Chronic Cigarette Smoking: Implications for Neurocognition and Brain Neurobiology

Int. J. Environ. Res. Public Health 2010, 7, 3760-3791; doi:10.3390/ijerph7103760
International Journal of
Environmental Research and
Public Health
ISSN 1660-4601
www.mdpi.com/journal/ijerph
Article
Chronic Cigarette Smoking: Implications for Neurocognition
and Brain Neurobiology
Timothy C. Durazzo 1,2,*, Dieter J. Meyerhoff 1,2 and Sara Jo Nixon 3,4
1 Department of Radiology and Biomedical Imaging, University of California,
505 Parnassus Avenue, M-391, San Francisco, CA 94143, USA
2 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.)
3 Department of Psychiatry, University of Florida, P.O. Box 100256, Gainesville, FL 32611, USA;
E-Mail: sjnixon@ufl.edu (S.J.N)
4 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.
Received: 9 September 2010; in revised form: 29 September 2010 / Accepted: 9 October 2010 /
Published: 21 October 2010
Abstract: 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
OPEN ACCESS
Int. J. Environ. Res. Public Health 2010, 7
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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.
Keywords: chronic cigarette smoking; neurocognition; neurobiology; neuroimaging; genetics
1. 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
Int. J. Environ. Res. Public Health 2010, 7
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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].
2. Neurocognitive Consequences of Chronic Cigarette Smoking (see Table 1).
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].
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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 ε4 (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].
Table 1. 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.
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Table 1. Cont.
Authors
[reference
number]
Smokers
(n)
NSC
(n)
Age group/
Mean age
or (range)
Neurocognitive measures
or domains assessed
Major findings (findings are
statistically significant unless
otherwise indicated)
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 risktaking
levels on the BART compared to
NSC. Smokers and NSC showed no
differences on the IGT.
Fried et al.
(2006) [25]
27 current
11 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 current
40 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
current
695 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 current
15 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.
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Table 1. Cont.
Authors
[reference
number]
Smokers
(n)
NSC
(n)
Age group/
Mean age
or (range)
Neurocognitive measures
or domains assessed
Major findings (findings are
statistically significant unless
otherwise indicated)
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 current
80 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 current
715 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 current
2,030 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.
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Table 1. Cont.
Authors
[Reference
Numbrer]
Smokers
(n)
NSC
(n)
Age group/
Mean age
or (range)
Neurocognitive
measures or domains
assessed
Major findings (findings are
statistically significant unless
otherwise indicated)
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 current
12 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]
current
former
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 current
288 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.
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Table 1. Cont.
Authors
[reference
number]
Smokers
(n)
NSC
(n)
Age group/
Mean age
or (range)
Neurocognitive measures
or domains assessed
Major findings (all reported finding
are statistically significant unless
otherwise indicated)
Galanis et al.
(1997) [46]
921 current
1,334 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 current
204 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 current
51 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 current
278 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.
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Table 1. Cont.
Authors
[reference
number]
Smokers (n) NSC (n) Age group/
Mean age
or (range)
Neurocognitive
measures or domains
assessed
Major findings (all reported finding
are statistically significant unless
otherwise indicated)
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 current
276 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 current
3,372 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 current
135 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 ApoEε4 allele.
Whalley
et al. (2005)
[41]
90 current
135 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.
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Table 1. Cont.
Authors
[reference
number]
Smokers (n) NSC
(n)
Age group/
Mean age
or (range)
Neurocognitive measures
or domains assessed
Major findings (findings are
statistically significant unless
otherwise indicated)
Fischer et al.
(2006) [47]
262current
75 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]
135current
246 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.
3. Neurobiological Consequences of Chronic Cigarette Smoking (See Table 2)
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.
3.1. 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
Int. J. Environ. Res. Public Health 2010, 7
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(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.
3.2. 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].
3.3. 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
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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].
Table 2. 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.
Int. J. Environ. Res. Public Health 2010, 7
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Table 2. Cont.
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)
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 current
9 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.
4. 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
Int. J. Environ. Res. Public Health 2010, 7
3773
neurocognition and brain neurobiology, as measured with functional neuroimaging methods
[i.e., functional MRI (fMRI), positron emission tomography (PET), single positron emission
tomography (SPECT)].
4.1. 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].
4.2. 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.
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3774
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].
5. 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.
5.1. 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.
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3775
5.2. 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.
6. 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,
Int. J. Environ. Res. Public Health 2010, 7
3776
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:
6.1. 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.
6.2. 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
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assessing decision making, risk taking and impulsivity. Consequently, the full scope of the
neurocognitive consequences associated with chronic smoking remains unclear.
6.3. 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.
6.4. 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.
6.5. 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.
6.6. 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.
7. 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,
Int. J. Environ. Res. Public Health 2010, 7
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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:
1. Concurrently assess cohorts of males and females ranging from young to older adults.
2. 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.
3. Employ comprehensive neurocognitive testing including behavioral measures of impulsivity,
decision-making and risk taking [24,195,196].
4. 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.
5. 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
Int. J. Environ. Res. Public Health 2010, 7
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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.
Acknowledgements
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.
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