Neurological Research

A Journal of Progress in Neurosurgery, Neurology and Neurosciences

ISSN: 0161-6412 (Print) 1743-1328 (Online) Journal homepage: http://www.tandfonline.com/loi/yner20

Abnormal white matter microstructure among

early adulthood smokers: a tract-based spatial
statistics study

Shuangkun Wang, Long Zuo, Tao Jiang, Peng Peng, Shuilian Chu & Dan Xiao

To cite this article: Shuangkun Wang, Long Zuo, Tao Jiang, Peng Peng, Shuilian Chu & Dan
Xiao (2017): Abnormal white matter microstructure among early adulthood smokers: a tract-based
spatial statistics study, Neurological Research, DOI: 10.1080/01616412.2017.1379277

To link to this article: http://dx.doi.org/10.1080/01616412.2017.1379277

Published online: 21 Sep 2017.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=yner20

Download by: [Australian Catholic University] Date: 22 September 2017, At: 03:22
 Neurological Research, 2017
https://doi.org/10.1080/01616412.2017.1379277

Abnormal white matter microstructure among early adulthood smokers: a

tract-based spatial statistics study
Shuangkun Wanga§, Long Zuoa§, Tao Jianga, Peng Penga, Shuilian Chub and Dan Xiaoc,d
a
Department of Radiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; bClinical Research Center, Beijing Chao-
Yang Hospital, Capital Medical University, Beijing, China; cTobacco Medicine and Tobacco Cessation Center, China-Japan Friendship Hospital,
Beijing, China; dWHO Collaborating Center for Tobacco Cessation and Respiratory Diseases Prevention, China-Japan Friendship Hospital,
Beijing, China

ABSTRACT ARTICLE HISTORY

Objectives: Cigarette smoking is an important risk factor of central nervous system diseases. Received 22 December 2016
However, the white matter (WM) integrity of early adulthood chronic smokers has not been Accepted 8 September 2017
attached enough importance to as it deserves, and the relationship between the chronic
Downloaded by [Australian Catholic University] at 03:22 22 September 2017

KEYWORDS
smoking effect and the WM is still unclear. The purpose of this study was to investigate whole Diffusion tensor imaging;
– brain WM microstructure of early adulthood smokers and explore the structural correlates of cigarette smokers; tract-
behaviorally relevant features of the disorder. based spatial statistics; white
Methods:  We compared multiple DTI-derived indices, including fractional anisotropy (FA), matter
mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD), between early adulthood
smokers (n = 19) and age-, education- and gender-matched controls (n = 23) using a whole-
brain tract-based spatial statistics approach. We also explored the correlations of the mean DTI
index values with pack-years and Fagerström Test for Nicotine Dependence.
Results:  The smokers showed increased FA in left superior longitudinal fasciculus (SLF), left
anterior corona radiate, left superior corona radiate, left posterior corona radiate, left external
capsule (EC), left inferior fronto-occipital fasciculus and sagittal stratum (SS), and decreased RD
in left SLF. There were significant negative correlations among the average FA in the left external
capsule and pack-years in smokers. In addition, significant positive correlation was found
between RD values in the left SLF and pack-years.
Discussion:  These findings indicate that smokers show microstructural changes in several
white-matter regions. The correlation between the cumulative effect and microstructural WM
alternations suggests that WM properties may become the new biomarkers in practice.

Introduction smokers has not been attached enough importance to

as it deserves, and the relationship between the chronic
Smoking refers to chronic smoking of tobacco in the
smoking effect and the WM is still unclear.
form of cigarettes [1]. Approximately 2 billion people
Diffusion tensor imaging (DTI) is a magnetic res-
worldwide use tobacco products, mostly in the form of
onance imaging (MRI) technique that can be used to
cigarettes, with tobacco smoking-related diseases result-
examine and quantify white matter microstructure.
ing in at least 6 million global deaths per year [2]. With a
Previous works have shown that DTI can be used to
population of 1.3 billion, China is now the world’s largest
detect in vivo alterations of WM in cigarette smokers
producer and consumer of tobacco and the annual num-
[7–12]. Several derived indices of DTI, including frac-
ber of deaths in China that are caused by tobacco will
tional anisotropy (FA), mean diffusivity (MD), axial dif-
rise from about 1 million in 2010 to 2 million in 2030
fusivity (AD) and radial diffusivity (RD), can be used to
and 3 million in 2050, unless there is widespread cessa-
quantitatively analyze white matter fiber integrity [13].
tion [3]. Published reports indicate that beside a wide
FA is a measure of the degree of anisotropy to reflect
disease spectrum, cigarette smoking is also an impor-
the Brownian motion of water molecules constrained
tant risk factor of central nervous system diseases, such
by brain tissue [14]. MD gives an overall measure of the
as stroke, vascular dementia and Alzheimer’s disease
water diffusion in a voxel or region. In addition, AD and
[4–6]. Investigations in humans found various func-
RD are thought to be useful in the evaluation of poten-
tional cerebral effects of cigarette smoking. However, the
tial pathological changes in white matter [15]. Previous
white matter (WM) integrity of early adulthood chronic
DTI studies reported contradictory effects of smoking

CONTACT  Dan Xiao  danxiao@263.net

§
These authors contributed equally to this work.
© 2017 Informa UK Limited, trading as Taylor & Francis Group
 2   S. WANG ET AL.
on WM. A significant reason of the inconsistent findings
of the changes in WM properties may due to various data
analysis methods (i.e. region of interest-based analysis
(ROI), voxel-based analysis (VBA) and tract-based spa-
tial statistics analysis (TBSS)). The TBSS is a relatively
new post-processing technique of DTI for mapping WM
changes. The VBA and TBSS are both hypothesis-free
and observer-independent method with great sensitivity
to spatially locate group differences in the DTI data [16].
They overcome the bias of the ROI, such as region-place-
ment preference and the absence of meaningful voxels
outside of the selected regions. Because restricting anal-
ysis to the center of the major WM tracts, the TBSS is
more suitable to analyze diffusion data than the VBA
which analyzes all brain regions or WM regions [17–20].
Compared with VBA, TBSS improves the reliability of
the statistical results by generating voxel-wise statistics
Downloaded by [Australian Catholic University] at 03:22 22 September 2017
without the need for perfect image alignment and spatial
smoothing. To our knowledge, few TBSS studies focused
on multiple DTI-derived indices in early adulthood
smokers and the influence of smoking on white matter
still remains unclear.
This study first used TBSS to investigate whole – brain
WM microstructure, indexed by FA, MD, AD, and RD
in early adulthood smokers compared with healthy
controls. We also explored the relationship of WM
alterations with clinical variables in smokers in order
to investigate the structural correlates of behaviorally
relevant features of the disorder.
Materials and methods
Participants
All participants provided their written consent to our
protocol that was approved by the ethics committee
of the Beijing Chao-yang Hospital. Participants Data
were collected from 19 cigarette smokers (recruited
from tobacco cessation clinic patients) and 23 healthy
non-smoking controls (recruited from the commu-
nity through advertisements). Age, gender, handed-
ness, education level and the clinical characteristics of
the two groups were matched (see details in Table 1).
Table 1. Clinical characteristics of smokers and non-smokers in
this study.
Smokers (n = 19) Non-smokers (n = 23) p value
Sex (male/female) 19/0 23/0
Age (years) 31.58 ± 9.63 32.81 ± 9.57 p = 0.379
Handedness 19/0 23/0
(right/left)
Levels of educa- 14.84 ± 3.39 15.89 ± 3.26 p = 0.386
tion (years)
Cigarettes/day 22.51 ± 8.34
Age at start of 17.05 ± 2.07
smoking (years)
Pack-years 18.82 ± 14.93
FTND 7.42 ± 1.39
Notes: Pack-years: Smoking years 3 daily consumption/20.
FTND = Fagerström Test of Nicotine Dependence.
The severity of nicotine addiction was assessed with
Fagerström Test of Nicotine Dependence (FTND) [21].
None of the smokers were currently trying to quit or
seeking tobacco cessation treatment and were required
to abstain from smoking for two hours before the MRI
session. No participant had a history of dependence
(current or past) on any drug other than nicotine. No
controls had smoked more than 25 cigarettes in their
lifetime and none in the past ten years.
Image acquisition
Experiments were performed on a Siemens 3.0-T scan-
ner (MAGNETOMV R Trio Tim System;Germany)
by using a standard 8-channel head coil receiver at
the Magnetic Resonance Center of Beijing Chao-Yang
Hospital.
MR conventional and Diffusion tensor scan was
acquired in all participants, first sagittal scanning, and
then scanned for axial plane, which parallel AC-PC
line. MR scanning including sagittal T1WI Sagittal 3D
T1WI Volume acquisition (TR = 1900 ms, TE = 2.52 ms,
TI = 900 ms, flip angle = 97°, FOV = 250 mm × 250 mm,
thickness = 5 mm, spacing = 1.5 mm) and T2WI (FSE
sequence, TR = 4500 ms, TE = 93 ms, thickness = 5 mm,
spacing = 1.5 mm, FOV 220 mm × 220 mm) and axial
FLAIR (TR = 8000 ms, TE = 86 ms, thickness = 5 mm,
spacing = 1.5 mm, FOV = 220 mm × 220 mm). Whole-
brain DTI was acquired using a single-shot, spin-
echo echo-planar imaging technique (TR  =  7700  ms,
TE = 104 ms, BW = 1396 Hz/Pixel, FOV = 220 × 220 mm,
matrix size = 128 × 128, 40 slices, thickness = 3.5 mm,
b value = 0 or 1000 s/mm2,directions = 20, NEX = 3).
Subjects were wearing anti-noise earplugs, and head
movement was minimized by soft foam padding.
Image preprocessing
All the DTI image processing were implemented using
a pipeline tool for analyzing brain diffusion images
(PANDA) [22], which incorporates FSL [23], Diffusion
Toolkit [24], PSOM [25], and MRIcron [26]. The pre-
processing procedure included five steps: (1) converting
DICOM files into NIfTI images by using the dcm2nii
tool embedded in MRIcron, (2) estimating the brain
mask by using the BET of FSL [27], (3) cropping the raw
images to remove the non-brain spaces by applying the
fslroi command of FSL, (4) correcting for the eddy-cur-
rent distortion of diffusion weighted images by employ-
ing the FLIRT command, (5) a voxel-based tensor matrix
and the diffusion tensor metrics were estimated with
dtifit command of FSL for each subject, including FA,
MD, AD, RD [28]. PANDA nonlinearly registered all of
the individual images to a standardized template in the
MNI space for across subjects’ comparison.
 NEUROLOGICAL RESEARCH   3

TBSS statistical analysis
The standard TBSS framework is performed by PANDA.
Firstly, the mean of all the aligned FA images was cre-
ated and skeletonized, resulting in a mean FA skeleton.
Secondly, the diffusion metric data from individual sub-
jects were projected onto the skeleton. Finally, individual
images with data on the skeleton were created.
The voxel-wise statistics in TBSS were carried out
using the ‘randomize’ tool for nonparametric test. In
this study, voxel-wise group comparisons were per-
formed using nonparametric, two-sample Student t-test
between smokers and healthy non-smoker controls. The
mean FA skeleton was used as a mask with the thresh-
old at 0.2, and the number of permutations was set to
5000. Threshold-free cluster enhancement was used to
enhance cluster-like structures in the data. The signifi-
cance threshold for between group differences was set at
Downloaded by [Australian Catholic University] at 03:22 22 September 2017
labels atlas). Then, the significant clusters were overlaid
on the ICBM-DTI-81 white-matter labels atlas. A series
of Pearson correlation analyses was performed to inves-
tigate relationships between the overlapped DTI index
values with pack-years as cumulative effect and FTND
as severity of smoking.
Results
Smoking and DTI indices in white matter
The WM regions with significantly different DTI prop-
erties were identified by the ICBM-DTI-81 white mat-
ter labels atlas. Compared with healthy non-smoking
controls, the smokers showed increased FA in left supe-
rior longitudinal fasciculus (SLF), left anterior corona
radiate (ACR), left superior corona radiate (SCR), left
posterior corona radiate (PCR), left external capsule

p < 0.05 (family-wise error corrected for multiple com-
parisons). Using the protocol of non-FA Images in TBSS,
the MD, AD, and RD images were aligned into MNI
space and projected onto the mean FA skeleton. The sta-
tistical analyses of these diffusion tensor metrics were
performed similar to the FA analysis. Statistically signif-
icant regions identified were reported on the basis of the
Johns Hopkins University International Consortium of
Brain Mapping DTI of 81 (ICBM-DTI-81 white-matter
(EC), left inferior fronto-occipital fasciculus (IFOF)
and sagittal stratum (SS) (p  <  0.05, FWE corrected)
(Figure  1); and decreased RD in left SLF (p < 0.05, FWE
corrected) (Figure 2); while no difference in AD and MD
was observed. As shown in Figure 3, the brain regions
with increased FA and decreased RD in smoker group
were overlapped and shown as a red color in the left
SLF which may be more associated with radial changes
Figure 4.

Figure 1. TBSS analysis (t-test) demonstrated significantly increased FA in early adulthood smokers comparing heathy controls.
Notes: Clusters are shown as red in color (FWE corrected p < 0.05). Anatomical labels were derived from the JHU ICBM-DTI-81 White Matter Labels and results
are shown overlaid on the mean FA and the mean FA skeleton (yellow). Abbreviations: FA = Fractional anisotropy; FWE = Family-wise error; TBSS = Tract-based
spatial statistics; ACR = Anterior corona radiate; EC = External capsule; SS = Sagittal stratum; SCR = Superior corona radiate; PCR = Posterior corona radiate;
SLF = Superior longitudinal fasciculus; IFOR = Inferior fronto-occipital fasciculus.
 4   S. WANG ET AL.
Downloaded by [Australian Catholic University] at 03:22 22 September 2017

Figure 2. TBSS analysis (t-test) demonstrated significantly decreased RD in early adulthood smokers comparing heathy controls.
Notes: Clusters are shown as red in color (FWE corrected p < 0.05). Anatomical labels were derived from the JHU ICBM-DTI-81 White Matter Labels and
results are shown overlaid on the mean FA mapping and the mean FA skeleton (yellow). Abbreviations: FA = Fractional anisotropy; RD = Radial diffusivity;
FWE = Family-wise error; TBSS = Tract-based spatial statistics; SLF = Superior longitudinal fasciculus.

Figure 3. WM with increased FA and decreased RD in early adulthood smokers were overlapped.
Notes: Anatomical labels were derived from the JHU ICBM-DTI-81 White Matter Labels and and results are shown overlaid on the mean FA mapping. The
clusters with increased FA were shown in red and decreased RD were shown in blue in the left SLF. Abbreviations: FA = Fractional anisotropy; RD = Radial
diffusivity; SLF = Superior longitudinal fasciculus.
 NEUROLOGICAL RESEARCH   5

Reproducibility
To examine the reproducibility of our findings reported,
we performed leave-one-out validations. Notably, the
sample size was relatively small and the split-half anal-
ysis may significantly reduce the statistical power of
the group comparisons. To validate the reproducibil-
ity and robustness of the TBSS findings without losing
statistical power, we performed a leave-one-out valida-
tion. Specifically, we left one smoker out of the sample
and performed the two samples t-test (i.e. 18 subjects
in smoke group vs. 23 subjects in control group). This
analysis included total 19 two samples t-test of FA or RD
values, respectively, comparing the values of FA or RD
extracted from WM clusters with statistical difference
according to the above TBSS statistical analysis. Then we
calculated reproductivity rates across the total 19 tests as
the reproducibility of the FA or RD differences between
Downloaded by [Australian Catholic University] at 03:22 22 September 2017

the smoke group and control group. Table 2 listed repro-

ductivity rates of FA or RD across these tests.

Discussion
In this study, we investigated global WM microstruc-
ture on multiple DTI-derived indices in early adulthood
smokers. Our study used TBSS to overcome the short-
comings of the ROI and the VBA in previous studies.
The weaknesses of ROI- and VBA-based methods are as
Figure 4.  (A) Correlation analysis results demonstrated that follows: First, the ROI boundaries are subjective in the
there were significant negative correlations among the average ROI method and the whole-brain white matter infor-
FA in the left EC and pack-year in smokers. (B) Significant mation may be neglected beyond the ROIs. Second, the
positive correlation was found between RD values in the left VBA method may encounter a number of smoothing
SLF and pack-years.
Abbreviations: SLF = Superior longitudinal fasciculus; pack-years = smoking and alignment problems. In order to alleviate the align-
years × daily consumption/20; EC = External capsule. ment problem, TBSS projects the individual FA values
onto a given FA skeleton without spatial smoothing [17].
Table 2. Leave-one-out sample validation.
Thus, our study improves objectivity and simplicity in
the interpretation of DTI results by using the TBSS
Left Left Left Left Left Left Left
SLF ACR SCR PCR EC SS IFOF
method.
It has been reported that populations of different
Fractional anisotropy
RR 100% 95.2% 100% 100% 100% 100% 100% origin (e.g. age, gender, and race) exhibits morphology
Radial diffusivity differences of the brains [29]. More and more evidence
RR 100% from substance dependent studies shows that the risk
Abbreviations: RR: Reproductivity rates; ACR = Anterior corona radiate;
of developing abuse and substantial long-term health
EC = External capsule; SS = Sagittal stratum; SCR = Superior corona risks vary across lifespan, especially in adolescence and
radiate; PCR = Posterior corona radiate; SLF = superior longitudinal adulthood [30]. According to Newman’s ‘Development
fasciculus; IFOR = Inferior fronto-occipital fasciculus.
Through Life’, life stages/age groups can be classi-
fied as infancy (0–2  years old), toddlerhood (2 and
Associations of clinical features of smoking with FA 3), early school age (4–6), middle childhood (6–12),
and RD early adolescence (12–18), later adolescence (18–24),
Correlation analysis results demonstrated that there were early adulthood (24–34), middle adulthood (34–60),
significant negative correlations among the average FA later adulthood (60–75), very old age (75+). Because
in the left external capsule and pack-year (r = −0.4946, the adverse effects of cigarette smoking on the CNS is
p = 0.0313) in smokers. In addition, significant positive chronic, the life stages/age groups should be an impor-
correlation was found between RD values in the left SLF tant factor to consider when examining of cigarette
and pack-years (r = 0.4726, p = 0.0410). abuse. Moreover, the brains of different populations (e.g.
Asians and westerners) may have different responses to
 6   S. WANG ET AL.
tobacco. We recruited smokers from Asian early adult-
hood males and our study is a pilot study to demonstrate
the characterization of smokers’ brain WM in the Asian
early adulthood males.
Our research yielded two major findings of FA char-
acterizing white matter abnormality from chronic nic-
otine use. Firstly, increased FA was found in multiple
white matter regions, including (left SLF, left ACR, left
SCR, left EC, left PCR, and left IFOF) in early adult-
hood smokers (age 32 ± 10) than in age-matched non-
smokers using TBSS. Secondly, FA in the left EC among
smokers is correlated negatively with cumulative effect
(pack-years). A possible explanation of these two seem-
ingly inconsistent results would be if smoking led to
above-normal FA in adolescent years when most peo-
ple begin, FA declined with continued smoking in early
adulthood [10–12].
Downloaded by [Australian Catholic University] at 03:22 22 September 2017
In the present study, we identified five relatively larger
clusters of increased FA in left SLF, left ACR, left SCR,
left PCR and left EC. The SLF is a large bundle of long
association fibers in the white matter of each cerebral
hemisphere connecting the parietal, occipital and tem-
poral lobes with ipsilateral frontal cortices [31]. The SLF
facilitates the formation of a bidirectional neural net-
work that is necessary for core processes such as atten-
tion, memory, emotions, and language [32]. We found
increased FA in the SLF as previous studies [9,33]. In
fact, the increased FA in SLF is one most frequently
reported among WM regions in adolescent/young adult
smokers compared with healthy controls [9,33–35], sug-
gesting that WM fibers increase consistently in young
adult smokers. However in mature adults, decreased
FA values are more commonly reported in the SLF
[11,12,36,37]. These differences appear to be related to
participant characteristics, where higher FA has been
reported in young adulthood and low frequent smokers,
and lower FA is reported in chronic smokers and adults.
The contrary findings of FA in SLF assume that the neg-
ative correlation between FA values and pack-year from
adolescent to adulthood.
The EC contains projection fibers interconnecting pre-
frontal and temporal areas with basal ganglia [31]. The
increased FA of EC in smokers has also been found in pre-
vious studies [34,35]. A previous TBSS study found that
regular smoking compared to nonsmoking was associated
with higher FA in the external capsule [34]. Our corre-
lation analysis demonstrated that there were significant
negative correlations among the average FA in the left
EC and pack-year (r = −0.4946, p = 0.0313) in smokers,
which supports the hypothesis that FA values might be
decreased from adolescence to young adulthood smokers.
The corona radiate is the most prominent projec-
tion fibers, which radiate out from the cortex and then
come together in the brain stem. In the ICBM-DTI-81
white-matter labels atlas, the corona radiate is divided
into three components, i.e. anterior CR, superior CR and
posterior CR. The anterior corona radiata has been rec-
ognized as a major WM tract connecting the prefrontal
lobe to deep gray nuclei and constitutes the frontal-sub-
cortical circuits [38]. The SCR connects frontal cortex
and the brain stem and spinal cord bidirectionally [39].
The PCR plays a role in carrying fibers of the optic radi-
ation [40]. In previous reports, FA values in the ACR,
SCR, and PCR were significantly higher in the smoking
group than in the control groups [34,35]. Our findings
were also in line with previous studies.
These fibers mentioned earlier are the key nodes
connecting the executive control network (ECN) [41].
Chronic nicotine exposure and resulting addiction affect
brain networks associated with executive function – a
cognitive construct strongly linked with addiction.
White matter tracts are the structural highways of our
brain, enabling information to travel quickly from one
brain region to another region [42]. Greater FA of WM
is preliminary evidence of variation in WM tracts con-
necting ECN regions in smokers. The differences in tract
integrity are corresponding to the altered ECN.
In our study, the IFOF and the SS have increased FA,
which have not been reported in adolescent/adult smok-
ers before. The IFOF connects the frontal and occipital
lobes and is involved in insula connectivity, and both
were believed to play an important role in emotional
regulation and cognition [43]. The SS is a vast and com-
plex bundle that connects the occipital lobe to the rest
of the brain [44].
Simultaneous assessment of multiple DTI-derived
indices is regarded as a more comprehensive analysis
of white-matter tissues and assists in interpretation of
FA values. As for RD, we found decreased RD in left
SLF, in line with previous studies [7,9,45]. Although it
is still being debated, it is generally believed that RD
mainly reflects the integrity and thickness of myelin
sheets, while AD may index the integrity of axons and
the organization of the fiber structure [46]. Thus, a sig-
nificant decrease in AD with an insignificant change in
RD was representative of axonal damage, and an increase
in RD with no change in AD was specifically suggestive
of demyelination. But recent studies have demonstrated
that because of a different orientation of the correspond-
ing principal eigenvector of DT, the eigenvalues do not
necessarily reflect the same underlying structural char-
acteristics in different datasets [47]. Radial diffusivity is
an inadequacy of scalar quantities to characterize myelin
content, unless accompanied by a thorough investiga-
tion of the principal direction of diffusion [48]. Cigarette
smoke exposures broadly inhibit expression of genes
needed for myelin synthesis and maintenance [4,49].
Our results support the opinion that smoking contrib-
utes to white matter degeneration, and therefore could
be a key risk factor for a number of neurodegenerative
diseases [35]. More specifically, the overlapped region
with decreased RD is included in the WM with increased

FA in left SLF. Correlation analysis showed significant
correlations between the smoking property (i.e. pack-
years) and the average RD values in the left SLF, while no
correlation between smoking properties (i.e. pack-years,
FTND) and average AD values in the region. The evi-
dence shows that more exposure to nicotine in chronic
smokers may lead to multitude of accumulation effects
on WM integrity as decreased RD.
The pathophysiological mechanisms of altered DTI
parameters are still unclear. Some research reports that
increased FA indicates increased myelination, while
other research indicates that increased FA could be the
result of vasogenic swelling within white-matter tracts
in response to chronic nicotine exposure [50]. The cur-
rent interpretation is lack of direct evidence [51,52]. It is
well known that low dose of nicotine activates nicotinic
acetylcholine receptors (nAChRs), which are widely
Downloaded by [Australian Catholic University] at 03:22 22 September 2017
distributed in the brain [53]. The stimulated nAChRs
may disturb cholinergic neurotransmission and induce
mRNA expression of glial cell line-derived neurotropic
factor [54,55]. The increased glial cell number and den-
sity can enhance anisotropy and narrow the extracel-
lular space, causing FA increasing and RD decreasing
[56]. However, as time goes by, smoking-induced blood
desaturation causes WM destruction in chronic phases
of smoking [57]. The possible mechanism of increased
FA and decreased RD in young adult smokers might
be associated that nicotine acting at nAChRs promotes
the activation or proliferation of glial cells. Further
research is therefore needed to characterize the mean-
ing of increased FA and decreased RD at the molecular
level among adult cigarette smokers.
Furthermore, our results validated hemispheric
asymmetry in early adulthood smokers in which the
left hemisphere contained increased FA and decreased
RD in smokers, a result supporting previously observed
findings [11]. The rest-state functional MRI about sub-
stance dependent individuals also shows greater left
hemisphere activity in the left ECN at rest [58]. The
white matter disruptions in the left hemisphere seem
be more susceptible to the effects of nicotine than the
right hemisphere.
A few limitations of our study warrant discussion.
The study is a cross-sectional design, and it cannot state
that cigarette smoking plays any causal role on these
observed changes, only that a correlation was observed.
Moreover, we will compare similar observation in any
neurodegenerative patients (smoker/non-smokers) and
show relevance to disease incidence. Another important
consideration is the relatively small sample size, so the
results might not be generalizable to wider populations;
therefore, the results should be interpreted as prelimi-
nary and in need of replication with more individuals,
and with more complete characterization of smoking
behavior. Further longitudinal studies on larger samples
would be necessary to confirm the current findings.
NEUROLOGICAL RESEARCH   7
Conclusion
Abnormal white matter microstructure of left hem-
isphere was revealed among cigarette smokers. Using
TBSS, We found increased FA within left SLF, ACR,
SCR, EC, PCR, and left IFOF, and decreased RD in left
SLF. Our data also recapitulated correlations between
DTI indices (i.e. FA, RD) with years of nicotine expo-
sure. These findings indicate that smokers show micro-
structural changes in several white-matter regions. The
correlation between the cumulative effect and micro-
structural WM alternations suggests that WM properties
may become the new biomarkers in practice. Our results
may contribute to the understanding of nicotine addic-
tion and the smoking-cessation research.
Author contributions
Dan Xiao was responsible for the study concept and
design. Shuangkun Wang and Long Zuo were respon-
sible for statistical analysis, interpretation of data and
drafted the manuscript. Dan Xiao and Tao Jiang pro-
vided critical revision of themanuscript. All authors
critically reviewed content and approved final version
for publication.
Disclosure statement
There are no conflicts of interest.
Funding
This work was supported by the National Natural Science
Foundation of China [grant number 81200066], [grant num-
ber 81541129].
References
 [1]  DeMarini DM. Genotoxicity of tobacco smoke and
tobacco smoke condensate: a review. Mutation research.
2004;567:447–474.
  [2] Organization WH. WHO report on the global tobacco
epidemic. The MPOWER package. Geneva Switzerland,
WHO. 2008;34:581.
  [3] Chen Z, Peto R, Zhou M, et al. Contrasting male and
female trends in tobacco-attributed mortality in China:
evidence from successive nationwide prospective cohort
studies. Lancet (London, England). 2015;386:1447–
1456.
  [4] Durazzo TC, Mattsson N, Weiner MW. Smoking and
increased Alzheimer’s disease risk: a review of potential
mechanisms. Alzheimer’s Dementia J Alzheimer’s
Assoc. 2014;10:S122–S145.
  [5] Swan GE, Lessov-Schlaggar CN. The effects of tobacco
smoke and nicotine on cognition and the brain.
Neuropsychol Rev. 2007;17:259–273.
 [6] Fischer F, Kraemer A. Health impact assessment for
second-hand smoke exposure in Germany-quantifying
estimates for ischaemic heart diseases, COPD, and
stroke. Int J Environ Res Publ Health. 2016;13:198.
 8   S. WANG ET AL.
  [7] Jacobsen LK, Picciotto MR, Heath CJ, et al. Prenatal
and adolescent exposure to tobacco smoke modulates
the development of white matter microstructure. J
Neurosci. 2007;27:13491–13498.
  [8] Paul RH, Grieve SM, Niaura R, et al. Chronic cigarette
smoking and the microstructural integrity of white
matter in healthy adults: a diffusion tensor imaging
study. Nicotine Tobacco Res. 2008;10:137–147.
  [9] Liao Y, Tang J, Deng Q, et al. Bilateral fronto-parietal
integrity in young chronic cigarette smokers: a diffusion
tensor imaging study. PLoS ONE. 2011;6:e26460.
[10]  Hudkins M, O’Neill J, Tobias MC, et al. Cigarette
smoking and white matter microstructure.
Psychopharmacology. 2012;221:285–295.
[11] Lin F, Wu G, Zhu L, et al. Heavy smokers show abnormal
microstructural integrity in the anterior corpus
callosum: a diffusion tensor imaging study with tract-
based spatial statistics. Drug Alcohol Dependence.
2013;129:82–87.
[12]  Umene-Nakano W, Yoshimura R, Kakeda S, et al.
Downloaded by [Australian Catholic University] at 03:22 22 September 2017
Abnormal white matter integrity in the corpus callosum
among smokers: tract-based spatial statistics. PLoS
ONE. 2014;9:e87890.
[13] Lim KO, Helpern JA. Neuropsychiatric applications of
DTI – a review. NMR Biomed. 2002;15:587–593.
[14] Hasan KM, Narayana PA. Retrospective measurement
of the diffusion tensor eigenvalues from diffusion
anisotropy and mean diffusivity in DTI. Magn Reson
Med. 2006;56:130–137.
[15]  Herrera JJ, Chacko T, Narayana PA. Histological
correlation of diffusion tensor imaging metrics in
experimental spinal cord injury. J Neurosci Res.
2008;86:443–447.
[16]  Alves GS, Oertel Knöchel V, Knöchel C, et al.
Integrating Retrogenesis theory to Alzheimer’s disease
pathology: insight from DTI-TBSS investigation of the
white matter microstructural integrity. BioMed Res Int.
2015;2015:291658.
[17] Smith SM, Jenkinson M, Johansen-Berg H, et al. Tract-
based spatial statistics: voxelwise analysis of multi-
subject diffusion data. NeuroImage. 2006;31:1487–
1505.
[18] Guo W, Liu F, Liu Z, et al. Right lateralized white matter
abnormalities in first-episode, drug-naive paranoid
schizophrenia. Neurosci Lett. 2012;531:5–9.
[19] Guo WB, Liu F, Xue ZM, et al. Altered white matter
integrity in young adults with first-episode, treatment-
naive, and treatment-responsive depression. Neurosci
Lett. 2012;522:139–144.
[20] Xu J, Potenza MN. White matter integrity and five-factor
personality measures in healthy adults. NeuroImage.
2012;59:800–807.
[21] Ebbert JO, Patten CA, Schroeder DR. The fagerström
test for nicotine dependence-smokeless tobacco
(FTND-ST). Addict Behav. 2006;31:1716–1721.
[22] Cui Z, Zhong S, Xu P, et al. PANDA: a pipeline toolbox
for analyzing brain diffusion images. Front Human
Neurosci. 2013;7:42.
[23] Smith SM, Jenkinson M, Woolrich MW, et al. Advances
in functional and structural MR image analysis and
implementation as FSL. NeuroImage. 2004;23:S208–
S219.
[24] Wang Y, Gupta A, Liu Z, et al. DTI registration in
atlas based fiber analysis of infantile Krabbe disease.
NeuroImage. 2011;55:1577–1586.
[25] Bellec P, Lavoie-Courchesne S, Dickinson P, et al. The
pipeline system for Octave and Matlab (PSOM): a
lightweight scripting framework and execution engine
for scientific workflows. Front Neuroinformat. 2012;6:7.
[26] Rorden C, Karnath HO, Bonilha L. Improving lesion-
symptom mapping. J Cognit Neurosci. 2007;19:1081–
1088.
[27] Smith SM. Fast robust automated brain extraction.
Human Brain Mapping. 2002;17:143–155.
[28] Basser PJ, Pierpaoli C. Microstructural and physiological
features of tissues elucidated by quantitative-diffusion-
tensor MRI. J Magn Reson Series B. 1996;111:209–219.
[29] Tang Y, Hojatkashani C, Dinov ID, et al. The construction
of a Chinese MRI brain atlas: a morphometric
comparison study between Chinese and Caucasian
cohorts. NeuroImage. 2010;51:33–41.
[30] Strashny A. Age of substance use initiation among
treatment admissions aged 18 to 30. The CBHSQ
Report, Rockville (MD), Substance Abuse and Mental
Health Services Administration (US); 2013.
[31] Schmahmann JD, Smith EE, Eichler FS, et al. Cerebral
white matter: neuroanatomy, clinical neurology, and
neurobehavioral correlates. Ann New York Acad Sci.
2008;1142:266–309.
[32] Petrides M, Pandya DN. Comparative cytoarchitectonic
analysis of the human and the macaque ventrolateral
prefrontal cortex and corticocortical connection
patterns in the monkey. Eur J Neurosci. 2002;16:291–
310.
[33] Jacobsen LK, Picciotto MR, Heath CJ, et al. Prenatal
and adolescent exposure to tobacco smoke modulates
the development of white matter microstructure. J
Neurosci Offic J Soc Neurosci. 2007;27:13491–13498.
[34] van Ewijk H, Groenman AP, Zwiers MP, et al. Smoking
and the developing brain: altered white matter
microstructure in attention-deficit/hyperactivity
disorder and healthy controls. Human Brain Mapping.
2015;36:1180–1189.
[35] Yu R, Deochand C, Krotow A, et al. Tobacco smoke-
induced brain white matter myelin dysfunction: potential
co-factor role of smoking in neurodegeneration. J
Alzheimer’s Dis JAD. 2015;50:133–148.
[36] Savjani RR, Velasquez KM, Thompson-Lake DG, et
al. Characterizing white matter changes in cigarette
smokers via diffusion tensor imaging. Drug Alcohol
Depend. 2014;145:134–142.
[37] Viswanath H, Velasquez KM, Thompson-Lake DG,
et al. Alterations in interhemispheric functional
and anatomical connectivity are associated with
tobacco smoking in humans. Front Human Neurosci.
2015;9:116.
[38] Kang K, Choi W, Yoon U, et al. Abnormal white matter
integrity in elderly patients with idiopathic normal-
pressure hydrocephalus: a tract-based spatial statistics
study. Eur Neurol. 2016;75:96–103.
[39] Schmahmann JD, Pandya DN. Disconnection
syndromes of basal ganglia, thalamus, and
cerebrocerebellar systems. Cortex J Devoted Study
Nerv Syst Behav. 2008;44:1037–1066.
[40] Jiang W, Shi F, Liu H, et al. Reduced white matter
integrity in antisocial personality disorder: a diffusion
tensor imaging study. Sci Rep. 2017;7:43002.
[41] Fedota JR, Stein EA. Resting-state functional
connectivity and nicotine addiction: prospects for
biomarker development. Ann New York Acad Sci.
2015;1349:64–82.
[42] van den Heuvel MP, Mandl RC, Kahn RS, et al.
Functionally linked resting-state networks reflect the
underlying structural connectivity architecture of the

human brain. Human Brain Mapping. 2009;30:3127–
3141.
[43] Catani M, Mecocci P, Tarducci R, et al. Proton
magnetic resonance spectroscopy reveals similar white
matter biochemical changes in patients with chronic
hypertension and early alzheimer’s disease. J Am
Geriatrics Soc. 2002;50:1707–1710.
[44] Jellison BJ, Field AS, Medow J, et al. Diffusion tensor
imaging of cerebral white matter: a pictorial review
of physics, fiber tract anatomy, and tumor imaging
patterns. AJNR Am J Neuroradiol. 2004;25:356–369.
[45] Yu D, Yuan K, Zhang B, et al. White matter integrity
in young smokers: a tract-based spatial statistics study.
Addict Biol. 2016;21:679–687.
[46] Song SK, Sun SW, Ramsbottom MJ, et al. Dysmyelination
revealed through MRI as increased radial (but
unchanged axial) diffusion of water. NeuroImage.
2002;17:1429–1436.
[47] Field AS, Alexander AL, Wu YC, et al. Diffusion tensor
eigenvector directional color imaging patterns in the
Downloaded by [Australian Catholic University] at 03:22 22 September 2017
evaluation of cerebral white matter tracts altered by
tumor. J Magn Reson Imaging JMRI. 2004;20:555–562.
[48] Wheeler-Kingshott CA, Cercignani M. About,
“axial” and “radial” diffusivities. Magn Reson Med.
2009;61:1255–1260.
[49] Cao J, Dwyer JB, Gautier NM, et al. Central myelin
gene expression during postnatal development in
rats exposed to nicotine gestationally. Neurosci Lett.
2013;553:115–120.
[50] Gazdzinski S, Durazzo TC, Studholme C, et al.
Quantitative brain MRI in alcohol dependence:
preliminary evidence for effects of concurrent chronic
cigarette smoking on regional brain volumes. Alcohol
Clin Exp Res. 2005;29:1484–1495.
NEUROLOGICAL RESEARCH   9
[51] Le Bihan D, Mangin JF, Poupon C, et al. Diffusion
tensor imaging: Concepts and applications. J Magn
Reson Imaging JMRI. 2001;13:534–546.
[52] Soares JM, Marques P, Alves V, et al. A hitchhiker’s guide
to diffusion tensor imaging. Front Neurosci. 2013;7:31.
[53] Slotkin TA, Cousins MM, Seidler FJ. Administration of
nicotine to adolescent rats evokes regionally selective
upregulation of CNS alpha 7 nicotinic acetylcholine
receptors. Brain Res. 2004;1030:159–163.
[54] Abreu-Villaca Y, Seidler FJ, Tate CA, et al. Nicotine is
a neurotoxin in the adolescent brain: critical periods,
patterns of exposure, regional selectivity, and dose
thresholds for macromolecular alterations. Brain Res.
2003;979:114–128.
[55] Slotkin TA, Ryde IT, Tate CA, et al. Lasting effects of
nicotine treatment and withdrawal on serotonergic
systems and cell signaling in rat brain regions: Separate
or sequential exposure during fetal development and
adulthood. Brain Res Bull. 2007;73:259–272.
[56] Takarada T, Nakamichi N, Kawagoe H, et al. Possible
neuroprotective property of nicotinic acetylcholine
receptors in association with predominant upregulation
of glial cell line-derived neurotrophic factor in
astrocytes. J Neurosci Res. 2012;90:2074–2085.
[57] Lui MM, Mak JC, Lai AY, et al. The Impact of
Obstructive Sleep Apnea and Tobacco Smoking on
Endothelial Function. Respir Int Rev Thoracic Dis.
2016;91:124–131.
[58] Krmpotich TD, Tregellas JR, Thompson LL, et al.
Resting-state activity in the left executive control
network is associated with behavioral approach and
is increased in substance dependence. Drug Alcohol
Depend. 2013;129:1–7.