Associating executive dysfunction with behavioral and socioemotional problems in children with epilepsy. A systematic review.

As children with epilepsy may have a number of learning and behavioral problems, it is important that insight into the underlying neurocognitive differences in these children, which may underlie these areas of challenge is gained. Executive function (EF) problems particularly are associated with specific learning abilities as well as behavioral problems. We aim to review systematically the current status of empirical studies on the association between EF problems and behavior and socioemotional problems in children with epilepsy. After search, 26 empirical studies were identified, most of them of moderate quality. Overall, attention problems were the most reported cognitive deficit in test assessment and the most reported problem by parents. In 54% of the studies, children with epilepsy scored below average compared to controls/normative samples on different aspects of EF. Most studies reported behavior problems, which ranged from mild to severe. Forty-two percent of the studies specifically reported relationships between EF deficits and behavioral problems. In the remaining studies, below average neuropsychological functioning seemed to be accompanied by above average reported behavioral problems. The association was most pronounced for cognitive control and attention in relation to externalizing behavior problems. This cognitive control is also associated with social functioning. Relevant epilepsy variables in this relationship were early age at onset and high seizure frequency.Future research should distinguish specific aspects of EF and take age into account, as this provides more insight on the association between EF and behavior in pediatric epilepsy, which makes it possible to develop appropriate and early intervention.

Executive and Daily Life Functioning Influence the Relationship Between ADHD and Mood Symptoms in University Students.

Objectives: Many studies have indicated a close relationship between ADHD and mood symptoms in university students. In the present study, we explore the role of daily functional impairments and executive functioning in the ADHD-mood relationship. Method: A total of 343 adults (126 males) filled out (a) the Conners' Adult ADHD Rating Scale, (b) the Depression Anxiety and Stress Scale, (c) the Weiss Functional Impairment Rating Scale, and (d) the Executive Function Index Scale. Results: The correlation between mood symptoms and ADHD was .48 (moderate correlation) and dropped to .15 (weak correlation) when controlling for functional problems and executive functioning. Hierarchical regression analyses showed that both functional impairments and executive functioning significantly explained 42% to 53% of the variance of mood symptoms. The addition of ADHD symptoms to the model slightly increased the explained mood variance by only 1%. Conclusion: These findings underline the role of experienced difficulties in triggering mood symptoms in ADHD symptomatology.

Working memory in pediatric frontal lobe epilepsy.

Thirty-two children with frontal lobe epilepsy (FLE) were assessed using different working memory measures. In addition, parents and teachers completed the working memory scale of the Behavioral Rating Inventory of Executive Functioning (BRIEF) to assess the children's "daily life behavior." Results suggested minimal working memory deficits as assessed with performance-based measures. However, the BRIEF showed more working memory deficits suggesting that, on a daily life level, working memory problems seem to be associated with FLE. We discuss why the results of the performance-based measures are not consistent with results of the BRIEF.HighlightsParents as well as teachers report working memory dysfunction in daily life to the same extent.Performance based measures show minimal deficits of working memory.Correlation between working memory tasks and proxy measures are low.

Cognitive control deficits in pediatric frontal lobe epilepsy.

Executive dysfunction and behavioral problems are common in children with epilepsy. Inhibition and shifting, both aspects of cognitive control, seem related to behavior problems and are thought to be driven mainly by the frontal lobes. We investigated if inhibition and shifting deficits are present in children with frontal lobe epilepsy (FLE). Secondly, we studied the relationship between these deficits and behavior problems. Thirty-one children were administered the Stroop Color Word Test and a digital version of the Wisconsin Card Sorting Test (WCST). Parents completed the Behavioral Rating Inventory for Executive Function (BRIEF) and the Achenbach scale (Child Behavior Checklist (CBCL)). About 20% of the children displayed significant low results on the Stroop Effect. About 60% showed shifting problems on the WCST. Parents reported cognitive control and behavioral deficits in about a third of the children. Also, behavioral problems and deficits in inhibition and shifting in daily life (BRIEF) seem to be related. There were no correlations between questionnaires and the Stroop and the WCST. Only in the group of children with many perseverative errors there were especially high correlations between Inhibit of the BRIEF.

Error monitoring and daily life executive functioning.

Error monitoring during task execution is reflected in post-error slowing (PES), which refers to the tendency to slow down performance after making an error in order to prevent future mistakes. The key question of the present study is whether poor error monitoring (reduced magnitude of PES) has negative consequences for daily life executive function skills, as well as functioning in different life settings such as work, family, social, and academic settings. Eighty-five university students performed a lexical decision task and completed The Executive Function Index Scale (EFI), and the Weiss Functional Impairments Rating Scale (WFIRS). Individual academic achievement was measured using the Grade Point Average. Statistical analysis revealed that a decreased magnitude of PES was weakly associated with less efficient planning (one of the executive functions). Results suggest that error monitoring, as measured by PES, was not associated with functioning in a naturalistic environment, but could be interpreted to some extent as an experimental marker of planning in daily life executive functioning.

Executive and behavioral functioning in pediatric frontal lobe epilepsy.

OBJECTIVE: Epilepsy, as a chronic and neurological disease, is generally associated with an increased risk for social and emotional behavior problems in children. These findings are mostly derived from studies on children with different epilepsy types. However, there is limited information about the associations between frontal lobe epilepsy (FLE) and cognitive and behavioral problems. The aim of this study was to examine relationships between FLE and executive and behavioral functioning reported by parents and teachers. MATERIAL AND METHODS: Teachers and parents of 32 children (18 boys, 14 girls, mean age 9; 2 years ±1;6) with a confirmed diagnosis of FLE completed the Behavioral Rating Inventory of Executive Function (BRIEF), the Child Behavior Checklist (CBCL), and Teacher Report Form (TRF). RESULTS: About 25 to 35% of the parents and teachers rated children in the abnormal range of the main scales of the BRIEF, CBCL, and TRF. Teachers tend to report more metacognition problems, whereas parents tend to report more behavior regulation problems. Children with left-sided FLE showed more problems than children with bilateral or right-sided FLE. The whole range of executive dysfunctioning is linked to behavioral dysfunctioning in FLE, but ratings vary across settings and informants. The epilepsy variables age of onset, lateralization, drug load, and duration of epilepsy had only a small and scattered contribution. CONCLUSION: Ratings on the BRIEF, CBCL, and TRF are moderately to highly correlated, suggesting a (strong) link between executive and behavioral functioning. Subtle differences between parents and teachers ratings suggest different executive function demands in various settings.

The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study.

The aim of this study was to examine Health-Related Quality of Life (HRQoL) of patients with Phenylketonuria (PKU) in three different age groups and to investigate the impact of metabolic control and tetrahydrobiopterin (BH4) treatment on HRQoL of these patients. Participants were 90 early-treated patients aged 7 to 40 years (M = 21.0, SD = 10.1) and 109 controls aged 7 to 40.8 years (M = 19.4, SD = 8.6). HRQoL was assessed with the (generic) TNO-AZL questionnaires. Overall, good HRQoL was reported for children below 12 years of age, although they were judged to be less autonomic than their healthy counterparts. Adolescents aged 12-15 years showed poorer HRQoL in the domain "cognitive functioning" compared to controls. For adults ≥16 years, poorer age-controlled HRQoL was found for the domains cognition, depressive moods, and anger, with a further trend for the domain "pain". With respect to metabolic control, only for adult PKU-patients robust associations were observed, indicating poorer functioning, most notably in the domains cognition, sleep, pain, sexuality and anger, with higher historical and concurrent Phe-levels. With respect to BH4-use, effects on HRQoL were again only observed for adult PKU-patients. After controlling for age and historical Phe-levels, small but significant differences in favor of adult BH4-users compared to non-users were observed for HRQoL-categories happiness, anger, and social functioning. Together, these results show that, particularly for adult PKU-patients, HRQoL-problems are evident and that many of these problems are related to (history of) metabolic control. Beneficial effects of BH4-use appear to be limited to those associated with relief from the practical burdens related to the strict dietary treatment regimen, i.e. general mood and sociability, whereas metabolic control is more strongly related to basic physical and cognitive functioning.

Long-Term Follow-Up of Cognition and Mental Health in Adult Phenylketonuria: A PKU-COBESO Study.

Cognitive and mental health problems in individuals with the inherited metabolic disorder phenylketonuria (PKU) have often been associated with metabolic control and its history. For the present study executive functioning (EF) was assessed in 21 PKU patients during childhood (T1, mean age 10.4 years, SD = 2.0) and again in adulthood (T2, mean age 25.8 years, SD = 2.3). At T2 additional assessments of EF in daily life and mental health were performed. Childhood (i.e. 0-12 years) blood phenylalanine was significantly related to cognitive flexibility, executive motor control, EF in daily life and mental health in adulthood (i.e. at T2). Patients with a greater increase in phenylalanine levels after the age of 12 performed more poorly on EF-tasks at T2. Group-based analyses showed that patients with phenylalanine <360 µmol/L in childhood and phenylalanine ≥360 µmol/L from age 13 onwards (n = 11) had better cognitive flexibility and executive motor control than those who had phenylalanine ≥360 µmol/L throughout life (n = 7), supporting the notion that phenylalanine should be below the recommended upper treatment target of 360 µmol/L during childhood for better outcome in adulthood. Despite some results indicating additional influence of phenylalanine levels between 13 and 17 years of age, evidence for a continued influence of phenylalanine levels after childhood on adult outcomes was largely lacking. This may be explained by the fact that the patients in the present study had relatively low phenylalanine levels during childhood (mean: 330 µmol/L, range: 219-581 µmol/L) and thereafter (mean Index of Dietary Control at T2: 464 µmol/L, range: 276-743 µmol/L), which may have buffered against transitory periods of poor metabolic control during adolescence and early adulthood.

Cognitive profile and mental health in adult phenylketonuria: A PKU-COBESO study.

OBJECTIVE: Despite early dietary treatment phenylketonuria patients have lower IQ and poorer executive functions compared to healthy controls. Cognitive problems in phenylketonuria have often been associated with phenylalanine levels. The present study examined the cognitive profile and mental health in adult phenylketonuria, in relation to phenylalanine levels and tetrahydrobiopterin treatment. METHOD: Fifty-seven early treated adult patients with phenylketonuria and 57 healthy matched controls (18-40 years) performed IQ subtests and executive function tests from the Amsterdam Neuropsychological Tasks. They also completed the Adult Self-Report on mental health problems. Analyses of variance were performed to examine group differences. RESULTS: Patients with phenylketonuria had normal IQs although lower than controls. They performed poorer on working memory, inhibitory control, and sustained attention tasks. Patients reported Depressive and Avoidant Personality problems more frequently. Specifically, patients with childhood and lifetime phenylalanine ≥360 µmol/L had poorer cognitive and mental health outcomes than controls. In a subset of patients, comparisons between patients on and off tetrahydrobiopterin showed that nontetrahydrobiopterin users (matched for childhood, pretreatment phenylalanine) were slower (on number of tasks) and reported more mental health problems. CONCLUSIONS: Adult patients had lower IQ and poorer executive functions than controls, resembling problems observed in younger patients with phenylketonuria, as well as more internalizing problems. Group differences and phenylalanine-outcome associations were smaller than those observed in younger populations. A subset of nontetrahydrobiopterin users, matched for childhood phenylalanine level, had a poorer outcome on some tests than tetrahydrobiopterin users, which might indicate an impact of tetrahydrobiopterin treatment beyond lowering phenylalanine. However, clinical relevance needs further investigation. (PsycINFO Database Record

Post-error adjustments and ADHD symptoms in adults: The effect of laterality and state regulation.

Evidence is accumulating that individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) do not adjust their responses after committing errors. Post-error response adjustments are taken to reflect, among others, error monitoring that is essential for learning, flexible behavioural adaptation, and achieving future goals. Many behavioural studies have suggested that atypical lateral brain functions and difficulties in allocating effort to protect performance against stressors (i.e., state regulation) are key factors in ADHD. Whether these factors contribute to the absence of post-error response adjustments in ADHD is unknown. The aim of the present study is to investigate the contribution of the left and right hemispheres and the deficiency in effort allocation to deviant post-error processing in adults with high ADHD symptoms. From a pool of 87 university students, two groups were formed: a group with higher (n=30) and a group with lower (n=26) scores on the ADHD index subscale of the Conners' Adult ADHD Rating Scales. The groups performed a lateralized lexical decision task with a fast and slower stimulus presentation rate. Post-error slowing and post-error response accuracy to stimuli presented in the left and right visual field were measured in each stimulus presentation rate. Results indicated that subjects with the lower ADHD scores slowed down and improved their response accuracy after errors, especially when stimuli were presented in the right visual field at the slower rate. In contrast, subjects with the higher ADHD scores showed no post-error adjustments. Results suggest that during lexical decision performance, impaired error processing in adults with ADHD is associated with affected ability of the left hemisphere to compensate for errors, especially when extra effort allocation is needed to meet task demands.

Linking state regulation, brain laterality, and self-reported attention-deficit/hyperactivity disorder (ADHD) symptoms in adults.

INTRODUCTION: Many clinical studies have shown that performance of subjects with attention-deficit/hyperactivity disorder (ADHD) is impaired when stimuli are presented at a slow rate compared to a medium or fast rate. According to the cognitive-energetic model, this finding may reflect difficulty in allocating sufficient effort to regulate the motor activation state. Other studies have shown that the left hemisphere is relatively responsible for keeping humans motivated, allocating sufficient effort to complete their tasks. This leads to a prediction that poor effort allocation might be associated with an affected left-hemisphere functioning in ADHD. So far, this prediction has not been directly tested, which is the aim of the present study. METHOD: Seventy-seven adults with various scores on the Conners' Adult ADHD Rating Scale performed a lateralized lexical decision task in three conditions with stimuli presented in a fast, a medium, and a slow rate. The left-hemisphere functioning was measured in terms of visual field advantage (better performance for the right than for the left visual field). RESULTS: All subjects showed an increased right visual field advantage for word processing in the slow presentation rate of stimuli compared to the fast and the medium rate. Higher ADHD scores were related to a reduced right visual field advantage in the slow rate only. CONCLUSIONS: The present findings suggest that ADHD symptomatology is associated with less involvement of the left hemisphere when extra effort allocation is needed to optimize the low motor activation state.

Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study.

OBJECTIVE: Early treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills. METHODS: Ninety five PKU-patients (mean age 21.6 ± 10.2 years) and 95 healthy controls (mean age 19.6 ± 8.7 years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, N = 30) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined. RESULTS: PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12 years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12 years. There were no differences with respect to social outcome measures between the BH4 and non-BH4 groups. CONCLUSION: PKU-patients have Phe-related difficulties with social-cognitive functioning and social skills. Problems seem to be more evident among adolescents and adults with PKU. High Phe-levels during childhood and early adolescence seem to be of greater influence than current and recent Phe-levels for these patients.

Environmental Stimulation Does Not Reduce Impulsive Choice in ADHD: A "Pink Noise" Study.

OBJECTIVE: The preference for sooner smaller over larger later rewards is a prominent manifestation of impulsivity in ADHD. According to the State Regulation Deficit (SRD) model, this impulsive choice is the result of impaired regulation of arousal level and can be alleviated by adding environmental stimulation to increase levels of arousal. METHOD: To test this prediction, we studied the effects of adding background "pink noise" on impulsive choice using a classical and new adjusting choice delay task in a sample of 25 children with ADHD and 28 controls. RESULTS: Children with ADHD made more impulsive choices than controls. Adding noise did not reduce impulsive choice in ADHD. CONCLUSION: The findings add to the existing evidence on impulsive choice in ADHD, but no evidence is found for the SRD model's explanation of this behavioral style. Alternative explanations for impulsive choice in ADHD are discussed.

Brain lateralization and self-reported symptoms of ADHD in a population sample of adults: a dimensional approach.

Many clinical studies reported a compromised brain lateralization in patients with Attention-Deficit/Hyperactivity Disorder (ADHD) without being conclusive about whether the deficit existed in the left or right hemisphere. It is well-recognized that studying ADHD dimensionally is more controlled for comorbid problems and medication effects, and provides more accurate assessment of the symptoms. Therefore, the present study applied the dimensional approach to test the relationship between brain lateralization and self-reported ADHD symptoms in a population sample. Eighty-five right-handed university students filled in the Conners' Adult ADHD Rating Scales and performed a lateralization reaction time task. The task consists of two matching conditions: one condition requires nominal identification for letters tapping left hemisphere specialization (Letter Name-Identity condition) and the other one requires physical and visuospatial identification for shapes tapping right hemisphere specialization (Shape Physical-Identity condition). The letters or shapes to be matched are presented in left or right visual field of a fixation cross. For both task conditions, brain lateralization was indexed as the difference in mean reaction time between left and right visual field. Linear regression analyses, controlled for mood symptoms reported by a depression, anxiety, and stress scale, showed no relationship between the variables. These findings from a population sample of adults do not support the dimensionality of lateralized information processing deficit in ADHD symptomatology. However, group comparison analyses showed that subjects with high level of inattention symptoms close to or above the clinical cut-off had a reduced right hemisphere processing in the Shape Physical-Identity condition.

Self-Reported ADHD Symptoms and Interhemispheric Interaction in Adults: A Dimensional Approach.

The present study applied the dimensional approach to test whether self-reported symptoms of Attention Deficit/Hyperactivity Disorder (ADHD) in adults are associated with the speed of interhemispheric interaction. A sample of first grade students (N = 112) completed Conners' Adult ADHD Rating Scales and letter matching reaction time tasks. In the tasks, participants had to match a single target letter displayed below the fixation cross, either on left or right visual field, with one of two letters displayed above the fixation cross, one letter on each visual field. For each task, identical letters were presented either within the same visual field (within hemisphere condition) or across visual fields (across hemisphere condition). Interhemispheric interaction was indexed as the difference in mean reaction time between within and across hemisphere conditions. Comorbid problems such as depression, anxiety, and stress may affect task performance and are controlled for in this study. Findings indicated that self-reported ADHD symptomology, especially hyperactivity, in the presence of stress was weakly but significantly associated with fast interhemispheric interaction.

Brain State Before Error Making in Young Patients With Mild Spastic Cerebral Palsy.

In the present experiment, children with mild spastic cerebral palsy and a control group carried out a memory recognition task. The key question was if errors of the patient group are foreshadowed by attention lapses, by weak motor preparation, or by both. Reaction times together with event-related potentials associated with motor preparation (frontal late contingent negative variation), attention (parietal P300), and response evaluation (parietal error-preceding positivity) were investigated in instances where 3 subsequent correct trials preceded an error. The findings indicated that error responses of the patient group are foreshadowed by weak motor preparation in correct trials directly preceding an error.

Is BRIEF a useful instrument in day to day care of patients with phenylketonuria?

OBJECTIVES: Despite early and continuous treatment many patients with phenylketonuria (PKU) still experience neurocognitive problems. Most problems have been observed in the domain of executive functioning (EF). For regular monitoring of EF, the use of the Behavior Rating Inventory of Executive Function (BRIEF) has been proposed. The aim of this study was to investigate whether the BRIEF is indeed a useful screening instrument in monitoring of adults with PKU. STUDY DESIGN: Adult PKU patients (n = 55; mean age 28.3 ± 6.2 years) filled out the BRIEF-A (higher scores=poorer EF) and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT). RESULTS: Forty-two percent of the PKU patients scored in the borderline/clinical range of the BRIEF-A. Six of the 55 patients (11%) scored >1 SD above the normative mean, mostly on the Metacognition Index. With respect to ANT measurements, patients mainly showed deficits in inhibitory control (34-36%) and cognitive flexibility (31-40%) as compared to the general Dutch population. No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed. Only with respect to inhibitory control, patients scored significantly worse on both BRIEF-A and ANT classifications. No other associations between classification according to the BRIEF-A and classifications according to the ANT tasks were found. CONCLUSIONS: Patients reporting EF problems in daily life are not necessarily those that present with core EF deficits. The results of this study suggest that regular self-administration of the BRIEF-A is not a sufficient way to monitor EF in adult PKU patients.

Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria.

OBJECTIVES: To compare the neurocognitive outcomes of patients with phenylketonuria (PKU) to determine whether decreasing phenylalanine (Phe) levels to <240 is preferable to the use of 360 µmol/L as an upper-target Phe level. An additional aim was to establish the influence of biochemical indices other than Phe on neurocognitive outcomes. STUDY DESIGN: Patients with PKU (n = 63; mean age 10.8 ± 2.3 years) and healthy controls (n = 73; mean age 10.9 ± 2.2 years) performed computerized tasks measuring neurocognitive functions (inhibitory control, cognitive flexibility, and motor control). Lifetime and concurrent blood Phe levels, Phe-to-tyrosine ratio (Phe:Tyr), and Phe variations were examined in relation to neurocognitive outcomes using nonparametric tests and regression analyses. RESULTS: Patients with PKU with Phe levels ≤240 µmol/L and healthy controls performed equally well. Patients with Phe levels between 240 and 360 µmol/L and ≥360 µmol/L performed more poorly than did controls across tasks. Patients with Phe levels ≤240 µmol/L performed significantly better than patients with levels between 240 and 360 µmol/L on tasks measuring inhibitory control and cognitive flexibility. Absolute Phe levels and Phe variation were the best predictors of motor control, whereas Phe:Tyr were the best predictors of inhibitory control. CONCLUSIONS: The results of this study suggest that upper Phe targets should be lowered to optimize neurocognitive outcomes. Moreover, Phe variation and Phe:Tyr appear to be of additional value in treatment monitoring.

The separation of ADHD inattention and hyperactivity-impulsivity symptoms: pathways from genetic effects to cognitive impairments and symptoms.

Both shared and unique genetic risk factors underlie the two symptom domains of attention deficit hyperactivity disorder (ADHD): inattention and hyperactivity-impulsivity. The developmental course and relationship to co-occurring disorders differs across the two symptom domains, highlighting the importance of their partially distinct etiologies. Familial cognitive impairment factors have been identified in ADHD, but whether they show specificity in relation to the two ADHD symptom domains remains poorly understood. We aimed to investigate whether different cognitive impairments are genetically linked to the ADHD symptom domains of inattention versus hyperactivity-impulsivity. We conducted multivariate genetic model fitting analyses on ADHD symptom scores and cognitive data, from go/no-go and fast tasks, collected on a population twin sample of 1,312 children aged 7-10. Reaction time variability (RTV) showed substantial genetic overlap with inattention, as observed in an additive genetic correlation of 0.64, compared to an additive genetic correlation of 0.31 with hyperactivity-impulsivity. Commission errors (CE) showed low additive genetic correlations with both hyperactivity-impulsivity and inattention (genetic correlations of 0.17 and 0.11, respectively). The additive genetic correlation between RTV and CE was also low and non-significant at -0.10, consistent with the etiological separation between the two indices of cognitive impairments. Overall, two key cognitive impairments phenotypically associated with ADHD symptoms, captured by RTV and CE, showed different genetic relationships to the two ADHD symptom domains. The findings extend a previous model of two familial cognitive impairment factors in combined subtype ADHD by separating pathways underlying inattention and hyperactivity-impulsivity symptoms.

Mental health and social functioning in early treated Phenylketonuria: the PKU-COBESO study.

This article presents a new Dutch multicenter study ("PKU-COBESO") into cognitive and behavioral sequelae of early and continuously treated Phenylketonuria (PKU) patients. Part of the study sample will consist of young adult PKU patients who have participated in a large neuropsychological study approximately 10 years ago, when they were 7-to-15-year-olds (Huijbregts et al., 2002 [1]). Their neurocognitive development will be mapped in association with their earlier and continued metabolic history, taking into account possible changes in, for instance, medication. A second part of the sample will consist of PKU patients between the ages of 7 and approximately 40 years (i.e., born in or after 1974, when neonatal screening was introduced in The Netherlands), who have not participated in the earlier neuropsychological study. Again, their cognitive functioning will be related to their metabolic history. With respect to aspects of cognition, there will be an emphasis on executive functioning. The concept of executive functioning will however be extended with further emphasis on the impact of cognitive deficits on the daily lives of PKU patients, aspects of social cognition, social functioning, and behavior/mental health (i.e., COgnition, BEhavior, SOcial functioning: COBESO). In addition to a description of the PKU-COBESO study, some preliminary results with respect to mental health and social functioning will be presented in this article. Thirty adult PKU patients (mean age 27.8, SD 6.4) and 23 PKU patients under the age of 18 years (mean age 11.0, SD 3.3) were compared to 14 (mean age 26.9 years, SD 5.9) and 7 matched controls (mean age 10.5, SD 2.6) respectively, with respect to their scores on the Adult Self-Report or Child Behavior Checklist (measuring mental health problems) and the Social Skills Checklist or Social Skills Rating System (measuring social skills). Whereas there were very few significant group differences (except for mental health problems in the internalizing spectrum for adult PKU patients), possibly due to the small control groups, several significant associations between mental health problems and Phe levels were observed for the PKU patients. Childhood Phe levels and internalizing problems for adult PKU patients were related; concurrent Phe was associated with both internalizing and externalizing behavioral problems for those under the age of 18. These preliminary results underline the importance of early dietary adherence.