Decreasing ADHD phenotypic heterogeneity: searching for neurobiological underpinnings of the restrictive inattentive phenotype
Eyup Sabri Ercan1, M.D.; Serkan Suren2, M.D.; Ali Bacanlı3, M.D.; Kemal Utku Yazıcı4, M.D.; Cem Callı5, M.D.; Onur Ozyurt6,Ph.D; Duygu Aygunes7,M.D.; Buket Kosova7, M.D.; Alexandre Rosa Franco8,9, Ph.D; Luis Augusto Rohde10,11, M.D., Ph.D.
1. Child and Adolescent Psychiatry Department, Medical Faculty, Ege University, Izmir, Turkey
2. Hospital for Psychiatry, Samsun, Turkey
3. Children Hospital, Gaziantep, Turkey
4. Child and Adolescent Psychiatry Department, Medical Faculty, Fırat University, Elazığ, Turkey
5. Radiology Department, Medical Faculty, Ege University
6. Institute of Biomedical Engineering, Bogazici University, Turkey
7. Medical Biology Department, Medical Faculty, Ege University
8. Brain Institute of Rio Grande do Sul (InsCer), PUCRS, Brazil
9. School of Engineering, PUCRS, Brazil
10. ADHD Outpatient Program, Hospital de Clinicas de Porto Alegre, Department of Psychiatry, Federal University of Rio Grande do Sul, Brazil
11. National Institute of Developmental Psychiatry for Children and Adolescents, Brazil
Corresponding author:Eyüp Sabri Ercan, M.D., Ph.D.
Professor of Child and Adolescent Psychiatry
Ege University Faculty of Medicine Department of Child and Adolescent Psychiatry, Izmir, Turkey
Telephone Number: +90 532 5222950 Fax Number: +90 232 4638891
E-mail Address:
Supplementary Material
Secondary analyses of the neuropsychological assessment
Since clear gender, age and IQ differences were found among groups, we ran secondary analyses (ANCOVA) controlling for the effect of these variables. The results did not change substantially (significance remained).(Supplementary Table 1a). Finally, since the proportion of comorbidity with ODD was substantially higher in the ADHD-C group, we ran analyses in a subgroup of patients and controls without ODD. The direction of findings remained the same (Supplementary Table 1b).
Supplementary Table 1a. Estimated marginal means of neuropsychological measures after adjustment for age, gender and WISC score
CNSVS / ADHD-C(n=101) / ADHD-I
(n=50) / ADHD-RI
(n=50) / TD
(n=100) / F / p*
Mean / Mean / Mean / Mean
Neurocognitive Index / 84,5 / 84,2 / 73,8 / 98,0 / 50,9 / <0,001
Total Memory Score / 82,4 / 86.3 / 90,8 / 97,8 / 6,9 / <0,001
Psychomotor Speed Score / 94.3 / 85.5 / 69.2 / 103.2 / 72,5 / <0,001
Reaction Time Score / 81.2 / 77.4 / 53.2 / 85.1 / 22,6 / <0,001
Total Attention Score / 75.3 / 80.1 / 77.8 / 103.2 / 55,9 / <0,001
Cognitive Flexibility Score / 85.1 / 88.2 / 84. / 104.2 / 47,8 / <0,001
CPT-Correct Response / 37,1 / 36,5 / 33,0 / 39,3 / 37,9 / <0,001
CPT-Omission Errors / 2,4 / 3,5 / 7,1 / 0,7 / 53,5 / <0,001
CPT-Commission Errors / 7,6 / 4,8 / 2,3 / 1,7 / 21,1 / <0,001
CPT-Reaction Time / 518,5 / 512,0 / 541,8 / 474,5 / 11,1 / <0,001
*ANCOVA test results
CNS-VS: computerized neuropsychological test - vital signs; CPT: continuous performance test. ADHD-C: attention-deficit/hyperactivity disorder, combined type; ADHD-I: attention deficit/hyperactivity disorder, predominantly inattentive type; ADHD-RI: attention deficit/hyperactivity disorder, restrictive inattentive type;; TD: Typically Developing Controls
Supplementary Table 1b. Neuropsychological measures for the four groups without ODD comorbidity
CNSVS / ADHD-CODD (-)(n=59) / ADHD-I
ODD (-)(n=46) / ADHD-RI
ODD (-)(n=50) / TD
(n=100) / F / P
Mean / SD / Mean / SD / Mean / SD / Mean / SD
Neurocognitive Index / 83.8 / 11.3 / 83.7 / 11.8 / 73.9 / 10.6 / 98.8 / 12.6 / 55.6 / 0,001 / RI<I,C<TD
Composite Memory Score / 84.3 / 20.2 / 85.9 / 23.6 / 89.1 / 18.0 / 97.0 / 17.8 / 6.4 / 0,001 / C,I < TD
Psychomotor Speed Score / 93.5 / 13.2 / 85.1 / 16.6 / 67.1 / 16.1 / 103.0 / 18.0 / 55.2 / 0,001 / RI< I < C < TD
Reaction Time Score / 81.8 / 24.0 / 78.2 / 19.5 / 51.4 / 26.5 / 84.4 / 32.9 / 17.0 / 0,001 / RI < I,C,TD
Total Attention Score / 74.7 / 24.0 / 81.9 / 17.6 / 77.9 / 12.4 / 104.3 / 13.3 / 50.2 / 0,001 / C, I, RI< TD
Cognitive Flexibility Score / 84.6 / 14.1 / 87.8 / 13.7 / 84.1 / 13.4 / 105.5 / 17.3 / 35.2 / 0,001 / C, I, RI< TD
CPT-Correct Response / 37.6 / 3.1 / 36.3 / 3.7 / 32.9 / 4.1 / 39.2 / 1.0 / 52.2 / 0,001 / RI<I,C<TD
CPT-Omission Errors / 2.2 / 2.9 / 3.6 / 3.7 / 7.1 / 4.1 / 0.8 / 1.1 / 54.1 / 0,001 / TD<C<I<RI
CPT-Commission Errors / 7.4 / 5.6 / 4.6 / 4.0 / 2.0 / 2.0 / 1.6 / 1.5 / 38.8 / 0,001 / TD,RI<I<C
CPT-Reaction Time / 521.0 / 83.7 / 504.7 / 87.1 / 536.0 / 70.4 / 473.5 / 76.0 / 8.5 / 0,001 / TD<C,RI
CNS-VS: computerized neuropsychological test - vital signs; CPT: continuous performance test. ADHD-C: attention-deficit/hyperactivity disorder,
combined type; ADHD-I: attention deficit/hyperactivity disorder, predominantly inattentive type; ADHD-RI: attention deficit/hyperactivity disorder,
restrictive inattentive type;ODD:Oppositional Defiant Disorder; TD: Typically Developing Controls
Supplementary Table 2: Sociodemographic and geneticcharacteristics and Go/No-Go scores for subjects that performed fMRI scans
Variable / ADHD-C / ADHD-I / ADHD-RI / TD / Group comparisonsAge - mean (SD) / 10.58 ±1.76 / 11.13 ±2.02 / 10.71 ±2.25 / 10.88 ± 1.36 / NS
Gender -% Male / 100 / 75 / 75 / 75 / NS
EstimatedIQ - mean (SD) / 112.5 ± 20.2 / 106.8 ±16.6 / 108.08±19.1 / 111.45±17.8 / NS
Comorbid -
ODD % / 33 / 12.5 / - / -
Genetics
DAT1 10R
Homozygosity -% / 50 / 58.3 / 41.7 / 41.7
DRD4 7R -
Carrier% / 0.4 / 8.3 / 29.1 / 8.3
Task performance
Errors
No-Go Condition Commission errors-% / 8.9 / 9.5 / 9.5 / 7.9 / N.S
Go Condition Omission errors - % / 3.9 / 5.1 / 6.6 / 2.9 / NS
Reaction time (RT)
(ms)
Go Condition / 397.0 / 398.9 / 445.5 / 392.3 / N.S
No-Go Condition / 412.4 / 362.3 / 433.3 / 389.9 / N.S
Successful task
Go + No-Go - % / 93.6 / 92.6 / 91.7 / 94.5 / N.S
ADHD-C: Attention-deficit/hyperactivity disorder, combined type; ADHD-I: Attention deficit/hyperactivity disorder, predominantly inattentive type; ADHD- RI: Attention deficit/hyperactivity disorder, restrictive inattentive type; TD: children with typical development, DAT1:Dopamine transporter gene, DRD4:dopamine D4 receptor gene, RT:reaction time