Stephan C. J. Huijbregts

Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS

Objective: To investigate the cognitive skills of patients with relapsing remitting multiple sclerosis (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) relative to healthy control subjects and to assess whether there is heterogeneity in the type of cognitive disabilities demonstrated by patients with different MS phenotypes. Methods: RRMS patients (n = 108), SPMS patients (n = 71), PPMS patients (n = 55), and healthy control subjects (n = 67) underwent neuropsychological assessment with the Brief Repeatable Battery of Neuropsychological Tests. Results: Relative to controls, cognitive performance of RRMS patients was deficient when tasks required higher-order working memory (WM) processes (Word List Generation, 10/36 Spatial Recall Test, Symbol Digit Modalities Test). PPMS and SPMS patients performed poorer than control subjects on all tasks. SPMS patients performed more poorly than PPMS patients when tasks required higher-order WM processes, except when speed of information processing played a relatively important role (Symbol Digit Modalities Test, Paced Auditory Serial Addition Test). Whereas RRMS patients generally performed better than the progressive subtypes, they showed relatively poor verbal fluency. Conclusion: MS patients with different disease courses have different cognitive profiles.

Executive function in early-treated phenylketonuria: Profile and underlying mechanisms

Despite early and continuous dietary intervention, individuals with early-treated phenylketonuria (PKU) experience significant neurocognitive sequelae. An area of cognitive ability that is believed to be particularly affected is executive function (EF). This paper provides a critical review of the evidence for EF impairment in early-treated PKU within the context of recent advances in neuropsychological theory and research. The most consistent findings of PKU-related EF impairment were in executive working memory and prepotent response inhibition. Surprisingly, findings on shifting ability and other more complex aspects of EF were largely equivocal. Cohort (e.g., age, phenylalanine (Phe) levels) and task (e.g., standard clinical versus experimental tasks) related differences likely contributed to the variability in findings reported by these studies. Day-to-day EF also appears to be impaired although the precise pattern of impairment remains unclear, as does the relationship between laboratory measures of EF and questionnaires assessing day-to-day EF. Similarly, whereas several studies have found a relationship between Phe levels and EF, the best predictor variable (e.g., concurrent Phe level, lifetime Phe level, Phe level variability) of current EF performance varied from study to study. Neurologic compromise related to dopamine deficiency, white matter abnormalities, and disruptions in functional connectivity likely underlies the EF impairments described in this review. In closing, this review identifies remaining unanswered questions and future avenues for research.

Cognitive control in adolescents with neurofibromatosis type 1

Neurofibromatosis Type 1 (NF1) is a genetic disorder characterized by partial loss of growth control that affects the central nervous system. NF1 has been consistently associated with cognitive dysfunction, although there is no consensus on the cognitive profile in NF1 or on brain-cognition relationships. To clarify the pattern of cognitive dysfunction, performance of 16 NF1 patients and 16 age- and sex-matched controls (mean age = 14.5 years, SD = 1.3) was compared on computerized tasks measuring perception, executive functioning (inhibitory control, cognitive flexibility, and working memory), and motor control. A further aim of this study was to contrast performance on tasks or task parts requiring varying levels of cognitive control to find out whether this could explain potential difficulties experienced by this population in different cognitive domains or at different stages of information processing. Repeated measures analyses of variance showed that group differences, indicating poorer performance of NF1 patients, varied as a function of the level of cognitive control required. Evidence was also found for more basic motor skill problems in NF1 patients. Furthermore, NF1 patients were generally slower than controls. Results are discussed in the context of what is known about brain-cognition relationships in NF1.

Maternal prenatal smoking, parental antisocial behavior, and early childhood physical aggression.

This study investigated joint effects of maternal prenatal smoking and parental history of antisocial behavior on physical aggression between ages 17 and 42 months in a population sample of children born in Québec (N = 1,745). An analysis of variance (ANOVA) showed significant main effects of maternal prenatal smoking and a significant interaction between maternal prenatal smoking and mothers history of antisocial behavior in the prediction of childrens probability to display high and rising physical aggression. The interaction indicated that the effects of heavy smoking during pregnancy (> or =10 cigarettes/day) were greater when the mother also had a serious history of antisocial behavior. The effects remained significant after the introduction of control variables (e.g., hostile-reactive parenting, family functioning, parental separation/divorce, family income, and maternal education). Another significant interaction not accounted for by control variables was observed for maternal prenatal smoking and family income, indicating more serious effects of maternal prenatal smoking under relatively low-income, conditions. Both interactions indicate critical adversities that, in combination with maternal prenatal smoking, have supra-additive effects on (the development of) physical aggression during early childhood. These findings may have implications for the selection of intervention targets and strategies.

Associations of Maternal Prenatal Smoking with Early Childhood Physical Aggression, Hyperactivity-Impulsivity, and Their Co-Occurrence

This study investigated associations between maternal prenatal smoking and physical aggression (PA), hyperactivity-impulsivity (HI) and co-occurring PA and HI between ages 17 and 42 months in a population sample of children born in Québec (Canada) in 1997/1998 (N=1745). Trajectory model estimation showed three distinct developmental patterns for PA and four for HI. Multinomial regression analyses showed that prenatal smoking significantly predicted children’s likelihood to follow different PA trajectories beyond the effects of other perinatal factors, parental psychopathology, family functioning and parenting, and socio-economic factors. However, prenatal smoking was not a significant predictor of HI in a model with the same control variables. Further multinomial regression analyses showed that, together with gender, presence of siblings and maternal hostile reactive parenting, prenatal smoking independently predicted co-occurring high PA and high HI compared to low levels of both behaviors, to high PA alone, and to high HI alone. These results show that maternal prenatal smoking predicts multiple behavior regulation problems in early childhood.

Key European guidelines for the diagnosis and management of patients with phenylketonuria

We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 μmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 μmol/L and 600 μmol/L, and lifelong treatment is recommended if the concentration is more than 600 μmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 μmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 μmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 μmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy.

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.

Hot and Cool Forms of Inhibitory Control and Externalizing Behavior in Children of Mothers who Smoked during Pregnancy: An Exploratory Study

This study examined whether children exposed to prenatal smoking show deficits in “hot” and/or “cool” executive functioning (EF). Hot EF is involved in regulation of affect and motivation, whereas cool EF is involved in handling abstract, decontextualized problems. Forty 7 to 9-year-old children (15 exposed to prenatal smoking, 25 non-exposed) performed two computerized tasks. The Sustained Attention Dots (SA-Dots) Task (as a measure of “cool” inhibitory control) requires 400 non-dominant hand and 200 dominant hand responses. Inhibitory control of the prepotent response is required for dominant hand responses. The Delay Frustration Task (DeFT) (as a measure of “hot” inhibitory control) consists of 55 simple maths exercises. On a number of trials delays are introduced before the next question appears on the screen. The extent of response-button pressing during delays indicates frustration-induced inhibitory control. Prenatally exposed children showed poorer inhibitory control in the DeFT than non-exposed children. A dose–response relationship was also observed. In addition, prenatally exposed children had significantly higher (dose-dependent) conduct problem- and hyperactivity-inattention scores. There were no significant group differences in inhibitory control scores from the SA-Dots. These results indicate that children exposed to prenatal smoking are at higher risk of hot but not cool executive function deficits.

Cognitive and Motor Control in Neurofibromatosis Type I: Influence of Maturation and Hyperactivity-Inattention

Thirty children and adolescents with Neurofibromatosis Type 1 (NF1) and thirty controls performed neuropsychological tasks with varying cognitive control demands. Group differences, indicating poorer performance of individuals with NF1, increased as a function of cognitive control demands. Group by age interactions indicated greater differences among younger participants with respect to inhibitory control and motor function. When more cognitive control was required, particularly in working memory tasks, group differences were present across different ages. Excluding children with an attention deficit hyperactivity disorder (ADHD) diagnosis, which is highly prevalent among individuals with NF1, and further statistical control for hyperactivity-inattention, also reduced group differences regarding motor function and inhibition, but a cognitive control deficit remained evident for children and adolescents with NF1.

Social information processing in children and adolescents with neurofibromatosis type 1

Aim  To examine social information processing in children and adolescents with neurofibromatosis type 1 (NF1).