing age [74–77]. These CT studies assessed whole brain volumes and did not report major anatomical subdivisions (e.g., frontal gray matter/white matter). An early MRI study with older adults examined global brain atrophy over a 5-year-interval and found higher pack years was related to increased ventricular volume in men and was associated with increased sulcal volume in women, after controlling for age and vascular risk factors [78]. More recent MRI studies have employed voxel-based morphological measures to assess the regional brain volumes and densities of the cortical gray matter (GM). Smokers aged 39.5 ± 10.3 years evidenced smaller volumes and lower tissue densities than did NSC in bilateral anterior frontal lobe regions; smokers also had smaller volume of the left dorsal cingulate cortex and lower GM density in the cerebellum. Anterior frontal cortex density was inversely related to pack-years [79]. Smokers aged 30.8 ± 7.5 years demonstrated widespread GM volume and density reductions relative to NSC [80], particularly in the bilateral frontal lobes, cingulate gyrus and insula. Non-demented older adult smokers (75.0 ± 3.4 years of age) exhibited reduced GM density in right precuneus, left posterior cingulate gyrus, right thalamus and bilateral precentral and middle frontal gyri compared to NSC [81].

A MR-based study employed diffusion tensor imaging (DTI) and voxel based morphometry to assess microstructural integrity and morphology, respectively, of the corpus callosum in middle aged chronic smokers [82]. Contrary to expectations, smokers demonstrated higher fractional anisotropy (FA; higher FA values are considered to reflect greater microstructural integrity [83,84]) in the body and total corpus callosum than did NSC and no volume differences were observed between smokers and NSC in the corpus callosum. However, smokers with high levels of nicotine dependence (as reflected by scores on the Fagerstrom Test for Nicotine Dependence) had significantly lower FA values than both smokers with low levels of nicotine dependence and NSC. It is widely recognized from population-based studies, with middle-aged and older adults, that chronic smoking is associated with increased incidence of regional white matter (WM) signal hyperintensities on standard MR imaging (e.g., T2-weighted and FLAIR) [85–89]. WM hyperintensities are associated with decreased cerebral blood perfusion [90,91] and neurocognitive dysfunction [92,93]. Overall, the degree of smoking-related morphological changes observed appears to be contingent on the method and brain region under consideration.

 Brain Biochemistry

A single volume proton (1H) MR spectroscopy study with chronic smokers (36 ± 11 years of age) observed lower N-acetylaspartate (NAA) concentration (surrogate marker of neuronal integrity [94,95]), in the left hippocampus relative to NSC. No group differences were observed for NAA in the anterior cingulate cortex (ACC), but choline-containing compound (Cho) levels (a marker of cell membrane turnover/synthesis [94,96]) were positively related to greater pack years in this region [97]. A single voxel 1H spectroscopy study of glutamate levels in the left hippocampus and ACC observed no differences among current smokers (35 ± 10 years of age), former smokers (42 ± 10 years of age) abstinent for 17 ± 3 years and NSC (33 ± 10 years of age) [98]. In the sole 1H spectroscopy study investigating gamma aminobutyric acid levels (GABA; neuromodulator involved in the development and maintenance of substance use disorders [99–101]) in chronic smokers, cortical GABA concentrations were lower in female smokers (and modulated by menstrual cycle phase), but GABA levels were not different between male smokers and NSC [102].

 Brain Perfusion

The vast majority of neuroimaging research on brain perfusion has investigated the effects of acute nicotine exposure, rather than the consequences of chronic cigarette smoking [18]. The few published reports specifically investigating chronic smokers indicate globally decreased brain perfusion relative to NSC, as measured by CT 133Xe inhalation [103,104] in older adults and single proton emission computed tomography (SPECT) [105] in adults aged 35.5 ± 8.4 years; perfusion was inversely related to cigarette pack-years [105]. In a Xe-CT-based longitudinal study with community-dwelling older adults, decreases in global cerebral perfusion were independently associated with chronic smoking controlling for other vascular risk factors [106,107].

 Neurocognitive and Neurobiological Effects of Acute Nicotine Exposure and Withdrawal

When investigating chronic cigarette smoking-induced neurobiological and neurocognitive dysfunction alone, or in conjunction with AUD and other conditions, it is important to distinguish the effects of acute nicotine ingestion and withdrawal from the potential consequences of chronic exposure to the multitude of noxious compounds contained in cigarette smoke. While not the focus of this review, the general findings and implications are discussed regarding the effects of acute nicotine on neurocognition and brain neurobiology, as measured with functional neuroimaging methods [i.e., functional MRI (fMRI), positron emission tomography (PET), single positron emission tomography (SPECT)].

Acute Nicotine Consumption, Nicotine Withdrawal and Neurocognition

Acute nicotine administration has been found to transiently improve some areas of neurocognition in NSC and individuals with attention deficit hyperactivity disorder and schizophrenia-spectrum disorders, most substantially on measures of sustained attention and working memory [17,19,108]. Acute nicotine administration in nicotine deprived smokers is associated with improved cognitive task performance [109,110], whereas several studies report decrements in neurocognitive performance with nicotine administration to NSC (see [19] for review). A recent meta-analysis conducted by Heishman and colleagues [111] suggests that acute smoking or nicotine consumption, independent of withdrawal effects, is associated with enhanced function in the following domains of function: fine motor skills, alerting attention accuracy and response time, orienting attention reaction time, short-term episodic memory accuracy and working memory reaction time (but not accuracy). In non-clinical chronic smokers, the adverse effects of nicotine withdrawal are not typically apparent on neurocognitive function until 8–12 hours after last nicotine dose [17,19,109,112]. Protracted duration from last cigarette smoked/nicotine administration to onset of withdrawal mediated disturbances in neurocognition is likely attributable to the maintenance of relatively high levels of plasma nicotine during waking hours due to repeated dosing of nicotine (via cigarettes) [113].

 Acute Nicotine Consumption, Nicotine Withdrawal and Neurobiological Function

Several functional neuroimaging (PET, SPECT, fMRI) studies in active chronic smokers (see [21,22] for review) and a few functional MRI studies addressed the acute effects of nicotine administration on brain activity during task activation in healthy non-smokers [17,18,20]. The effects of acute cigarette smoking on functional neuroimaging modalities in non-smokers have not been investigated [18,20]. In chronic smokers, functional neuroimaging studies investigating responses to acute smoking or nicotine administration have shown are that acute nicotine administration is associated with decreased global cerebral blood flow, increased activity in the dorsolateral, inferior and mesial frontal and orbitofrontal regions, thalamus and visual processing regions (see [21,22]). In chronic smokers deprived of tobacco for more than 2 hours, acute cigarette smoking elicits different patterns of relative perfusion responses, with increases of the order of 6–8% in the anterior frontal and cingulate cortices as well as decreases in cerebellum and occipital lobes that were associated with plasma nicotine levels [18,114,115]. Some studies report a 7–10% decrease in global glucose utilization following acute nicotine administration in chronic smokers deprived of nicotine for 8 hours or more [116,117]. Depending on the nature of the task, results suggest acute nicotine administration in smokers and non-smokers is associated with increased regional blood flow/brain activity and improves task performance or decreases blood flow/oxygenation level-dependent activity and task performance [18,20]. As discussed by Sharma and Brody [22], the reported regionally specific findings may be influenced by whether or not activity was standardized to whole brain blood flow.

Overall, the effects of acute nicotine administration on neurocognition and functional imaging measures appear to depend on duration of nicotine deprivation, the brain region studied, resting versus activation conditions, and the neurocognitive domain investigated [18].

 Potential Biological Mechanisms Contributing to Chronic Cigarette Smoking-Induced Neurocognitive and Neurobiological Dysfunction

Nicotine is one of more than 4000 compounds composing the particulate and gas phases of cigarette smoke [5,8,118]. In addition to nicotine, scores of these compounds are bioactive and may affect tissue locally in the oral cavity, the upper and lower respiratory systems, and distally via the systemic circulation. The many potentially cytotoxic compounds in cigarette smoke (e.g., carbon monoxide, aldehydes, ketones, nitrosamines, dihydroxybenzenes) [119] may directly compromise neuronal and cellular membrane function of cerebral tissue. There are several potential mechanisms that may contribute independently, or in concert, to the neurobiological and neurocognitive abnormalities in chronic smokers. These mechanisms may operate in a direct and/or indirect manner. The following overview is based on in vivo and in vitro studies of animals and humans.

Direct Mechanisms

A significant number of potentially cytotoxic compounds (e.g., carbon monoxide, free radicals and their precursors, nitrosamines, phenolic compounds, and other polynuclear aromatic compounds [119]), are found in the gas and particulate phases of cigarette smoke, which may be directly cytotoxic, damage neuronal or glial cell organelles and promote oxidative damage ([120], Muscat, 2004 #13479, [121,122]). For example, carbon monoxide (CO) levels are significantly higher in smokers [123], and this elevation is associated with decreased effective hemoglobin concentrations, diminished oxygen carrying capacity of erythrocytes [124], as well as a diminished efficiency of the mitochondrial respiratory chain [125]. Furthermore, cigarette smoke also contains high concentrations of free radical species (e.g., reactive nitrogen species; reactive oxygen species, ROS) known to promote oxidative damage or stress to cellular structures as well as to macromolecules including membrane lipids, proteins, carbohydrates and DNA [126]. The radical species in the particulate matter of cigarette smoke are long-lived (i.e., hours to months) compared to those in the gas phase [5], and can compromise organs other than the lungs [120,127]. In vivo chronic exposure of rat brain tissue to cigarette smoke significantly decreases membrane-bound ATPases, which alters ion homeostasis, and leads to increased Ca2+ and Na+ levels in the cytosol of various cell types [128], as well as increased Ca2+ in mitochondria [122], which is associated with neuronal injury or death [129]. Increased mitochondrial Ca2+ secondary to cigarette condensate exposure is associated with damage to the inner mitochondrial membrane (e.g., membrane swelling) and vacuolization of the matrix. Importantly, nicotine delivered independently of cigarette smoke does not appear to produce these adverse affects [122]. Nicotine administration in adolescent rats does, however, evoke cell injury and loss throughout the brain, with significant effects in the hippocampus of female rats but not males [130,131]. In general, the mechanisms underlying the observed nicotine-induced cell injury remain to be fully explicated.

 Indirect Mechanisms

In vivo chronic cigarette smoke exposure is also associated with decreased enzyme-based free radical scavenger (e.g., superoxide dismutase, catalase, glutathione reductase) and non-enzyme-based radical scavenger (e.g., glutathione and vitamins A, C and E) concentrations in rat brains [132,133]. This may render brain tissue more vulnerable to oxidative damage by radical species generated by cellular metabolism or other exogenous sources. The brain, in general, is exceedingly susceptible to oxidative damage because of high levels of unsaturated fatty acids in the composition of cell membranes and myelin. Additionally, chronic cigarette smoking is related to nocturnal hypoxia [7] as well as chronic obstructive pulmonary disease and other conditions that may impair lung function [8]. Decreased lung function is associated with poorer neurocognition and increased subcortical atrophy in older adults [134]. Chronic smoking increases the risk for atherosclerosis [9], as well as abnormalities in vascular endothelial morphology and function [135–138], which may alter cerebral perfusion. Additionally, nicotine administered through means other than cigarette smoke may alter or impair vasomotor reactivity of cerebral arterioles through upregulation of Ca2+ channels and/or modulation of nitric oxide [136]. These processes may impact the functional integrity (e.g., vasomotor reactivity/responsivity) of the cerebrovasculature and may, at least partially, contribute to the decreased regional cerebral blood flow [114,115,139] and/or white matter disease [85,87–89,140,141] observed in chronic smoking. Both the neocortex and underlying WM are vulnerable to the effects of diffuse ischemia (see [142] and references therein). Correspondingly, it has been suggested that late-myelinating areas such as the frontal and temporal lobes may be particularly vulnerable to increased oxidative stress and cerebral hypoperfusion [143,144], both of which have been described in chronic smokers.

Chronic smoking is also associated with central obesity (often reflected in increased body mass index; BMI) and/or insulin resistance [145], which, in turn, are reported to adversely affect brain neurobiology [146–149] and neurocognition [146,150].

In summary, although nicotine is likely the principal bioactive agent that underlies the addictive properties of tobacco smoke [19,151–154], the reviewed literature suggests that the majority of adverse neurobiological and neurocognitive effects of chronic cigarette smoking are a function of the direct and indirect consequences of continual exposure of the cardiopulmonary system, cerebrovascular system and brain parenchyma to the combination of non-nicotine combustion products contained in cigarette smoke [13,14,155]. However, a significant amount of data regarding potential mechanisms contributing to the neurobiological and neurocognitive abnormalities observed in humans is derived from in vitro and animal studies. Consequently, it is unclear if all potential mechanisms are generalizable to humans.

 Discussion

The cumulative body of research reviewed suggests chronic cigarette smoking is associated with deficiencies in auditory-verbal learning and/or memory, general intellectual abilities, visual search speeds, processing speed, cognitive flexibility, working memory and executive functions, across a wide age range. With advancing age, chronic smoking is related to abnormal decline in reasoning, memory and global cognitive function, and may increase the risk for both vascular dementia and Alzheimer’s Disease. However, several studies showed a weak or no association with smoking status and neurocognition. Chronic smoking is related to structural and biochemical abnormalities in multiple brain regions, particularly the anterior dorsolateral, mesial frontal cortex, limbic system and underlying WM. A dose-response relationship is suggested between cigarette smoking, neurocognition and neurobiological function. The reviewed literature suggests the adverse neurobiological and neurocognitive effects of chronic cigarette smoking in humans may be related to the direct and indirect consequences of continual exposure of the cardiopulmonary system, cerebrovascular system and/or brain parenchyma to the combustion products of cigarette smoke. However, the potential mechanisms contributing to the neurobiological abnormalities observed are derived from in vitro and animal studies. Consequently, it is unclear if these mechanisms are actually operational in humans. Furthermore, it is uncertain to what extent, if any, the reported neurocognitive and neurobiological abnormalities reported in smokers are influenced by premorbid or comorbid factors. Overall, the following methodological limitations are present in the reviewed literature:

Confounding Variables

Potentially confounding medical conditions (e.g., hypertension, diabetes, insulin-resistance, chronic obstructive pulmonary disease, atherosclerosis, neurodegenerative diseases) and comorbid alcohol use/misuse, substance use/misuse, and psychiatric conditions (particularly mood disorders) were not consistently screened or statistically accounted for in many studies. Several psychiatric disorders known to have adverse effects on brain neurobiology and neurocognition are highly prevalent in chronic smokers, including anxiety disorders [156], attention deficit/hyperactivity disorder [157,158], alcohol and substance use disorders [13,157,159], mood disorders [160,161], and schizophrenia-spectrum disorders [162,163]. Additionally, the potential influence of sex, exercise, diet, body mass index, exposure to secondary/environmental smoke, nicotine withdrawal and genetic predispositions [e.g., ApoE4 genotype, single nucleotide polymorphisms in nicotinic acetlycholinergic receptors (nAChr), brain derived neurotrophic factor (BDNF), dopamine receptor D2 (DRD2), catechol-O-methyl transferace (COMT)] were not considered. The aforementioned factors are likely mediators or moderators of brain neurobiology and neurocognition in controls and addictive disorders [146,147,149,164–181]. Finally, the potential effects of nicotine withdrawal on the primary measures of interest were not addressed in many studies.

 Limited Scope of Neurocognitive Assessment

Overall, there are a limited number of studies in each age group that conducted a comprehensive assessment of neurocognition. Additionally, measures of executive function (e.g., Categories Test, Wisconsin Card Sorting Test, Wechsler Adult Intelligence Scale-III Matrix Reasoning) were seldom administered. In older adults, many of the population-based research used single screening measures of global cognitive function (e.g., MMSE), or employed a composite score based on a limited number of tests primarily used to assess the severity of cognitive dysfunction in neurodegenerative diseases. Additionally, only two studies [29,63] investigated the effects of chronic smoking on tasks specifically assessing decision making, risk taking and impulsivity. Consequently, the full scope of the neurocognitive consequences associated with chronic smoking remains unclear.

 Limited Number of Neurocognitive Studies in Young Adults

The vast majority of studies investigating the neurocognitive consequences of chronic cigarette smoking have been conducted in middle aged and older adults. There is a particular shortage of studies in the 30–40 years of age range.

 Limited Number of Neuroimaging Studies

Previous neuroimaging research assessing the chronic effects of cigarette smoking has been primarily restricted to a few CT and MR-based studies of brain morphology, metabolites or blood flow, which primarily targeted neocortical and subcortical GM. Only one study investigated WM integrity via DTI. Prospective multimodal neuroimaging studies thoroughly examining WM morphology, biochemistry and perfusion of regional cerebral WM have not been conducted. Assessment of the cerebral WM is vital to better understand the extent of potential neurobiological dysfunction associated with chronic cigarette smoking.

 Limited Longitudinal Research

The vast majority of studies assessing the neurocognitive and neurobiological consequences of chronic smoking are cross-sectional in design. The few longitudinal neurocognitive and neuroimaging-based studies were conducted with older adult cohorts.

 Absence of MR-based Studies Examining Relationships between Brain Neurobiology and Neurocognition

No study has concurrently combined MR-based neurobiological measures with comprehensive neurocognitive assessment in order to study the correspondence between brain function and neurocognition. Studies relating MR-based brain volumetric and metabolite measures to neurocognition in substance dependent populations have observed different patterns/relationships for smokers and non-smokers [182,183] suggesting a differential use of compensatory functions in smokers and non-smokers to accomplish the same task.

 Conclusions

Increasing evidence suggests that chronic smoking in community-dwelling participants is associated with diminished function of multiple neurocognitive abilities and neurobiological abnormalities. The cumulative pattern of neurocognitive findings suggests dysfunction prominently in neurocircuitry implicated in decision making, impulse control, judgment, planning and reasoning skills, and in the initiation and maintenance of substance use disorders [184–187]. Specifically, the pattern of the neurocognitive and neurobiological findings in chronic smokers points to abnormalities in the brain reward system [186–188]. Major components of the brain reward system include (but are not limited to) the dorsolateral prefrontal cortex, orbitofrontal cortex, insula, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, ventral tegmental area and other nuclei in the basal forebrain and ventral pallidum [186,189–191]. Plastic changes in the brain reward system are implicated in the development and maintenance of all substance use disorders, including nicotine dependence, and other maladaptive behaviors [186–188,192–194]. However, the actual mechanisms promoting the neurocognitive and neurobiological abnormalities reported in chronic smokers are unclear and premorbid variables(e.g., genetic vulnerabilities) must also be considered as potential contributing factor. More specifically, the neurobiological and neurocognitive abnormalities reported in the reviewed studies may represent premorbid risk factors for the development and maintenance of nicotine dependence and/or premorbid vulnerabilities that were compounded by the effects of chronic smoking. Additionally, as many studies of the neurocognitive consequences of chronic smoking were conducted with older adults, the reported findings may be influenced by a survivor effect [43].

To assist in clarifying the factors contributing to the reported neurocognitive and neurobiological dysfunction, studies are needed that:

Concurrently assess cohorts of males and females ranging from young to older adults.

Employ prospective multi-modality neuroimaging studies (i.e., combining brain morphology, biochemistry, perfusion, and metabolism in the same cohort), with particular attention to the brain reward system.

Employ comprehensive neurocognitive testing including behavioral measures of impulsivity, decision-making and risk taking [24,195,196].

Consider genetic factors (e.g., ApoE genotype, single nucleotide polymorphisms in BDNF, nAChr, DRD2, COMT, glutamate receptors) implicated in the development and maintenance of substance use disorders (see [197–200]). Such an approach would better delineate the extent and magnitude of the neurobiological and neurocognitive consequences of chronic cigarette smoking, the roles of common genetic variations in vulnerability to nicotine dependence and their inter-relationships.

Employ prospective serial longitudinal studies to assess changes in neurobiology and neurocognition over extended periods in chronic smokers (e.g., >5 years). Additionally, it is vital to conduct prospective pre-and-post neuroimaging and neurocognitive studies with individuals engaging in smoking cessation programs to determine if smoking-related neurobiological and neurocognitive abnormalities recover with smoking cessation, and to assess the effect of pharmacologic interventions (e.g., nicotine replacement, varenicline) on neurobiological and neurocognitive changes. Such longitudinal studies will assist in determining if the neurocognitive and/or neurobiological abnormalities observed in cross-sectional studies are related to premorbid factors.

In conclusion, chronic cigarette smoking appears to be associated with demonstrable abnormalities in brain neurobiology and neurocognition in cross-sectional research across the lifespan, and is related to abnormal rates of brain volume loss in the elderly. However, the mechanisms promoting these abnormalities have yet to be explicated in humans. To better understand the factors associated with the reported neurocognitive and neurobiological abnormalities, longitudinal research combining comprehensive neurocognitive assessment with neuroimaging of brain metabolites, microstructure, macroscopic morphology, brain function and genetic vulnerabilities are necessary. Such longitudinal studies are required to inform the development of more effective pharmacological and behavioral interventions to reduce the ever-increasing worldwide mortality and morbidity associated with the modifiable health risk that is chronic cigarette smoking.

This material is the result of work supported by NIH DA 024136 (TCD), AA10788 (DJM) and DA 13677 and U54 RR025208 (Nelson, PI; SJN, Co-Investigator) with resources and the use of facilities at the San Francisco Veterans Administration Medical Center, San Francisco, CA, USA.

 References and Notes DeMariniDMGenotoxicity of tobacco smoke and tobacco smoke condensate: A reviewMutat Res200456744747410.1016/j.mrrev.2004.02.00115572290 GiovinoGAEpidemiology of tobacco use in the United StatesOncogene2002217326734010.1038/sj.onc.120580812379876 JhaPPetoRZatonskiWBorehamJJarvisMJLopezADSocial inequalities in male mortality, and in male mortality from smoking: Indirect estimation from national death rates in England and Wales, Poland, and North AmericaLancet200636836737010.1016/S0140-6736(06)68975-716876664 DomePLazaryJKalaposMPRihmerZSmoking, nicotine and neuropsychiatric disordersNeurosci. Biobehav. Rev20103429534210.1016/j.neubiorev.2009.07.01319665479 AmbroseJABaruaRSThe pathophysiology of cigarette smoking and cardiovascular disease: An updateJ Am Coll Cardiol2004431731173710.1016/j.jacc.2003.12.04715145091 BoudreauxEDFrancisJLCarmack TaylorCLScarinciICBrantleyPJChanging multiple health behaviors: Smoking and exercisePrev. Med20033647147810.1016/S0091-7435(02)00048-812649056 CasasolaGGAlvarez-SalaJLMarquesJASanchez-AlarcosJMTashkinDPEspinosDCigarette smoking behavior and respiratory alterations during sleep in a healthy populationSleep Breath20026192410.1055/s-2002-2315211917260 BartalMHealth effects of tobacco use and exposureMonaldi. Arch. Chest Dis20015654555411980288 BolegoCPoliAPaolettiRSmoking and genderCardiovasc. Res20025356857610.1016/S0008-6363(01)00520-X11861027 GareyKWNeuhauserMMRobbinsRADanzigerLHRubinsteinIMarkers of inflammation in exhaled breath condensate of young healthy smokersChest2004125222610.1378/chest.125.1.2214718416 HawkinsBTBrownRCDavisTPSmoking and ischemic stroke: A role for nicotineTrends Pharmacol. Sci200223788210.1016/S0165-6147(02)01893-X11830264 TsushimaYTanizakiYAokiJEndoKMR detection of microhemorrhages in neurologically healthy adultsNeuroradiology200244313610.1007/s00234010064911942497 DurazzoTCMeyerhoffDJNeurobiological and neurocognitive effects of chronic cigarette smoking and alcoholismFront Biosci2007124079410010.2741/237317485360 SwanGELessov-SchlaggarCNThe Effects of Tobacco Smoke and Nicotine on Cognition and the BrainNeuropsychol. Rev20071725927310.1007/s11065-007-9035-917690985 CeballosNATobacco use, alcohol dependence, and cognitive performanceJ. Gen. Psychol200613337538810.3200/GENP.133.4.375-38817128957 WatersAJSuttonSRDirect and indirect effects of nicotine/smoking on cognition in humansAddict. Behav200025294310.1016/S0306-4603(99)00023-410708317 SaccoKABannonKLGeorgeTPNicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disordersJ Psychopharmacol20041845747410.1177/026988110404727315582913 BrodyALFunctional brain imaging of tobacco use and dependenceJ. Psychiatr. Res20064040441810.1016/j.jpsychires.2005.04.01215979645 MansvelderHDvan AerdeKICoueyJJBrussaardABNicotinic modulation of neuronal networks: From receptors to cognitionPsychopharmacology (Berl)200618429230510.1007/s00213-005-0070-z McClernonFJGilbertDGHuman functional neuroimaging in nicotine and tobacco research: Basics, background, and beyondNicotine Tob. Res2004694195910.1080/1462220041233133739415801569 AzizianAMonterossoJO’NeillJLondonEDMagnetic resonance imaging studies of cigarette smokingNicotine PsychopharmacologySpringer-Verlag Berlin HeidelbergBerlin, Germany2009113143 SharmaABrodyAIn vivo brain imaging of human exposure to nicotine and tobaccoNicotine PsychopharmacologySpringer-Verlag Berlin HeidelbergBerlin, Germany2009145171 JacobsenLKKrystalJHMenclWEWesterveldMFrostSJPughKREffects of smoking and smoking abstinence on cognition in adolescent tobacco smokersBiol. Psychiat200557566610.1016/j.biopsych.2004.10.02215607301 YakirARigbiAKanyasKPollakYKahanaGKarniOEitanRKertzmanSLererBWhy do young women smoke? III. Attention and impulsivity as neurocognitive predisposing factorsEur. Neuropsychopharmacol20071733935110.1016/j.euroneuro.2006.09.00417141485 FriedPAWatkinsonBGrayRNeurocognitive consequences of cigarette smoking in young adults—A comparison with pre-drug performanceNeurotoxicol. Teratol20062851752510.1016/j.ntt.2006.06.00316904287 SpilichGJJuneLRennerJCigarette smoking and cognitive performanceBr. J. Addict1992871313132610.1111/j.1360-0443.1992.tb02740.x1392553 WeiserMZarkaSWerbeloffNKravitzELubinGCognitive test scores in male adolescent cigarette smokers compared to non-smokers: A population-based studyAddiction201010535836310.1111/j.1360-0443.2009.02740.x19919595 WallstenTSPleskacTJLejuezCWModeling behavior in a clinically diagnostic sequential risk-taking taskPsychol. Rev200511286288010.1037/0033-295X.112.4.86216262471 LejuezCWAklinWMJonesHARichardsJBStrongDRKahlerCWReadJPThe Balloon Analogue Risk Task (BART) differentiates smokers and nonsmokersExp. Clin. Psychopharmacol200311263310.1037/1064-1297.11.1.2612622341 HillRDNilssonLGNybergLBackmanLCigarette smoking and cognitive performance in healthy Swedish adultsAge Ageing20033254855010.1093/ageing/afg06712958006 StarrJMDearyIJFoxHCWhalleyLJSmoking and cognitive change from age 11 to 66 years: A confirmatory investigationAddict. Behav200632636816650620 KalmijnSvan BoxtelMPVerschurenMWJollesJLaunerLJCigarette smoking and alcohol consumption in relation to cognitive performance in middle ageAm. J. Epidemiol200215693694410.1093/aje/kwf13512419766 PaulRHBrickmanAMCohenRAWilliamsLMNiauraRPogunSClarkCRGunstadJGordonECognitive status of young and older cigarette smokers: Data from the international brain databaseJ Clin. Neurosci20061345746510.1016/j.jocn.2005.04.01216678725 EdelsteinSLKritz-SilversteinDBarrett-ConnorEProspective association of smoking and alcohol use with cognitive function in an elderly cohortJ. Womens Health199871271128110.1089/jwh.1998.7.12719929860 ErnstMHeishmanSJSpurgeonLLondonEDSmoking history and nicotine effects on cognitive performanceNeuropsychopharmacology20012531331910.1016/S0893-133X(01)00257-311522460 GeorgeTPVessicchioJCTermineASahadyDMHeadCAPepperWTKostenTRWexlerBEEffects of smoking abstinence on visuospatial working memory function in schizophreniaNeuropsychopharmacology200226758510.1016/S0893-133X(01)00296-211751034 RazaniJBooneKLesserIWeissDEffects of cigarette smoking history on cognitice functioning in healthy older adultsAm J Geriatr Psychiatry20041240441115249278 CaspersKArndtSYucuisRMcKirganLSpinksREffects of alcohol- and cigarette-use disorders on global and specific measures of cognition in middle-age adultsJ. Stud. Alcohol Drugs20107119220020230716 DearyIJPattieATaylorMDWhitemanMCStarrJMWhalleyLJSmoking and cognitive change from age 11 to age 80J. Neurol. Neurosurg Psychiatry2003741003100710.1136/jnnp.74.7.100312810808 RichardsMJarvisMJThompsonNWadsworthMECigarette smoking and cognitive decline in midlife: evidence from a prospective birth cohort studyAm. J. Public Health20039399499810.2105/AJPH.93.6.99412773367 WhalleyLJFoxHCDearyIJStarrJMChildhood IQ, smoking, and cognitive change from age 11 to 64 yearsAddict. Behav200530778810.1016/j.addbeh.2004.04.01415561450 HillRDResidual effects of cigarette smoking on cognitive performance in normal agingPsycho. l Aging1989425125410.1037/0882-7974.4.2.251 SabiaSMarmotMDufouilCSingh-ManouxASmoking history and cognitive function in middle age from the Whitehall II studyArch. Intern. Med20081681165117310.1001/archinte.168.11.116518541824 HuadongZJuanDJingchengLYanjiangWMengZHongboHStudy of the relationship between cigarette smoking, alcohol drinking and cognitive impairment among elderly people in ChinaAge Ageing20033220521010.1093/ageing/32.2.20512615566 StewartMCDearyIJFowkesFGPriceJFRelationship between lifetime smoking, smoking status at older age and human cognitive functionNeuroepidemiology200626839210.1159/00009025316352911 GalanisDJPetrovitchHLaunerLJHarrisTBFoleyDJWhiteLRSmoking history in middle age and subsequent cognitive performance in elderly Japanese-American men. The Honolulu-Asia Aging StudyAm. J. Epidemiol199714550751510.1093/oxfordjournals.aje.a0091389063340 FischerPZehetmayerSBauerKHuberKJungwirthSTraglKHRelation between vascular risk factors and cognition at age 75Acta Neurol. Scand2006114849010.1111/j.1600-0404.2006.00597.x16867029 WangLvan BelleGKukullWBLarsonEBPredictors of functional change: A longitudinal study of nondemented people aged 65 and olderJ. Am. Geriatr. Soc2002501525153410.1046/j.1532-5415.2002.50408.x12383150 IkiMIshizakiHAaltoHStarckJPyykkoISmoking habits and postural stabilityAm. J. Otolaryngol19941512412810.1016/0196-0709(94)90061-28179103 OttAAndersenKDeweyMELetenneurLBrayneCCopelandJRDartiguesJFKragh-SorensenPLoboAMartinez-LageJMStijnenTHofmanALaunerLJEffect of smoking on global cognitive function in nondemented elderlyNeurology20046292092410.1212/01.WNL.0000115110.35610.8015037693 CervillaJAPrinceMMannASmoking, drinking, and incident cognitive impairment: A cohort community based study included in the Gospel Oak projectJ. Neurol. Neurosurg. Psychiatry20006862262610.1136/jnnp.68.5.62210766894 DufouilCTzourioCBrayneCBerrCAmouyelPAlperovitchAInfluence of apolipoprotein E genotype on the risk of cognitive deterioration in moderate drinkers and smokersEpidemiology20001128028410.1097/00001648-200005000-0000910784244 LaunerLJFeskensEJKalmijnSKromhoutDSmoking, drinking, and thinking. The Zutphen Elderly StudyAm. J. Epidemiol199614321922710.1093/oxfordjournals.aje.a0087328561155 ReitzCLuchsingerJTangMXMayeuxREffect of smoking and time on cognitive function in the elderly without dementiaNeurology20056587087510.1212/01.wnl.0000176057.22827.b716186526 HeffernanTMLingJParrottACBuchananTScholeyABRodgersJSelf-rated everyday and prospective memory abilities of cigarette smokers and non-smokers: A web-based studyDrug Alcohol Depend20057823524110.1016/j.drugalcdep.2004.11.00815893154 CerhanJRFolsomARMortimerJAShaharEKnopmanDSMcGovernPGHaysMACrumLDHeissGCorrelates of cognitive function in middle-aged adults. Atherosclerosis Risk in Communities (ARIC) Study InvestigatorsGerontology1998449510510.1159/0000219919523221 LaunerLJAndersenKDeweyMELetenneurLOttAAmaducciLABrayneCCopelandJRDartiguesJFKragh-SorensenPLoboAMartinez-LageJMStijnenTHofmanARates and risk factors for dementia and Alzheimer’s disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of DementiaNeurology199952788410.1212/WNL.52.1.789921852 OttASlooterAJHofmanAvan HarskampFWittemanJCvan BroeckhovenCvan DuijnCMBretelerMMSmoking and risk of dementia and Alzheimer’s disease in a population-based cohort study: the Rotterdam StudyLancet19983511840184310.1016/S0140-6736(97)07541-79652667 MerchantCTangMXAlbertSManlyJSternYMayeuxRThe influence of smoking on the risk of Alzheimer’s diseaseNeurology1999521408141210.1212/WNL.52.7.140810227626 AnsteyKJvon SandenCSalimAO’KearneyRSmoking as a risk factor for dementia and cognitive decline: A meta-analysis of prospective studiesAm. J. Epidemiol200716636737810.1093/aje/kwm11617573335 TyasSLWhiteLRPetrovitchHWebster RossGFoleyDJHeimovitzHKLaunerLJMid-life smoking and late-life dementia: The Honolulu-Asia Aging StudyNeurobiol. Aging20032458959610.1016/S0197-4580(02)00156-212714116 SakuraiYKanazawaIAcute effects of cigarettes in non-deprived smokers on memory, calculation and executive functionsHum Psychopharmacol20021736937310.1002/hup.42412415558 BusinelleMSAppersonMRKendzorDETerleckiMACopelandALThe relative impact of nicotine dependence, other substance dependence, and gender on Bechara Gambling Task performanceExp. Clin. Psychopharmacol20081651352010.1037/a001351019086772 SchinkaJAVanderploegRDRogishMGravesABMortimerJAOrdoricPIEffects of the use of alcohol and cigarettes on cognition in elderly adultsJ. Int. Neuropsychol. Soc2002881181810.1017/S135561770286009X12240745 SchinkaJABelangerHMortimerJAGravesABEffects of the use of alcohol and cigarettes on cognition in elderly African American adultsJ. Int. Neuropsychol. Soc2003969069712901775 ChenWTWangPNWangSJFuhJLLinKNLiuHCSmoking and cognitive performance in the community elderly: A longitudinal studyJ. Geriatr. Psychiatry Neurol200316182210.1177/089198870225051012641368 SchinkaJAVanderploegRDRogishMOrdoricaPIEffects of alcohol and cigarette use on cognition in middle-aged adultsJ. Int. Neuropsychol. Soc2002868369012164677 FordABMefroucheZFriedlandRPDebanneSMSmoking and cognitive impairment: A population-based studyJ. Am. Geriatr. Soc1996449059098708298 HebertLEScherrPABeckettLAAlbertMSRosnerBTaylorJOEvansDARelation of Smoking and Low-to-moderate Alcohol Consumption to Change in Cognitive Function: A Longitudinal Study in a Defined Community of Older PersonsAm. J. Epidemiol19931378818918484379 ElwanOHassanAAAbdel NaseerMElwanFDeifREl SerafyOEl BanhawyEEl FatatryMBrain aging in a sample of normal Egyptians cognition, education, addiction and smokingJ. Neurol. Sci1997148798610.1016/S0022-510X(96)05336-19125393 SpilichGJJuneLRennerJCigarette smoking and cognitive performanceBr. J. Addict1992871313132610.1111/j.1360-0443.1992.tb02740.x1392553 LejuezCWReadJPKahlerCWRichardsJBRamseySEStuartGLStrongDRBrownRAEvaluation of a behavioral measure of risk taking: The Balloon Analogue Risk Task (BART)J. Exp. Psychol. Appl20028758410.1037/1076-898X.8.2.7512075692 RazaniJBooneKLesserIWeissDEffects of cigarette smoking history on cognitive functioning in healthy older adultsAm. J. Geriatr. Psychiatry20041240441115249278 AkiyamaHMeyerJSMortelKFTerayamaYThornbyJKonnoSNormal human aging: Factors contributing to cerebral atrophyJ. Neurol. Sci1997152394910.1016/S0022-510X(97)00141-X9395125 HayeeAHaqueAAnwarullahARabbaniMSmoking enhances age related brain atrophy—A quantitative study with computed tomographyBangladesh Med. Res. Counc. Bull20032911812415053274 KubotaKMatsuzawaTFujiwaraTYamaguchiTItoKWatanabeHOnoSAge-related brain atrophy enhanced by smoking: A quantitative study with computed tomographyTohoku J. Exp. Med198715330331110.1620/tjem.153.3033441922 SwanGEDeCarliCMillerBLReedTWolfPACarmelliDBiobehavioral characteristics of nondemented older adults with subclinical brain atrophyNeurology2000542108211410.1212/WNL.54.11.210810851372 LongstrethWTJrArnoldAMManolioTABurkeGLBryanNJungreisCAO’LearyDEnrightPLFriedLClinical correlates of ventricular and sulcal size on cranial magnetic resonance imaging of 3,301 elderly people. The Cardiovascular Health Study. Collaborative Research GroupNeuroepidemiology200019304210.1159/00002623510654286 BrodyALMandelkernMAJarvikMELeeGSSmithECHuangJCBotaRGBartzokisGLondonEDDifferences between smokers and nonsmokers in regional gray matter volumes and densitiesBiol. Psychiatry200455778410.1016/S0006-3223(03)00610-314706428 GallinatJMeisenzahlEJacobsenLKKalusPBierbrauerJKienastTWitthausHLeopoldKSeifertFSchubertFStaedtgenMSmoking and structural brain deficits: A volumetric MR investigationEur. J. Neurosci2006241744175010.1111/j.1460-9568.2006.05050.x17004938 AlmeidaOPGarridoGJLautenschlagerNTHulseGKJamrozikKFlickerLSmoking is associated with reduced cortical regional gray matter density in brain regions associated with incipient Alzheimer diseaseAm. J. Geriatr. Psychiatry200816929810.1097/JGP.0b013e318157cad218165464 PaulRHGrieveSMNiauraRDavidSPLaidlawDHCohenRSweetLTaylorGClarkRCPogunSGordonEChronic cigarette smoking and the microstructural integrity of white matter in healthy adults: A diffusion tensor imaging studyNicotine Tob. Res20081013714710.1080/1462220070176782918188754 LimKOHelpernJANeuropsychiatric applications of DTI—A reviewNMR Biomed20021558759310.1002/nbm.78912489105 SundgrenPCDongQGomez-HassanDMukherjiSKMalyPWelshRDiffusion tensor imaging of the brain: Review of clinical applicationsNeuroradiology20044633935010.1007/s00234-003-1114-x15103435 FukudaHKitaniMCigarette smoking is correlated with the periventricular hyperintensity grade of brain magnetic resonance imagingStroke19962764564910.1161/01.STR.27.4.6458614923 JeerakathilTWolfPABeiserAMassaroJSeshadriSD’AgostinoRBDeCarliCStroke risk profile predicts white matter hyperintensity volume: the Framingham StudyStroke2004351857186110.1161/01.STR.0000135226.53499.8515218158 LongstrethWTJrArnoldAMBeauchampNJJrManolioTALefkowitzDJungreisCHirschCHO’LearyDHFurbergCDIncidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: The Cardiovascular Health StudyStroke200536566110.1161/01.STR.0000149625.99732.6915569873 DingJNietoFJBeauchampNJLongstrethWTJrManolioTAHetmanskiJBFriedLPA prospective analysis of risk factors for white matter disease in the brain stem: The Cardiovascular Health StudyNeuroepidemiology20032227528210.1159/00007119012902622 LongstrethWTJrManolioTAArnoldABurkeGLBryanNJungreisCAEnrightPLO’LearyDFriedLClinical correlates of white matter findings on cranial magnetic resonance imaging of 3,301 elderly people. The Cardiovascular Health StudyStroke1996271274128210.1161/01.STR.27.8.12748711786 MarstrandJRGardeERostrupERingPRosenbaumSMortensenELLarssonHBCerebral perfusion and cerebrovascular reactivity are reduced in white matter hyperintensitiesStroke20023397297610.1161/01.STR.0000012808.81667.4B11935046 BisschopsRHvan der GraafYMaliWPvan der GrondJHigh total cerebral blood flow is associated with a decrease of white matter lesionsJ. Neurol20042511481148510.1007/s00415-004-0569-y15645347 DeCarliCMurphyDGTranhMGradyCLHaxbyJVGilletteJASalernoJAGonzales-AvilesAHorwitzBRapoportSIThe effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adultsNeurology1995452077208410.1212/WNL.45.11.20777501162 Gunning-DixonFMRazNThe cognitive correlates of white matter abnormalities in normal aging: a quantitative reviewNeuropsychology20001422423210.1037/0894-4105.14.2.22410791862 RossBBlumlSMagnetic resonance spectroscopy of the human brainAnat. Rec2001265548410.1002/ar.105811323770 MoffettJRRossBArunPMadhavaraoCNNamboodiriAMN-Acetylaspartate in the CNS: From neurodiagnostics to neurobiologyProg. Neurobiol2007818913110.1016/j.pneurobio.2006.12.00317275978 MillerBLChangLBoothRErnstTCornfordMNikasDMcBrideDJendenDJIn vivo 1H MRS choline: Correlation with in vitro chemistry/histologyLife Sci1996581929193510.1016/0024-3205(96)00182-88637421 GallinatJLangUEJacobsenLKBajboujMKalusPvon HaeblerDSeifertFSchubertFAbnormal hippocampal neurochemistry in smokers: Evidence from proton magnetic resonance spectroscopy at 3 TJ. Clin. Psychopharmacol200727808410.1097/JCP.0b013e31802dffde17224719 GallinatJSchubertFRegional cerebral glutamate concentrations and chronic tobacco consumptionPharmacopsychiatry200740646710.1055/s-2007-97014417447175 EnochMAPharmacogenomics of alcohol response and addictionAm. J. Pharmacogenomics2003321723210.2165/00129785-200303040-0000112930156 GeorgeTPO’MalleySSCurrent pharmacological treatments for nicotine dependenceTrends Pharmacol. Sci200425424810.1016/j.tips.2003.11.00314723978 HeinzASchaferMHigleyJDKrystalJHGoldmanDNeurobiological correlates of the disposition and maintenance of alcoholismPharmacopsychiatry200336Suppl 3S25525814677088 EppersonCNO’MalleySCzarkowskiKAGueorguievaRJatlowPSanacoraGRothmanDLKrystalJHMasonGFSex, GABA, and nicotine: The impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopyBiol. Psychiatry200557444815607299 RogersRLMeyerJSShawTGMortelKFHardenbergJPZaidRRCigarette Smoking Decreases Cerebral Blood Flow Suggesting Increased Risk for StrokeJAMA1983250279628006644957 YamashitaKKobayashiSYamaguchiSKitaniMTsunematsuTEffect of smoking on regional cerebral blood flow in the normal aged volunteersGerontology1988341992043181770 RourkeSBDupontRMGrantILehrPPLamoureuxGHalpernSYeungDWReduction in cortical IMP-SPET tracer uptake with recent cigarette consumption in a young group of healthy males. San Diego HIV Neurobehavioral Research CenterEur. J. Nucl. Med1997244224279096094 MeyerJSRauchGRauchRAHaqueARisk factors for cerebral hypoperfusion, mild cognitive impairment, and dementiaNeurobiol. Aging20002116116910867201 AkiyamaHMeyerJSMortelKFTerayamaYThornbyJIKonnoSNormal human aging: Factors contributing to cerebral atrophyJ. Neurol. Sci199715239499395125 RezvaniAHLevinEDCognitive effects of nicotineBiol. Psychiatry20014925826711230877 MendrekAMonterossoJSimonSLJarvikMBrodyAOlmsteadRDomierCPCohenMSErnstMLondonEDWorking memory in cigarette smokers: Comparison to non-smokers and effects of abstinenceAddict. Behav20063183384416009504 ParrottACNicotine psychobiology: How chronic-dose prospective studies can illuminate some of the theoretical issues from acute-dose researchPsychopharmacology (Berl)2006184567576 HeishmanSJKleykampBASingletonEGMeta-analysis of the acute effects of nicotine and smoking on human performancePsychopharmacology (Berl)2010210453469 XuJMendrekACohenMSMonterossoJRodriguezPSimonSLBrodyAJarvikMDomierCPOlmsteadRErnstMLondonEDBrain activity in cigarette smokers performing a working memory task: effect of smoking abstinenceBiol. Psychiatry20055814315016038685 HukkanenJJacobP3rdBenowitzNLMetabolism and disposition kinetics of nicotinePharmacol. Rev2005577911515734728 DominoEFNiLXuYKoeppeRAGuthrieSZubietaJKRegional cerebral blood flow and plasma nicotine after smoking tobacco cigarettesProg. Neuropsychopharmacol. Biol. Psychiatry20042831932714751429 RoseJEBehmFMWestmanECMathewRJLondonEDHawkTCTurkingtonTGColemanREPET studies of the influences of nicotine on neural systems in cigarette smokersAm. J. Psychiatry200316032333312562580 DominoEFMinoshimaSGuthrieSKOhlLNiLKoeppeRACrossDJZubietaJEffects of nicotine on regional cerebral glucose metabolism in awake resting tobacco smokersNeuroscience200010127728211074150 StapletonJMGilsonSFWongDFVillemagneVLDannalsRFGraysonRFHenningfieldJELondonEDIntravenous nicotine reduces cerebral glucose metabolism: A preliminary studyNeuropsychopharmacology20032876577212655323 BatesCJarvisMConnollyGTobacco Additives: Cigarette Engineering and Nicotine AddictionMassachusetts Tobacco Control ProgramBoston, MA, USA1999123 FowlesJBatesMNoitonDThe Chemical Constituents in Cigarettes and Cigarette Smoke: Priorities for Harm ReductionEpidemiology and Toxicology GroupPorirua, New Zealand2000165 ParkEMParkYMGwakYSOxidative damage in tissues of rats exposed to cigarette smokeFree Radic. Biol. Med19982579869655525 MuscatJEKleinmanWColosimoSMuirALazarusPParkJRichieJPJrEnhanced protein glutathiolation and oxidative stress in cigarette smokersFree Radic. Biol. Med20043646447014975449 YangYMLiuGTInjury of mouse brain mitochondria induced by cigarette smoke extract and effect of vitamin C on it in vitroBiomed. Environ. Sci20031625626614631831 DeveciSDeveciFAcikYOzanAThe measurement of exhaled carbon monoxide in healthy smokers and non-smokersResp. Med200498551556 MacdonaldGKondorNYousefiVGreenAWongFAquino-ParsonsCReduction of carboxyhaemoglobin levels in the venous blood of cigarette smokers following the administration of carbogenRadiother. Oncol20047336737115588884 AlonsoJRCardellachFCasademontJMiroOReversible inhibition of mitochondrial complex IV activity in PBMC following acute smokingEur. Respir. J20042321421814979494 MoriartySEShahJHLynnMJiangSOpenoKJonesDPSternbergPOxidation of glutathione and cysteine in human plasma associated with smokingFree Radic. Biol. Med2003351582158814680681 PandaKChattopadhyayRChattopadhyayDJChatterjeeIBVitamin C prevents cigarette smoke-induced oxidative damage in vivoFree Radic. Biol. Med20002911512410980400 AnbarasiKVaniGBalakrishnaKDeviCSEffect of bacoside A on membrane-bound ATPases in the brain of rats exposed to cigarette smokeJ. Biochem. Mol. Toxicol200519596515736152 XiaoAYWeiLXiaSRothmanSYuSPIonic mechanism of ouabain-induced concurrent apoptosis and necrosis in individual cultured cortical neuronsJ. Neurosci2002221350136211850462 Abreu-VillacaYSeidlerFJTateCASlotkinTANicotine is a neurotoxin in the adolescent brain: critical periods, patterns of exposure, regional selectivity, and dose thresholds for macromolecular alterationsBrain Res200397911412812850578 SlotkinTANicotine and the adolescent brain: insights from an animal modelNeurotoxicol. Teratol20022436938412009492 Mendez-AlvarezESoto-OteroRSanchez-SelleroILopez-Rivadulla LamasMIn vitro inhibition of catalase activity by cigarette smoke: relevance for oxidative stressJ. Appl. Toxicol1998184434489840751 AnbarasiKVaniGBalakrishnaKDeviCSEffect of bacoside A on brain antioxidant status in cigarette smoke exposed ratsLife Sci2006781378138416226278 SachdevPSAnsteyKJParslowRAWenWMallerJKumarRChristensenHJormAFPulmonary function, cognitive impairment and brain atrophy in a middle-aged community sampleDement. Geriatr. Cogn. Disord20062130030816484809 HawkinsBTBrownRCDavisTPSmoking and ischemic stroke: A role for nicotine?Trends Pharmacol. Sci200223788211830264 GerzanichVZhangFWestGASimardJMChronic nicotine alters NO signaling of Ca(2+) channels in cerebral arteriolesCirc. Res20018835936511179206 TerborgCBramerSWeillerCRotherJShort-term effect of cigarette smoking on CO(2)-induced vasomotor reactivity in man: A study with near-infrared spectroscopy and tanscranial Doppler sonographyJ. Neurol. Sci2002205152012409178 Michael PittiloRCigarette smoking, endothelial injury and cardiovascular diseaseInt. J. Exp. Pathol20008121923010971743 ZubietaJLombardiUMinoshimaSGuthrieSNiLOhlLEKoeppeRADominoEFRegional cerebral blood flow effects of nicotine in overnight abstinent smokersBiol. Psychiatry20014990691311377408 JeerakathilTWolfPABeiserAHaldJKAuRKaseCSMassaroJMDeCarliCCerebral microbleeds: Prevalence and associations with cardiovascular risk factors in the Framingham StudyStroke2004351831183515155954 LiaoDCooperLCaiJTooleJBryanNBurkeGShaharENietoJMosleyTHeissGThe prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: the ARIC StudyNeuroepidemiology1997161491629159770 ChalelaJAWolfRLMaldjianJAKasnerSEMRI identification of early white matter injury in anoxic-ischemic encephalopathyNeurology20015648148511222791 BartzokisGAge-related myelin breakdown: A developmental model of cognitive decline and Alzheimer’s diseaseNeurobiol Aging200425518author reply 49–62.14675724 BartzokisGQuadratic trajectories of brain myelin content: Unifying construct for neuropsychiatric disordersNeurobiol. Aging2004254962 ChioleroAFaehDPaccaudFCornuzJConsequences of smoking for body weight, body fat distribution, and insulin resistanceAm. J. Clin. Nutr20088780180918400700 ConvitALinks between cognitive impairment in insulin resistance: An explanatory modelNeurobiol Aging200526Suppl 1313516246463 WardMACarlssonCMTrivediMASagerMAJohnsonSCThe effect of body mass index on global brain volume in middle-aged adults: A cross sectional studyBMC Neurol200552316321166 HaltiaLTViljanenAParkkolaRKemppainenNRinneJONuutilaPKaasinenVBrain white matter expansion in human obesity and the recovering effect of dietingJ. Clin. Endocrinol. Metab2007923278328417536002 GazdzinskiSKornakJWeinerMWMeyerhoffDJBody mass index and magnetic resonance markers of brain integrity in adultsAnn. Neurol20086365265718409192 JeongSKNamHSSonMHSonEJChoKHInteractive effect of obesity indexes on cognitionDement. Geriatr. Cogn. Disord200519919615591798 DaniJADe BiasiMCellular mechanisms of nicotine addictionPharmacol. Biochem. Behav20017043944611796143 MansvelderHDDe RoverMMcGeheeDSBrussaardABCholinergic modulation of dopaminergic reward areas: Upstream and downstream targets of nicotine addictionEur. J. Pharmacol200348011712314623355 VallejoYFBuissonBBertrandDGreenWNChronic nicotine exposure upregulates nicotinic receptors by a novel mechanismJ. Neurosci2005255563557215944384 VolkowNDFowlerJSDingYSWangGJGatleySJImaging the neurochemistry of nicotine actions: Studies with positron emission tomographyNicotine Tob Res19991Suppl 2S127132discussion S139–140.11768169 HausteinKOSmoking tobacco, microcirculatory changes and the role of nicotineInt. J. Clin. Pharmacol. Ther199937768510082171 BreslauNNovakSPKesslerRCPsychiatric disorders and stages of smokingBiol. Psychiatry200455697614706427 RohdePKahlerCWLewinsohnPMBrownRAPsychiatric disorders, familial factors, and cigarette smoking: II. Associations with progression to daily smokingNicotine Tob. Res2004611913214982696 OhlmeierMDPetersKTe WildtBTZedlerMZiegenbeinMWieseBEmrichHMSchneiderUComorbidity of alcohol and substance dependence with attention-deficit/hyperactivity disorder (ADHD)Alcohol Alcoholism200843300304 SchumannAHapkeUMeyerCRumpfHJJohnUPrevalence, characteristics, associated mental disorders and predictors of DSM-IV nicotine dependenceEur. Addict. Res200410293414665803 PaperwallaKNLevinTTWeinerJSaravaySMSmoking and depressionMed Clin North Am20048814831494xxi FergussonDMGoodwinRDHorwoodLJMajor depression and cigarette smoking: Results of a 21-year longitudinal studyPsychol. Med2003331357136714672244 SmithRCSinghAInfanteMKhandatAKloosAEffects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophreniaNeuropsychopharmacology20022747949712225705 DolanSLSaccoKATermineASeyalAADudasMMVessicchioJCWexlerBEGeorgeTPNeuropsychological deficits are associated with smoking cessation treatment failure in patients with schizophreniaSchizophr. Res20047026327515329302 PignattiRBertellaLAlbaniGMauroAMolinariESemenzaCDecision-making in obesity: A study using the Gambling TaskEat. Weight Disord20061112613217075239 CotmanCWBerchtoldNCExercise: A behavioral intervention to enhance brain health and plasticityTrends Neurosci20022529530112086747 DishmanRKBerthoudHRBoothFWCotmanCWEdgertonVRFleshnerMRGandeviaSCGomez-PinillaFGreenwoodBNHillmanCHKramerAFLevinBEMoranTHRusso-NeustadtAASalamoneJDVan HoomissenJDWadeCEYorkDAZigmondMJNeurobiology of exerciseObesity (Silver Spring)200614345356 HillmanCHEricksonKIKramerAFBe smart, exercise your heart: Exercise effects on brain and cognitionNat. Rev. Neurosci20089586518094706 DumanRSNeurotrophic factors and regulation of mood: role of exercise, diet and metabolismNeurobiol Aging200526Suppl 1889316226350 ParrottMDGreenwoodCEDietary influences on cognitive function with aging: From high-fat diets to healthful eatingAnn. N. Y. Acad. Sci2007111438939717986600 WadleyVGMcClureLAHowardVJUnverzagtFWGoRCMoyCSCrowtherMRGomezCRHowardGCognitive status, stroke symptom reports, and modifiable risk factors among individuals with no diagnosis of stroke or transient ischemic attack in the REasons for Geographic and Racial Differences in Stroke (REGARDS) StudyStroke2007381143114717322077 GustafsonDLissnerLBengtssonCBjorkelundCSkoogIA 24-year follow-up of body mass index and cerebral atrophyNeurology2004631876188115557505 NgTPFengLNitiMYapKBAlbumin, haemoglobin, BMI and cognitive performance in older adultsAge Ageing20083742342918495687 AtkinsonHHCesariMKritchevskySBPenninxBWFriedLPGuralnikJMWilliamsonJDPredictors of combined cognitive and physical declineJ. Am. Geriatr. Soc2005531197120216108938 BretskyPGuralnikJMLaunerLAlbertMSeemanTEThe role of APOE-epsilon4 in longitudinal cognitive decline: MacArthur Studies of Successful AgingNeurology2003601077108112682309 CabezaRCognitive neuroscience of aging: Contributions of functional neuroimagingScand. J. Psychol20014227728611501741 CataniMCherubiniAHowardRTarducciRPelliccioliGPPiccirilliMGobbiGSeninUMecocciP(1)H-MR spectroscopy differentiates mild cognitive impairment from normal brain agingNeuroreport2001122315231711496102 CharltonRAMcIntyreDJHoweFAMorrisRGMarkusHSThe relationship between white matter brain metabolites and cognition in normal aging: The GENIE studyBrain Res2007116410811617632090 EliasMFEliasPKSullivanLMWolfPAD’AgostinoRBObesity, diabetes and cognitive deficit: The Framingham Heart StudyNeurobiol Aging200526Suppl 1111616223549 FinkelDReynoldsCAMcArdleJJPedersenNLAge changes in processing speed as a leading indicator of cognitive agingPsychol. Aging20072255856817874954 MeyerhoffDJDurazzoTCProton magnetic resonance spectroscopy in alcohol use disorders: A potential new endophenotype?Alcohol Clin. Exp. Res2008321146115818540913 RigbiAKanyasKYakirAGreenbaumLPollakYBen-AsherELancetDKertzmanSLererBWhy do young women smoke? V. Role of direct and interactive effects of nicotinic cholinergic receptor gene variation on neurocognitive functionGenes Brain Behav2008716417217559419 DurazzoTCGazdzinskiSBanysPMeyerhoffDJBrain metabolite concentrations and neurocognition during short-term recovery from alcohol dependence: Preliminary evidence of the effects of concurrent chronic cigarette smokingAlcohol Clin. Exp. Res20063053955116499496 GazdzinskiSDurazzoTCStudholmeCSongEBanysPMeyerhoffDJQuantitative brain MRI in alcohol dependence: preliminary evidence for effects of concurrent chronic cigarette smoking on regional brain volumesAlcohol Clin. Exp. Res2005291484149516131857 CummingsJLFrontal-subcortical circuits and human behaviorJ. Psychosom Res1998446276289678739 Saint-CyrJAFrontal-striatal circuit functions: context, sequence, and consequenceJ. Int. Neuropsychol. Soc2003910312712570364 KalivasPWVolkowNDThe neural basis of addiction: a pathology of motivation and choiceAm. J. Psychiatry20051621403141316055761 BalerRDVolkowNDDrug addiction: the neurobiology of disrupted self-controlTrends Mol. Med20061255956617070107 KalivasPWO’BrienCDrug addiction as a pathology of staged neuroplasticityNeuropsychopharmacology20083316618017805308 MakrisNOscar-BermanMJaffinSKHodgeSMKennedyDNCavinessVSMarinkovicKBreiterHCGasicGPHarrisGJDecreased volume of the brain reward system in alcoholismBiol. Psychiatry20086419220218374900 PaulusMPNeural basis of reward and craving—A homeostatic point of viewDialogues Clin Neurosci2007937938718286798 VolkowNDWangGJFowlerJSTelangFOverlapping neuronal circuits in addiction and obesity: Evidence of systems pathologyPhilos. Trans. R Soc. Lond. B Biol. Sci20083633191320018640912 KoobGFAlcoholism: allostasis and beyondAlcohol Clin. Exp. Res20032723224312605072 LubmanDIYucelMPantelisCAddiction, a condition of compulsive behaviour? Neuroimaging and neuropsychological evidence of inhibitory dysregulationAddiction2004991491150215585037 WangZFaithMPattersonFTangKKerrinKWileytoEPDetreJALermanCNeural substrates of abstinence-induced cigarette cravings in chronic smokersJ. Neurosci200727140351404018094242 MitchellSHMeasuring impulsivity and modeling its association with cigarette smokingBehav. Cogn. Neurosci. Rev2004326127515812110 VanderVeenJWCohenLMCukrowiczKCTrotterDRThe role of impulsivity on smoking maintenanceNicotine Tob. Res2008101397140418686188 HodgkinsonCAYuanQXuKShenPHHeinzELobosEABinderEBCubellsJEhlersCLGelernterJMannJRileyBRoyATabakoffBToddRDZhouZGoldmanDAddictions biology: Haplotype-based analysis for 130 candidate genes on a single arrayAlcohol Alcoholism200843505515 HuangWPayneTJMaJZLiMDA functional polymorphism, rs6280, in DRD3 is significantly associated with nicotine dependence in European-American smokersAm. J. Med. Genet. Part B2008147B110911518348205 BatraVPatkarAABerrettiniWHWeinsteinSPLeoneFTThe genetic determinants of smokingChest20031231730173912740294 HoftNRCorleyRPMcQueenMBSchlaepferIRHuizingaDEhringerMAGenetic Association of the CHRNA6 and CHRNB3 Genes with Tobacco Dependence in a Nationally Representative SampleNeuropsychopharmacology20093469870618704094 Tables

Neurocognitive studies of chronic smoking in adults (sorted by age group, then year of publication).

Authors [reference number] Smokers (n) NSC (n) Age group/Mean age or (range) Neurocognitive measures or domains assessed Major findings (all reported findings are statistically significant unless otherwise indicated)
Jacobsen et al. (2005) [23] 41 current 32 Adolescents & Young adults/16.8 ± 1.2 Hopkins Verbal Learning Test-Revised n-back task (measure of working memory, Connors Continuous Performance Task, auditory and visual selective attention, verbal and visuospatial divided attention Smokers demonstrated poorer working memory than NSC. Earlier age of smoking onset was related to poorer working memory. Male smokers were inferior to female smokers on measures of selective and divided attention.
Spilich et al. (1992) [71] 45 current 45 Young adults/19.2 ± 1.2 Visual search speed/accuracy, sustained visual attention, working, memory, information processing speed Smokers performed worse than NSC on all measures of sustained attention and information processing speed.
Elwan et al. (1997) [70] 60 current 69 Young adults through older adults/49.9 ± 3.8 (20–76) Paced Auditory Serial Attention Test, Trail Making Test A and B No significant differences observed between smokers and NSC on any measure.
Lejuez et al. (2002) [72] 26 current 34 Young adults/20.1 ± 2.8 Balloon Analogue Risk Task (BART), Iowa Gambling Task (IGT) Smokers demonstrated increased risk-taking levels on the BART compared to NSC. Smokers and NSC showed no differences on the IGT.
Fried et al. (2006) [25] 27 current11 former 64 Young adults/(17–21) WAIS-III, Wechsler Memory Scale-III, Peabody Picture Vocabulary, Test of Variables of Attention Overall, current smokers performed worse than NSC on measures of receptive and expressive language, oral arithmetic and auditory-verbal memory.
Yakir et al. (2007) [24] 91 current40 former 151 Young adults (all female)/23.9 ± 2.2 CogScan (v4.0): a comprehensive battery assessing information processing speed, sustained attention, fine motor skills, auditory-verbal and visuospatial memory, reasoning and impulsivity. Current smokers showed poorer sustained attention, impulse control and planning/reasoning than NSC. Former smokers had poorer impulse control and planning/reasoning than NSC. Current and former smokers were not significantly different on any measure.
Weiser et al. (2009) [27] 5762 current695 former 13,764 Young adults (all males)/(18–21) Measures of verbal comprehension, verbal and non-verbal abstraction, and mathematical knowledge, Individual measures combined to form composite score of general IQ. Current and former smokers performed worse than NSC, although the difference between former smokers and NSC was trivial with respect to effect size after adjustment for socioeconomic status. Current smokers who smoked more than 11 cigarettes per day showed the poorest performance relative to NSC.
Ernst et al. (2001) [35] 14 current15 former 9 Young and Middle aged adults/(21–45) Domains assessed were verbal reasoning and working memory. Current smokers and former smokers showed poorer working memory than NSC. Current smokers had poorer working memory than former smokers.
Sakurai and Kanazawa (2002) [62] 20 current 20 Young and Middle aged Adults/(23–41) Measures of auditory-verbal learning and memory, mental arithmetic, and verbal fluency No differences between smokers and NSC on any task.
Paul et al. (2006) [33] 62 current 62 Young and middle aged adults/28.1 ± 7.2, 55.2 ± 7.3 Domains assessed included executive function, finger tapping speed, learning and memory, sustained attention, word fluency, working memory Smokers performed more poorly than NSC on one measure of executive function. Middle aged smokers showed poorer auditory-verbal memory than aged NSC and young adult smokers.
George et al. (2002) [36] 29 current 16 Middle aged adults/41.5 ± 10.3 Domains assessed were visuospatial working memory, cognitive flexibility Smokers exhibited worse visuospatial working memory.
Schinka et al. (2002) [67] 174 current80 former 204 Middle aged adults/38.4 ± 2.3 CVLT, WAIS-R Block Design, Rey-Osterreith Complex Figure, Wisconsin Card Sorting Test, Paced Auditory Serial Attention Test, Grooved Pegboard, semantic fluency, global cognitive function Higher pack years of smoking was related to lower global cognitive functioning.
Kalmijn et al. (2002) [32] 529 current715 former 619 Middle aged adults/56.4 ± 7.1 Domains assessed were auditory-verbal and visuospatial learning and memory, cognitive flexibility, processing speed, global cognitive function Current smokers showed poorer cognitive flexibility and processing speed than NSC. No differences between former smokers and NSC on any measure.
Sabia et al. (2008) [43] 815 current2,030 former 2,543 Middle age adults/56 ± 6 Mill Hill Vocabulary Test, measures of verbal and semantic fluency, verbal and mathematical reasoning, auditory verbal learning In cross-sectional analyses, smoking history was associated with increased risk of poor memory. Over 4–7 years, current smokers and recent former smokers showed significantly greater declines in reasoning than never smokers. No significant declines in cognitive function were observed in former smokers.
Cerhan et al. (1998) [56] 13,913 total participants, numbers of current, former smokers and NSC not provided NA Middle age and older adults/(45–69) WAIS-R Digit Symbol Test, measures of auditory-verbal memory and verbal fluency Current smokers demonstrated poorer performance on Digit Symbol and auditory-verbal memory. For smokers, greater lifetime number of cigarettes was related to poorer Digit Symbol and auditory-verbal memory performance.
Hill et al. (2003) [30] 164 current 438 Middle aged & older adults/NA WAIS-R Block Design and measures of auditory-verbal learning and memory, general knowledge, word comprehension Smokers, irrespective of age performed worse than NSC on Block Design and on measures of auditory-verbal memory.
Razani et al. (2004) [73] 125 former or never smokers. Groups were retro-spectively divided into non/light, moderate heavy and heavy smokers based on pack years. Only 2 of 127 subjects were active smokers. NA Middle aged & older adults 65.9 ± 8.3 WAIS-R Digit Symbol and Digit Span, WMS-R Logical Memory and Visual Reproduction, Rey-Osterrieth Complex Figure—Immediate Recall, Stroop Word and color trials, WCST Heavy smokers performed worse than moderate smokers and non/light smokers on the WCST.
Hill (1989) [42] 11 current12 former 53 Older adults/71.6 ± 4.9 WAIS-R Block Design, Digit Symbol, and Digit Span; WMS Logical Memory and Associative Memory, Bender Gestalt, Cross Off Task, word fluency and Digit Symbol. At the baseline assessment current smokers performed worse than former smokers and NSC on the Cross Off task. At reassessment (15 months after baseline), current smokers performed worse than former and current smokers on the Cross Off Task and Digit Symbol.
Hebert et al. (1993) [69] currentformer Older adults/(65 to ≥ 80) Measures of auditory-verbal memory, working memory and orientation Current and former smokers showed no significant decline over a 3-year period on any measure relative to NSC after control for age, sex, education and income.
Launer et al. (1996) [53] 110 current288 former 91 Older adults/75 ± 4.5 MMSE Smokers performed worse on the MMSE than NSC after correction for age, education and alcohol consumption. Over a 3-year period, current smokers with cardiovascular disease and/or diabetes showed the greatest decline in MMSE scores.
Ford et al. (1996) [68] 259 current and former smokers combined 369 Older adults/>75 Pfeiffer Short Portable Mental Status Questionnaire (PSPMSQ) Baseline and change over 4 years on the PSPMSQ was not associated with smoking status.
Galanis et al. (1997) [46] 921 current1,334 former 1,174 Older adults/77.4 ± 4.6 Cognitive Abilities Screening Test (CASI): includes task of attention, concentration abstraction, judgment, verbal and verbal fluency. A composite CASI score was formed from the individual components. After adjustment for age, education and Japanese acculturation, current and former smokers had lower CASI score than never smokers. Higher risk of impaired performance on CASI scores was associated with current and former smoking.
Edelstein et al. (1998) [34] 114 current 407 Older adults/72.0 ± 9.2 MMSE, Trail Making Test Part–B, Buschke Selective Reminding Test, Modified Version of WMS Visual Reproduction, semantic fluency and auditory-verbal memory. No differences between male smokers and male NSC. Female smokers demonstrated poorer performance than female NSC on the MMSE.
Cervilla et al. (2000) [51] 80 current204 former 134 Older adults/(65–95) Organic Brain Syndrome Scale (OBS) (measure of orientation to person time, place and context) After controlling for sex, age, alcohol consumption, education, depression and baseline cognitive function, current smokers had a 3.7 fold risk of impaired performance on the OBS after one year.
Schinka et al. (2002) [64] 334 participants with various smoking and alcohol use histories. 61 Older adults/(60–84) MMSE, Hopkins Verbal Learning Test, Stroop Color Word test, Trail Making Test Part–B No significant effects were found for alcohol or cigarette consumption on any measure.
Chen et al. (2003) [66] 195 current51 former 68 Older adults/72 ± 6 Cognitive Abilities Screening Instrument (measure of global cognitive function) No significant group differences on the Cognitive Abilities Screening Instrument.
Deary et al. (2003) [39] 126 current278 former 387 Older adults/75.6 ± 5.4 Moray House Test (MHT). Included measures of verbal, numerical, and verbal reasoning. Global MHT score formed from the individual components. After adjusting for MHT score at age 11 years of age, education and sex, current smokers had lower MHT scores than NSC and former smokers. NSC and former smokers were not different.
Schinka et al. (2003) [65] 30 current 86 Older adults/(60–84) MMSE, Hopkins Verbal Learning Test, Stroop Color-Word Test Pack years significantly predicted MMSE and auditory-verbal memory scores, but only accounted for 1.8% of variance in auditory-verbal memory.
Huadong et al. (2003) [44] 720 current276 former 1,976 Older adults/>60 MMSE Current smokers had 2.3 greater risk of impaired MMSE score (i.e., <17) relative to NSC after adjustment for age, sex, education, occupation and alcohol use.
Ott et al. (2004) [50] 2,037 current3,372 former 3,800 Older adults/>65 MMSE Current smokers relative to never smokers showed a greater rate of decrease in MMSE scores over approximately 2 years controlled for age, sex, education, baseline MMSE, history of myocardial infarction, and cerebrovascular accident. Higher pack years was associated with higher rate of decline in MMSE.
Reitz et al. (2005) [54] 90 current135 former 184 Older adults/75.6 ± 5.4 MMSE, Boston Diagnostic Aphasia Evaluation: Boston Naming Test, Category Naming, Phrase Repetition, Complex Ideational Material, WAIS-R Similarities, Nonverbal Identities and Oddities from The DRS, Rosen Drawing Test, Buschke Selective Reminding Test, Benton Visual Retention Test. Over approximately five years, there was no association between current or former smoking status and change in cognition in those <75 years of age. For those >75 years of age, current smokers showed greater decline in memory than former smokers and NSC. The memory declines were greatest in current smokers who were not carriers of the ApoEɛ4 allele.
Whalley et al. (2005) [41] 90 current135 former 184 Older adults/64 Raven’s Standard Progressive Matrices, Rey Auditory Verbal Learning Test, WAIS-R Digit Symbol and Block Design, Uses of Common Objects Test and a composite measure of all tests. After adjusting for childhood IQ, age, education, occupation, lung function, any history of smoking was associated with lower scores on Digit Symbol.
Fischer et al. (2006) [47] 262 current75 former NA Older adults/75 MMSE Longer duration of smoking was associated with lower MMSE after adjusting for vascular risk factors and use of antihypertensive medication.
Stewart et al. (2006) [45] 135 current246 former 217 Older adults/64.5 ± 6.5 Raven’s Standard Progressive Matrices, Rey Auditory Verbal Learning Test, Trail Making Test, Digit Symbol Test, Mill Hill Vocabulary Scale (MHS), MMSE and a composite measure of all tests. In men, after adjusting for age, blood pressure and total cholesterol, higher pack years was associated lower scores on Auditory-verbal leaning, Digit Symbol Test, MHS in men. In women, higher pack years was associated with lower MMSE. In women, current smoking status was associated with poorer auditory-verbal learning.
Starr et al. (2006) [31] 289 total participants. Number of smokers, NSC, not provided NA Older adults/64 and 66 Raven’s Standard Progressive Matrices, Rey Auditory Verbal Learning Test, WAIS-R Digit Symbol and Block Design, Uses of Common Objects Test Current smokers performed worse NSC and former smokers on auditory-verbal learning and information processing speed after adjusting for childhood IQ.

Note. DRS: Mattis Dementia Rating Scale; MMSE: Mini Mental Status Examination; NA: Not available; NSC: non-smoking (never-smoker) control; WAIS-III: Wechsler Adult Intelligence Scale-3rd Edition; WAIS-R: Wechsler Adult Intelligence-Revised; WMS-R: Wechsler Memory Scale-Revised.

Computerized tomography and magnetic resonance neuroimaging studies of chronic smoking in adults (sorted by imaging modality, then age group).

Authors [reference number] Smokers (n) NSC (n) Age group/mean age or (range) Neuroimaging modality Major findings (all findings are statistically significant unless otherwise indicated)
Akiyama et al. (1997) [74] 104 current and former smokers combined 173 Young to older adults/(22–89) CT (volumetric and cortical perfusion) A history of smoking (i.e., current or former smoking) was associated with lower global cerebral perfusion after control for hypertension, WM disease and age. Over approximately 3 years, smokers showed greater decrease in global perfusion and greater global atrophy than NSC.
Kubota et al. (1987) [76] 159 current Non-smoking group contained 177 never and 17 “light” smokers NA Middle aged and older adults/(40–69) CT Current smokers from 50 to 69 showed greater global atrophy than never/light smokers.
Hayee et al. (2003) [75] 219 current, Non-smoking group contained 183 never smokers and 17 “light” smokers NA Middle aged and older adults/(40–70) CT Current smokers between 50–70 years of age showed greater global atrophy than the non-smoking group.
Brody et al. (2004) [79] 19 current 17 Young to older adults/(21–65) MRI Smokers showed lower volumes and densities in the anterior frontal lobe GM, smaller volume of the left dorsal anterior cingulate gyrus, and lower GM density of the right cerebellum relative to NSC. Higher pack years was associated with lower anterior frontal GM.
Gallinat et al. (2006) [80] 22 current 23 Adults/30.6 ± 7.7 MRI Smokers demonstrated smaller GM volumes and densities in frontal, temporal and occipital regions compared to NSC. Smokers also showed lower volume or density in the thalamus, cerebellum and other subcortical nuclei/regions. Higher pack years was related to lower frontal, temporal and cerebellar GM volume.
Paul et al. (2008) [82] 10 current 10 Middle aged adults/38.5 ± 13.4 MRI (diffusion tensor imaging) Smokers showed higher fractional anisotropy (FA) in the body and whole corpus callosum than NSC. Smokers with low Fagerstrom Test for Nicotine Dependence scores (mean = 1.6) showed higher FA in the whole corpus callosum than smokers with high scores (mean = 5.6).
Longstreth et al. (2000) [78] 3,301 total participants, numbers of NSC, and smokers not provided NA Older adults/>65 MRI Over 5 years, higher pack years in men was related to increased ventricular volume in men and associated with increased sulcal volume in women, after control for age and vascular risk factors.
Almeida et al. (2008) [81] 39 current 39 Older adults/75.4 ± 3.3 MRI Smokers showed decreased GM densities in the posterior cingulate gyrus and precuneus bilaterally, right thalamus and right precentral gyrus.
Epperson et al. (2005) [102] 16 current 20 Adults/34 ± 11 MRS Gamma-aminobutyric acid (GABA) levels n the occipital GM were not different between NSC and male smokers. Female smokers showed a significant reduction in GABA levels during the follicular phase of the menstrual cycle. GABA levels showed no changes after 48 hours of smoking cessation in both males and females.
Gallinat et al. (2007) [97] 13 current 13 Adults/36.6 ± 10.1 MRS Smokers showed lower N-acetylaspartate levels than NSC in the left hippocampus. Higher pack years was related to higher choline-containing compounds in the anterior cingulate gyrus.
Gallinat and Schubert (2007) [98] 13 current9 Former 13 Adults/36.1 ± 9.8 MRS No significant group differences were observed in glutamate levels of the anterior cingulate cortex and left hippocampus.

Note. CT: computed tomography; GM: Gray Matter; MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy; NA: not available; NSC: non-smoking (never-smoker) control; WM: white matter.