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Supplementary Material
Table S1. Detailed information about the administered tests.
Executive Functions Domains
Neuropsychological Tests Description Raw Score
ASDMean (SD)
[Range]
TPMean (SD)
[Range]
Attention
Digit Forward (Wechsler Scales)
The subject must repeat sequences of numbers in the same order as presented aloud by the examiner. Maximum number
of recalled items
5.14(0.85)[4-7]
6.00(1.30)[4-9]
Continuous Performance Test II
A letter at once is sequentially presented on the computer screen. The subject must respond to targets (all letters excepting ‘X’) by pressing the space bar and refrain from responding to non-targets (letter ‘X’).
Number of correct responses
296.76(25.27)[218-323]
308.48(23.02)[231-328]
Mean hit reaction time
0.64sec(0.28)[0.32-1.41]
0.48sec(0.18)[0.26-1.13]
Working Memory
Digit Backward (Wechsler Scales)
The subject must repeat sequences of numbers in the reverse order as presented aloud by the examiner.
Maximum number of recalled items
4.0(0.95)[2-6]
4.52(1.33)[2-7]
Number-Letter Sequencing
(Wechsler Scales)
A randomly ordered sequence of number and letters are presented aloud by the examiner. The subject is asked to respond by stating the number first in ascending order and the letter second in alphabetical order.
Maximum number of recalled items
4.62(0.92)[2-6]
5.0(1.0)[4-7]
Mental Flexibility
Mental Trail Making Test
This test has two parts. On part A the participant must draw a line linking a set of numbers in ascending order (1-25). On the part B the participant must draw a line linking alternating numbers and letters in ascending order (1, A, 2, B- 13). In all trials the participant must do it as quickly but as accurately as possible.
(Time to complete TMT(B)-Time to
complete TMT(A))/Time to complete TMT(A)
1.32min(0.67)[0.13-2.62]
1.43min(0.81)[0.09-2.98]
Wisconsin Card Sorting Test
A number of stimulus cards are presented to the participant. The figures on the cards vary according to three perceptual dimensions (color, form, number). The subject must find the correct classification principle by trial and error and examiner feedback (‘Yes’=correct match; ‘No’=incorrect match), as a way of learning for future decision. The cards need to be matched first by colour, then by form and finally by number. After 10 consecutive correct answers, the rule changes without warning, demanding a
Number of perseverative
errors
24.43(15.55)[3-77]
14.81(11.36)[3-45]
Number of errors 48.52(22.0)[12-96]
31.81(21.52)[7-85]
flexible shift in the set.Executive Functions
DomainsNeuropsychological
Tests Description Raw ScoreASD
Mean (SD)[Range]
TPMean (SD)
[Range]
Number of perseverative
responses
29.71(20.73)[3-101]
17.19(13.11)[3-52]
Response Inhibition
Continuous Performance Test II
A letter at once is sequentially presented on the computer screen. The subject must respond to targets (all letters excepting ‘X’) by pressing the space bar and refrain from responding to non-targets (letter ‘X’).
Number of Commissions
24.43(6.74)[12-34]
17.95(7.9)[3-35]
Colour Word Stroop Test (STROOP)
Three different pages are presented to the subject: (1) a word page with color words printed in black ink, (2) a color page with ‘Xs’ printed in color, and a color-word page with words from the first page printed in colors from the second page (the color and the word do not match). The must read the words in (1) or naming the ink colors in (2) and (3) as quickly as possible within a time limit (45 seconds).
Interference score
-0.03(4.02)[-7.0-6.61]
4.02(10.2)[-27.0-18.72]
Problem Solving Wisconsin Card Sorting Test
A number of stimulus cards are presented to the participant. The figures on the cards vary according to three perceptual dimensions (color, form, number). The subject must find the correct classification principle by trial and error and examiner feedback (‘Yes’=correct match; ‘No’=incorrect match), as a way of learning for future decision. The cards need to be matched first by colour, then by form and finally by number. After 10 consecutive correct answers, the rule changes without warning, demanding a flexible shift in the set.
Number of categories completed
56.29(17.39)[3-84]
62.71(17.74)[13-89]
Conceptual level responses
4.05(1.72)[0-6]
5.43(1.08)[2-6]
Number of correct responses
69.14(12.93)[32-86]
72.19(11.78)(43-97)
ASD = Male participants with autism spectrum disorders; TP = Typically developing male participants; SD = Standard Deviation.
Table S2. Image Quality Ratings of the T1-weighted images.
Participant IQR Participant IQR1 81.13 22 80.142 80.99 23 80.933 75.64 24 80.864 79.49 25 82.175 83.12 26 81.306 75.06 27 81.277 80.36 28 79.488 76.99 29 79.969 80.80 30 75.06
10 80.60 31 80.6911 79.40 32 79.4512 81.73 33 81.7413 79.55 34 80.8214 71.36 35 81.6715 80.76 36 82.1716 82.57 37 81.4017 78.48 38 78.5318 81.31 39 78.8119 78.18 40 82.0420 80.56 41 76.1821 82.03 42 82.87
IQR, Image Quality Rating.
Tests of different neuroimaging projects such as ADNI, IXI, INDI, OASIS, PPMI etc. demonstrated that published structural MRI data overall got good IQRs (http://dbm.neuro.uni-jena.de/cat/index.html#QA). Please note that excellent IQRs (> 90%) are defined for extraordinary good images that were acquired by
repeated long-time scans with ultra-high resolution on high field systems and that typical scientific data is expected to get good to satisfactory ratings (90%-70%, see also http://dbm.neuro.uni-jena.de/cat/index.html#QA).Table S3. Between-group differences on four measures of DTI data quality.
ASD = Male participants with autism spectrum disorders; TP = Typically developing male participants; SD = Standard Deviation
ASD TP pAverage translation mean (SD) 0.936 (0.154) 1.1040(0.505) 0.16
Average rotation mean (SD) 0.005(0.003) 0.007 (0.008) 0.44
Percentage bad slices mean (SD) 0 (0) 0 (0)
Average Dropout score mean (SD) 1 (0) 1 (0)
Table S4. F and p values for the effect of Diagnosis, Age and Diagnosis-by-Age interaction on the executive function domains. q-values obtained after FDR correction are also provided.
ANCOVA Models (Effects) ATT WM MF RI PS
Diagnosis F-value 8.366 3.116 4.578 13.093 4.235p-value 0.006 0.086 0.039 0.001 0.046q-value 0.039 0.241 0.144 0.009 0.161
Age F-value 1.261 9.349 7.785 2.204 4.131p-value 0.268 0.004 0.008 0.146 0.049q-value 0.500 0.026 0.048 0.347 0.164
Diagnosis by Age F-value 0.081 1.938 0.133 0.014 0.004p-value 0.777 0.172 0.718 0.907 0.949q-value 0.852 0.389 0.821 0.946 0.969
FDR corrected (alpha = 0.05). ATT= Attention; WM = Working Memory; MF = Mental Flexibility; RI = Response Inhibition; PS = Problem Solving.
Table S5. Pearson’s r and p values for the within-groups correlations between the executive function domains and age. q-values obtained after FDR correction are also provided.
Correlations ATT WM MF RI PS
Age
ASD r-value 0.194 0.242 0.295 0.208 0.263p-value 0.399 0.291 0.194 0.366 0.250q-value 0.623 0.518 0.410 0.583 0.488
TP r-value 0.169 0.552 0.546 0.255 0.391p-value 0.464 0.009 0.009 0.265 0.080q-value 0.672 0.050 0.050 0.497 0.228
FDR corrected (alpha = 0.05). ATT= Attention; WM = Working Memory; MF = Mental Flexibility; RI = Response Inhibition; PS = Problem Solving. ASD = Male participants with autism spectrum disorders; TP = Typically developing male participants.
Table S6. F and p values for the effect of Diagnosis, Age and Diagnosis-by-Age interaction on the white matter measurements per tract. q-values obtained after FDR correction are also provided.
ANCOVA Models (Effects)
FA MD RD
Diagnosis Age Diagnosis by Age Diagnosis Age Diagnosis
by Age Diagnosis Age Diagnosis by Age
Forceps MajorF-value 0.570 8.188 0.017 0.313 11.832 6.492 1.967 18.628 0.029p-value 0.455 0.007 0.897 0.579 0.001 0.015 0.169 <0.0005 0.866q-value 0.666 0.042 0.947 0.741 0.013 0.073 0.386 0.002 0.924
Forceps MinorF-value 0.494 10.402 3.77 2.886 27.014 1.846 1.837 11.618 11.656p-value 0.486 0.003 0.060 0.098 <0.0005 0.182 0.183 0.002 0.002q-value 0.691 0.018 0.187 0.266 0.001 0.401 0.402 0.013 0.013
Left ATRF-value 0.778 19.649 5.223 1.191 4.247 10.631 0.537 31.309 13.769p-value 0.383 <0.0005 0.028 0.282 0.046 0.002 0.468 <0.0005 0.001q-value 0.606 0.002 0.114 0.509 0.162 0.017 0.673 <0.0005 0.007
Left CABF-value 0.357 3.41 0.773 1.072 20.119 11.22 0.308 7.416 3.369p-value 0.554 0.073 0.385 0.307 <0.0005 0.002 0.582 0.0100 0.074q-value 0.74 0.216 0.606 0.526 0.002 0.014 0.742 0.053 0.218
Left CCGF-value 0.018 19.081 4.933 1.820 5.104 3.830 0.34 25.992 6.372p-value 0.893 <0.0005 0.032 0.185 0.030 0.058 0.564 <0.0005 0.016q-value 0.945 0.002 0.126 0.399 0.117 0.185 0.737 0.001 0.075
Left CSTF-value 0.956 6.464 2.262 0.357 15.554 4.430 0.376 19.573 4.285p-value 0.334 0.015 0.141 0.554 <0.0005 0.042 0.543 <0.0005 0.045q-value 0.553 0.073 0.339 0.738 0.004 0.153 0.736 0.002 0.160
Left ILFF-value 2.238 5.403 <0.0005 0.188 20.113 3.783 4.036 14.12 0.757p-value 0.143 0.026 0.986 0.667 <0.0005 0.059 0.052 0.001 0.390q-value 0.342 0.106 0.990 0.799 0.002 0.188 0.171 0.006 0.610
ANCOVA Models (Effects)
FA MD RD
Diagnosis Age Diagnosis by Age Diagnosis Age Diagnosis
by Age Diagnosis Age Diagnosis by Age
Left SLF-PF-value 0.540 6.268 0.455 1.89 12.667 2.77 0.455 11.561 1.255p-value 0.467 0.017 0.504 0.177 0.001 0.104 0.504 0.002 0.270q-value 0.673 0.078 0.706 0.396 0.010 0.279 0.708 0.013 0.501
Left SLF-TF-value 0.038 7.637 1.028 0.527 8.904 1.722 0.933 14.443 2.530p-value 0.846 0.009 0.317 0.472 0.005 0.197 0.34 0.001 0.120q-value 0.911 0.050 0.531 0.675 0.032 0.410 0.559 0.006 0.310
Left UNCF-value 2.399 1.203 1.253 2.092 16.675 3.893 2.705 2.419 0.015p-value 0.130 0.280 0.270 0.156 <0.0005 0.056 0.108 0.128 0.902q-value 0.318 0.509 0.500 0.367 0.003 0.181 0.285 0.319 0.944
Right ATRF-value 0.222 10.879 1.222 2.085 4.706 1.134 0.655 26.463 5.206p-value 0.640 0.002 0.276 0.157 0.036 0.294 0.423 <0.0005 0.028q-value 0.782 0.016 0.508 0.367 0.137 0.513 0.632 0.001 0.114
Right CABF-value 0.144 7.001 1.357 0.195 16.575 3.776 0.502 10.168 2.942p-value 0.706 0.012 0.251 0.661 <0.0005 0.059 0.483 0.003 0.094q-value 0.817 0.060 0.488 0.795 0.003 0.188 0.688 0.020 0.259
Right CCGF-value 0.924 37.561 5.485 0.185 4.342 1.344 0.17 35.673 3.469p-value 0.343 <0.0005 0.025 0.670 0.044 0.254 0.682 <0.0005 0.070q-value 0.556 <0.0005 0.104 0.799 0.157 0.490 0.803 <0.0005 0.211
Right CSTF-value 0.792 8.761 1.327 0.105 11.67 0.929 0.314 21.42 1.463p-value 0.379 0.005 0.257 0.748 0.002 0.341 0.578 <0.0005 0.234q-value 0.601 0.033 0.49 0.842 0.013 0.557 0.742 0.001 0.461
ANCOVA Models (Effects)
FA MD RD
Diagnosis Age Diagnosis by Age Diagnosis Age Diagnosis
by Age Diagnosis Age Diagnosis by Age
Right ILFF-value 0.629 18.945 0.075 1.196 10.504 0.271 0.01 18.347 2.512p-value 0.433 <0.0005 0.786 0.281 0.002 0.605 0.919 <0.0005 0.121q-value 0.64 0.002 0.858 0.509 0.018 0.76 0.952 0.002 0.310
Right SLF-PF-value 0.011 12.072 0.059 0.355 5.228 4.204 0.014 17.872 0.718p-value 0.917 0.001 0.81 0.555 0.028 0.047 0.908 <0.0005 0.402q-value 0.954 0.012 0.875 0.738 0.115 0.162 0.946 0.002 0.623
Right SLF-TF-value 2.513 16.775 1.071 0.107 14.205 0.908 0.08 24.837 1.940p-value 0.121 <0.0005 0.307 0.746 0.001 0.347 0.779 <0.0005 0.172q-value 0.311 0.003 0.524 0.843 0.006 0.56 0.852 0.001 0.390
Right UNCF-value 0.245 5.573 0.082 0.005 16.886 1.318 0.64 9.784 1.867p-value 0.624 0.023 0.776 0.944 <0.0005 0.258 0.429 0.003 0.180q-value 0.769 0.103 0.852 0.97 0.003 0.489 0.636 0.023 0.398
FDR corrected (alpha = 0.05). ATR = Anterior Thalamic Radiation, CAB = Cingulum Angular Bundle, CCG = Cingulum Cingulate Gyrus, CST = Corticospinal Tract, ILF = Inferior Longitudinal Fasciculus, SLF-P = Superior Longitudinal Fasciculus – Parietal, SLF-T = Superior Longitudinal Fasciculus – Temporal, UNC = Uncinate Fasciculus, FA=Fractional Anisotropy, MD=Mean Diffusivity, RD=Radial Diffusivity.
Table S7. F and p values for the effect of each executive function domain and Diagnosis-by-EF domain performance on the white matter microstructure measurements for the Forceps Minor, Left Anterior Thalamic Radiation, and Left Cingulum Angular Bundle. q-values obtained after FDR correction are also provided.
FDR corrected (alpha = 0.05). Significant results (uncorrected; alpha = 0.05)
ANCOVA Models (Effects)
Forceps Minor Left Anterior Thalamic Radiation Left Cingulum Angular Bundle
FA MD RD FA MD RD FA MD RD
AttentionF-value 1.068 1.587 0.377 0.097 0.072 0.164 1.011 0.363 0.678
p-value 0.308 0.216 0.543 0.757 0.791 0.688 0.321 0.551 0.416q-value 0.524 0.432 0.735 0.84 0.86 0.807 0.537 0.735 0.631
AttentionBy
Diagnosis
F-value 0.000 3.65 0.175 1.452 0.351 2.496 0.395 2.355 2.114p-value 0.995 0.064 0.678 0.236 0.557 0.123 0.534 0.133 0.154q-value 0.995 0.198 0.8 0.461 0.735 0.310 0.732 0.324 0.365
Working Memory
F-value 0.032 0.707 0.49 1.831 1.899 6.039 1.618 6.879 7.681p-value 0.86 0.406 0.488 0.184 0.177 0.019 0.211 0.013 0.009q-value 0.919 0.625 0.69 0.398 0.396 0.087 0.43 0.063 0.050
Working MemoryBy
Diagnosis
F-value 0.082 0.67 0.178 1.757 0.659 4.361 0.011 4.491 1.818p-value 0.776 0.418 0.676 0.193 0.422 0.044 0.918 0.041 0.186q-value 0.852 0.631 0.800 0.408 0.632 0.157 0.949 0.150 0.398
Mental Flexibility
F-value 0.353 0.262 0.644 4.827 0.696 0.889 0.566 0.216 0.325p-value 0.556 0.611 0.427 0.034 0.409 0.352 0.457 0.645 0.572q-value 0.735 0.761 0.636 0.131 0.627 0.565 0.666 0.785 0.741
Mental FlexibilityBy
Diagnosis
F-value 1.144 0.491 2.097 7.352 1.509 2.653 0.295 0.906 0.253
p-value 0.292 0.488 0.156 0.010 0.227 0.112 0.59 0.347 0.618q-value 0.513 0.69 0.365 0.054 0.450 0.292 0.748 0.559 0.767
ANCOVA Models (Effects)
Forceps Minor Left Anterior Thalamic Radiation Left Cingulum Angular Bundle
FA MD RD FA MD RD FA MD RD
Response Inhibition F-value 1.808 0.270 1.002 6.545 0.192 2.304 0.582 0.476 0.670p-value 0.187 0.606 0.323 0.015 0.664 0.138 0.451 0.495 0.418q-value 0.399 0.759 0.538 0.072 0.797 0.332 0.661 0.697 0.631
Response InhibitionBy
Diagnosis
F-value 1.884 0.002 0.108 5.767 0.563 1.033 0.353 0.017 0.023p-value 0.178 0.965 0.744 0.021 0.458 0.316 0.556 0.898 0.880q-value 0.396 0.976 0.839 0.095 0.666 0.531 0.735 0.943 0.933
Problem Solving
F-value 3.059 0.686 5.428 0.148 3.500 0.176 0.340 0.282 0.001p-value 0.089 0.413 0.025 0.703 0.069 0.678 0.563 0.599 0.977q-value 0.245 0.628 0.106 0.815 0.210 0.800 0.737 0.753 0.983
Problem SolvingBy
Diagnosis
F-value 4.238 1.832 7.071 2.582 4.205 1.337 0.701 0.93 0.002
p-value 0.047 0.184 0.012 0.117 0.047 0.255 0.408 0.341 0.966q-value 0.161 0.398 0.059 0.303 0.161 0.489 0.626 0.555 0.976
Table S8. Validation of findings declared as significant in Step 3 (Diagnostic differences in the relationship between executive function domain performance and white matter microstructure measurements) using bootstrap sampling technique and random permutation of data. Blue shaded cells correspond to results from 5000 samples generated using bootstrap sampling technique. Orange shaded cells correspond to results from 5000 random datasets built randomly permuting the data.
Figure S1. The eighteen major white matter tracts reconstructed using the Tracts Constrained by UnderLying Anatomy (TRACULA) software.
Orig
inal
val
ue
Mea
n B
oots
trap
Con
fiden
ce In
terv
al
Boo
tstra
p (L
ower
Li
mit)
Con
fiden
ce In
terv
al
Boo
tstra
p (U
pper
Li
mit)
Mea
n Pe
rmut
atio
ns
Con
fiden
ce In
terv
al
Perm
utat
ions
(Low
er L
imit)
Con
fiden
ce In
terv
al
Perm
utat
ions
(Upp
er L
imit)
Cum
ulat
ive
Prob
abili
ty o
f the
O
rigin
al V
alue
in th
e R
ando
m D
istri
butio
n
Figure 3 a.FA Left Anterior Thalamic Radiation - Response Inhibition
ANCOVA ModelF (RI) 6.545 8.075 7.912 8.237 1.130 1.084 1.176 0.018F (RI-by-Diagnosis) 5.767 7.283 7.115 7.45 0.710 0.681 0.738 0.004
Within-Groups Correlations
r (TP) 0.504 0.504 0.498 0.509 0.002 -0.004 0.008 0.014r (ASD) -0.133 -0.111 -0.118 -0.104 -0.002 -0.008 0.004 0.706
Figure 3 b.RD Forceps Minor - Problem Solving
ANCOVA ModelF (PS) 5.428 7.268 7.068 7.468 0.978 0.938 1.017 0.020F (PS-by-Diagnosis) 7.071 9.173 8.93 9.417 0.831 0.798 0.865 0.012
Within-Groups Correlations
r (TP) -0.448 -0.419 -0.426 -0.413 -0.004 -0.010 0.003 0.969r (ASD) 0.149 0.161 0.155 0.167 0.000 -0.006 0.007 0.265
Figure 3 c.RD Left Cingulum Angular Bundle - Working Memory
ANCOVA ModelF (WM) 7.681 9.207 9.026 9.387 1.262 1.210 1.315 0.014F (WM-by-Diagnosis) 7.681 3.102 3.015 3.189 0.598 0.573 0.623 0.001
Within-Groups Correlations
r (TP) -0.420 -0.408 -0.413 -0.404 0.003 -0.003 0.01 0.970
r (ASD) -0.148 -0.116 -0.122 -0.109 0.003 -0.004 0.009 0.744
Figure S2. Scatter plots depicting the EF domain performance–WMS measurements relationship (r, p), controlling for the effect of age, for tracts where a significant effect of EF domain and/or diagnosis-by-EF domain performance were found (uncorrected). ASD = Male participants with autism spectrum disorders, TP = Typically developing male participants, FA = Fractional Anisotropy, MD = Mean Diffusion, RD = Radial Diffusion, FMinor = Forceps Minor, ATR = Anterior Thalamic Radiation, CAB = Cingulum Angular Bundle.