Title

Altered frontal pole development affects selfgenerated spatial working memory in ADHD

Author(s)新井, 清義Citation

大阪大学, 2016, 博士論文

Version Type VoR
URL

https://doi.org/10.18910/56160

rights
Note

Osaka University Knowledge Archive : OUKA
https://ir.library.osaka-u.ac.jp/
Osaka University

Altered frontal pole development affects self-generated spatial
working memory in ADHD
（ADHD 児における自発性空間ワーキングメモリ施行時の前頭葉の活動：
NIRS を用いた発達的変化の検討）

大阪大学大学院
大阪大学・金沢大学・浜松医科大学・千葉大学・福井大学
連合小児発達学研究科
新井 清義

２０１６年３月 博士学位論文

Brain & Development xxx (2015) xxx–xxx
www.elsevier.com/locate/braindev

Original article

Altered frontal pole development aﬀects self-generated
spatial working memory in ADHD
Sumiyoshi Arai a, Yuko Okamoto a,b, Toru Fujioka c,d, Keisuke Inohara c,e,
Makoto Ishitobi c,f, Yukiko Matsumura c, Minyoung Jung a,b, Kaori Kawamura g,
Shinichiro Takiguchi d,h, Akemi Tomoda a,b,d, Yuji Wada c, Michio Hiratani g,
Naomi Matsuura i, Hirotaka Kosaka a,b,c,d,⇑aDevelopmental Emotional Intelligence, Division of Developmental Higher Brain Functions, Department of Child Development United Graduate
School of Child Development, University of Fukui, Japanb
Research Center for Child Mental Development, University of Fukui, Japanc
Department Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Japand
Department of Child and Adolescent Psychological Medicine, University of Fukui, Japane
Department of Informatics, Graduate School of Informatics and Engineering, The University of Electro-Communications, Japanf
Department of Child and Adolescent Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Japang
Hiratani Clinic for Developmental Disorders of Children, JapanhAdvanced Biomedical Sciences Course, Graduate School of Medical Sciences, University of Fukui, Japani
Tokyo University of Social Welfare, Japan
Received 2 June 2015; received in revised form 2 October 2015; accepted 23 November 2015

Abstract
Background: Spatial working memory (SWM) dysfunction is a feature of attention deﬁcit hyperactivity disorder (ADHD). Previous studies suggested that behavioral performance in self-generated SWM improves through development in children with andwithout ADHD. Nevertheless, developmental changes in the neural underpinnings of self-generated SWM are unknown.
Method: Using near-infrared spectroscopy, hemodynamic activity in the prefrontal cortex (PFC) was measured in 30 children
with ADHD (9.5 ± 1.6 years-old) and 35 TD children (9.0 ± 1.6 years-old) while they performed a self-generated SWM task. We
then investigated correlations between age and behavioral performance, and between age and hemodynamic activity in the PFC
for each group.
Results: Both groups showed a negative correlation with age and number of errors [ADHD: r(28) = 0.37, p = 0.040; TD: r(33)= 0.59, p < 0.001], indicating that self-generated SWM improves through development. The TD group showed a positive correlation between age and oxygenated hemoglobin in the frontal pole [10ch: r(33) = 0.41, p = 0.013; 11ch; r(33) = 0.44, p = 0.008]
and bilateral lateral PFC [4ch: r(33) = 0.34, p = 0.049; 13ch; r(33) = 0.54, p = 0.001], while no signiﬁcant correlation was foundin the ADHD group. Furthermore, regression slopes for the frontal pole signiﬁcantly diﬀered between the TD and ADHD groups[10ch: t(61) = 2.35, p = 0.021; 11ch: t(61) = 2.05, p = 0.044].
Conclusion: Children with ADHD showed abnormalities in functional maturation of the frontal pole, which plays a role inmanipulating and maintaining information associated with self-generated behavior.
Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

⇑ Corresponding author at: Research Center for Child Mental Development, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji, Fukui
910-1193, Japan. Tel.: +81 776 61 8363; fax: +81 776 61 8136.
E-mail address: hirotaka@u-fukui.ac.jp (H. Kosaka).

http://dx.doi.org/10.1016/j.braindev.2015.11.005
0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Arai S et al. Altered frontal pole development aﬀects self-generated spatial working memory in ADHD. Brain
Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.11.005

2

S. Arai et al. / Brain & Development xxx (2015) xxx–xxx

Keywords: Attention deﬁcit hyperactivity disorder (ADHD); Cambridge Automated Neuropsychological Battery (CANTABÒ); Near-infrared
spectroscopy (NIRS); Self-generated spatial working memory (SWM); Development; Prefrontal cortex (PFC)

1. Introduction
Attention deﬁcit hyperactivity disorder (ADHD) isdeﬁned as age-inappropriate behavior, with core symptoms of inattention, impulsivity, and hyperactivity [1].
Individuals with ADHD have diﬃculty in self-directedbehavior toward solving a problem or achieving a future
goal [2]. Such diﬃculty is considered to be induced bydeﬁcits in executive function (EF) [2], which is an overarching term referring to a neuropsychological processthat enables cognitive, emotional, and physical selfcontrol [3]. Previous studies have shown that dysfunction of EF could predict subsequent academic and occupational functioning [4]. Therefore, EF dysfunction inchildren with ADHD, which could lead to diﬃculty in
self-directed behavior, is associated with various outcomes in each developmental stage, such as academicor occupational status.
EF is considered to include various components suchas working memory (WM), response inhibition, cognitive ﬂexibility, and planning. Among the various EF
components, a deﬁcit in working memory has been proposed to be the origin of the core symptoms of ADHD
[5]. WM is a limited-capacity system responsible formaintaining and manipulating cognitive representationsof stimuli, searching for same or similar stimuli in memory, and maintaining appropriate behavior responses[6]. Although there are several types of WM (e.g., verbal
or auditory), a number of recent behavioral studies haveexamined spatial working memory (SWM) in children
with ADHD [7–9] using tasks requiring maintenanceand manipulation of spatial information of visually presented objects. In a meta-analysis, Kasper et al. [10]found that individuals with ADHD show lower SWM
task performance than TD individuals [10]. In thesestudies, SWM ability of individuals with ADHD was
frequently examined by the n-back task or the SWM
set of the Cambridge Neuropsychological Test Automated Battery (CANTABÒ). Although both tasks
require maintenance and manipulation of spatial information, sources of the spatial information in each task
are diﬀerent. For example, during the n-back task,
which is an externally generated task, experimentersprovide subjects with information related to object locations; thus, subjects are required to maintain and manipulate externally generated spatial information. In
contrast, the memorization of object locations is dependent on both externally generated information and one’s
own behavior during a self-generated task [11]; this isalso true for behavior performed during the SWM bat-tery of the CANTABÒ. Because the functions (i.e.,sources of visuo-spatial information) in the self- andexternally generated SWM tasks are diﬀerent, it has
been considered that children with ADHD might experience diﬀerent problems when performing two tasks.
Although previous studies have shown that children
with ADHD have trouble with both self- [7–9] andexternally [12,13] generated SWM tasks, it has been suggested that developmental changes in behavioral performances are diﬀerent between the two tasks [14,15]. For
example, Westerberg et al. [15] conducted a crosssectional study to compare developmental changes inbehavioral performance on an externally generated
SWM task (i.e., spatial span task) between individuals
with and without ADHD (aged 8–15-years-old). They
showed that improvement of behavioral performance
during development was greater in the typically developed (TD) group than in the ADHD group [15]. On
the other hand, Coghill et al. [14] conducted a longitudinal study to examine developmental changes in behavioral performance on the SWM battery of the
CANTABÒ, a self-generated SWM task, for boys withand without ADHD from 10 to 14-years-old. Interestingly, their group found that boys with ADHD andTD showed equivalent improvement in SWM performance through development [14]. These ﬁndings suggest
the possibility that the developmental trajectory related
to diﬀerent brain activities varies between these twotasks.
Although examining the developmental trajectory ofbrain activities during SWM tasks is relevant for elucidating the pathophysiology of ADHD, which will providing important information for selecting treatment
strategies including pharmacotherapy, only two studies
have examined developmental changes in brain activity
during an externally generated SWM task [12,13]. For
TD children, it is believed that activation in the lateralprefrontal cortex (PFC), which is relevant for maintaining and manipulating information during a WM task,
increases through development during externallygenerated SWM tasks [16–18]. Electroencephalogram(EEG) studies have shown diﬀerent functional maturation in the PFC during externally generated SWM tasks
between individuals with ADHD and TD individuals[12,13]. For instance, Myatchin et al. [13] showed that
TD children tend to exhibit decreases in within-subject
variability in terms of EEG amplitude in the frontal
area, reﬂecting ﬂuctuations in the intensity of taskrelevant processing. In contrast, they observed delayed
decrements in within-subject EEG amplitude variability

Please cite this article in press as: Arai S et al. Altered frontal pole development aﬀects self-generated spatial working memory in ADHD. Brain
Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.11.005

S. Arai et al. / Brain & Development xxx (2015) xxx–xxx

in the frontal area for individuals with ADHD. Theseﬁndings suggest that delayed functional maturation in
the lateral PFC of children with ADHD might lead toabnormal developmental changes in SWM ability during externally generated tasks. With regard to selfgenerated tasks, Christoﬀ et al. [11] have suggested that,along with the lateral PFC, the frontal pole is needed
when self-generated information is evaluated andmanipulated. If functional maturation in the lateral
PFC or the frontal pole contributes to improvement ofself-generated SWM behavioral performance throughchildhood development [14,19–21], activation in the lateral PFC and the frontal pole might change throughdevelopment in both children with and without ADHD.
However, despite the importance of elucidating thecause of diﬃculty in self-directed behavior in ADHD,
no studies have examined developmental changes inneural responses of the PFC during self-generated
SWM tasks in children with and without ADHD.
We utilized the SWM battery of the CANTABÒ as
the self-generated SWM task, and since the method
requires a touch screen for the presentation of visual
stimuli and correcting responses, we could not examine
brain activity using a magnetic resonance imaging(MRI) scanner. Because near-infrared spectroscopy(NIRS) only requires the use of a relatively small device,
which is suitable for touch screen technology [22–24], we
utilized NIRS to examine activation in the PFC. Previous NIRS studies found abnormal activation in the
PFC for individuals with ADHD performing EF tasks
such as a response inhibition task [25–27], and spatial
working memory task [24]. Thus, NIRS is a powerfultool to detect PFC dysfunction in individuals withADHD.
In the present study, we examined developmental
changes in the activation of the PFC in children with
ADHD and TD children while they performed selfgenerated SWM tasks. During the experiment, participants performed the SWM battery of the CANTABÒ

3

while oxyhemoglobin [oxy-Hb] concentration was measured by NIRS. At ﬁrst, we investigated correlations
between age and behavioral performance, and between
age and [oxy-Hb] for each group. We then compared
regression slopes between children with ADHD and
TD children to determine if developmental trajectories
in behavioral performance, as well as activation in the
PFC, were altered in children with ADHD.
2. Methods
2.1. Participants
Thirty boys with ADHD and 35 TD boys participated in this study (Table 1). Participants were excluded
if they had major sensory handicaps (e.g., paralysis,
deafness, and blindness), a history of brain damage, epilepsy, or a low full-scale intelligence quotient (FSIQ)(<80). The protocol used for this study was approvedby the ethics committee of the University of Fukui
and the Tokyo University of Social Welfare (25-99
and 23-03, respectively). The study was conducted inaccordance with the Declaration of Helsinki. After acomplete explanation of the study, written informed
consent was obtained from all participants and theirparents. For all participants, we measured intelligencequotient (IQ) scores using the Wechsler Intelligence
Scale for children (WISC-IV) (Japanese WISC-IV Publication Committee), and severity of ADHD symptoms
using the Japanese version of the ADHD-Rating
Scale-IV [28], which has been validated in a clinical sample [29].
2.1.1. ADHD group
Thirty boys with ADHD (age range, 7–13 years;
mean age, 9.5 ± 1.6 years) were recruited from the outpatient unit at the Department of Child and Adolescent
Psychological Medicine of University of Fukui Hospitaland Hiratani Clinic for Developmental Disorders ofTable 1
Characteristics of participants.

NumberAge
FSIQ
ADHD-RS-IV
Total score
Inattention score
Hyperactivity and impulsivity score
Comorbidity
Learning disorder

ADHD

TD

t values

p values30
9.5 ± 1.6
100.5 ± 13.335
9.0 ± 1.6
106.4 ± 10.7

1.33
1.98

0.188
0.052

26.3 ± 13.8
17.6 ± 9.5
12.7 ± 7.3

5.7 ± 4.2
3.9 ± 3.1
1.9 ± 1.7

8.42
8.08
8.48

<0.001*<0.001*<0.001*5

0ADHD, attention deﬁcit/hyperactivity disorder; TD, typical development; FSIQ, full scale intelligence quotient; ADHD-RS-IV, ADHD-Rating
Scale-IV [21].
Age, FSIQ score, and ADHD-RS-IV scores are shown as mean ± SD.
*
p < 0.01 with independent-sample t-test comparing ADHD and TD.

Please cite this article in press as: Arai S et al. Altered frontal pole development aﬀects self-generated spatial working memory in ADHD. Brain
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S. Arai et al. / Brain & Development xxx (2015) xxx–xxx

Table 2
SWM battery of the CANTABÒ score.

SWM (between errors score)

ADHD

TD

t valuep value25.2 ± 11.3

21.1 ± 12.3

1.38

0.171

ADHD, attention deﬁcit/hyperactivity disorder; TD, typical development; SWM, spatial working memory.
Between errors score is shown as mean ± SD. Independent-sample t-test comparing ADHD and TD.

Table 3
Correlation between age and [oxy-Hb].
ADHD

2ch
3ch
4ch
5ch
6ch
7ch
8ch
9ch
10ch
11ch
12ch
13ch
14ch
15ch

TD

r

p valuer

p value

0.09
0.12
0.02
0.17
0.20
0.26
0.01
0.10
0.15
0.10
0.00
0.22
0.05
0.19

0.634
0.518
0.907
0.351
0.279
0.164
0.956
0.601
0.422
0.590
0.989
0.249
0.808
0.315

0.30
0.17
0.34
0.02
0.08
0.25
0.02
0.08
0.41
0.44
0.15
0.54
0.10
0.30

0.082
0.319
0.049*
0.907
0.662
0.151
0.900
0.648
0.013*
0.008**
0.390
0.001**
0.565
0.077

ADHD, attention deﬁcit/hyperactivity disorder; TD, typicaldevelopment.
*
p < 0.05, **p < 0.01 with correlation analysis between age and integration value of [oxy-Hb] for each group.

Children. Three pediatric neurologists (S.T., A.T., andM.H.) diagnosed participants based on Diagnostic andStatistical Manual of Mental Disorders, Fifth Edition(DSM-5) classiﬁcations [1]. None of the participants
with ADHD had ODD, anxiety disorder, or autism
spectrum disorder (ASD). However, ﬁve participants
with ADHD had learning disorders. Although all participants with ADHD received methylphenidate via an
osmotically controlled release oral delivery system(OROS), participants ceased taking all medications
24 h prior to the start of the experiment.
2.1.2. TD group
Thirty-ﬁve TD boys (age range, 7–13 years; meanage, 9.0 ± 1.6 years) were recruited from the local community as healthy controls. Children were not included
if they had any psychiatric diagnosis or had family members with social- or attention-related problems. To
exclude the presence of ADHD or ASD, all TD participants underwent an extensive child psychiatric examination, which was conducted by a pediatricneurologist according to DSM-5 criteria.
2.1.3. Index comparisons between groups
There was no signiﬁcant group diﬀerence in age[t(63) = 1.33, p = 0.188] and FSIQ [t(63) = 1.98,

p = 0.052], while the ADHD Rating Scale-IV (ADHDRS-IV) total score [t(63) = 8.42, p < 0.001], inattention
score [t(63) = 8.08, p < 0.001], and hyperactive andimpulsivity score [t(63) = 8.48, p < 0.001] was signiﬁcantly higher in the ADHD group than in the TD group.
There were no signiﬁcant correlations between age and
FSIQ [ADHD: r(28) = 0.24, p = 0.190; TD: r(33)= 0.12, p = 0.483], and between age and ADHD-RSIV total score [ADHD: r(28) = 0.06, p = 0.766; TD:r(33) = 0.29, p = 0.090] in each group. Therefore,
intellectual ability and ADHD severity were ruled out
as confounding factors, which allowed us to compare[oxy-Hb] between ADHD and TD, and to test the relationship between brain activation and age.
2.2. Experimental procedure
2.2.1. Experimental setup
We employed the SWM battery of the CANTABÒ asa self-generated SWM task (Fig. 1) to assess developmental changes in self-generated SWM and activationin the PFC. During the SWM battery, participants wereshown a number of colored squares (boxes) displayed ona touch screen and were required to ﬁnd a blue token
hidden within one of the boxes. Once the token was
found, it was moved to another box. Participants were
informed that the token would not be moved to thesame place; therefore, they had to resist returning to a
box where a token had previously been found. Returning to an empty box where a target had already beenfound was referred to as a ‘‘between error”. Because previous behavioral studies have suggested that individuals
with ADHD face severe diﬃculty when eight boxes arepresented in the task (versus 6 or 4) [8,30,31], we measured behavioral performance and neural response usingeight boxes.
2.2.2. NIRS
While participants performed the SWM battery of
the CANTABÒ, the relative concentration of [oxy-Hb]
and deoxyhemoglobin was measured using a multichannel NIRS system (OEG-16; Spectratech Inc., Tokyo,
Japan). In this system, near-infrared laser diodes withtwo diﬀerent wavelengths (approximately 770 and
840 nm) were used to emit near-infrared light. The reemitted light was detected with avalanche photodiodes
that were located 30 mm from the emitters. The temporal resolution of acquisition was 0.65 s. The system

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5

measures oxy-Hb at a depth of approximately 30 nm
below the scalp [32]. In this system, six emitters andsix detectors were placed at alternate points on a 2  6grid, enabling us to detect signals in 16 channels. The
center of the probe matrix was placed on Fpz (International 10–20 system) [33], and the bottom left andbottom right corners were located around F7 and F8,
respectively, as previously reported [34].
2.3. Data analysis

2.3.2. NIRS data
Because participants were young children and theirhead circumference was small, the right edge of the
1ch and the left edge of the 16ch were excluded fromthe analysis. As a previous study reported oxy-Hb as amore sensitive indicator of brain activation [34], we
focused on changes in oxy-Hb. The measurement principles used in this study were based on the modiﬁed Beer–
Lambert law, for which [oxy-Hb] is calculated fromchanges in light attenuation at a given measurement
point [35]. In this study, we conducted 8 boxes after 4boxes and 6 boxes to enable the SWM battery of the
CANTABÒ to be conducted. Because the duration
between the 8 boxes and 6 boxes was short, we set thestart point without any duration as the baseline. We
then calculated the integration value of [oxy-Hb] within
30 s from the start of the SWM battery using BRain
Analyzer (BR systems, Tokyo, Japan). Similar to the
behavioral data analysis, we performed a correlation
analysis between age and integration value of [oxy-Hb]
for each group, and then compared the two regression
slopes between ADHD and TD groups.
3. Results
3.1. Behavioral results
Between errors during the eight-box SWM battery
for all participants are shown in Table 2 and Fig. 2.
Between errors for the ADHD and TD groups were25.2 ± 11.3 and 21.1 ± 12.3, respectively. Both ADHD
and TD groups showed a negative correlation with
between errors and age [ADHD: r(28) = 0.38,
p = 0.040; TD: r(33) = 0.59, p < 0.001] (Fig. 2). There
was no signiﬁcant group diﬀerence in these slopes [t(61)= 1.13, p = 0.262]. An independent t-test did notreveal a signiﬁcant group diﬀerence with regard to errors

Fig. 1. Spatial working memory (SWM) battery of the CANTABÒ.
The SWM of the CANTABÒ is a self-generated task that is based on
foraging behavior. Participants are required to search an array for ahidden token without revising locations where tokens had beenpreviously found. SWM, spatial working memory; CANTABÒ,Cambridge Automated Neuropsychological Battery.

Number o Between errors

2.3.1. Behavioral data
In order to examine if self-generated SWM ability
improved through development, we conducted a correlation analysis between age and between errors madeby ADHD and TD groups. We then compared theregression slopes between ADHD and TD groups to testfor diﬀerences in developmental changes.

60● ADHD r = -0.38, p = 0.040

50

● TD

r = -0.59, p < 0.001

11

12

40
30
20
10
0

6

7

8

9

10

13

Participants' age
Fig. 2. Correlations between age and between errors. Regression lines
for the ADHD group (red line) and TD group (blue line), respectively.
ADHD, attention deﬁcit/hyperactivity disorder; TD, typicaldevelopment.

[t(63) = 1.38, p = 0.171]. However, when we conducted
an analysis of covariate (ANCOVA) to exclude the eﬀectof age, there was a signiﬁcant diﬀerence between ADHD
and TD groups [F(1,62) = 5.29, p = 0.025], indicatingthat between errors in the ADHD group were signiﬁcantly higher than those in TD group. Collectively, bothgroups showed a developmental improvement of behavioral performance, although self-generated SWM ability
was slightly lower in the ADHD group.
3.2. NIRS results
3.2.1. Correlation analysis between age and [oxy-Hb]
For the TD group, integration values of [oxy-Hb]
were signiﬁcantly correlated with age in 4ch and 13ch
corresponding to the bilateral lateral PFC [36] [4ch: r(33) = 0.34, p = 0.049; 13ch: r(33) = 0.54, p = 0.001]

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S. Arai et al. / Brain & Development xxx (2015) xxx–xxx

Fig. 3. Developmental changes of integration values of [oxy-Hb] during performance of a self-generated SWM task for the ADHD and TD groups.
(A) Channels revealed signiﬁcant correlations between age and [oxy-Hb] in each group. Red circle shows channels with signiﬁcant correlations
between age and [oxy-Hb]. (B) Comparison of two regression slopes between ADHD and TD groups. Regression lines for the ADHD group (redline) and TD group (blue line), respectively, are shown. oxy-Hb, oxyhemoglobin; ADHD, attention deﬁcit/hyperactivity disorder; TD; typicaldevelopment *p < 0.05.

and in 10ch and 11ch corresponding to the frontal pole[36] [10ch: r(33) = 0.41, p = 0.013; 11ch: r(33) = 0.44,
p = 0.008] (Table 3 and Fig. 3A). On the other hand,none of the channels showed signiﬁcant correlations
with age for the ADHD group (Table 3 and Fig. 3A).
Within channels showed a signiﬁcant correlation
between age and integration value of [oxy-Hb] for the
TD group [4ch: r(33) = 0.34, p = 0.049; 10ch: r(33)= 0.41, p = 0.013; 11ch: r(33) = 0.44, p = 0.008; 13ch: r(33) = 0.54, p = 0.001], and a comparison of slopes
between ADHD and TD groups revealed signiﬁcantdiﬀerences in 10ch and 11ch [10ch: t(61) = 2.35,
p = 0.021; 11ch: t(61) = 2.05, p = 0.044], but not in
4ch and 13ch [4ch: t(61) = 1.33, p = 0.189; 13ch: t(61)= 0.88, p = 0.382] (Fig. 3B).
3.2.2. Group diﬀerences in [oxy-Hb] of older participants(10-years-old)
Similar to the present study, previous studies also
showed that young TD children (until around 10years-old) did not exhibit enough PFC activation[16–18]; therefore, we examined whether older TD

Please cite this article in press as: Arai S et al. Altered frontal pole development aﬀects self-generated spatial working memory in ADHD. Brain
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participants (over 10-years-old) showed stronger activation in the frontal pole (i.e., 10 and 11ch) than older
ADHD participants. An independent t-test revealed thatthe mean integration value of [oxy-Hb] was higher in the
TD group than in the ADHD group in the 10ch [t(19)= 2.33, p = 0.031], while no signiﬁcant diﬀerence wasfound in the 11ch [t(19) = 1.02, p = 0.321].

7

with ADHD [7–9], but also for adults with ADHD
[30,31] during self-generated SWM tasks. These studies
suggest that lower self-generated SWM ability continues
into adolescence and adulthood. Collectively, our results
conﬁrmed that both children with ADHD and TD children improve SWM performance during self-generated
SWM tasks, but that children with ADHD exhibit lower
ability.

4. Discussion
4.2. NIRSIn the present study, both TD and ADHD groups
showed a negative correlation between age and numberof errors. In addition, our study showed that SWM performance was higher in the TD group than in the
ADHD group when we excluded the eﬀect of age. Thus,
both children with and without ADHD showed
improved SWM performance during self-generated
SWM tasks through development; however, children
with ADHD exhibited lower ability. On the other hand,
the two groups showed diﬀerent developmental changes
in terms of neural response. The TD group showed apositive correlation between age and the integration
value of [oxy-Hb] in the frontal pole and bilateral lateral
PFC, while no signiﬁcant correlation was found in the
ADHD group. Furthermore, regression slopes for thefrontal pole signiﬁcantly diﬀered between TD and
ADHD groups. To the best of our knowledge, this is
the ﬁrst study to examine developmental changes in
PFC activation during self-generated SWM tasks inboth children with ADHD and TD children.
4.1. Behavioral performance
Our study showed signiﬁcant improvements in behavioral performance of both ADHD and TD groups
through development, and this developmental trajectory
was not diﬀerent. In cross-sectional studies such as theone conducted in the present report, it is important toconsider confounding factors such as intellectual ability
and severity of ADHD symptoms. However, participants’ FSIQ was not diﬀerent between groups. Moreover, FSIQ and ADHD-RS score were not correlatedwith age. Thus, the improvement of scores in SWM
tasks cannot be explained by intellectual ability or theseverity of ADHD symptoms. Therefore, our ﬁndings
imply that both children with and without ADHD show
equivalent improvements in SWM ability during selfgenerated SWM tasks. Similar to our ﬁndings, previous
studies have reported improvements in self-generated
SWM performance through development in both TD
children [19–21] and children with ADHD [14]. In addition, our results showed that SWM performance waslower in the ADHD group than in the TD group when
we exclude the eﬀect of age. Previous studies have also
reported lower SWM performance not only for children

4.2.1. Increased activation in the PFC of TD children
Our results showed that activation in the bilateral lateral PFC and frontal pole of TD children increased
through development. As discussed in the previous paragraph, individual intellectual ability and severity of
ADHD symptoms cannot explain the developmental
changes that we observed. Considering that the lateral
PFC and frontal pole play an important role in externally and self-generated information [11], our results
suggest that functional maturation in regions associatedwith visuo-spatial information processing occur during
school-age in TD children. Further, this might contribute to the improvement in self-generated SWM
ability.
Similar to the present study, previous functional MRI
studies using externally generated SWM tasks have consistently reported an increase in lateral PFC activation
with age in TD children [16–18]. Because an increasein activation was found in the lateral PFC in both externally and self-generated SWM tasks, functional maturation in the lateral PFC (i.e., maintaining andmanipulating externally generated information) could
contribute to developmental changes in behavioral performance. In contrast, these studies also showed nochange in activation in the frontal pole of TD boys
[16–18]. Thus, increased activation in the frontal polethrough development was only found during selfgenerated SWM tasks. Based on these ﬁndings, we
speculate that functional maturation in the lateral PFC
contributes to the improvement of externally and selfgenerated SWM tasks, while functional maturation in
the frontal pole is only relevant for the improvementof self-generated SWM tasks.
While some previous studies have not shown developmental changes in frontal pole activation [16,17], Schweinsburg et al. [18] reported that TD boys show
developmental decreases in activation of the frontal poleduring an externally generated SWM task. Thus, thepresent study suggests that a developmental increase inactivation of the frontal pole is speciﬁc to selfgenerated SWM tasks. It is possible that functional
maturation not only in the lateral PFC but also in thefrontal pole could be relevant for improvements in
self-generated SWM.

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8

S. Arai et al. / Brain & Development xxx (2015) xxx–xxx

4.2.2. No changes in activation of the PFC for children
with ADHD
In contrast to the TD group, children with ADHD
showed no developmental changes in activation of thelateral PFC and frontal pole. Furthermore, we found asigniﬁcant group diﬀerence in the developmental trajectory of activation of the frontal pole (i.e., 10ch and11ch), and older TD participants (over 10-years-old)showed stronger activation in the frontal pole (i.e.,10ch) than older ADHD participants. Because there
were fewer children in the ADHD group (n = 30) thanin the TD group (n = 35), the lack of signiﬁcant correlation between age and integration of [oxy-Hb] may havebeen caused by the smaller sample size for the ADHD
group. However, this is unlikely because even if the sample size was 35 (the same sample size as the TD group), a
correlation coeﬃcient equal to or greater than 0.33
would be required for p < 0.05, and the maximum r
value for each channel in the ADHD group was 0.26,
which was well below 0.33. As discussed above, individual intellectual ability and severity of ADHD symptoms
cannot be confounding factors of the results. Therefore,
our results suggest that children with ADHD haveabnormalities in functional maturation of the frontal
pole associated with self-generated SWM. The abnormal
developmental changes associated with activation in the
PFC might be related to delayed anatomical maturation
for children with ADHD. For instance, Shaw et al. conducted a longitudinal structural MRI study to examine
the developmental trajectory of cortical thickness forchildren with ADHD and TD children [34]. They founda similar order of cortical maturation between children
with and without ADHD in that primary sensory areas
attained peak cortical thickness before polymodal,
higher-order association areas. However, children with
ADHD showed signiﬁcant delays in attaining peak cortical thickness in the PFC [34], indicating that anatomical maturation in the PFC is delayed in children with
ADHD as compared to TD children. Based on theseﬁndings, we speculate that delayed anatomical maturation leads to abnormal developmental changes of activation in the PFC for children with ADHD during
self-generated SWM tasks.
Despite the lack of increased activation in the PFC,
the ADHD group showed signiﬁcant improvements in
SWM performance. These ﬁndings imply that, for children with ADHD, increased activation in other brain
regions might contribute to the improved SWM seen
through development. Although the current literature
focuses on activation of the PFC during self-generated
SWM tasks for individuals with ADHD, neuroimaging
studies examining various executive functions or WM
have reported compensatory brain activation in regions
other than the PFC, including the occipital region [37],middle and superior temporal gyri [38], posterior cingulate [38] and supplementary motor area [39]. For

instance, Schweitzer et al. [37] conducted a positronemission tomography study to compare regional cerebral ﬂow (rCBF) changes for individuals with and without ADHD during an auditory working memory task
(Paced Auditory Serial Addition Task (PASAT)).
During the PASAT, single-digit numbers are presented
binaurally and subjects are instructed to add each number to the preceding number and vocalize their answers.
While task-related changes in rCBF in TD individuals
were more prominent in the frontal and temporal
regions, individuals with ADHD showed more widespread activation that was primarily located in theoccipital regions. These results suggest that individuals
with ADHD use alternative strategies and brain regions
during a working memory task due to impaired PFC
functioning. Based on these ﬁndings, we speculate that
acquiring compensatory functions in the other regions
induces improvement of self-generated SWM performance for children with ADHD.
4.2.3. Limitations and future studies
Six limitations of the present study should be noted.
First, all participants with ADHD were being chronically administered methylphenidate, which they ceased
taking at least 24 h prior to the experimental task; therefore, developmental changes in SWM performance andactivation of the PFC might have been due to, or alteredby, chronic administration of methylphenidate. Somestudies have suggested that psychostimulant treatment,
which includes methylphenidate, may normalize brain
structure. For example, Nakao et al. [40] reported thatpsychostimulant treatment correlates with increasing(i.e., more normal) gray matter volume in the basal ganglia. On the other hand, Semrud et al. [41] reported thatthe anterior cingulate cortex (ACC) volume is signiﬁcantly smaller in a treated naı̈ve ADHD group than intreated ADHD and control groups. Thus, they suggested a relationship between previous treatment history
and volumetric changes of the ACC in children with
ADHD. Along with the PFC, these brain areas (i.e.,basal ganglia and ACC) also play an important role in
WM. Thus, it is possible that the improvements in
SWM of children with ADHD in the present study were
due to normalization of brain development by methylphenidate treatment. To elucidate purely developmental
changes in SWM performance and PFC activation inchildren with ADHD, examination of drug-naı̈ve participants is needed. Second, because of the limited age
group in the present study (7–13 years), we were unable
to examine whether inactivation of the PFC during theself-generated SWM task continued to adulthood.
Myatchin et al. [13] have shown greater variability in
EEG amplitude for children with ADHD than for TD
children in younger (13–14 years), but not older(15–16 years) participants. Therefore, activation of the
PFC during self-generated SWM tasks in children with

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S. Arai et al. / Brain & Development xxx (2015) xxx–xxx

ADHD might increase with older age. Examination of
PFC activation during self-generated SWM tasks inadolescents with ADHD is necessary to elucidate thisquestion. Third, we utilized a cross-sectional study inwhich individual diﬀerences might have been a confounding factor. Therefore, a longitudinal study is necessary to depict more accurate developmental changes.
Fourth, in the present study we focused only on activation of the PFC. Therefore, we were unable to examine
other brain regions, which might have shown compensatory activation. Additional NIRS approaches thatcan measure activation in the whole brain or other neuroimaging techniques such as functional MRI and magnetoencephalography (MEG) will better address thisquestion. Fifth, we set the start point as the baseline,
although previous NIRS studies set a baseline periodwith a certain length of time before the task period.
Because two previous NIRS studies utilized very shortbaseline times (i.e., 1–2 s) and recovery and post periods
were not set [42,43], it is unlikely that our deﬁnition of
baseline was a critical problem in the present study.
However, because the validity of setting a baseline without a duration has not been conﬁrmed, future research isneeded to verify the validity of our analysis method.
Sixth, although Sato et al. [44] demonstrated that temporal changes in NIRS signals in the activated area weresigniﬁcantly correlated with the BOLD signals in thegray matter rather than with skin blood ﬂow measured
by laser Doppler, several NIRS studies have suggested
that subcutaneous blood ﬂow can be a confounding factor for task-related changes in NIRS signals [45,46]. In
the present study, we did not measure skin blood ﬂow;
therefore, we cannot rule out the possibility that skinblood ﬂow aﬀected the results of present study. Thus,
the replication of the present ﬁndings in the absence ofskin blood ﬂow is necessary.
5. Conclusion
Our study showed that while SWM ability improvedin both ADHD and TD groups through development,children with ADHD exhibited lower ability. We also
found that children with ADHD showed abnormalities
in the functional maturation of the frontal pole, whichplays a role in manipulating and maintaining information from self-generated behavior.
Funding
This study was funded in part by Grants-in-Aid forYoung Scientists B from the Japan Society for the Promotion of Science (15K19718). A part of this study was
the result of the Center of Community by the MEXT,
and the ‘‘Integrated research on neuropsychiatric disorders” performed under the Strategic Research Programfor Brain Sciences from MEXT and AMED.

9

Acknowledgements
We would like to express our sincere appreciation to
the participants and their families, who generously andcourageously participated in this research.
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