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Neuroscience and Biobehavioral Reviews 68 (2016) 838847

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews


journal homepage: www.elsevier.com/locate/neubiorev

Review article

A systematic review and meta-analysis of tract-based spatial statistics


studies regarding attention-decit/hyperactivity disorder
Lizhou Chen (PhD) a,1 , Xinyu Hu (PhD) a,1 , Luo Ouyang (MS) b , Ning He (MD) c,1 ,
Yi Liao (MD) a , Qi Liu (MM) a , Ming Zhou (MM) a , Min Wu (PhD) a ,
Xiaoqi Huang (PhD, MD) a, , Qiyong Gong (PhD, MD) a,
a

Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, PR China
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
c
Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, PR China
b

a r t i c l e

i n f o

Article history:
Received 9 January 2016
Received in revised form 18 July 2016
Accepted 19 July 2016
Available online 20 July 2016
Keywords:
Meta-analysis
Attention-decit/hyperactivity disorder
Diffusion tensor imaging
Tract-based spatial statistics
Fractional anisotropy
Seed-based d mapping

a b s t r a c t
Diffusion tensor imaging (DTI) studies that use tract-based spatial statistics (TBSS) have demonstrated
the microstructural abnormalities of white matter (WM) in patients with attention-decit/hyperactivity
disorder (ADHD); however, robust conclusions have not yet been drawn. The present study integrated
the ndings of previous TBSS studies to determine the most consistent WM alterations in ADHD via a
narrative review and meta-analysis. The literature search was conducted through October 2015 to identify
TBSS studies that compared fractional anisotropy (FA) between ADHD patients and healthy controls.
FA reductions were identied in the splenium of the corpus callosum (CC) that extended to the right
cingulum, right sagittal stratum, and left tapetum. The rst two clusters retained signicance in the
sensitivity analysis and in all subgroup analyses. The FA reduction in the CC splenium was negatively
associated with the mean age of the ADHD group. We hypothesize that, in addition to the fronto-striatalcerebellar circuit, the disturbed WM matter tracts that integrate the bilateral hemispheres and posteriorbrain circuitries play a crucial role in the pathophysiology of ADHD.
2016 Elsevier Ltd. All rights reserved.

Contents
1.
2.

3.

4.
5.
6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
2.1.
Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
2.2.
Quality assessment checklist and narrative review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
2.3.
SDM meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
3.1.
Characteristics of the studies included in the meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
3.2.
Quality assessment and narrative review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
3.3.
SDM meta-analysis results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
Conicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846

Corresponding authors at: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, No. 37 Guo Xue Xiang, Chengdu
610041, PR China.
E-mail addresses: julianahuang@163.com (X. Huang), qiyonggong@hmrrc.org.cn (Q. Gong).
1
These authors have contributed equally to this study.
http://dx.doi.org/10.1016/j.neubiorev.2016.07.022
0149-7634/ 2016 Elsevier Ltd. All rights reserved.

L. Chen et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 838847

839

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
Appendix A.
Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846

1. Introduction
Attention-decit/hyperactivity disorder (ADHD) is a commonly diagnosed neurodevelopmental disorder that begins during
childhood and is characterized by age-inappropriate levels of
hyperactivity, impulsivity and inattention (American Psychiatric
Association, 2013). The worldwide prevalence of ADHD is over 5%
among school-age children (Polanczyk et al., 2007), and 65% of
those cases continue into adulthood (Faraone et al., 2006). Magnetic resonance imaging (MRI) is extensively used in research to
elucidate the pathogenesis of ADHD and has primarily embraced a
neuronal network model of the fronto-striatal-cerebellar circuit,
which can explain some of the disturbances in patients. Recent
evidence has additionally suggested anomalies in a number of different networks involving large-scale brain regions, such as the
interhemispheric pathways and the occipital and temporal lobes
(Castellanos and Proal, 2012). In morphometric studies, consistent
reductions have been reported in total cerebral white matter (WM)
volume, all four lobes and specic structures such as the corpus
callosum (CC) (Krain and Castellanos, 2006; McAlonan et al., 2007;
Seidman et al., 2005). One review even observed a more predominant volume reduction of WM than gray matter (GM) in patients
with ADHD (Castellanos et al., 2002). The above evidence demonstrates that WM abnormalities play an important role in ADHD
pathophysiology.
Compared with macrostructural MRI for morphometric
changes, diffusion tensor imaging (DTI) enables researchers
to examine WM properties at a microstructural level (Basser,
1995). Fractional anisotropy (FA) is the most commonly used DTI
parameter for investigating the anisotropy that quanties the
directionality of diffusion. FA is regarded as a relatively nonspecic
biomarker for brain WM microstructural architecture and neuropathology (Alexander et al., 2007). Other diffusion parameters
often used in DTI studies include mean diffusivity (MD), which
reects the magnitude of diffusion in WM pathways; axial diffusivity (AD) and radial diffusivity (RD). The latter two parameters
provide complementary information to help understand the FA
or MD changes, reecting the diffusion parallel with and perpendicular to the axon, respectively. Concerning the approaches used
to analyze parameters, whole-brain analyses such as voxel-based
analysis (VBA) and tract-based spatial statistics (TBSS) provide
better comparability across studies than region-of-interest (ROI)
analyses because they overcome the bias of region-placement
preference and the absence of meaningful voxels outside of the
selected regions. In the past, whole-brain DTI studies of ADHD have
successfully identied increased and decreased FA in various brain
regions, including the prefrontal WM, temporal WM, cingulum
bundle, CC, and cerebellum (Krain and Castellanos, 2006; Valera
et al., 2007).
To resolve the inconsistency across different studies, van Ewijk
and colleagues conducted a literature review of pertinent DTI
studies on ADHD and a coordinate-based meta-analysis of nine
whole-brain studies (seven VBA and two TBSS studies) in 2011 (van
Ewijk et al., 2012). Although it was useful at the time, this study
has limitations. For example, although VBA and TBSS both explore
whole-brain WM alterations, they have inherent methodical differences that make combined meta-analysis problematic. TBSS was
specically developed to analyze diffusion data (Smith et al., 2006),
and it restricts analysis to the center of the major WM tracts (in
contrast with VBA, which analyzes all WM regions). Many recent

studies have used this approach and, in fact, there have been more
TBSS studies published than VBA studies. Thus, it is possible and
timely to perform a meta-analysis based solely on TBSS studies.
Previous literature has demonstrated marked delays in cortical
maturation among children with ADHD compared with typically
developing controls (Shaw et al., 2007), although these ADHD
patients might progressively catch up with age (Nakao et al., 2011).
Moreover, the use of medication, especially methylphenidate,
might normalize structural WM and GM changes as well as the trajectory of cortical development in patients with ADHD (Schweren
et al., 2013). Much evidence also suggests the presence of a gender
effect in ADHD, especially in children and adolescents (Biederman
et al., 2002). The male-to-female ratio in youth with ADHD ranges
from 2:1 to 9:1 (Biederman et al., 2004), and clinical manifestations and cognitive impairments differ between genders (Gershon,
2002). Thus, developmental trajectory, medication use and gender are associated with the pathophysiology and disease process of
ADHD.
Given the above research, the current study sought to identify
the most prominent and replicable WM microstructural abnormalities based on TBSS studies of ADHD and review the ndings.
A meta-analysis was performed using seed-based d mapping
(SDM) software, which enables the results from individual studies
to be weighted and controlled for multiple moderators including demographics, clinical information and imaging factors. More
importantly, SDM considers null results in a meta-analysis, and
it has been successfully applied in other neuropsychiatric studies
using TBSS (Welton et al., 2015). In addition, a multiple regression analysis was applied to explore the potential effects of age,
medication use and gender on WM microstructural differences.

2. Methods
2.1. Study selection
Comprehensive online searches for pertinent literature were
performed using the PubMed, Web of Science, EMBASE, EBSCO,
Clinical Key and Science Direct databases. All of the included studies were peer-reviewed articles published before October 2015.
The key search terms were attention-decit hyperactivity disorder, ADHD or hyperkinetic; tract-based spatial statistical
or TBSS; diffusion tensor or DTI; and fractional anisotropy
or FA. Moreover, all of the review articles and their references
were manually searched. All of the yielded articles were assessed
for potential suitability, and the articles that met the following
inclusion criteria were included in the meta-analysis: (i) published
in English in a peer-reviewed journal, (ii) included participants
with a primary diagnosis of ADHD and a group of healthy controls, (iii) reported a TBSS comparison between patients with ADHD
and healthy controls, (iv) used signicance thresholds for data that
were either corrected for multiple comparisons or uncorrected
with spatial extent thresholds, and (v) reported the whole-brain
results of FA alterations in a stereotactic space using the threedimensional standard coordinates (Talairach or MNI) of group
changes. The corresponding authors of articles that did not report
whole-brain coordinates but were otherwise suitable for metaanalysis were contacted for additional information. Theoretical
studies and reviews were excluded. Studies that used multiple
independent patient samples were separately compared with same

840

L. Chen et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 838847

healthy control groups, and the appropriate results were regarded


as separate datasets.
Two authors independently searched the literature, examined
the retrieved articles, and extracted and crosschecked data. If agreement was not obtained, then another author mediated. Moreover,
the coordinates in each study were extracted for meta-analysis.
The analyzed coordinates in each study had to be under the same
statistical threshold; i.e., when a given study reported coordinates
from both corrected and uncorrected thresholds, we chose only the
corrected ones.
2.2. Quality assessment checklist and narrative review
Study quality was evaluated using a 15-point checklist to provide an objective description of the rigorousness of the individual
studies. The checklist was developed from previous meta-analyses
focusing on structural MRI variables (Du et al., 2014; Shepherd
et al., 2012; Welton et al., 2015). Modications were made to
reect the critical characteristics of DTI studies in ADHD as suggested by previous empirical reviews (Jones et al., 2013; Le Bihan
and Johansen-Berg, 2012). Using this checklist, we assessed both
the clinical and demographic aspects of every study as well as the
imaging-specic methodologies (for the full criteria and scores for
each included study, see Supplementary Table 1). Although the
checklist was not designed as an assessment tool, it provided an
objective indication of the rigor of the individual studies. When a
particular criterion was met, one point was given; if it was partially met, a half-point was assigned; and when the information
was not provided, zero points were assigned. At least two authors
conducted this work independently, and any study with inconsistent ratings was discussed until a consensus score was obtained. For
inclusion in the present study, an assessed study had to have a score
above 7.5 points (i.e., 50% of the total score). The narrative review
of the TBSS studies was discussed in the following sequence: nonadult studies with positive FA ndings, adult studies with positive
FA ndings and adult studies with negative FA ndings.
2.3. SDM meta-analysis
The meta-analysis was performed using SDM software (version
4.31, http://www.sdmproject.com) following a standardized process to compare the FA changes between patients with ADHD and
healthy controls. In brief, SDM creates effect size and variance maps
based on the peak coordinates of each included study and then analyses them via traditional random-effects meta-analytic methods.
In particular, a TBSS template based on the FMRIB58 FA skeleton
(heep://www.fmrib.ox.ac.uk/fsl) was provided to restrict the analysis to the same WM tracts that were available in the TBSS studies.
The major analyses were complemented by analyses of robustness.
First, a jackknife sensitivity analysis was conducted that consisted
of repeated iterations of the meta-analysis excluding one study at
a time to establish whether the results were reliable; results that
were no longer signicant in two or more iterations were rejected.
Second, the possibility of publication bias for resultant clusters was
examined using Eggers test via STATA (www.stata.cn), in which
any result showing p < 0.05 was regarded as having signicant
publication bias. Moreover, we examined the statistical (betweenstudy) heterogeneity of individual clusters using a random--effects
model with Q statistics. Areas showing signicant heterogeneity
that also overlapped with the main ndings were explored using
meta-regressions to understand the sources of variability among
the studies.
The meta-regressions were analyzed with age, the percentage of
patients on medication, and the percentage of male patients in each
study as independent variables. Furthermore, we planned on performing subgroup analyses of pediatric and adolescent samples vs.

Fig. 1. Flow chart for identifying ADHD studies.

adult samples, medicated samples vs. non-medicated samples, and


male samples vs. female samples if sufcient datasets were available. All of these analytical processes referred to the SDM tutorial
and related publications (Radua et al., 2014). As described in previous meta-analyses, a threshold of p = 0.005 with a peak of Z 1 and a
cluster extent of 10 voxels was adopted for the meta-analyses and
heterogeneity analyses, whereas the more conservative threshold
of p = 0.0005 was used for the meta-regression analyses and only
considered when signicant slopes were accompanied by signicant differences at one extreme.
3. Results
3.1. Characteristics of the studies included in the meta-analysis
A total of 470 patients with ADHD and 477 matched healthy controls, along with 46 coordinates extracted from 10 studies (Bode
et al., 2014; Chuang et al., 2013; Cooper et al., 2014; Cortese et al.,
2013; de Luis-Garca et al., 2015; Nagel et al., 2011; OConaill et al.,
2015; Onnink et al., 2015; Silk et al., 2009; van Ewijk et al., 2014)
were analyzed. The demographic and methodological information
is summarized in Table 1. The ow chart of the search strategy is
presented in Fig. 1. Of all of the studies, two recruited two subgroups
of patients; one recruited persistent or remitted ADHD subgroups
(Cortese et al., 2013), and the other recruited patients who did or did
not receive treatment (van Ewijk et al., 2012). No study used overlapping patients samples, and a total of 12 datasets were extracted
from 10 studies.
Four datasets from 3 studies that recruited adult patients (Bode
et al., 2014; Cortese et al., 2013; van Ewijk et al., 2014) were analyzed, and 8 datasets from 7 studies that were conducted with
non-adult patients (i.e., children and adolescents) were analyzed.
One study included 8- to 30-year-old participants (van Ewijk et al.,
2014); however, because its group mean age was under 18 years
old, it was assigned to the group of non-adult studies.
Seven datasets were analyzed from 5 studies that recruited only
males (Chuang et al., 2013; Cooper et al., 2014; Cortese et al., 2013;
de Luis-Garca et al., 2015; Silk et al., 2009). Other than two datasets

Table 1
The characteristics of the ADHD studies included in the meta-analysis.
Study

Medicationa , %

Age, years

IQ

ADHD

HC

ADHD

HC

ADHD

HC

Silk

15 (15)

15 (15)

12.6 (2.4)

12.9 (2.6)

PIQ: 111.6 (9.2)


VIQ: 111.9 (9.7)

Nagel

20 (4)

20 (13)

8.31 (0.70)

8.05 (0.69)

PIQ: 104.9
(11.5) VIQ:
102.9 (14.7)
115.4 (12.9)

Chuang

12 (12)

14 (14)

14.8 (1.4)

15.7 (NA)

Cortese PER

15 (15)

47 (47)

41.8 (3.0)

Cortese REM
Bode
Cooper
van Ewijk

25 (25)
30 (21)
17 (17)
170 (115)

47 (47)
30 (22)
17 (17)
107 (52)

de Luis-Garca NT
de Luis-Garca UT
OConaill
Onnink

16 (16)
24 (24)
19 (17)
107 (41)

26 (26)
26 (26)
21 (16)
109 (47)

Study information
MRI Telsa

Directions

Statistical threshold

Major ndings (ADHD relative


to healthy controls)

20

28

Corrected by NPT

Increased FA in R.CG, L.UF, L.ILF

106.5 (12.8)

15

20

Corrected by AlphaSim

99.3 (11.7)

102.4 (9.3)

91.7

1.5

na

Corrected by NPT

41.1 (3.0)

99.3 (13.0)

111.1 (14.3)

92

Corrected by TFCE

41.3 (2.6)
22.59 (0.76)
15.6 (1.3)
17.3 (3.3)

41.1 (3.0)
23.09 (0.64)
16.9 (1.2)
16.4 (3.1)

103.8 (13.1)
98.17 (18.22)
87.6 (9.8)
97.8 (14.7)

111.1 (14.3)
110.00 (22.48)
106.9 (7.6)
104.5 (13.7)

92
0
58.8
90.3

3
1.5
3
1.5

6
40
60
60

Corrected by TFCE
Corrected by NDMS
Corrected by TFCE
Corrected by TFCE

7.62 (1.36)
8.50 (1.1)
11.93 (1.33)
35.00 (10.30)

8.23 (1.53)
8.23 (1.53)
12.60 (1.29)
36.08 (10.97)

100.3 (18.2)
103.3 (13.3)
95.79 (16.97)
108.13 14.43

120.3 (14.5)
120.3 (14.5)
107.81 (13.08)
110.97 15.36

0
100
78.9
81

1.5
1.5
3
1.5

25
25
20
34

Corrected by TFCE
Corrected by TFCE
Uncorrected
Corrected by TFCE

Decreased FA in B.UF, B.ILF,


R.ACR, L.PCR, L.ICP, R.SLF, R.SCR
Decreased FA in R.MCP, L.CST,
L.ILF, R.IC, L.OR, CC splenium,
L.ACR, R.PCR
Decreased FA in R.SS, R.EC,
R.RIC, R.ACR
Decreased FA in R.PCR, R.SCR
Increased FA in L.forceps minor
No signicant FA alteration
Decreased FA in L.ATR, B.CST,
B.IC, B.SLF, B.IFOF, L. temporal
white matter, CC (splenium,
isthmus, forceps major, body)
No signicant FA alteration
No signicant FA alteration
No signicant FA alteration
Decreased FA in CC (body,
splenium), R.PCR, R.SCR. R.PTR.
R.Tapetum

L. Chen et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 838847

Participants, n (males)

ACR: anterior corona radiata; ADHD: attention-decit/hyperactivity disorder; ATR: anterior thalamic radiation; B: bilateral; CG: cingulum; CST: corticospinal tract; EC: external capsule; FA: fractional anisotropy; HC: healthy
controls; ICP: inferior cerebellar peduncle; IC: internal capsule; IFOF: inferior fronto-occipital fasciculus; ILF: inferior longitudinal fasciculus; L: left; MCP: middle cerebellar peduncle; OR: optic radiation; PCR: posterior corona
radiata; PTR: posterior thalamic radiation; R: right; RIC: retrolenticular part of internal capsule; SCR: superior corona radiata; SLF: superior longitudinal fasciculus; SS: sagittal stratum; UF: uncinate fasciculus.
a
Indicates patients who received medication during scanning or had a past history of medication (but washed out before scanning); only those who were never medicated were excluded.

841

842

L. Chen et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 838847

with non-medicated patients (de Luis-Garca et al., 2015; OConaill


et al., 2015), all of the datasets included patients with histories of
ADHD medication use or those taking medication at the time of
scanning. Therefore, subgroups of meta-analyses were performed
for the non-adult samples, the medicated-patient samples and the
male-only samples; the reverse situation was precluded given that
the number of studies was too small to draw reliable conclusions.
3.2. Quality assessment and narrative review
The mean quality score of the included datasets was 82.5% 7.7,
and all of the articles surpassed the minimum quality threshold
(Supplementary Table 1). The item that deducted the most points
was patient comorbidity, followed by medication status, sample
size, subtype status and acquisition parameters, such as magnet
strength, number of diffusion gradient directions and b-value.
The rst TBSS study on ADHD was published in 2008 (Silk et al.,
2009); it compared a group of boys and male adolescents with
ADHD with matched controls. After multiple comparisons were
corrected for, increased FA was detected in the right occipitoparietal region, left inferior frontal region/striatum and left inferior
temporal region. The WM tracts that underlie these regions are the
cingulum, uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF). No between-group difference in MD was observed. In
addition, probabilistic tractography revealed anterior and posterior
thalamic radiation, the genu and splenium of the CC, and the superior longitudinal fasciculus (SLF). Subsequent ROI analysis showed
that the FA increase likely resulted from both higher AD and lower
RD, which might represent a lesser degree of neuronal branching.
Another study that focused on children younger than 9 years
old with ADHD (Nagel et al., 2011) found decreased FA in the bilateral UF, bilateral ILF, right anterior radiata (ACR), superior corona
radiata (SCR), left posterior corona radiata (PCR), left inferior cerebellar peduncle, and right SLF. Moreover, lower MD in the posterior
limb of the internal capsule and fronto-parietal WM and greater MD
in the frontolimbic WM were observed. In subsequent ROI analysis, lower AD, higher RD, or both were observed for the areas
that showed an FA or MD difference, and these differences were
most apparent in the frontolimbic WM. Thus, the authors of that
study suggested that children with ADHD have delayed or reduced
myelination in these areas. In addition, via a regression model,
the authors found that none of the clusters that showed an FA or
MD difference had signicant association with either inattention
or hyperactivity symptoms in ADHD patients after correction for
multiple comparisons.
One brief report investigated the FA difference between a
group of male adolescents with ADHD and matched controls
(Chuang et al., 2013) and found decreased FA in widespread
WM tracts including the middle cerebellar peduncle, corticospinal
(CST)/corticobulbar tract, left ILF, internal capsule, left optic radiation, bilateral splenium of the CC, right PCR and left ACR.
The largest TBSS study examined 170 patients with ADHD comprising 80 unaffected siblings and 107 healthy controls (van Ewijk
et al., 2014), all 830 years old. It revealed a widespread pattern
of reduced FA in the bilateral hemispheres and MD in the right
hemisphere in the ADHD group. Decreased FA was found in the left
anterior thalamic radiation, bilateral CST, bilateral internal capsule,
bilateral SLF, bilateral inferior fronto-occipital fasciculus (IFOF), left
temporal WM and subparts of the CC (splenium, isthmus, forceps
major, body), whereas decreased MD involved the right CST, right
ILF, right IFOF and right SLF. In subsequent ROI analysis, unaffected
siblings resembled individuals with ADHD with regard to decreased
FA but had MD similar to that of healthy controls. Thus, the FA
reduction was suggested to be because of a familial vulnerability to
ADHD. In addition, the authors found that a higher ADHD symptom
count was consistently associated with increased FA and decreased

MD in the ADHD group, whereas no such relationship was found in


unaffected siblings or healthy controls.
The rst TBSS study to use an adult sample was a 33-year longitudinal report that investigated a group of male probands and
matched controls in a follow-up wave throughout their forties
(Cortese et al., 2013). Fifteen patients with persistent ADHD and
25 remitters were compared with 47 healthy controls. Decreased
FA was detected in both groups of patients with ADHD compared
with controls; the involved WM tracts included the right ILF, right
IFOF, right external capsule, right retrolenticular part of the internal capsule and right ACR in patients with persistent ADHD as well
as the right PCR and right SCR in patients with remitted ADHD.
Thus, the authors suggested that the FA reductions observed among
adults with childhood ADHD might be an enduring trait of ADHD
regardless of current disease status.
Another TBSS study investigated 30 drug-naive young adults
with remitted ADHD compared with 30 matched controls aged
2223 years (Bode et al., 2014). These authors found increased FA
in the left forceps minor in the ADHD group compared with controls. In addition, whole brain voxel-wise analysis of eigenvalues
found that 2 was signicantly reduced in the left forceps minor
and that 1 was signicantly reduced in the vicinity extending to
the genu of CC; these results corroborated those found by the rst
study conducted by Silk that increased FA was related to decreased
RD. In addition, no between-group differences were observed with
regard to MD.
One recent TBSS study recruited a sample of 107 adults with
ADHD and 109 gender-, age- and IQ-matched controls (Onnink
et al., 2015) and performed between-group voxel-wise analysis
using FA, MD, AD and RD. Lower FA was found in the CC (body, splenium, tapetum), right SCR, right PCR, and right posterior thalamic
radiation (TR) of the ADHD group. Higher MD and RD were found
in overlapping and more widespread areas in both hemispheres,
encompassing the internal and external capsule, SS, fornix, and SLF.
No between-group differences were observed for AD. Furthermore,
a subsequent ROI approach was conducted for those regions showing signicant FA or MD changes. It revealed that FA and MD were
not associated with symptom severity; however, worse inhibition
performance was associated with reduced FA, and more impulsive
decision making was associated with increased MD. The authors
attributed their ndings to aberrant myelination in white matter
tracts and proposed that such aberrations may contribute to poor
inhibition and greater impulsivity but appear to be independent of
disease severity.
Apart from the aforementioned ndings of signicant FA alteration, three published studies (4 datasets) failed to nd FA
differences between ADHD patients and healthy controls. One
investigated a group of male adolescents with ADHD who showed
autism spectrum disorder traits (Cooper et al., 2014); this study also
found no signicant group differences in MD, AD and RD. Another
study compared among children with alcohol-related neurodevelopmental disorder, those additionally with ADHD and typically
developing matched controls; it revealed no signicant FA or MD
differences between those with ADHD and controls, even without correction for multiple comparisons (OConaill et al., 2015).
Another study explored subgroups of methylphenidate-treated and
non-medicated children with ADHD (de Luis-Garca et al., 2015),
and no subgroup showed any signicant FA or MD alteration at
the threshold level of p < 0.05 (corrected by threshold-free cluster enhancement, TFCE). A tendency towards signicance (p < 0.1)
was only observed for the never-medicated patients, who showed
decreased FA in WM regions that likely represented the right SS,
right IFOF, right cerebral peduncles, bilateral TR, and left SCR. However, the authors also carried out a tractography-based analysis
(using the Geometric Tractography Selection technique), and a signicant MD difference was found among the three groups: patients

L. Chen et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 838847

843

who underwent treatment had lower MD than did both healthy


controls and patients without treatment in the ILF, UF and the isthmus part of the CC. However, no differences were found between
patients without treatment and healthy controls.
The above main ndings of each study are outlined in Supplementary Table 2. In summary, the majority of TBSS studies
that reported signicant between-group FA differences found
decreased FA in patients with ADHD (6 of 8 datasets). Some studies
also examined MD, AD and RD differences using whole-skeleton or
ROI methods and found that higher RD usually accompanied lower
FA (Nagel et al., 2011; Onnink et al., 2015). Two datasets found
increased FA in patient groups showing lower RD with or without
higher AD (Bode et al., 2014; Silk et al., 2009). The MD ndings
were less consistent among studies compared with FA ndings:
two datasets reported decreased MD (Nagel et al., 2011; van Ewijk
et al., 2014), two reported increased MD (Nagel et al., 2011; Onnink
et al., 2015) and ve reported no signicant MD differences (Cooper
et al., 2014; de Luis-Garca et al., 2015; OConaill et al., 2015; Silk
et al., 2009), and the relationship between MD and FA varied among
studies.
3.3. SDM meta-analysis results
The results of the pooled meta-analysis are provided in Table 2
and Fig. 2. Compared with controls, reduced FA was found in the
splenium of the CC, the right sagittal stratum (SS), and the left tapetum of the CC of patients with ADHD. Cluster breakdowns showed
that these clusters contained WM tracts of the CC (splenium part),
right cingulum, right IFL, bilateral IFOF, and left tapetum. None of
the clusters showed signicant publication bias based on Eggers
test (p > 0.05); (Egger et al., 1997), and no FA increases were identied.
As Supplementary Table 3 shows, a jackknife sensitivity analysis revealed that these clusters were highly reliable, especially the
clusters in the CC splenium and the right SS, which were signicant for all iterations. Subgroup analyses of the non-adult studies
and medicated studies revealed all three of the clusters that were
identied in the pooled analysis; however, the subgroup analysis
of the male studies failed to identify the cluster located in the left
tapetum.
Signicant between-group heterogeneity was detected in the
splenium of the CC and the right SS. Additional meta-regression
analyses revealed that the FA values of two subparts of the cluster
in the CC splenium were negatively associated with the mean age
of the patients. Both subparts were identied as the CC by SDM;
we labeled them as anterior (coordinates [22, 26, 38], r = 0.338,
permutation-derived p < 0.0001) and posterior (coordinates [20,
40, 36], r = 0.312, permutation-derived p < 0.0001) for the purpose
of description (Fig. 3).
4. Discussion
The current study pooled TBSS studies on ADHD to conduct a
quantitative meta-analysis and provide a narrative review of extant
ndings. To the best of our knowledge, no similar previous work has
been performed. Our work is timely because a sufcient number of
high-quality TBSS studies recently became available. The results of
the narrative review demonstrated FA abnormalities in distributed,
distinguished WM regions in children, adolescents and adults with
ADHD. The affected tracts primarily involve commissural bers that
connect bilateral hemispheres (e.g., CC), association bers that link
occipital, frontal and temporal regions (e.g., ILF, IFOF, uncinate fasciculus), and projection bers that pass through the corona radiata
and cerebellum (e.g., the corticospinal tract and cerebellar peduncle). In addition, four datasets failed to nd FA differences using

Fig. 2. Three clusters with decreased FA were identied in patients with ADHD compared with healthy controls: the splenium of the CC extending to the right cingulum,
the right SS, and the left CC tapetum.

group comparisons. The quantitative meta-analysis found that the


most robust WM alterations found in ADHD-TBSS studies were
located in the splenium of the CC, the right SS and the left tapetum, and the tracts of the right cingulum, right ILF and bilateral
IFOF were all involved. A signicant negative association was found
between the mean age of patients with ADHD and the FA values of
the two clusters in the CC splenium. Subgroup analyses of nonadult studies, male studies, and medicated studies failed to repeat
the reduced FA found in the left tapetum in an analysis of only male
patients with ADHD; however, all other clusters remained signicant. Thus, the microstructural changes in the CC splenium and the
right SS appear to be robust in children and adolescents with ADHD,
male patients with ADHD, and patients with ADHD who received
medication. Together, our results indicate that the interruptions
in the WM tracts are related to interhemispheric communication,
posterior brain circuitries and the limbic system.
The pathological meaning of FA reduction is complex because
brain FA can be inuenced by many factors such as regional
myelination levels, the degree of intra-voxel ber crossing, axonal
density and average axonal diameter (Beaulieu, 2002). Previous
studies have suggested that FA reduction occurs through increased
RD, decreased AD, or both (Nagel et al., 2011; Onnink et al., 2015).
Animal models have shown that increased RD is associated with
the dysmyelination of the nerve sheath, whereas decreased AD is
more related to axonal damage (Song et al., 2002; Sun et al., 2007).
Compared with FA, MD is generally more associated with changes
of intercellular space (Alexander et al., 2007; Tievsky et al., 1999).
Among ADHD studies that detected MD differences, some reported
increased MD along with decreased FA in overlapping regions in
patients with ADHD (Konrad et al., 2010; Pavuluri et al., 2009).
Other studies, however, found heterogeneous situations. For example, using a tractography method, Lawrence et al. (Lawrence et al.,
2013) found both patients and their unaffected siblings had higher
MD than did healthy controls in the ATR, forceps minor, and SLF,

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L. Chen et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 838847

Table 2
Regional differences in FA between patients with ADHD and healthy controls.
WM Tract

Voxels, n

MNI Coordinates (peak voxel)


x

SDM z value

p, uncorrected

Cluster breakdown (voxels, n)

Corpus callosum (328)


Right cingulum (35)
Right inferior longitudinal fasciculus (94)
Right inferior fronto-occipital fasciculus (33)
Left inferior fronto-occipital fasciculus (15)
Corpus callosum tapetum (15)

CC splenium

363

16

34

28

2.111

Right SS

127

42

28

12

1.669

0.000007331

Left CC tapetum

30

32

32

1.097

0.000600994

CC: corpus callosum; FA: fractional anisotropy; MNI: Montreal Neurological Institute; SDM: Seed-based d mapping; SS: sagittal stratum; WM: white matter.

Fig. 3. The meta-regression results showing that the FA values of two subparts in the CC splenium were negatively associated with the mean age of patients with ADHD:
the anterior part (right, r = 0.338, permutation-derived p < 0.0001) and posterior part (left, r = 0.312, permutation-derived p < 0.0001). The effects sizes shown in the graphs
needed to create the plots were extracted. Larger dots indicate larger sample sizes.

which was suggested to indicate a familial liability for ADHD. Furthermore, as no tested tracts showed a signicant FA difference,
the authors suspected that MD might be a more sensitive biological marker for ADHD and/or that FA effects were more variable or
restricted to specic aspects of tracts that were missed by the tractography method. In contrast, van Ewijk and colleagues (van Ewijk
et al., 2014) found that subjects with ADHD showed decreased FA
and MD in non-overlapping areas in comparison with healthy controls. However, unaffected siblings resembled patients with regard
to decreased FA but had MD similar to that of controls. The authors
thus suggested that the FA reduction, but not the MD reduction, was
due to a familial vulnerability to ADHD. Such study discrepancies
in MD results may be related to methodological differences, as suggested by van Ewijk, or other unidentied factors to be identied
in future meta-analysis with adequate evidence of MD (if possible,
AD and RD should also be analyzed). Moreover, as these diffusion
parameters are subject to different interpretations among different
analyses, the combined use of essential indexes is recommended.
The CC is the largest WM bundle that connects the bilateral
cerebral hemispheres, transferring excitatory and inhibitory signals (McNally et al., 2010). The present study found decreased
FA in the splenium of the CC extending to the posterior portion of the right cingulum, thereby suggesting an interruption
in the inter-hemispheric communication of the posterior brain
within the limbic network. The splenium connects the bilateral
occipital, temporal and posterior parietal areas (Hofer and Frahm,
2006), inuencing the speed of visual information transmission
and dynamically distributing processing resources (Putnam et al.,
2010). Thus, the decits along the splenium pathway might be
related to the inattention, distractibility, and visual dysfunctions
observed among patients with ADHD. Moreover, because the CC
is the major bridge across the two hemispheres, its decits might
also disentangle the lateralization problems observed among those
with ADHD (Giedd et al., 2001). In healthy controls, there is an information transfer asymmetry between the two hemispheres, with
more rapid transfer from the right to left side than in the opposite
direction (Miller, 1996). Some researchers have found this normal
asymmetry to be altered in ADHD patients, and the impairments

appear to be specic to the right frontal (Cao et al., 2006) and parietal (Filipek et al., 1997) areas and to the associated connections
to subcortical structures, such as the limbic system (Stefanatos and
Wasserstein, 2001). Therefore, the disturbed microstructure in the
CC may also reect abnormalities of the left or right hemisphere
cells of origin. One EEG study using a simple reaction time laterality task found that, relative to healthy controls, ADHD patients
of the inattentive subtype showed slower right-to-left transfer,
whereas patients of the combined subtype exhibited faster leftto-right transfer, which demonstrated a lateralization dysfunction
in ADHD patients of different subtypes (Rolfe et al., 2007). Across
previous DTI studies in ADHD, altered FA was found in different
subdivisions of the CC of patients with ADHD (Chen et al., 2015;
Chuang et al., 2013; Onnink et al., 2015; van Ewijk et al., 2014). Our
meta-analysis suggested that the abnormal microstructure of the
splenium appears to be more robust than the other subdivisions
associated with this disorder. This nding is in line with previous meta-analyses of structural MRI studies (Putnam et al., 2010;
Seidman et al., 2005) that conclude that the volume reduction of
the posterior CC (including the splenium) was the most replicated
structural biomarker of children with ADHD.
We also found that the cluster in the CC splenium extended to
the right posterior cingulum, a limbic structure that carries major
efferent and afferent bers to the PCC and participates in attention
regulation (Langevin et al., 2014) and internally directed cognition
(Hahn et al., 2007). Previous diffusion studies that used methods
other than TBSS have also revealed that the cingulum shows altered
FA in patients with ADHD; however, the results are inconsistent
(Chen et al., 2015; Konrad et al., 2010; Makris et al., 2008). For
example, some studies that used VBA and tractography reported
lower FA in the cingulum of adults and youths with ADHD compared with healthy controls (Konrad et al., 2010; Makris et al.,
2008). Conversely, two other VBA studies found that children with
ADHD had higher FA scores than did healthy controls (Chen et al.,
2015; Peterson et al., 2011). Thus, the current ndings together
with previous evidence highlight the role that the limbic network
plays in ADHD and reveal that the reduced FA in the cingulum might
be more predominant across TBSS studies.

L. Chen et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 838847

The decreased FA observed in the right SS (which contains tracts


of the right IFOF and ILF) and the left IFOF tract identied in the cluster of left tapetum underscore the involvement of the long-range
WM connections among the occipital, temporal and frontal lobes
in patients with ADHD. The SS is a large WM tract that is oriented
in a sagittal plane along the temporal and occipital lobes, and it
has been associated with altered FA in patients with ADHD according to VBA (Konrad et al., 2010) and ROI (Peterson et al., 2011)
studies. IFOF is a major ber bundle that runs through the SS. It
is a direct pathway that connects the frontal and occipital lobes
as well as the parietal and posterior temporal cortices (Catani and
Thiebaut de Schotten, 2008). These regions are involved in attention
(Barkley, 1997), visual processing (Lenz et al., 2010) and language
(Axer et al., 2013). In particular, the IFOF is related to attention
set-shifting; thus, its decits might account for the distractibility
problem in patients with ADHD (Kvickstrom et al., 2011). The ILF
is another WM bundle within the SS that spatially overlaps with
the IFOF along a portion of their pathways. This bundle directly
connects the occipital lobe with the anterior portion of the temporal lobe and, compared with IFOF, is an indirect pathway that
links the frontal regions by anteriorly joining the uncinate fasciculus (Ashtari, 2012). The ILF relays visual information that supports
visual perception and object recognition (Tusa and Ungerleider,
1985); thus, the altered FA observed in this tract might underlie
the visual memory decits found among patients with ADHD. The
ILF also integrates the functional components of the ventral frontoparietal attention system (Li et al., 2009), which might also be
related to the attention problems of ADHD patients. These ndings
of temporal lobe WM connections along with our prior nding in
the splenium of CC, which mainly links the bilateral occipital lobes,
reects the role of posterior brain circuitries in ADHD. The occipital
lobes have close interactions with the dorsal attentional network,
the key nodes of which are located in the intraparietal sulcus and
the frontal eye elds, to focus on goal-directed behaviors and to
resist irrelevant interferences (Capotosto et al., 2009). Regions of
the temporal lobe, particularly the MT+ region of middle temporal
gyrus, are structurally and functionally associated with the visual
cortex in the occipital lobe (Yeo et al., 2011). The WM connections among them allows direct, rapid access of visual information
from anterior temporal structures to the occipital lobe (Catani et al.,
2003). Thus, the WM microstructural disruptions in posterior brain
circuitries may be neuroimaging biomarkers related to the visual
and attention problems in patients with ADHD.
Moreover, our nding of decreased FA in the WM tracts of the
left tapetum also emphasizes the involvement of the CC splenium.
The tapetum is a bundle of WM projections from the splenium that
sweep inferiorly along the lateral margin of the posterior horn of
the lateral ventricle and project into the temporal lobes (Wakana
et al., 2004). These projections constitute the bilateral temporotemporal lobe pathways that participate in language ability (Northam
et al., 2012) and auditory information transfer (Westerhausen et al.,
2009), which are often decient in patients with ADHD. As such,
further examination of inter-hemispheric communication through
the CC, especially the splenium, might be instrumental for understanding this disorder.
Regression analysis revealed that two subparts of the CC showed
signicant negative relationships with the mean age of the ADHD
groups, which ranged from 7.62 to 41.8 years old, suggesting a
potential effect of age on the WM microstructure development
of patients with ADHD. This analysis also showed that older participants had lower FA values. Previous studies have consistently
demonstrated that a curvilinear relationship exists between the
microstructure of the CC and age in healthy people, in whom the
FA in both the entire CC and its subdivisions follow an inverted
U-shaped curve across age, peaking in young adulthood between
21 and 29 years of age (Lebel et al., 2010; Ota et al., 2006). Previ-

845

ous ADHD studies have suggested that the development of cortical


thickness is delayed in ADHD patients compared with healthy controls (Shaw et al., 2007). The median age at which 50% of the cortical
points had attained peak thickness was 10.5 years old for children
with ADHD, which was signicantly later than the median age of 7.5
years for typically developing controls. Thus, our regression analysis suggests that an anomalous microstructural WM develops along
a CC trajectory in patients with ADHD, which might be analogous
to GM abnormalities.
Compared with a previous meta-analysis of DTI studies in
ADHD that revealed disturbed WM, supporting the fronto-striatalcerebellar circuitry theory (e.g., clusters with altered FA located
in the right anterior corona radiata, right forceps minor, bilateral
internal capsule, and left cerebellum); (van Ewijk et al., 2012), the
present meta-analysis predominantly highlighted the role of interhemispheric communication and the posterior brain circuitries,
especially the occipital- and temporal-lobe-related pathways. This
discrepancy might be explained in numerous ways. Firstly, we only
analyzed TBSS studies via an updated literature search, thus the
different studies and ndings evaluated between the two metaanalyses may explain their different conclusions. For example, four
of our included studies reported clusters with altered FA in the CC
(Bode et al., 2014; Chuang et al., 2013; Onnink et al., 2015; van
Ewijk et al., 2014), whereas only one included study of the previous meta-analysis clearly reported CC results (Qiu et al., 2011). This
is also the case for internal capsule and cerebellum, which were
revealed by previous meta-analysis. However, only two studies
included in the present meta-analysis provide support for altered
FA in these two regions respectively (cerebellum: Chuang et al., &
Nagel et al.,; internal capsule: Chuang et al., & van Ewijk et al.,).
Secondly, the inclusion of only TBSS studies in the present metaanalysis avoided any bias caused by methodological differences in
diffusion data processing. One previous study comparing the TBSS
and the traditional VBA methods found that the results varied from
each other (Abe et al., 2010), and the possible explanation concerns the mis-registration and smoothing problems with VBA and
the insensitivity of the FA changes outside of the local WM bundle
centers for TBSS. Thirdly, the present study evaluated recent literature, the majority of which had not been previously published
when the previous meta-analysis was conducted. Thus, differences
in sample characteristics (e.g., with regard to age, gender, subtype
and medication status) may also have contributed to the differences
between the two meta-analyses. Finally, the present meta-analysis
used SDM software, which differs from the previously used activation likelihood estimation (ALE) software; the main advancement
of SDM is that it considers null results. Because null results are
less likely to be published than positive ndings, their inclusion
in the meta-analysis can reduce the possibility of publication bias
(Thornton and Lee, 2000).

5. Limitations
Several limitations of the present study should be taken into
account. First, as is inherent in all coordinate-based methods,
our meta-analysis used the coordinates from the included studies
rather than the original t-statistic maps, which limits the accuracy of the results to a certain degree (Radua et al., 2012). Second,
two pairs of datasets used the same control samples (Cortese et al.,
2013; de Luis-Garca et al., 2015); however, because we focused on
the alterations in the patient groups, we considered this decision to
be appropriate. Third, because the effect sizes of unpublished studies are usually smaller than those of published studies (Lipsey and
Wilson, 1993), caution must be taken to not overestimate the overall effect sizes or SDM values. Given the numerous null results from
the studies that were included in the current meta-analysis, we

846

L. Chen et al. / Neuroscience and Biobehavioral Reviews 68 (2016) 838847

believe that this particular concern is minor. Finally, the main purpose of our subgroup analyses was to verify the ndings revealed
by the overall meta-analysis. Considering that the numbers of nonadult and male studies were relatively small (8 and 7 respectively),
the results of the subgroup analysis should be interpreted with
caution.
6. Conclusion
In conclusion, we qualitatively and quantitatively reviewed the
ndings of published TBSS studies on ADHD. Although these studies
differed in their sample characteristics and scanning procedures,
the use of TBSS enabled relatively high comparability across the
literature because its data processing and analyzing pipeline is relatively standardized. The increasing number of TBSS studies has
shown that a variety of WM tracts are affected in patients with
ADHD. The present meta-analysis of FA ndings found that the most
evident and consistent WM differences were located in the splenium of the CC extending to the right cingulum, the right SS and
left tapetum; furthermore, they involve the WM tracts that connect
the bilateral hemispheres, the occipital lobe-related neurocircuitry,
and the limbic system. In particular, altered microstructures in the
CC splenium and the right SS were robustly present in all sensitivity and subgroup analyses. These ndings suggest that, beyond the
classic fronto-striatal-cerebellar circuit, the left-right and posterior
brain WM pathways in the pathophysiology of ADHD deserve more
research attention.
Conicts of interest
All of the authors report no biomedical nancial interests or
potential conicts of interest.
Acknowledgements
This work was supported by the National Natural Science
Foundation (Grant Nos. 81171488, 81227002, and 81220108013),
the National Key Technologies R&D Program (Program No.
2012BAI01B03) and the Program for Changjiang Scholars and Innovative Research Team (PCSIRT, Grant No. IRT1272) in University of
China.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.neubiorev.2016.
07.022.
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