Cortical morphology as a shared neurobiological substrate of attention-deficit/hyperactivity symptoms and executive functioning: a population-based pediatric neuroimaging study

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Fig. 1
Significant clusters of vertex-wise associations between (A) Child Behavior Checklist (CBCL) attention-deficit/hyperactivity problems scores and cortical thickness, (B) CBCL attention-deficit/hyperactivity problems scores and local gyrification index and (C) Developmental Neuropsychological Assessment (NEPSY-II-NL) attention and executive functioning scores and local gyrification index. Clusters indicate regions of a thinner cortex/less gyrification in relation to more symptoms/worse functioning. LH = left hemisphere; RH = right hemisphere.
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Fig. 2
Multiple mediation model estimating the total indirect effect of the Child Behavior Checklist (CBCL) attention-deficit/hyperactivity problems (ADHP) score on the Developmental Neuropsychological Assessment (NEPSY) attention and executive functioning (ATT/EF) score through the selected cortical clusters (M1 = a1b1, …. M4 = a4b4) and the direct effect of the CBCL ADHP score on the NEPSY attention and EF score (c′).

Table 1

Demographic and clinical characteristics of the study sample

Characteristic	Total valid observations (n = 776)	Mean ± SD^*
Child characteristics
Male sex, %	776	52.4
Nationality, %	776
Dutch		70.8
Other Western		6.8
Non-Western		22.4
Age, yr
NEPSY-II-NL assessment	776	7.98 ± 0.98
Brain imaging	776	7.97 ± 0.99
CBCL assessment	776	6.03 ± 0.40
CBCL attention-deficit/ hyperactivity problems score	776	3.77 ± 2.90
Nonverbal IQ score	710	102.81 ± 14.34
Gestational age at birth, wk	775	39.97 ± 1.77
Birth weight, g	776	3470.41 ± 546.56
Psychostimulant use, % yes	753	2.9
Maternal characteristics
Education level, %	764
High		57.2
Medium		31.0
Low		11.8
Alcohol use during pregnancy, %	722
Never		34.6
Until pregnancy was known		14.3
Continued occasionally during pregnancy		40.4
Continued frequently during pregnancy^†		10.7
Smoking during pregnancy, %	749
Never		78.6
Until pregnancy was known		6.3
Continued during pregnancy		15.1
Household income, %	743
> €2000		77.1
€1200–2000		17.0
< €1200		5.9

CBCL = Child Behavior Checklist; NEPSY = Developmental Neuropsychological Assessment; SD = standard deviation.
↵* Unless otherwise indicated.
↵† Frequent continued use was defined as ≥ 1 drink per week during at least 2 trimesters of pregnancy.

Table 2

Cluster-wise regression analyses of the association between CBCL ADHP score, NEPSY-II-NL ATT/EF score and cortical thickness^*

Cluster	Detection				Retention				Retained for mediation anaysis^§

	CBCL ADHP and cortical thickness				NEPSY-II-NL ATT/EF and cortical thickness clusters identified with CBCL ADHP

	b (95% CI)	β	p value^†	Model R²^‡	b (95% CI)	β	p value^§	Model R²^‡
Left hemisphere
Caudal middle frontal	−0.04 (−0.06 to −0.02)	−0.14	< 0.001	0.05	0.04 (−0.01 to 0.10)	0.06	0.12	0.04	No
Right hemisphere
Postcentral	−0.05 (−0.06 to −0.03)	−0.22	< 0.001	0.09	0.02 (−0.02 to 0.06)	0.04	0.34	0.04	No
Lateral occipital	−0.05 (−0.07 to −0.03)	−0.19	< 0.001	0.06	0.05 (−0.01 to 0.10)	0.06	0.09	0.03	Yes
Superior temporal	−0.05 (−0.07 to −0.03)	−0.16	< 0.001	0.07	0.01 (−0.05 to 0.07)	0.02	0.64	0.04	No
Cuneus	−0.04 (−0.06 to −0.02)	−0.15	< 0.001	0.06	0.00 (−0.05 to 0.05)	0.00	0.96	0.04	No

Cluster	NEPSY-II-NL ATT/EF and cortical thickness				CBCL ADHP and cortical thickness clusters identified with NEPSY-II-NL ATT/EF				Retained for mediation anaysis^§

	b (95% CI)	β	p value^†	Model R²^‡	b (95% CI)	β	p value^§	Model R²^‡

Left hemisphere
None found	—	—	—	—	N/A	N/A	N/A	N/A	N/A
Right hemisphere
None found	—	—	—	—	N/A	N/A	N/A	N/A	N/A

ADHP = attention-deficit/hyperactivity problems; ATT/EF = attention and executive functioning; CBCL = Child Behavior Checklist; CI = confidence interval; N/A = not applicable; NEPSY = Developmental Neuropsychological Assessment.
↵* The CBCL ADHP and NEPSY ATT/EF scores were square root transformed, therefore b values are not interpretable. Both determinant (CBCL/NEPSY) and outcome (thickness) were residualized for age during assessment/scanning. Analyses adjusted for child sex, nationality, gestational age at birth, birth weight, psychostimulant use, IQ, maternal education, drinking during pregnancy, smoking during pregnancy and household income. A higher CBCL ADHP score indicates more attention and hyperactivity symptoms, and a higher NEPSY score indicates better functioning.
↵† To identify clusters in the discovery phase, the α level was set to 0.05.
↵‡ The explained variance (model R²) is provided for the whole model, including covariates.
↵§ To define clusters as consistent and select them for the mediation analysis, the α level was set to 0.1 (association at trend level or significant).

Table 3

Cluster-wise regression analyses of the association between CBCL ADHP score, NEPSY-II-NL ATT/EF score and gyrification^*

Cluster	Detection				Retention				Retained for mediation anaysis^§

	CBCL ADHP and gyrification				NEPSY-II-NL ATT/EF and gyrification clusters identified with CBCL ADHP

	b (95% CI)	β	p value^†	Model R²^‡	b (95% CI)	β	p value^§	Model R²^‡
Left hemisphere
Frontal/temporal/parietal (LH1)	−0.03 (−0.05 to −0.02)	−0.14	< 0.001	0.15	0.02 (−0.02 to 0.07)	0.04	0.29	0.14	No
Superior parietal/postcentral (LH2)	−0.04 (−0.06 to −0.01)	−0.11	0.006	0.09	0.03 (−0.03 to 0.10)	0.04	0.32	0.08	No
Right hemisphere
Frontal/temporal/parietal (RH1)	−0.03 (−0.05 to −0.02)	−0.13	< 0.001	0.15	0.04 (−0.01 to 0.10)	0.06	0.12	0.14	No

Cluster	NEPSY-II-NL ATT/EF and gyrification				CBCL ADHP and gyrification clusters identified with NEPSY-II-NL ATT/EF				Retained for mediation analysis^§

	b (95% CI)	β	p value^†	Model R²^‡	b (95% CI)	β	p value^§	Model R²^‡

Left hemisphere
Inferior parietal (LH3)	0.06 (0.01 to 0.12)	0.08	0.030	0.08	−0.02 (−0.04 to 0.01)	−0.06	0.13	0.07	No
Frontal (LH4)	0.05 (0.01 to 0.09)	0.09	0.020	0.07	−0.02 (−0.04 to −0.01)	−0.10	0.007	0.08	Yes
Right hemisphere
Frontal/parietal (RH2)	0.09 (0.03 to 0.15)	0.11	0.004	0.10	−0.02 (−0.05 to 0.00)	−0.07	0.07	0.10	Yes
Frontal/temporal (RH3)	0.10 (−0.01 to 0.21)	0.07	0.07	0.11	−0.04 (−0.08 to 0.00)	−0.07	0.05	0.11	No
Occipital (RH4)	0.06 (0.01 to 0.12)	0.08	0.023	0.05	−0.02 (−0.04 to 0.00)	−0.08	0.05	0.04	Yes

ADHP = attention-deficit/hyperactivity problems; ATT/EF = attention and executive functioning; CBCL = Child Behavior Checklist; CI = confidence interval; NEPSY = Developmental Neuropsychological Assessment.
↵* The CBCL ADHP and NEPSY ATT/EF scores were square root transformed, therefore b values are not interpretable. Both determinant (CBCL/NEPSY) and outcome (gyrification) were residualized for age during assessment/scanning. Analyses adjusted for child sex, nationality, gestational age at birth, birth weight, psychostimulant use, IQ, maternal education, drinking during pregnancy, smoking during pregnancy and household income. A higher CBCL ADHP score indicates more attention and hyperactivity symptoms, a higher NEPSY score indicates better functioning.
↵† To identify clusters in the discovery phase, the α-level was set to 0.05.
↵‡ The explained variance (model R²) is provided for the whole model, including covariates.
↵§ To define clusters as consistent and select them for the mediation analysis, the α-level was set to 0.1 (association at trend level or significant).