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1.  Altered neural connectivity during response inhibition in adolescents with attention-deficit/hyperactivity disorder and their unaffected siblings 
NeuroImage : Clinical  2015;7:325-335.
Response inhibition is one of the executive functions impaired in attention-deficit/hyperactivity disorder (ADHD). Increasing evidence indicates that altered functional and structural neural connectivity are part of the neurobiological basis of ADHD. Here, we investigated if adolescents with ADHD show altered functional connectivity during response inhibition compared to their unaffected siblings and healthy controls.
Response inhibition was assessed using the stop signal paradigm. Functional connectivity was assessed using psycho-physiological interaction analyses applied to BOLD time courses from seed regions within inferior- and superior frontal nodes of the response inhibition network. Resulting networks were compared between adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and controls (N = 125).
Control subjects showed stronger functional connectivity than the other two groups within the response inhibition network, while subjects with ADHD showed relatively stronger connectivity between default mode network (DMN) nodes. Stronger connectivity within the response inhibition network was correlated with lower ADHD severity, while stronger connectivity with the DMN was correlated with increased ADHD severity. Siblings showed connectivity patterns similar to controls during successful inhibition and to ADHD subjects during failed inhibition. Additionally, siblings showed decreased connectivity with the primary motor areas as compared to both participants with ADHD and controls.
Subjects with ADHD fail to integrate activation within the response inhibition network and to inhibit connectivity with task-irrelevant regions. Unaffected siblings show similar alterations only during failed stop trials, as well as unique suppression of motor areas, suggesting compensatory strategies. These findings support the role of altered functional connectivity in understanding the neurobiology and familial transmission of ADHD.
•We investigate the neural connectivity during response inhibition using PPI.•We investigate connectivity in participants with ADHD, their siblings and controls.•Participants with ADHD show lower connectivity within the response inhibition network.•Participants with ADHD show higher connectivity with the default mode network.•Unaffected siblings show unique patterns of compensatory activation.
PMCID: PMC4297885  PMID: 25610797
ADHD, attention deficit/hyperactivity disorder; CD, conduct disorder; DMN, default mode network; GEE, generalized estimating equations; ICV, intraindividual coefficient of variance; ODD, oppositional defiant disorder; RD, reading disorder; ROI, region of interest; SSRT, stop-signal reaction time; SST, Stop-signal task; SI, supplementary information; WM, white matter; ADHD; PPI; Connectivity; Siblings; Response inhibition
2.  Brain Volumetric Correlates of Autism Spectrum Disorder Symptoms in Attention Deficit/Hyperactivity Disorder 
PLoS ONE  2014;9(6):e101130.
Autism spectrum disorder (ASD) symptoms frequently occur in subjects with attention deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural correlates, no study to date has investigated these structural correlates within a framework that robustly accounts for the phenotypic overlap between the two disorders. The presence of ASD symptoms was measured by the parent-reported Children’s Social and Behavioural Questionnaire (CSBQ) in ADHD subjects (n = 180), their unaffected siblings (n = 118) and healthy controls (n = 146). ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners’ ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of ASD symptom scores were analysed by modelling ASD symptom scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. ASD symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. ASD scores were predicted by the interaction between WM and GM volumes. Increasing ASD score was associated with greater GM volume. Equivocal results from previous structural studies in ADHD and ASD may be due to the fact that comorbidity has not been taken into account in studies to date. The current findings stress the need to account for issues of ASD comorbidity in ADHD.
PMCID: PMC4076257  PMID: 24979066
3.  Executive Functioning in Highly Talented Soccer Players 
PLoS ONE  2014;9(3):e91254.
Executive functions might be important for successful performance in sports, particularly in team sports requiring quick anticipation and adaptation to continuously changing situations in the field. The executive functions motor inhibition, attention and visuospatial working memory were examined in highly talented soccer players. Eighty-four highly talented youth soccer players (mean age 11.9), and forty-two age-matched amateur soccer players (mean age 11.8) in the age range 8 to 16 years performed a Stop Signal task (motor inhibition), the Attention Network Test (alerting, orienting, and executive attention) and a visuospatial working memory task. The highly talented soccer players followed the talent development program of the youth academy of a professional soccer club and played at the highest national soccer competition for their age. The amateur soccer players played at a regular soccer club in the same geographical region as the highly talented soccer players and play in a regular regional soccer competition. Group differences were tested using analyses of variance. The highly talented group showed superior motor inhibition as measured by stop signal reaction time (SSRT) on the Stop Signal task and a larger alerting effect on the Attention Network Test, indicating an enhanced ability to attain and maintain an alert state. No group differences were found for orienting and executive attention and visuospatial working memory. A logistic regression model with group (highly talented or amateur) as dependent variable and executive function measures that significantly distinguished between groups as predictors showed that these measures differentiated highly talented soccer players from amateur soccer players with 89% accuracy. Highly talented youth soccer players outperform youth amateur players on suppressing ongoing motor responses and on the ability to attain and maintain an alert state; both may be essential for success in soccer.
PMCID: PMC3954684  PMID: 24632735
4.  The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data 
Thompson, Paul M. | Stein, Jason L. | Medland, Sarah E. | Hibar, Derrek P. | Vasquez, Alejandro Arias | Renteria, Miguel E. | Toro, Roberto | Jahanshad, Neda | Schumann, Gunter | Franke, Barbara | Wright, Margaret J. | Martin, Nicholas G. | Agartz, Ingrid | Alda, Martin | Alhusaini, Saud | Almasy, Laura | Almeida, Jorge | Alpert, Kathryn | Andreasen, Nancy C. | Andreassen, Ole A. | Apostolova, Liana G. | Appel, Katja | Armstrong, Nicola J. | Aribisala, Benjamin | Bastin, Mark E. | Bauer, Michael | Bearden, Carrie E. | Bergmann, Ørjan | Binder, Elisabeth B. | Blangero, John | Bockholt, Henry J. | Bøen, Erlend | Bois, Catherine | Boomsma, Dorret I. | Booth, Tom | Bowman, Ian J. | Bralten, Janita | Brouwer, Rachel M. | Brunner, Han G. | Brohawn, David G. | Buckner, Randy L. | Buitelaar, Jan | Bulayeva, Kazima | Bustillo, Juan R. | Calhoun, Vince D. | Cannon, Dara M. | Cantor, Rita M. | Carless, Melanie A. | Caseras, Xavier | Cavalleri, Gianpiero L. | Chakravarty, M. Mallar | Chang, Kiki D. | Ching, Christopher R. K. | Christoforou, Andrea | Cichon, Sven | Clark, Vincent P. | Conrod, Patricia | Coppola, Giovanni | Crespo-Facorro, Benedicto | Curran, Joanne E. | Czisch, Michael | Deary, Ian J. | de Geus, Eco J. C. | den Braber, Anouk | Delvecchio, Giuseppe | Depondt, Chantal | de Haan, Lieuwe | de Zubicaray, Greig I. | Dima, Danai | Dimitrova, Rali | Djurovic, Srdjan | Dong, Hongwei | Donohoe, Gary | Duggirala, Ravindranath | Dyer, Thomas D. | Ehrlich, Stefan | Ekman, Carl Johan | Elvsåshagen, Torbjørn | Emsell, Louise | Erk, Susanne | Espeseth, Thomas | Fagerness, Jesen | Fears, Scott | Fedko, Iryna | Fernández, Guillén | Fisher, Simon E. | Foroud, Tatiana | Fox, Peter T. | Francks, Clyde | Frangou, Sophia | Frey, Eva Maria | Frodl, Thomas | Frouin, Vincent | Garavan, Hugh | Giddaluru, Sudheer | Glahn, David C. | Godlewska, Beata | Goldstein, Rita Z. | Gollub, Randy L. | Grabe, Hans J. | Grimm, Oliver | Gruber, Oliver | Guadalupe, Tulio | Gur, Raquel E. | Gur, Ruben C. | Göring, Harald H. H. | Hagenaars, Saskia | Hajek, Tomas | Hall, Geoffrey B. | Hall, Jeremy | Hardy, John | Hartman, Catharina A. | Hass, Johanna | Hatton, Sean N. | Haukvik, Unn K. | Hegenscheid, Katrin | Heinz, Andreas | Hickie, Ian B. | Ho, Beng-Choon | Hoehn, David | Hoekstra, Pieter J. | Hollinshead, Marisa | Holmes, Avram J. | Homuth, Georg | Hoogman, Martine | Hong, L. Elliot | Hosten, Norbert | Hottenga, Jouke-Jan | Hulshoff Pol, Hilleke E. | Hwang, Kristy S. | Jack, Clifford R. | Jenkinson, Mark | Johnston, Caroline | Jönsson, Erik G. | Kahn, René S. | Kasperaviciute, Dalia | Kelly, Sinead | Kim, Sungeun | Kochunov, Peter | Koenders, Laura | Krämer, Bernd | Kwok, John B. J. | Lagopoulos, Jim | Laje, Gonzalo | Landen, Mikael | Landman, Bennett A. | Lauriello, John | Lawrie, Stephen M. | Lee, Phil H. | Le Hellard, Stephanie | Lemaître, Herve | Leonardo, Cassandra D. | Li, Chiang-shan | Liberg, Benny | Liewald, David C. | Liu, Xinmin | Lopez, Lorna M. | Loth, Eva | Lourdusamy, Anbarasu | Luciano, Michelle | Macciardi, Fabio | Machielsen, Marise W. J. | MacQueen, Glenda M. | Malt, Ulrik F. | Mandl, René | Manoach, Dara S. | Martinot, Jean-Luc | Matarin, Mar | Mather, Karen A. | Mattheisen, Manuel | Mattingsdal, Morten | Meyer-Lindenberg, Andreas | McDonald, Colm | McIntosh, Andrew M. | McMahon, Francis J. | McMahon, Katie L. | Meisenzahl, Eva | Melle, Ingrid | Milaneschi, Yuri | Mohnke, Sebastian | Montgomery, Grant W. | Morris, Derek W. | Moses, Eric K. | Mueller, Bryon A. | Muñoz Maniega, Susana | Mühleisen, Thomas W. | Müller-Myhsok, Bertram | Mwangi, Benson | Nauck, Matthias | Nho, Kwangsik | Nichols, Thomas E. | Nilsson, Lars-Göran | Nugent, Allison C. | Nyberg, Lars | Olvera, Rene L. | Oosterlaan, Jaap | Ophoff, Roel A. | Pandolfo, Massimo | Papalampropoulou-Tsiridou, Melina | Papmeyer, Martina | Paus, Tomas | Pausova, Zdenka | Pearlson, Godfrey D. | Penninx, Brenda W. | Peterson, Charles P. | Pfennig, Andrea | Phillips, Mary | Pike, G. Bruce | Poline, Jean-Baptiste | Potkin, Steven G. | Pütz, Benno | Ramasamy, Adaikalavan | Rasmussen, Jerod | Rietschel, Marcella | Rijpkema, Mark | Risacher, Shannon L. | Roffman, Joshua L. | Roiz-Santiañez, Roberto | Romanczuk-Seiferth, Nina | Rose, Emma J. | Royle, Natalie A. | Rujescu, Dan | Ryten, Mina | Sachdev, Perminder S. | Salami, Alireza | Satterthwaite, Theodore D. | Savitz, Jonathan | Saykin, Andrew J. | Scanlon, Cathy | Schmaal, Lianne | Schnack, Hugo G. | Schork, Andrew J. | Schulz, S. Charles | Schür, Remmelt | Seidman, Larry | Shen, Li | Shoemaker, Jody M. | Simmons, Andrew | Sisodiya, Sanjay M. | Smith, Colin | Smoller, Jordan W. | Soares, Jair C. | Sponheim, Scott R. | Sprooten, Emma | Starr, John M. | Steen, Vidar M. | Strakowski, Stephen | Strike, Lachlan | Sussmann, Jessika | Sämann, Philipp G. | Teumer, Alexander | Toga, Arthur W. | Tordesillas-Gutierrez, Diana | Trabzuni, Daniah | Trost, Sarah | Turner, Jessica | Van den Heuvel, Martijn | van der Wee, Nic J. | van Eijk, Kristel | van Erp, Theo G. M. | van Haren, Neeltje E. M. | van ‘t Ent, Dennis | van Tol, Marie-Jose | Valdés Hernández, Maria C. | Veltman, Dick J. | Versace, Amelia | Völzke, Henry | Walker, Robert | Walter, Henrik | Wang, Lei | Wardlaw, Joanna M. | Weale, Michael E. | Weiner, Michael W. | Wen, Wei | Westlye, Lars T. | Whalley, Heather C. | Whelan, Christopher D. | White, Tonya | Winkler, Anderson M. | Wittfeld, Katharina | Woldehawariat, Girma | Wolf, Christiane | Zilles, David | Zwiers, Marcel P. | Thalamuthu, Anbupalam | Schofield, Peter R. | Freimer, Nelson B. | Lawrence, Natalia S. | Drevets, Wayne
Brain Imaging and Behavior  2014;8(2):153-182.
The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
PMCID: PMC4008818  PMID: 24399358
Genetics; MRI; GWAS; Consortium; Meta-analysis; Multi-site
5.  Executive Function and IQ Predict Mathematical and Attention Problems in Very Preterm Children 
PLoS ONE  2013;8(2):e55994.
Objective of this study was to examine the impact of executive function (EF) on mathematical and attention problems in very preterm (gestational age ≤ 30 weeks) children. Participants were 200 very preterm (mean age 8.2 ± 2.5 years) and 230 term children (mean age 8.3 ± 2.3 years) without severe disabilities, born between 1996 and 2004. EFs assessed included verbal fluency, verbal working memory, visuospatial span, planning, and impulse control. Mathematics was assessed with the Dutch Pupil Monitoring System and parents and teachers rated attention problems using standardized behavior questionnaires. The impact of EF was calculated over and above processing speed indices and IQ. Interactions with group (very preterm versus term birth status) were examined. Analyses were conducted separately for two subsamples: children in preschool and children in primary school. Very preterm children performed poorer on tests for mathematics and had more parent and teacher rated attention problems than term controls (ßs>.11, Ps<.01). IQ contributed unique variance to mathematics in preschool and in primary school (ßs>.16, Ps<.007). A significant interaction of group with IQ (ß = −. 24, P = .02) showed that IQ contributed unique variance to attention problems as rated by teachers, but that effects were stronger for very preterm than for term infants. Over and above IQ, EF contributed unique variance to mathematics in primary school (ß = .13, P<.001), to parent rated inattention in preschool and in primary school (ßs>−.16, Ps<.04), and to teacher rated inattention in primary school (ß = −.19; ß = .19, Ps<.009). In conclusion, impaired EF is, over and above impaired IQ, an important predictor for poor mathematics and attention problems following very preterm birth.
PMCID: PMC3563540  PMID: 23390558
6.  Neurofeedback to improve neurocognitive functioning of children treated for a brain tumor: design of a randomized controlled double-blind trial 
BMC Cancer  2012;12:581.
Neurotoxicity caused by treatment for a brain tumor is a major cause of neurocognitive decline in survivors. Studies have shown that neurofeedback may enhance neurocognitive functioning. This paper describes the protocol of the PRISMA study, a randomized controlled trial to investigate the efficacy of neurofeedback to improve neurocognitive functioning in children treated for a brain tumor.
Efficacy of neurofeedback will be compared to placebo training in a randomized controlled double-blind trial. A total of 70 brain tumor survivors in the age range of 8 to 18 years will be recruited. Inclusion also requires caregiver-reported neurocognitive problems and being off treatment for more than two years. A group of 35 healthy siblings will be included as the control group. On the basis of a qEEG patients will be assigned to one of three treatment protocols. Thereafter patients will be randomized to receive either neurofeedback training (n=35) or placebo training (n=35). Neurocognitive tests, and questionnaires administered to the patient, caregivers, and teacher, will be used to evaluate pre- and post-intervention functioning, as well as at 6-month follow-up. Siblings will be administered the same tests and questionnaires once.
If neurofeedback proves to be effective for pediatric brain tumor survivors, this can be a valuable addition to the scarce interventions available to improve neurocognitive and psychosocial functioning.
Trial registration NCT00961922.
PMCID: PMC3530427  PMID: 23217162
Brain tumor; Child; Survivors; Attention; Memory; Processing speed; Neurocognitive functioning; Intervention; Neurofeedback; Protocol; RCT; Double-blind
7.  Reward and Punishment Sensitivity in Children with ADHD: Validating the Sensitivity to Punishment and Sensitivity to Reward Questionnaire for Children (SPSRQ-C) 
This study validates the Sensitivity to Punishment and Sensitivity to Reward Questionnaire for children (SPSRQ-C), using a Dutch sample of 1234 children between 6–13 years old. Factor analysis determined that a 4-factor and a 5-factor solution were best fitting, explaining 41% and 50% of the variance respectively. The 4-factor model was highly similar to the original SPSRQ factors found in adults (Punishment Sensitivity, Reward Responsivity, Impulsivity/Fun-Seeking, and Drive). The 5-factor model was similar to the 4-factor model, with the exception of a subdivision of the Punishment Sensitivity factor into a factor with ‘social-fear’ items and a factor with ‘anxiety’ items. To determine external validity, scores of three groups of children with attention deficit hyperactivity disorder (ADHD) were compared on the EFA models: ADHD-only (n = 34), ADHD and autism spectrum disorder (ADHD+ASD; n = 22), ADHD and oppositional defiant disorder (ADHD+ODD; n = 22). All ADHD groups scored higher than typical controls on Reward Responsivity and on the ‘anxiety’ factor (n = 75). The ADHD-only and ADHD+ODD group scored higher than other groups on Impulsivity/Fun-Seeking and Drive, while the ADHD+ASD group scored higher on Punishment Sensitivity. The findings emphasize the value of the SPSRQ-C to quickly and reliably assess a child’s sensitivity to reinforcement, with the aim to provide individually-tailored behavioral interventions that utilize reward and reprimands.
PMCID: PMC3268965  PMID: 21789519
ADHD; ASD; ODD; Punishment; Reward; Questionnaire; SPSRQ
8.  Double disadvantage: a case control study on health-related quality of life in children with sickle cell disease 
Low health-related quality of life (HRQoL) of children with sickle cell disease (SCD) may be associated with consequences of the disease, or with the low socio-economic status (SES) of this patient population. The aim of this study was to investigate the HRQoL of children with SCD, controlling for SES by comparing them to healthy siblings (matched for age and gender), and to a Dutch norm population.
The HRQoL of 40 children with homozygous SCD and 36 healthy siblings was evaluated by the KIDSCREEN-52. This self-report questionnaire assesses ten domains of HRQoL. Differences between children with SCD and healthy siblings were analyzed using linear mixed models. One-sample t-tests were used to analyze differences with the Dutch norm population. Furthermore, the proportion of children with SCD with impaired HRQoL was evaluated.
In general, the HRQoL of children with SCD appeared comparable to the HRQoL of healthy siblings, while children with SCD had worse HRQoL than the Dutch norm population on five domains (Physical Well-being, Moods & Emotions, Autonomy, Parent Relation, and Financial Resources). Healthy siblings had worse HRQoL than the Dutch norm population on three domains (Moods & Emotions, Parent Relation, and Financial Resources). More than one in three children with SCD and healthy siblings had impaired HRQoL on several domains.
These findings imply that reduced HRQoL in children with SCD is mainly related to the low SES of this patient population, with the exception of disease specific effects on the physical and autonomy domain. We conclude that children with SCD are especially vulnerable compared to other patient populations, and have special health care needs.
PMCID: PMC2988059  PMID: 20977722
9.  Inhibition, Reinforcement Sensitivity and Temporal Information Processing in ADHD and ADHD+ODD: Evidence of a Separate Entity? 
Journal of Abnormal Child Psychology  2009;37(8):1123-1135.
This study compared children with ADHD-only, ADHD+ODD and normal controls (age 8–12) on three key neurocognitive functions: response inhibition, reinforcement sensitivity, and temporal information processing. The goal was twofold: (a) to investigate neurocognitive impairments in children with ADHD-only and children with ADHD+ODD, and (b) to test whether ADHD+ODD is a more severe from of ADHD in terms of neurocognitive performance. In Experiment 1, inhibition abilities were measured using the Stop Task. In Experiment 2, reinforcement sensitivity and temporal information processing abilities were measured using a Timing Task with both a reward and penalty condition. Compared to controls, children with ADHD-only demonstrated impaired inhibitory control, showed more time underestimations, and showed performance deterioration in the face of reward and penalty. Children with ADHD+ODD performed in-between children with ADHD-only and controls in terms of inhibitory controls and the tendency to underestimate time, but were more impaired than controls and children with ADHD-only in terms of timing variability. In the face of reward and penalty children with ADHD+ODD improved their performance compared to a neutral condition, in contrast to children with ADHD-only. In the face of reward, the performance improvement in the ADHD+ODD group was disproportionally larger than that of controls. Taken together the findings suggest that, in terms of neurocognitive functioning, comorbid ADHD+ODD is a substantial different entity than ADHD-only.
PMCID: PMC2766046  PMID: 19543967
ADHD; ODD; Comorbidity; Inhibition; Time production; Reward; Motivation; Reinforcement; Neuropsychology
10.  Neuropsychological measures probably facilitate heritability research of ADHD 
Previous studies, in which cognitive and motor neuropsychological tasks were administered to 816 children from Attention-Deficit/Hyperactivity Disorder (ADHD)- and control-families, showed that various of these measures appeared useful for genetic research in ADHD by forming candidate endophenotypes: underlying, heritable, vulnerability traits that mark an enhanced liability for developing ADHD. The current study extends these findings by showing that six of these ten measures correlate more strongly between siblings than an ADHD composite, suggesting these measures may have a larger heritability than ADHD itself. Significant sibling cross-correlations also suggested that six of ten neuropsychological measures related to similar familial (and heritable) factors as ADHD, suggesting these measures to be useful for ADHD genetic research. An aggregated neuropsychological composite appeared to be the most powerful, since it correlated more strongly between siblings than most individual task measures. These findings suggest heritability research in ADHD will probably be facilitated by including neuropsychological measures.
PMCID: PMC3895968  PMID: 18635338
Endophenotype; Phenotype; ADHD; Heritability; Neuropsychology; Siblings
11.  How Distinctive are ADHD and RD? Results of a Double Dissociation Study 
Journal of Abnormal Child Psychology  2009;37(7):1007-1017.
The nature of the comorbidity between Attention-Deficit/Hyperactivity Disorder (ADHD) and Reading Disability (RD) was examined using a double dissociation design. Children were between 8 and 12 years of age and entered into four groups: ADHD only (n = 24), ADHD+RD (n = 29), RD only (n = 41) and normal controls (n = 26). In total, 120 children participated in the study; 38 girls and 82 boys. Both ADHD and RD were associated with impairments in inhibition and lexical decision, although inhibition and lexical decision were more severely impaired in RD than in ADHD. Visuospatial working memory deficits were specific to children with only ADHD. It is concluded that there was overlap on lexical decision and to a lesser extent on inhibition between ADHD and RD. In ADHD, impairments were dependent on IQ, which suggest that the overlap in lexical decision and inhibition is different in origin for ADHD and RD. The ADHD only group was specifically characterized by deficits in visuospatial working memory. Hence, no double dissociation between ADHD and RD was found on executive functioning and lexical decision.
PMCID: PMC2734255  PMID: 19488850
ADHD; RD; Comorbidity; Executive functioning; Lexical decision
12.  Executive Function in Very Preterm Children at Early School Age 
We examined whether very preterm (≤30 weeks gestation) children at early school age have impairments in executive function (EF) independent of IQ and processing speed, and whether demographic and neonatal risk factors were associated with EF impairments. A consecutive sample of 50 children (27 boys and 23 girls) born very preterm (mean age = 5.9 years, SD = 0.4, mean gestational age = 28.0 weeks, SD = 1.4) was compared to a sample of 50 age-matched full-term controls (23 girls and 27 boys, mean age = 6.0 years, SD = 0.6) with respect to performance on a comprehensive EF battery, assessing the domains of inhibition, working memory, switching, verbal fluency, and concept generation. The very preterm group demonstrated poor performance compared to the controls on all EF domains, even after partialing out the effects of IQ. Processing speed was marginally related to EF. Analyses with demographic and neonatal risk factors showed maternal education and gestational age to be related to EF. This study adds to the emerging body of literature showing that very preterm birth is associated with EF impairments.
PMCID: PMC2734253  PMID: 19488851
Executive function; Very preterm; IQ; Speed of processing
13.  Comorbid Problems in ADHD: Degree of Association, Shared Endophenotypes, and Formation of Distinct Subtypes. Implications for a Future DSM 
We aimed to assess which comorbid problems (oppositional defiant behaviors, anxiety, autistic traits, motor coordination problems, and reading problems) were most associated with Attention-Deficit/Hyperactivity Disorder (ADHD); to determine whether these comorbid problems shared executive and motor problems on an endophenotype level with ADHD; and to determine whether executive functioning (EF)—and motor-endophenotypes supported the hypothesis that ADHD with comorbid problems is a qualitatively different phenotype than ADHD without comorbid problems. An EF—and a motor-endophenotype were formed based on nine neuropsychological tasks administered to 816 children from ADHD—and control-families. Additional data on comorbid problems were gathered using questionnaires. Results indicated that oppositional defiant behaviors appeared the most important comorbid problems of ADHD, followed by autistic traits, and than followed by motor coordination problems, anxiety, and reading problems. Both the EF—and motor-endophenotype were correlated and cross-correlated in siblings to autistic traits, motor coordination problems and reading problems, suggesting ADHD and these comorbid problems may possibly share familial/genetic EF and motor deficits. No such results were found for oppositional defiant behaviors and anxiety. ADHD in co-occurrence with comorbid problems may not be best seen as a distinct subtype of ADHD, but further research is warranted.
Electronic supplementary material
The online version of this article (doi:10.1007/s10802-009-9312-6) contains supplementary material, which is available to authorized users.
PMCID: PMC2708322  PMID: 19308723
Attention-deficit/Hyperactivity disorder; Comorbidity; Endophenotype; Phenotype; DSM-V
14.  Speed, Variability, and Timing of Motor Output in ADHD: Which Measures are Useful for Endophenotypic Research? 
Behavior Genetics  2007;38(2):121-132.
Attention-Deficit/Hyperactivity Disorder (ADHD) shares a genetic basis with motor coordination problems and probably motor timing problems. In line with this, comparable problems in motor timing should be observed in first degree relatives and might, therefore, form a suitable endophenotypic candidate. This hypothesis was investigated in 238 ADHD-families (545 children) and 147 control-families (271 children). A motor timing task was administered, in which children had to produce a 1,000 ms interval. In addition to this task, two basic motor tasks were administered to examine speed and variability of motor output, when no timing component was required. Results indicated that variability in motor timing is a useful endophenotypic candidate: It was clearly associated with ADHD, it was also present in non-affected siblings, and it correlated within families. Accuracy (under- versus over-production) in motor timing appeared less useful: Even though accuracy was associated with ADHD (probands and affected siblings had a tendency to under-produce the 1,000 ms interval compared to controls), non-affected siblings did not differ from controls and sibling correlations were only marginally significant. Slow and variable motor output without timing component also appears present in ADHD, but not in non-affected siblings, suggesting these deficits not to be related to a familial vulnerability for ADHD. Deficits in motor timing could not be explained by deficits already present in basic motor output without a timing component. This suggests abnormalities in motor timing were predominantly related to deficient motor timing processes and not to general deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD.
PMCID: PMC2257997  PMID: 18071893
ADHD; Siblings; Endophenotype; Motor timing; Motor speed; Motor variability
15.  Relationship between endophenotype and phenotype in ADHD 
It has been hypothesized that genetic and environmental factors relate to psychiatric disorders through the effect of intermediating, vulnerability traits called endophenotypes. The study had a threefold aim: to examine the predictive validity of an endophenotypic construct for the ADHD diagnosis, to test whether the magnitude of group differences at the endophenotypic and phenotypic level is comparable, and to investigate whether four factors (gender, age, IQ, rater bias) have an effect (moderation or mediation) on the relation between endophenotype and phenotype.
Ten neurocognitive tasks were administered to 143 children with ADHD, 68 non-affected siblings, and 120 control children (first-borns) and 132 children with ADHD, 78 non-affected siblings, and 113 controls (second-borns) (5 – 19 years). The task measures have been investigated previously for their endophenotypic viability and were combined to one component which was labeled 'the endophenotypic construct': one measure representative of endophenotypic functioning across several domains of functioning.
The endophenotypic construct classified children with moderate accuracy (about 50% for each of the three groups). Non-affected children differed as much from controls at the endophenotypic as at the phenotypic level, but affected children displayed a more severe phenotype than endophenotype. Although a potentially moderating effect (age) and several mediating effects (gender, age, IQ) were found affecting the relation between endophenotypic construct and phenotype, none of the effects studied could account for the finding that affected children had a more severe phenotype than endophenotype.
Endophenotypic functioning is moderately predictive of the ADHD diagnosis, though findings suggest substantial overlap exists between endophenotypic functioning in the groups of affected children, non-affected siblings, and controls. Results suggest other factors may be crucial and aggravate the ADHD symptoms in affected children.
PMCID: PMC2267799  PMID: 18234079
16.  Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study 
Addiction Biology  2010;15(4):491-503.
Abnormal cue reactivity is a central characteristic of addiction, associated with increased activity in motivation, attention and memory related brain circuits. In this neuroimaging study, cue reactivity in problem gamblers (PRG) was compared with cue reactivity in heavy smokers (HSM) and healthy controls (HC). A functional magnetic resonance imaging event-related cue reactivity paradigm, consisting of gambling, smoking-related and neutral pictures, was employed in 17 treatment-seeking non-smoking PRG, 18 non-gambling HSM, and 17 non-gambling and non-smoking HC. Watching gambling pictures (relative to neutral pictures) was associated with higher brain activation in occipitotemporal areas, posterior cingulate cortex, parahippocampal gyrus and amygdala in PRG compared with HC and HSM. Subjective craving in PRG correlated positively with brain activation in left ventrolateral prefrontal cortex and left insula. When comparing the HSM group with the two other groups, no significant differences in brain activity induced by smoking cues were found. In a stratified analysis, the HSM subgroup with higher Fagerström Test for Nicotine Dependence scores (FTND M = 5.4) showed higher brain activation in ventromedial prefrontal cortex, rostral anterior cingulate cortex, insula and middle/superior temporal gyrus while watching smoking-related pictures (relative to neutral pictures) than the HSM subgroup with lower FTND scores (FTND M = 2.9) and than non-smoking HC. Nicotine craving correlated with activation in left prefrontal and left amygdala when viewing smoking-related pictures in HSM. Increased regional responsiveness to gambling pictures in brain regions linked to motivation and visual processing is present in PRG, similar to neural mechanisms underlying cue reactivity in substance dependence. Increased brain activation in related fronto-limbic brain areas was present in HSM with higher FTND scores compared with HSM with lower FTND scores.
PMCID: PMC3014110  PMID: 20840335
Addiction; cue reactivity; fMRI; impulse control disorder; nicotine dependence; pathological gambling
17.  Contingency Learning in Alcohol Dependence and Pathological Gambling: Learning and Unlearning Reward Contingencies 
Patients with alcohol dependence (AD) and pathological gambling (PG) are characterized by dysfunctional reward processing and their ability to adapt to alterations of reward contingencies is impaired. However, most neurocognitive tasks investigating reward processing involve a complex mix of elements, such as working memory, immediate and delayed rewards, and risk-taking. As a consequence, it is not clear whether contingency learning is altered in AD or PG. Therefore, the current study aimed to examine performance in a deterministic contingency learning task, investigating discrimination, reversal, and extinction learning.
Thirty-three alcohol-dependent patients (ADs), 28 pathological gamblers (PGs), and 18 healthy controls (HCs) performed a contingency learning task in which they learned stimulus–reward associations that were first reversed and later extinguished while receiving deterministic feedback throughout. Accumulated points, number of perseverative errors and trials required to reach a criterion in each learning phase were compared between groups using nonparametric Kruskal–Wallis rank-sum tests. Regression analyses were performed to compare learning curves.
PGs and ADs did not differ from HCs in discrimination learning, reversal learning, or extinction learning, on the nonparametric tests. Regression analyses, however, showed differences in the initial speed of learning: PGs were significantly faster in discrimination learning compared to ADs, and both PGs and ADs learned slower than HCs in the reversal learning and extinction phases of the task.
Learning rates for reversal and extinction were slower for the alcohol-dependent group and PG group compared to HCs, suggesting that reversing and extinguishing learned contingencies require more effort in ADs and PGs. This implicates a diminished flexibility to overcome previously learned contingencies.
PMCID: PMC4171748  PMID: 24821534
Reversal Learning; Extinction Learning; Alcohol Dependence; Pathological Gambling; Orbitofrontal Cortex

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