The influence of Generalized Anxiety Disorder on Executive Functions in children with ADHD.

The present study was aimed at verifying whether the presence of generalized anxiety disorder (GAD) affects executive functions in children with attention-deficit hyperactivity disorder (ADHD). Two groups of children with ADHD were selected for the study according to the presence or absence of GAD. The first group of 28 children with ADHD with GAD (mean age: 9 ± 1.2; males/females: 24/4) was matched for gender, age, IQ, psychiatric comorbidity with a second group of 29 children with ADHD without GAD (mean age: 8.8 ± 0.7; males/females: 26/3). The two groups with ADHD were compared to 28 typically developing children (mean age: 8.3 ± 1.3; males/females: 23/5) on different measures involving processes especially important in inhibitory control such as rule maintenance, stimulus detection, action selection and action execution. Our results indicated that, differently from children with ADHD with GAD, only the group with ADHD without GAD showed a deficit in inhibitory control. Comorbid subgroups should be differentiated, especially, to develop specific and efficient therapeutic interventions in ADHD.

Proactive and reactive control of movement are differently affected in Attention Deficit Hyperactivity Disorder children.

Attention-Deficit/Hyperactivity Disorder children are impaired in the ability to interrupt an ongoing action in relation to a sudden change in the environment (reactive control, measured by stop signal reaction time, SSRT). Less investigated is the ability to control the response when it is known in advance that it will be required to stop (proactive control, measured by change in Reaction time, RT). The study is aimed at exploring both the reactive and the proactive inhibitory control in a group of ADHD children compared to a group of age-matched controls. ADHD children (N=28) and Controls (N=28) performed 4 tasks: 2 tasks required to respond to the appearance of the go-signals (go task and nostop task) and 2 tasks to respond to the go signals in a context in which sometimes a restrain or suppression of the response was required (go-nogo task and stop task). ADHD children showed a longer SSRT compared to controls. Both groups showed an increment in RT by comparing the go-nogo to the go task and an increment in RT and SD by comparing the stop to the nostop task. ADHD children showed higher intra-individual variability (SD) compared to controls only in the stop and nostop task. ADHD children showed impaired reactive control but preserved proactive control, and the physical appearance of the go signal affected their reaction times intra-individual variability. A comparison between the reactive and proactive controls helps in defining neuropsychological profiles of ADHD children and can inspires therapeutic behavioral-cognitive strategies for response control.

CDH13 is associated with working memory performance in attention deficit/hyperactivity disorder.

Different analytic strategies, including linkage, association and meta-analysis support a role of CDH13 in the susceptibility to attention deficit/hyperactivity disorder (ADHD). CDH13 codes for cadherin 13 (or H-cadherin), which is a member of a family of calcium-dependent cell-cell adhesion proteins and a regulator of neural cell growth. We tested the association between CDH13 on three executive functioning tasks that are promising endophenotypes of ADHD. An adjusted linear regression analysis was performed in 190 ADHD-affected Dutch probands of the IMAGE project. Three executive functions were examined: inhibition, verbal and visuo-spatial working memory (WM). We tested 2632 single nucleotide polymorphisms (SNPs) within CDH13 and 20 kb up- and downstream of the gene (capturing regulatory sequences). To adjust for multiple testing within the gene, we applied stringent permutation steps. Intronic SNP rs11150556 is associated with performance on the Verbal WM task. No other SNP showed gene-wide significance with any of the analyzed traits, but a 72-kb SNP block located 446 kb upstream of SNP rs111500556 showed suggestive evidence for association (P-value range 1.20E-03 to 1.73E-04) with performance in the same Verbal WM task. This study is the first to examine CDH13 and neurocognitive functioning. The mechanisms underlying the associations between CDH13 and the clinical phenotype of ADHD and verbal WM are still unknown. As such, our study may be viewed as exploratory, with the results presented providing interesting hypotheses for further testing.

The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ.

BACKGROUND: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. METHOD: Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS: Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

PDD symptoms in ADHD, an independent familial trait?

The aims of this study were to investigate whether subtle PDD symptoms in the context of ADHD are transmitted in families independent of ADHD, and whether PDD symptom familiality is influenced by gender and age. The sample consisted of 256 sibling pairs with at least one child with ADHD and 147 healthy controls, aged 5-19 years. Children who fulfilled criteria for autistic disorder were excluded. The Children's Social Behavior Questionnaire (CSBQ) was used to assess PDD symptoms. Probands, siblings, and controls were compared using analyses of variance. Sibling correlations were calculated for CSBQ scores after controlling for IQ, ADHD, and comorbid anxiety. In addition, we calculated cross-sibling cross-trait correlations. Both children with ADHD and their siblings had higher PDD levels than healthy controls. The sibling correlation was 0.28 for the CSBQ total scale, with the CSBQ stereotyped behavior subscale showing the strongest sibling correlation (r = 0.35). Sibling correlations remained similar in strength after controlling for IQ and ADHD, and were not confounded by comorbid anxiety. Sibling correlations were higher in female than in male probands. The social subscale showed stronger sibling correlations in elder than in younger sibling pairs. Cross-sibling cross-trait correlations for PDD and ADHD were weak and not-significant. The results confirm that children with ADHD have high levels of PDD symptoms, and further suggest that the familiality of subtle PDD symptoms in the context of ADHD is largely independent from ADHD familiality.

Deficits in visuo-spatial working memory, inhibition and oculomotor control in boys with ADHD and their non-affected brothers.

Few studies have assessed visuo-spatial working memory and inhibition in attention-deficit/hyperactivity disorder (ADHD) by recording saccades and consequently little additional knowledge has been gathered on oculomotor functioning in ADHD. Moreover, this is the first study to report the performance of non-affected siblings of children with ADHD, which may shed light on the familiality of deficits. A total of 14 boys with ADHD, 18 non-affected brothers, and 15 control boys aged 7-14 years, were administered a memory-guided saccade task with delays of three and seven seconds. Familial deficits were found in accuracy of visuo-spatial working memory, percentage of anticipatory saccades, and tendency to overshoot saccades relative to controls. These findings suggest memory-guided saccade deficits may relate to a familial predisposition for ADHD.

Support for an independent familial segregation of executive and intelligence endophenotypes in ADHD families.

BACKGROUND: Impairments in executive functioning (EF) and intelligence quotient (IQ) are frequently observed in children with attention deficit hyperactivity disorder (ADHD). The aim of this paper was twofold: first, to examine whether both domains are viable endophenotypic candidates for ADHD and second to investigate whether deficits in both domains tend to co-segregate within families. METHOD: A large family-based design was used, including 238 ADHD families (545 children) and 147 control families (271 children). Inhibition, visuospatial and verbal working memory, and performance and verbal IQ were analysed. RESULTS: Children with ADHD, and their affected and non-affected siblings were all impaired on the EF measures and verbal IQ (though unimpaired on performance IQ) and all measures correlated between siblings. Correlations and sibling cross-correlations were not significant between EF and IQ, though they were significant between the measures of one domain. Group differences on EF were not explained by group differences on IQ and vice versa. The discrepancy score between EF and IQ correlated between siblings, indicating that siblings resembled each other in their EF-IQ discrepancy instead of having generalized impairments across both domains. Siblings of probands who had an EF but not IQ impairment, showed a comparable disproportionate lower EF score in relation to IQ score. The opposite pattern was not significant. CONCLUSIONS: The results supported the viability of EF and IQ as endophenotypic candidates for ADHD. Most findings support an independent familial segregation of both domains. Within EF, similar familial factors influenced inhibition and working memory. Within IQ, similar familial factors influenced verbal and performance IQ.

Differential family and peer environmental factors are related to severity and comorbidity in children with ADHD.

Behavioral genetic studies imply that salient environmental influences operate within families, making siblings in a family different rather than similar. This study is the first one to examine differential sibling experiences (as measured with the Sibling Inventory of Differential Experience) and its effect on behavioral outcomes within ADHD families. Subjects were 45 Dutch ADHD probands and their unaffected siblings (n = 45) aged 10-18 years. ADHD probands and their unaffected siblings reported differences in sibling interaction, parental treatment, and peer characteristics. These nonshared environmental influences were related to both the severity of ADHD symptoms as well as to comorbid problem behaviors. These findings suggest that environmental influences that operate within ADHD families appear relevant to the severity of problem behaviors of ADHD children and their siblings.

Co-transmission of conduct problems with attention-deficit/hyperactivity disorder: familial evidence for a distinct disorder.

Common disorders of childhood and adolescence are attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). For one to two cases in three diagnosed with ADHD the disorders may be comorbid. However, whether comorbid conduct problems (CP) represents a separate disorder or a severe form of ADHD remains controversial. We investigated familial recurrence patterns of the pure or comorbid condition in families with at least two children and one definite case of DSM-IV ADHDct (combined-type) as part of the International Multicentre ADHD Genetics Study (IMAGE). Using case diagnoses (PACS, parental account) and symptom ratings (Parent/Teacher Strengths and Difficulties [SDQ], and Conners Questionnaires [CPTRS]) we studied 1009 cases (241 with ADHDonly and 768 with ADHD + CP), and their 1591 siblings. CP was defined as > or =4 on the SDQ conduct-subscale, and T > or = 65, on Conners' oppositional-score. Multinomial logistic regression was used to ascertain recurrence risks of the pure and comorbid conditions in the siblings as predicted by the status of the cases. There was a higher relative risk to develop ADHD + CP for siblings of cases with ADHD + CP (RRR = 4.9; 95%CI: 2.59-9.41); p < 0.001) than with ADHDonly. Rates of ADHDonly in siblings of cases with ADHD + CP were lower but significant (RRR = 2.9; 95%CI: 1.6-5.3, p < 0.001). Children with ADHD + CP scored higher on the Conners ADHDct symptom-scales than those with ADHDonly. Our finding that ADHD + CP can represent a familial distinct subtype possibly with a distinct genetic etiology is consistent with a high risk for cosegregation. Further, ADHD + CP can be a more severe disorder than ADHDonly with symptoms stable from childhood through adolescence. The findings provide partial support for the ICD-10 distinction between hyperkinetic disorder (F90.0) and hyperkinetic conduct disorder (F90.1).

Motor coordination problems in children and adolescents with ADHD rated by parents and teachers: effects of age and gender.

OBJECTIVE: ADHD is frequently accompanied by motor coordination problems. However, the co-occurrence of poor motor performance has received less attention in research than other coexisting problems in ADHD. The underlying mechanisms of this association remain unclear. Therefore, we investigated the prevalence of motor coordination problems in a large sample of children with ADHD, and the relationship between motor coordination problems and inattentive and hyperactive/impulsive symptoms. Furthermore, we assessed whether the association between ADHD and motor coordination problems was comparable across ages and was similar for both genders. METHOD: We investigated 486 children with ADHD and 269 normal controls. Motor coordination problems were rated by parents (Developmental Coordination Disorder Questionnaire) and teachers (Groningen Motor Observation Scale). RESULTS: Parents and teachers reported motor coordination problems in about one third of children with ADHD. Problems of fine and gross motor skills, coordination skills and motor control were all related to inattentive rather than hyperactive/impulsive symptoms. Relative to controls, motor coordination problems in ADHD were still present in teenagers according to parents; the prevalence diminished somewhat according to teachers. Boys and girls with ADHD were comparably affected, but motor performance in controls was better in girls than in boys. CONCLUSIONS: Motor coordination problems were reported in one third of children with ADHD and affected both boys and girls. These problems were also apparent in adolescents with ADHD. Clinicians treating children with ADHD should pay attention to co-occurring motor coordination problems because of the high prevalence and the negative impact of motor coordination problems on daily life.

Oculomotor capture in ADHD.

It is generally thought that deficits in response inhibition form an important area of dysfunction in patients with attention-deficit/hyperactivity disorder (ADHD). However, recent research using visual search paradigms seems to suggest that these inhibitory deficits do not extend towards inhibiting irrelevant distractors. Using an oculomotor capture task, the present study investigated whether boys with ADHD and their nonaffected brothers are impaired in suppressing reflexive eye movements to a task-irrelevant onset distractor. Results showed that boys with ADHD had slower responses than controls, but were as accurate in their eye movements as controls. Nonaffected brothers showed similar problems in the speed of responding as their affected brothers, which might suggest that this deficit relates to a familial risk for developing the disorder. Importantly, all three groups were equally captured by the distractor, which shows that boys with ADHD and their brothers are not more distracted by the distractor than are controls. Saccade latency and the proportion of intrusive saccades were related to continuous dimensions of ADHD symptoms, which suggests that these deficits are not simply present or absent, but rather indicate that the severity of these deficits relate to the severity of ADHD. The finding that boys with ADHD (and their nonaffected brothers) did not have problems inhibiting irrelevant distractors contradicts a general response inhibition deficiency in ADHD, which may be explained by the relatively independency of working memory in this type of response inhibition.

Physical activity and executive functions in the elderly with mild cognitive impairment.

The primary goal of the present study was to examine whether in the elderly with mild cognitive impairment (MCI), the effect of physical activity measured directly following treatment, was reflected in an improvement in cognitive functioning in general or in executive functions (EF) in particular. Secondly, this study aimed to compare the effectiveness of two types of intervention, with varying intensities: walking and hand/face exercises. Forty-three frail, advanced elderly subjects (mean age: 86) with MCI were randomly divided into three groups, namely, a walking group (n=15), a group performing hand and face exercises (n=13), and a control group (n=15). All subjects received individual treatment for 30 minutes a day, three times a week, for a period of six weeks. A neuropsychological test battery, administered directly after cessation of treatment, assessed cognitive functioning. The results show that although a (nearly) significant improvement in tasks appealing to EF was observed in both the walking group and the hand/face group compared to the control group, the results should be interpreted with caution. Firm conclusions about the effectiveness of mild physical activity on EF in the oldest old can only be drawn after studies with larger number of subjects.

Motor function under lower and higher controlled processing demands in early and continuously treated phenylketonuria.

This study examined motor control in 61 early and continuously treated patients with phenylketonuria (PKU) and 69 control participants, aged 7 to 14 years. The pursuit task demanded concurrent planning and execution of unpredictable movements, whereas the tracking task required a highly automated circular movement that could be planned in advance. PKU patients showed significantly poorer motor control in both tasks compared with control participants. Deficits were particularly observed for younger patients (age < 11 years). Differences between control participants and PKU patients were significantly greater in the pursuit task compared with the tracking task, indicating more serious deficits when a higher level of controlled processing is required. Correlations with historical phenylalanine levels indicated a later maturation of the level of control required by the pursuit task compared with the tracking task.

The neuropsychological profile of early and continuously treated phenylketonuria: orienting, vigilance, and maintenance versus manipulation-functions of working memory.

In this paper, we review neuropsychological test results of early and continuously treated Phenylketonuria (PKU) patients. To increase insight into the neuropsychological profile of this population, we have attempted to place the results within an attentional network model [Images of the mind, 1994], which proposes interacting but dissociable attentional networks for orienting, vigilance, and executive control of attention. Executive control of attention is discussed against the background of the process-specific theory of working memory (WM) [Handbook of neuropsychology, 1994], which postulates a distinction between the 'maintenance'-function of WM and the 'manipulation and monitoring'-function. Neuropsychological results are presented for 67 early and continuously treated PKU patients and 73 controls aged 7-14 years. Four neuropsychological tasks were employed to measure orienting, mnemonic processing, interference suppression, and top-down control in visual search. No differences were found in orienting and the maintenance-function of WM. In addition to previously reported impairments in sustained attention/vigilance and inhibition of prepotent responding, PKU patients exhibited deficits when top-down control was required in a visual search task, but showed no impairment when interference suppression was required. It is discussed how the specific neuropsychological impairments in PKU may be a consequence of mid-dorsolateral prefrontal cortex (DLPFC) dysfunctioning due to deficiencies in catecholamine modulation.

The Acute versus Chronic Pain Questionnaire (ACPQ) and actual pain experience in older people.

The Acute versus Chronic Pain Questionnaire (ACPQ) was applied to older people. Two groups emerged from an analysis of which an item of each pair (an acute and a chronic affective item) was considered to cause the most suffering. One group of subjects comprised those who expected to suffer more from one or more acute pain items (high-ACPQ group, n = 35). A second group emerged for whom none of the acute items was considered to be a burden (low-ACPQ group, n = 33). It was hypothesized that, compared to the low-ACPQ group, the subjects with high-ACPQ scores selected acute ACPQ-items due to a decline in the experience of chronic affective pain. This hypothesis predicted lower scores on the chronic ACPQ-items and lower scores on scales evaluating the subjects' own chronic affective pain. The results showed that, irrespective of the group, the chronic ACPQ-items were considered to produce the most burdens. However, compared with the low-ACPQ group, the high-ACPQ group reported experiencing significantly more pain from the acute ACPQ-items. Moreover, the latter group indicated suffering less pain from their own chronic pain conditions. The present findings suggest that the selection of one or more acute items of the ACPQ (high-ACPQ group) may point to an alteration in subjects' actual pain experience.

Cranial electrostimulation (CES) in patients with probable Alzheimer's disease.

In one study, behavioral disorders of patients with vascular dementia reacted positively to cranial electrostimulation (CES). In the present study, it was examined whether CES could improve cognition and (affective) behavior in patients with probable Alzheimer's disease (AD). Eighteen AD patients, divided into an experimental and a placebo group, were treated for 30 min per day, 5 days a week, for 6 weeks. No improvements in cognition and (affective) behavior were found after CES.

Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations.

Fifty-seven 7-14-year-old early- and continuously treated phenylketonuria (PKU) patients and 65 matched controls performed a sustained attention task. PKU patients with plasma phenylalanine (phe) levels higher than 360 micromol/l at the time of testing exhibited, compared to controls, lower speed of information processing, a lower ability to inhibit task-induced cognitive interference, less consistent performance, and a stronger decrease of performance level over time. Patients with concurrent phe levels lower than 360 micromol/l did not differ from controls and were significantly better than patients with levels higher than 360 micromol/l. Strong relationships were found with task performance for phe levels during the pre-school years and between ages 5 and 7. These correlations were stronger than those between concurrent phe level and task performance. Significant multiple regression models were found with age accounting for the largest proportion of variance of tempo and tempo fluctuation, and lifetime phe levels (particularly phe level between ages 5 and 7) accounting for the largest proportion of variance of the relative number of inhibition errors and its increase over time. Phe level between ages 5 and 7 also contributed significantly to the variance of tempo and tempo fluctuation. Neuropsychological outcome was independent of IQ. The results indicate that strict dietary adherence during these periods is beneficial to attentional control later in life. We suggest that phe levels should be maintained under 360 micromol/l until approximately age 12, when development of attentional control approaches an adult level.

Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population.

This study addressed two questions: is there an effect of dietary interventions that induce relatively small changes in phenylalanine (Phe) concentration on neuropsychological outcome of early- and continuously treated phenylketonuria (PKU) patients, and are there differences in effects for PKU children and adolescents? To answer the first question, the effect of a short-term dietary intervention (1-2 weeks) was compared for patients whose Phe concentrations increased vs those whose Phe concentrations decreased. Controls were tested twice to control for learning effects. To answer the second question, the effect of dietary interventions was examined in younger patients (aged 7-10 years) and older patients (aged 11-14 years). The effect of dietary interventions was determined with three neuropsychological tasks: one requiring sustained attention; a second demanding maintenance in working memory; and a third in which complex operations were performed in working memory. Relatively small fluctuations in Phe concentration were found to influence neuropsychological task performance of PKU patients. Patients whose Phe concentrations decreased at the second assessment showed generally more improvement than controls. Patients whose Phe concentrations had increased showed minimal improvement or deterioration of task performance. The strongest effects were observed when sustained attention and manipulation of working memory content were required. There were some indications of a greater sensitivity of younger patients to fluctuations in Phe concentration.

DSM-IV internal construct validity: when a taxonomy meets data.

The use of DSM-IV based questionnaires in child psychopathology is on the increase. The internal construct validity of a DSM-IV based model of ADHD, CD, ODD, Generalised Anxiety, and Depression was investigated in 11 samples by confirmatory factor analysis. The factorial structure of these syndrome dimensions was supported by the data. However, the model did not meet absolute standards of good model fit. Two sources of error are discussed in detail: multidimensionality of syndrome scales, and the presence of many symptoms that are diagnostically ambiguous with regard to the targeted syndrome dimension. It is argued that measurement precision may be increased by more careful operationalisation of the symptoms in the questionnaire. Additional approaches towards improved conceptualisation of DSM-IV are briefly discussed. A sharper DSM-IV model may improve the accuracy of inferences based on scale scores and provide more precise research findings with regard to relations with variables external to the taxonomy.

Response execution and inhibition in children with AD/HD and other disruptive disorders: the role of behavioural activation.

This study was aimed at (a) replicating findings of slow and variable response execution and slow response inhibition in Attention Deficit/Hyperactivity Disorder (AD/HD). (b) investigating whether these deficits are specifically related to AD/HD or may also be observed in Oppositional Defiant Disorder (ODD), and children comorbid for AD/HD+ODD, and (c) examining the role of activation level in task performance of children with AD/HD. To meet these aims, the stop paradigm was administered at three levels of activation, using a slow, medium, and fast presentation rate of stimuli, to 4 groups of children: 24 AD/HD children, 21 children with ODD, 27 children with comorbid AD/HD + ODD, and 41 normal controls. As hypothesized, children with AD/HD exhibited a slow response execution process with considerable variability in the speed of responding compared to normal controls. Slow response execution was also observed in the comorbid AD/HD+ODD group but not in the pure ODD group. Larger variability in the speed of responding was common to all disruptive groups compared with controls. In contrast to our hypothesis, no group differences emerged for inhibitory functioning. Finally, the slow event rate condition caused a further deterioration in the speed of the response execution process in both the AD/HD group and ODD group.