Functional MRI, structural MRI and school performance in extremely preterm/extremely low birth weight children

Purpose: Numbers of extremely preterm (EPT) children who survive is steadily increasing, and the majority of these children are in need of help at school. The purpose of this regional, clinical controlled cohort study was to compare anatomy and function of the brain in EPT/extremely low birth weight (ELBW) and term born children at eleven years of age, and study the relation to school performance and cognitive skills. Brain anatomy findings were also compared to young adults born very preterm. Method: A population based cohort of all EPT/ELBW (gestational age (GA) < 28 weeks or birth weight (BW) < 1000g) children born in Hordaland or Sogn- og Fjordane in 1999-2000, was the basis for this thesis. An additional cohort of very preterm (VPT, GA 28-31) young adults (19 years) was included. Both cohorts were compared to a randomly selected, age appropriate term born control group. In paper I, frequency and magnitude of cerebral brain pathology assessed by magnetic resonance imaging (MRI) in EPT, VPT and term born children/young adults were investigated. In paper II, a possible difference in blood oxygen level dependent (BOLD) activation, assessed by functional magnetic resonance imaging (fMRI) and performance during a working memory/selective attention task (the n-back/Stroop task), between EPT/ELBW and term born children was analysed. In paper III, a possible association between school performance, assessed by compulsory national school tests, scores on a working memory/selective attention task, BOLD activation during this task and prematurity was investigated. Results: Paper I: An increased frequency of MRI pathology was found in both the EPT and the VPT cohorts compared to their respective term born control groups. The frequency was higher in the EPT than the VPT group, but also higher in the EPT controls than the VPT controls. Group differences were mainly limited to mild pathology. Paper II: When performing a working memory/selective attention task, the eleven year old regional EPT/ELBW cohort showed the same pattern of brain activation as the term born control group, but the intensity was significantly reduced. The main areas of activation were the prefrontal and parietal areas and the anterior cingulate cortex (ACC). The EPT/ELBW children had fewer correct responses, particularly in the cognitively more demanding settings. Paper III: There was no significant difference in school performance between the children born EPT/ELBW and at term. There was a significant positive association between correct responses on the n-back/Stroop task and school performance, independent of prematurity (r=0.41, p=0.004). BOLD activation was associated with response accuracy on the n-back/Stroop task, but not with school performance. The BOLD activation pattern in children scoring high versus low on the n-back/Stroop task was different compared to the pattern in preterm versus term born control children. Conclusions: The same structural MRI pathology was found in subjects born EPT, VPT and at term, but less frequently in those born at term. MRI lesions were more common in the EPT than the VPT group, but also in the EPT control group compared to the VPT control group. Lack of objective criteria for differentiating mild pathology from normality at the different ages may be the cause of differences in the term born groups. The fMRI study demonstrated that working memory and selective attention capacity was reduced in EPT/ELBW children compared to term born controls, with a matching reduction in BOLD activation in areas responsible for cognitive control. High BOLD brain activation was associated with better cognitive performance. Although cognitive performance was positively associated with school performance, BOLD activation did not reflect school performance

Interdisciplinary Approaches Suggested for Children With Multiple Hospital Referrals Presenting With Non-specific Conditions

Aims: To describe the care patterns of patients with repeated referrals to both mental and somatic specialist healthcare, and to study their diagnostic processes. Methods: In a previous register study patients aged 6–12 years referred to Haukeland University Hospital from 2013 to 2015, we found 922 children with at least three referrals including both somatic and mental health services. Of these, more than one in four (250) were randomly selected and observed from their first hospital episode ever and further after inclusion followed during their next three referrals or until July 2017. Data on referral patterns and diagnostics were collected from patient hospital records. Results: Mean number of referrals was 6.5 prior to inclusion and 4.2 in the follow-up period. At the end of the study period 15% of patients still had a non-specific diagnosis. During the follow-up period, more than half of the children were again referred across the border between somatic and mental healthcare. Conclusion: Very complex care patterns were found for these patients, who were repeatedly being referred and “crossing over” between mental and somatic healthcare. This indicates a need for more interdisciplinary-based approaches both within specialist care and between different care levels to broaden the perspective and achieve shorter time lag before reaching a diagnostic conclusion.publishedVersio

Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R

De novo mutations in GNAO1, the gene encoding the major neuronal G protein Gαo, cause a spectrum of pediatric encephalopathies with seizures, motor dysfunction, and developmental delay. Of the &gt;80 distinct missense pathogenic variants, many appear to uniformly destabilize the guanine nucleotide handling of the mutant protein, speeding up GTP uptake and deactivating GTP hydrolysis. Zinc supplementation emerges as a promising treatment option for this disease, as Zn2+ ions reactivate the GTP hydrolysis on the mutant Gαo and restore cellular interactions for some of the mutants studied earlier. The molecular etiology of GNAO1 encephalopathies needs further elucidation as a prerequisite for the development of efficient therapeutic approaches. In this work, we combine clinical and medical genetics analysis of a novel GNAO1 mutation with an in-depth molecular dissection of the resultant protein variant. We identify two unrelated patients from Norway and France with a previously unknown mutation in GNAO1, c.509C&gt;G that results in the production of the Pro170Arg mutant Gαo, leading to severe developmental and epileptic encephalopathy. Molecular investigations of Pro170Arg identify this mutant as a unique representative of the pathogenic variants. Its 100-fold-accelerated GTP uptake is not accompanied by a loss in GTP hydrolysis; Zn2+ ions induce a previously unseen effect on the mutant, forcing it to lose the bound GTP. Our work combining clinical and molecular analyses discovers a novel, biochemically distinct pathogenic missense variant of GNAO1 laying the ground for personalized treatment development.</p