Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis.

Hereditary tyrosinemia Type 1 (HT-1) is a rare metabolic disease where the enzyme catalyzing the final step of tyrosine breakdown is defect, leading to accumulation of toxic metabolites. Nitisinone inhibits the degradation of tyrosine and thereby the production of harmful metabolites, however, the concentration of tyrosine also increases. We investigated the relationship between plasma tyrosine concentrations and cognitive functions and how tyrosine levels affected enzyme activities of human tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2). Eight Norwegian children between 6 and 18 years with HT-1 were assessed using questionnaires measuring Attention Deficit Hyperactivity Disorder (ADHD)-symptoms and executive functioning. Recent and past levels of tyrosine were measured and the enzyme activities of TH and TPH2 were studied at conditions replicating normal and pathological tyrosine concentrations. We observed a significant positive correlation between mean tyrosine levels and inattention symptoms. While TH exhibited prominent substrate inhibition kinetics, TPH2 activity also decreased at elevated tyrosine levels. Inhibition of both enzymes may impair syntheses of dopamine, noradrenaline, and serotonin in brain tissue. Inattention in treated HT-1 patients may be related to decreased production of these monoamines. Our results support recommendations of strict guidelines on plasma tyrosine levels in HT-1. ADHD-related deficits, particularly inattention, should be monitored in HT-1 patients to determine whether intervention is necessary.

Multimodal treatment in children and adolescents with attention-deficit/hyperactivity disorder: a 6-month follow-up.

BACKGROUND: Different treatment approaches aimed at reducing attention-deficit/hyperactivity disorder (ADHD) core symptoms are available. However, factors such as intolerance, side-effects, lack of efficacy, high new technology costs, and placebo effect have spurred on an increasing interest in alternative or complementary treatment. AIM: The aim of this study is to explore efficacy of multimodal treatment consisting of standard stimulant medication (methylphenidate) and neurofeedback (NF) in combination, and to compare it with the single treatment in 6-month follow-up in ADHD children and adolescents. METHODS: This randomized controlled trial with 6-month follow-up comprised three treatment arms: multimodal treatment (NF + MED), MED alone, and NF alone. A total of 130 ADHD children/adolescents participated, and 62% completed the study. ADHD core symptoms were recorded pre-/post-treatment, using parents' and teachers' forms taken from Barkley's Defiant Children: A Clinician's Manual for Assessment and Parent Training, and a self-report questionnaire. RESULTS: Significant ADHD core symptom improvements were reported 6 months after treatment completion by parents, teachers, and participants in all three groups, with marked improvement in inattention in all groups. However, no significant improvements in hyperactivity or academic performance were reported by teachers or self-reported by children/adolescents, respectively, in the three groups. Changes obtained with multimodal treatment at 6-month follow-up were comparable to those with single medication treatment, as reported by all participants. CONCLUSIONS: Multimodal treatment using combined stimulant medication and NF showed 6-month efficacy in ADHD treatment. More research is needed to explore whether multimodal treatment is suitable for ADHD children and adolescents who showed a poor response to single medication treatment, and for those who want to reduce the use of stimulant medication.

Ventricular dilatation in ex-prematures: only confined to the occipital region? MRI-based normative standards for 19-year-old ex-prematures without major handicaps.

BACKGROUND: Premature birth may be associated with white matter injury later developing with widening of the ventricles. However, population-based data on normal ventricular size by age are sparse, making the evaluation of possible ventricular dilatation difficult. PURPOSE: To present the linear measurements of the ventricular system, to compare these to subjectively assessed ventricular size, and to examine differences in ventricular size between ex-prematures and controls. MATERIAL AND METHODS: Eligible survivors (n = 113) from the initial birth cohort (n = 217, born in 1986-1988, birth weight <2000 g) underwent MRI during 2006-2007. One hundred and three were ex-premature and included in the study. The ventricular size was subjectively judged by a pediatric neuroradiologist, and scored as normal, mildly, moderately, or severely dilated. Objective measurements, including width and depth of the frontal and occipital horns, were performed in a blinded fashion, by a pediatric radiologist. RESULTS: The normative standards for different parts of the ventricular system in ex-premature young adults varied considerably. We found significant associations between the objective measurements and the subjectively classification of ventricular dilatation. Ex-prematures had smaller heads than those born term (control group). After adjustment for head circumference, there were no significant group differences regarding the frontal horns, but the occipital horns were proportionately wider among ex-prematures. CONCLUSION: Young adults born prematurely, with a birth weight <2000 g, do not have larger lateral ventricles than healthy controls born term, even after correcting for a smaller head size. However, they do have larger occipital horns, confirming previous studies and strengthening our belief of a specific vulnerability of the occipital region.

Neurofeedback for the treatment of children and adolescents with ADHD: a randomized and controlled clinical trial using parental reports.

BACKGROUND: A randomized and controlled clinical study was performed to evaluate the use of neurofeedback (NF) to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. METHODS: The ADHD population was selected from an outpatient clinic for Child and Adolescent Mental Health in Norway. Ninety-one of the 275 children and adolescents ranging in age from 6 to 18 years (10.5 years) participated in 30 sessions of an intensive NF program. The reinforcement contingency was based on the subjects' production of cortical beta1 activity (15-18 Hz). The ADHD participants were randomized into three groups, with 30 in the NF group, 31 controls in a group that was given methylphenidate, and 30 in a group that received NF and methylphenidate. ADHD core symptoms were reported by parents using the parent form of the Clinician's Manual for Assessment by Russell A. Barkley. RESULTS: Ninety-one children and adolescents were effectively randomized by age, sex, intelligence and distribution of ADHD core symptoms. The parents reported significant effects of the treatments, but no significant differences between the treatment groups were observed. CONCLUSIONS: NF was as effective as methylphenidate at treating the attentional and hyperactivity symptoms of ADHD, based on parental reports. TRIAL REGISTRATION: Current Controlled Trials NCT01252446.

Pre-schoolers Referred to a Child and Adolescent Mental Health Clinic: A Hospital Quality Improvement Report.

OBJECTIVE: Aim of the study was to evaluate the patient pathway from referral to assessment and diagnosis of pre-schoolers referred to a Child and Adolescent Mental Health Clinic (CAMHC) in Norway. METHOD: Following data were collected retrospectively from medical records over a 2-year study period: data from clinical interviews for diagnostic evaluation, observation findings in kindergartens and the CAMHC, and results from medical examinations. The times taken from referral to first contact with the CAMHC, then to the first evaluation, and finally to diagnosis were assessed. RESULTS: Of 13 402 pre-schoolers, 88 (0.7%) were referred to the CAMHC, of which 15 refused assessment and 69 completed a diagnostic assessment. Of the assessed children, 15 (21%) did not meet any criteria for an International Classification of Diseases, Tenth revision (ICD-10) diagnosis, 26 (38%) were diagnosed with developmental disorders, and 10 (14%) were given a non-specific diagnosis. For those children without a specific diagnosis, the mean time taken from referral to CAMHC assessment and diagnosis was longer, although not statistically significant, compared with those with a specific diagnosis (P = .52). No significant correlation between referral symptoms and final diagnosis was found. CONCLUSIONS: Pre-schoolers referred to the CAMHC have an increased risk of having developmental disorders. Furthermore, 1 in 5 of the children had comorbidities. We propose more effective health care service by developing an interdisciplinary approach for the management of these children.

Intellectual Disability in KATP Channel Neonatal Diabetes.

OBJECTIVE: Neonatal diabetes has been shown to be associated with high neuropsychiatric morbidity in a genotype-phenotype-dependent manner. However, the specific impact of different mutations on intellectual functioning is still insufficiently characterized. Specifically, only a small number of subjects with developmental delay have been comprehensively assessed, creating a knowledge gap about patients carrying the heaviest burden. RESEARCH DESIGN AND METHODS: We assessed the intellectual functioning and mental health of the complete Norwegian population with KATP channel neonatal diabetes. Eight sulfonylurea-treated children (five with the p.V59M genotype [KCNJ11]) were assessed using age-matched control subjects with type 1 diabetes. The investigations included a physical and motor developmental examination, cerebral MRI, psychometrical examination, and questionnaires assessing intellectual capabilities and psychiatric morbidity. RESULTS: A strong genotype-phenotype correlation was found, revealing the p.V59M genotype as highly associated with substantial intellectual disability, with no significant correlation with the time of sulfonylurea initiation. Consistent with previous studies, other genotypes were associated with minor cognitive impairment. Cerebral MRI verified normal brain anatomy in all but one child. CONCLUSIONS: We here presented a comprehensive assessment of intellectual functioning in the largest cohort of p.V59M subjects to date. The level of intellectual disability revealed not only changes the interpretation of other psychological measures but downplays a strong protective effect of sulfonylurea. Within the scope of this study, we could not find evidence supporting an early treatment start to be beneficial, although a weaker effect cannot be ruled out.

Prenatal and Neonatal Factors Predicting Sleep Problems in Children Born Extremely Preterm or With Extremely Low Birthweight.

Objective: Prematurely born children have been reported to have more sleep problems throughout childhood than children born at term. The aim of this study was to explore if prenatal or neonatal factors can predict sleep problems at age 11 years in children born extremely preterm (EPT). Method: A prospective observational study of all infants who were born EPT in Norway in 1999 and 2000. Prenatal and neonatal data were collected by all Norwegian obstetric and pediatric departments. Parental questionnaire mapped sleep problems and sleep habits at the age of 11 years. Results: Of the 372 eligible children, 221 participated. Of those, 28.1% snored, 27.5% had difficulty falling asleep or frequent awakenings and 17.2% suffered from daytime sleepiness. The mean sleep duration was 9.4 h (range 4.3-11.0 h). Smoking in pregnancy predicted snoring (odds ratio 4.3). Neonatal cerebral hemorrhage and being born small for gestational age predicted difficulty falling asleep or frequent awakenings (odds ratio 2.2 and 2.3). Other morbidities during pregnancy or the newborn period, gestational age or the burden of treatment in the neonatal intensive care unit did not predict sleep problems. None of the studied prenatal or neonatal factors predicted daytime sleepiness or sleep duration <9 h. Conclusion: Of numerous prenatal and neonatal factors, only smoking during pregnancy, being born small for gestational age and cerebral hemorrhage predicted sleep problems at 11 years of age among these children born EPT.

Functional MRI in prenatally opioid-exposed children during a working memory-selective attention task.

BACKGROUND: Opioid induced cerebral changes may contribute to neuropsychological difficulties, like attention problems, frequently reported in prenatally opioid-exposed children. Reduced regional brain volumes have been shown after prenatal opioid exposure, but no study to date has explored the possible impact of prenatal opioids on brain activation patterns. MATERIALS AND METHODS: A hospital-based sample of prenatally opioid-exposed school-aged children (n = 11) and unexposed controls (n = 12) underwent functional magnetic resonance imaging (fMRI) during a combined working memory-selective attention task. Within-group- and between-group analyses of blood-oxygen-level-dependent (BOLD) activation were performed using the SPM12 software package and group differences in task performance were analyzed using Cox proportional hazards modeling. RESULTS: Overall, similar patterns of task related parietal and prefrontal BOLD activations were found in both groups. The opioid-exposed group showed impaired task performance, and during the most cognitive demanding versions of the working memory-selective attention task, increased activation in prefrontal cortical areas was found in the opioid-exposed group compared to controls. CONCLUSION: Our findings suggest that prenatal opioids affect later brain function, visible through changes in BOLD activation patterns. However, results should be considered preliminary until replicated in larger samples better suited to control for potential confounding factors.

Brain morphology in school-aged children with prenatal opioid exposure: A structural MRI study.

BACKGROUND: Both animal and human studies have suggested that prenatal opioid exposure may be detrimental to the developing fetal brain. However, results are somewhat conflicting. Structural brain changes in children with prenatal opioid exposure have been reported in a few studies, and such changes may contribute to neuropsychological impairments observed in exposed children. AIM: To investigate the association between prenatal opioid exposure and brain morphology in school-aged children. STUDY DESIGN: A cross-sectional magnetic resonance imaging (MRI) study of prenatally opioid-exposed children and matched controls. SUBJECTS: A hospital-based sample (n=16) of children aged 10-14years with prenatal exposure to opioids and 1:1 sex- and age-matched unexposed controls. OUTCOME MEASURES: Automated brain volume measures obtained from T1-weighted MRI scans using FreeSurfer. RESULTS: Volumes of the basal ganglia, thalamus, and cerebellar white matter were reduced in the opioid-exposed group, whereas there were no statistically significant differences in global brain measures (total brain, cerebral cortex, and cerebral white matter volumes). CONCLUSIONS: In line with the limited findings reported in the literature to date, our study showed an association between prenatal opioid exposure and reduced regional brain volumes. Adverse effects of opioids on the developing fetal brain may explain this association. However, further research is needed to explore the causal nature and functional consequences of these findings.

Cerebral Magnetic Resonance Imaging in Children With Prenatal Drug Exposure.

This study aimed to evaluate cerebral magnetic resonance imaging (MRI) scans of children with prenatal drug exposure in a clinical context. A hospital-based cohort of 10- to 14-year-old children, prenatally exposed to alcohol, opioids, and polysubstances, and a group of sex- and age-matched controls were examined with cerebral MRI. Scans obtained from 34 exposed children and 40 controls were scored based on the presence and degree of pathology by an experienced pediatric neuroradiologist blinded to the participants' background. Overall visual detectable MRI pathology was found in 35% of the exposed children and 33% of the controls (odds ratio = 1.08; 95% confidence interval = 0.36-3.25). No specific imaging pattern following prenatal drug exposure was seen by the means of simple visual analysis of cerebral MRI scans. Although cerebral MRI is feasible, it is probably of limited value in the clinical assessment of children with prenatal drug exposure.

Self-reported efficacy of neurofeedback treatment in a clinical randomized controlled study of ADHD children and adolescents.

BACKGROUND: Many non-pharmacological treatments for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have been attempted, but reports indicate that most are ineffective. Although neurofeedback (NF) is a treatment approach for children with ADHD that remains promising, a variety of appropriate measures have been used in reporting and evaluating its effect. OBJECTIVE: To report the self-evaluations of NF treatment by children and adolescents with ADHD. METHODS: Randomized controlled trial in 91 children and adolescents with ADHD, aged less than 18 years (mean, 11.2 years) participated in a 30-session program of intensive NF treatment. Participants were randomized and allocated by sequentially numbered sealed envelopes into three groups: methylphenidate (MPH) as an active control group, and two trial groups NF with MPH, and NF alone. ADHD core symptoms and school performance were given on a scale of 1 to 10 using a self-reporting questionnaire, and the changes in these scores after treatment were used as the self-reported evaluation. Basic statistical methods (descriptive, analyses of variance, exact χ (2) test, and paired t-test) were used to investigate the baseline data. Changes in ADHD core symptoms and treatment effects were investigated using a general linear model for repeated measures. RESULTS: Eighty participants completed the treatment study and 73 (91%) responded sufficiently on the self-reporting questionnaires. The treatment groups were comparable in age, sex, and cognition as well as in the baseline levels of core ADHD symptoms. All treatments resulted in significant improvements regarding attention and hyperactivity (P<0.001), and did not differ from each other in effectiveness. However, a significant treatment effect in school performance was observed (P=0.042), in which only the NF group showed a significant improvement. CONCLUSION: The self-reported improvements in ADHD core symptoms and school performance shortly after treatment indicate NF treatment being promising in comparison with medication, suggesting NF as an alternative treatment for children and adolescents who do not respond to MPH, or who suffer side effects. Further long-term follow-up is needed.

Cerebral magnetic resonance imaging findings in children born extremely preterm, very preterm, and at term.

BACKGROUND: The aim of this study was to compare findings on cerebral MRI scans of infants born extremely preterm (i.e., gestation < 28 weeks, very preterm; gestation 28-31 weeks) and at term. METHODS: MRI scans obtained in a cohort of 29 extremely preterm children at 11 years, 51 very preterm young adults at 19 years, and respective term-born controls were scored according to presence and degree of MRI pathology. RESULTS: MRI pathology was found in 76% of the extremely preterm children vs 31% of their controls (odds ratio 4.3; 95% confidence interval, 1.5-137.5) and in 55% of the very preterm group vs 19% of their controls (odds ratio 5.2; 95% confidence interval, 2.5-10.9). The distribution of moderate and severe pathology did not differ among the groups. CONCLUSIONS: The extremely preterm, very preterm, and term subjects shared the same morphological pathology, revealing no specific preterm MRI pattern, but both premature cohorts had higher frequencies. Differences were mainly limited to mild pathology. Whether MRI lesions were more common in the extremely preterm than in the very preterm group is uncertain as the difference in frequency was similar in the two control groups, suggesting a lack of objective criteria for differentiating mild pathology from normality or that MRI scans normally differ at 11 and 19 years of age.