[Childhood, adolescence and the risk of addiction: a developmental perspective]. / Enfance, adolescence et risque d'addiction : une perspective développementale.

The period between the ages of 0 and 25 is a crucial phase in human development, during which many aspects of physical, psychological, personality, behavioral and health development take place. Important neurobiological changes during adolescence play a key role in their natural propensity to seek reward, putting them at greater risk of different kind of addictive behaviours. In addition, childhood adversity can foster the emergence of vulnerabilities which, for some, increases the risk of addiction by the time they reach adolescence. This article describes the normal development of the brain from childhood to adulthood, and its influence on addictive behaviours.

La période entre 0 et 25 ans est une phase cruciale du développement humain, au cours de laquelle de nombreux aspects physiques, psychologiques, de la personnalité, du comportement et de la santé se forment. D'importants changements neurobiologiques durant l'adolescence jouent un rôle essentiel dans la propension naturelle des jeunes à rechercher la récompense, ce qui les rend plus à risque de différents types de comportements addictifs. De plus, l'adversité rencontrée pendant l'enfance peut favoriser l'émergence d'une vulnérabilité augmentant, pour certains, le risque d'addictions lorsqu'ils atteignent l'adolescence. Cet article décrit le développement normal du cerveau de l'enfance à l'âge adulte ainsi que l'influence de ce dernier sur les comportements en lien avec les addictions.

Self-Regulation of Attention in Children in a Virtual Classroom Environment: A Feasibility Study.

Attention is a crucial cognitive function that enables us to selectively focus on relevant information from the surrounding world to achieve our goals. Impairments in sustained attention pose challenges, particularly in children with attention deficit hyperactivity disorder, a neurodevelopmental disorder characterized by impulsive and inattentive behavior. While psychostimulant medications are the most effective ADHD treatment, they often yield unwanted side effects, making it crucial to explore non-pharmacological treatments. We propose a groundbreaking protocol that combines electroencephalography-based neurofeedback with virtual reality (VR) as an innovative approach to address attention deficits. By integrating a virtual classroom environment, we aim to enhance the transferability of attentional control skills while simultaneously increasing motivation and interest among children. The present study demonstrates the feasibility of this approach through an initial assessment involving a small group of healthy children, showcasing its potential for future evaluation in ADHD children. Preliminary results indicate high engagement and positive feedback. Pre- and post-protocol assessments via EEG and fMRI recordings suggest changes in attentional function. Further validation is required, but this protocol is a significant advancement in neurofeedback therapy for ADHD. The integration of EEG-NFB and VR presents a novel avenue for enhancing attentional control and addressing behavioral challenges in children with ADHD.

Cortical alterations after very preterm birth and the association with socio-emotional abilities from childhood to early adolescence.

Very preterm birth (VPT; <32 weeks' gestation) leads to a situation where crucial steps of brain development occur in an abnormal ex utero environment, translating to vulnerable cortical and subcortical development. Associated with this atypical brain development, children and adolescents born VPT are at a high risk of socio-emotional difficulties. In the current study, we unravel developmental changes in cortical gray matter (GM) concentration in VPT and term-born controls aged 6-14 years, together with their associations with socio-emotional abilities. T1-weighted images were used to estimate signal intensities of brain tissue types in a single voxel (GM, white matter, and cortico-spinal fluid) and extract GM concentration disentangled from the presence of partial volume effects (PVEs). General linear model analysis was used to compare groups. Socio-emotional abilities were assessed and associations with GM concentration were explored using univariate and multivariate analyses. The effects of prematurity were far-reaching, with intricated patterns of increases and decreases of GM concentration mainly in frontal, temporal, parietal, and cingular regions. Better socio-emotional abilities were associated with increased GM concentration in regions known to be involved in such process for both groups. Our findings suggest that the trajectory of brain development following VPT birth may be fundamentally distinctive and impact socio-emotional abilities.

Corpus callosum structural characteristics in very preterm children and adolescents: Developmental trajectory and relationship to cognitive functioning.

Previous studies suggest that structural alteration of the corpus callosum, i.e., the largest white matter commissural pathway, occurs after a preterm birth in the neonatal period and lasts across development. The present study aims to unravel corpus callosum structural characteristics across childhood and adolescence in very preterm (VPT) individuals, and their associations with general intellectual, executive and socio-emotional functioning. Neuropsychological assessments, T1-weighted and multi-shell diffusion MRI were collected in 79 VPT and 46 full term controls aged 6-14 years. Volumetric, diffusion tensor and neurite orientation dispersion and density imaging (NODDI) measures were extracted on 7 callosal portions using TractSeg. A multivariate data-driven approach (partial least squares correlation) and a cohort-based age normative modelling approach were used to explore associations between callosal characteristics and neuropsychological outcomes. The VPT and a full-term control groups showed similar trends of white-matter maturation over time, i.e., increase FA and reduced ODI, in all callosal segments, that was associated with increase in general intellectual functioning. However, using a cohort-based age-related normative modelling, findings show atypical pattern of callosal development in the VPT group, with reduced callosal maturation over time that was associated with poorer general intellectual and working memory functioning, as well as with lower gestational age.

The effect of mindfulness-based intervention on neurobehavioural functioning and its association with white-matter microstructural changes in preterm young adolescents.

Very preterm (VPT) young adolescents are at high risk of executive, behavioural and socio-emotional difficulties. Previous research has shown significant evidence of the benefits of mindfulness-based intervention (MBI) on these abilities. This study aims to assess the association between the effects of MBI on neurobehavioral functioning and changes in white-matter microstructure in VPT young adolescents who completed an 8-week MBI program. Neurobehavioural assessments (i.e., neuropsychological testing, parents- and self-reported questionnaires) and multi-shell diffusion MRI were performed before and after MBI in 32 VPT young adolescents. Combined diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) measures were extracted on well-defined white matter tracts (TractSeg). A multivariate data-driven approach (partial least squares correlation) was used to explore associations between MBI-related changes on neurobehavioural measures and microstructural changes. The results showed an enhancement of global executive functioning using parent-reported questionnaire after MBI that was associated with a general pattern of increase in fractional anisotropy (FA) and decrease in axonal dispersion (ODI) in white-matter tracts involved in executive processes. Young VPT adolescents with lower gestational age at birth showed the greatest gain in white-matter microstructural changes after MBI.

Large-scale brain network dynamics in very preterm children and relationship with socio-emotional outcomes: an exploratory study.

BACKGROUND: Children born very preterm (VPT; <32 weeks' gestation) are at high risk of neurodevelopmental and behavioural difficulties associated with atypical brain maturation, including socio-emotional difficulties. The analysis of large-scale brain network dynamics during rest allows us to investigate brain functional connectivity and its association with behavioural outcomes. METHODS: Dynamic functional connectivity was extracted by using the innovation-driven co-activation patterns framework in VPT and full-term children aged 6-9 to explore changes in spatial organisation, laterality and temporal dynamics of spontaneous large-scale brain activity (VPT, n = 28; full-term, n = 12). Multivariate analysis was used to explore potential biomarkers for socio-emotional difficulties in VPT children. RESULTS: The spatial organisation of the 13 retrieved functional networks was comparable across groups. Dynamic features and lateralisation of network brain activity were also comparable for all brain networks. Multivariate analysis unveiled group differences in associations between dynamical functional connectivity parameters with socio-emotional abilities. CONCLUSION: In this exploratory study, the group differences observed might reflect reduced degrees of maturation of functional architecture in the VPT group in regard to socio-emotional abilities. Dynamic features of functional connectivity could represent relevant neuroimaging markers and inform on potential mechanisms through which preterm birth leads to neurodevelopmental and behavioural disorders. IMPACT: Spatial organisation of the retrieved resting-state networks was comparable between school-aged very preterm and full-term children. Dynamic features and lateralisation of network brain activity were also comparable across groups. Multivariate pattern analysis revealed different patterns of association between dynamical functional connectivity parameters and socio-emotional abilities in the very preterm and full-term groups. Findings suggest a reduced degree of maturation of the functional architecture in the very preterm group in association with socio-emotional abilities.

The effect of a mindfulness-based intervention on executive, behavioural and socio-emotional competencies in very preterm young adolescents.

Very preterm (VPT) children and adolescents show executive, behavioural and socio-emotional difficulties that persists into adulthood. This study aims to assess the effectiveness of a mindfulness-based intervention (MBI) in improving these competencies in VPT young adolescents using a randomised controlled trial design. 56 young adolescents aged 10-14 years, born before 32 gestational weeks, were randomly assigned to an "intervention" or a "waiting" group and completed an 8-week MBI in a cross-over design. Executive, behavioural and socio-emotional competencies were assessed at three different time points via parent and self-reported questionnaires, neuropsychological testing and computerised tasks. The data were analysed using an intention-to-treat approach with linear regression modelling. Our findings show a beneficial effect of MBI on executive, behavioural and socio-emotional competencies in VPT young adolescents measured by parent questionnaires. Increased executive competencies were also observed on computerised task with enhanced speed of processing after MBI. Two subgroups of participants were created based on measures of prematurity, which revealed increased long-term benefits in the moderate-risk that were not observed in the high-risk subgroups of VPT young adolescents. MBI seems a valuable tool for reducing detrimental consequences of prematurity in young adolescents, especially regarding executive, behavioural and socio-emotional difficulties.Clinical Trial Registration ClinicalTrials, NCT04638101. Registered 20 November 2020-Retrospectively registered, https://clinicaltrials.gov/show/NCT04638101 .

Improving executive, behavioural and socio-emotional competences in very preterm young adolescents through a mindfulness-based intervention: Study protocol and feasibility.

BACKGROUND: Very preterm (VPT) children and adolescents show executive, behavioural and socio-emotional difficulties that persist into adulthood. Despite the promising role of mindfulness-based intervention (MBI) in improving theses competences in children and adolescents, the effectiveness of an MBI has not been assessed in a VPT population so far. AIMS: To describe the protocol and to evaluate the feasibility and acceptability of a clinical trial on an 8-week MBI program to enhance executive and socio-emotional competences in a cohort of VPT young adolescents. STUDY DESIGN: A randomised controlled trial (RCT) and a pre-post intervention designs. PARTICIPANTS: 164 VPT young adolescents from 10 to 14 years old, born before 32 gestational weeks, without major intellectual, sensory or physical impairments, and attending mainstream school, were invited to participate in an 8-week MBI program. OUTCOME MEASURES: Completion rate of the study was recorded. Acceptability, satisfaction and attendance measures of the MBI were collected using self-reported questionnaires and registration of attendance. RESULTS: Of the 63 participants who were enrolled in the study (38.2% of families invited to participate), 52 (82.5%) completed all assessments. Acceptability was high as shown by the high attendance rate in the sessions and the feedback evaluation questionnaire. CONCLUSIONS: Our findings suggest that an MBI is feasible to implement and show a high acceptability among participants. The use of an RCT design in our study constitutes the gold standard for testing the efficacy of such intervention in VPT young adolescents. If effective, the MBI program could potentially be a valuable tool for improving executive and socio-emotional competences in the vulnerable VPT population. TRIAL REGISTRATION: ClinicalTrials, NCT04638101. Registered 19 November 2020 - retrospectively registered, https://clinicaltrials.gov/show/NCT04638101.

Altered orbitofrontal activation in preterm-born young adolescents during performance of a reality filtering task.

Preterm birth is one of the main causes for neurodevelopmental problems, and has been associated with a wide range of impairments in cognitive functions including executive functions and memory. One of the factors contributing to these adverse outcomes is the intrinsic vulnerability of the premature brain. Neuroimaging studies have highlighted structural and functional alterations in several brain regions in preterm individuals across lifetime. The orbitofrontal cortex (OFC) is crucial for a multitude of complex and adaptive behaviours, and its structure is particularly affected by premature birth. Nevertheless, studies on the functional impact of prematurity on the OFC are still missing. Orbitofrontal Reality filtering (ORFi) refers to the ability to distinguish if a thought is relevant to present reality or not. It can be tested using a continuous recognition task and is mediated by the OFC in adults and typically developing young adolescents. Therefore, the ORFi task was used to investigate whether OFC functioning is affected by prematurity. We compared the neural correlates of ORFi in 35 young adolescents born preterm (below 32 weeks of gestation) and aged 10 to 14 years with 25 full term-born controls. Our findings indicate that OFC activation was required only in the full-term group, whereas preterm young adolescents did not involve OFC in processing the ORFi task, despite being able to correctly perform it.

Bi-allelic loss of ERGIC1 causes relatively mild arthrogryposis.

Arthrogryposis describes the presence of multiple joint-contractures. Clinical severity of this phenotype is variable, and more than 400 causative genes have been proposed. Among these, ERGIC1 is a recently reported candidate encoding a putative transmembrane protein of the ER-Golgi interface. Two homozygous missense variants have been reported in patients with relatively mild non-syndromic arthrogryposis. In a consanguineous family with two affected siblings presenting congenital arthrogryposis and some facial dysmorphism we performed prenatal array-CGH, postnatal targeted exome and genome sequencing. Genome sequencing identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents. Our observations validate the pathogenic role of ERGIC1 in congenital arthrogryposis and demonstrate that complete loss of function causes a relatively mild phenotype. These findings will contribute to improve genetic counseling of ERGIC1 mutations.

Shedding light on excessive crying in babies.

BACKGROUND: Excessive and inconsolable crying behavior in otherwise healthy infants (a condition called infant colic (IC)) is very distressing to parents, may lead to maternal depression, and in extreme cases, may result in shaken baby syndrome. Despite the high prevalence of this condition (20% of healthy infants), the underlying neural mechanisms of IC are still unknown. METHODS: By employing the latest magnetic resonance imaging (MRI) techniques in newborns, we prospectively investigated whether newborns' early brain responses to a sensory stimulus (smell) is associated with a subsequent crying behavior. RESULTS: In our sample population of 21 healthy breastfed newborns, those who developed IC at 6 weeks exhibited brain activation and functional connectivity in primary and secondary olfactory brain areas that were distinct from those in babies that did not develop IC. Different activation in brain regions known to be involved in sensory integration was also observed in colicky babies. These responses measured shortly after birth were highly correlated with the mean crying time at 6 weeks of age. CONCLUSIONS: Our results offer novel insights into IC pathophysiology by demonstrating that, shortly after birth, the central nervous system of babies developing IC has already greater reactivity to sensory stimuli than that of their noncolicky peers. IMPACT: Shortly after birth, the central nervous system of colicky infants has a greater sensitivity to olfactory stimuli than that of their noncolicky peers. This early sensitivity explains as much as 48% of their subsequent crying behavior at 6 weeks of life. Brain activation patterns to olfactory stimuli in colicky infants include not only primary olfactory areas but also brain regions involved in pain processing, emotional valence attribution, and self-regulation. This study links earlier findings in fields as diverse as gastroenterology and behavioral psychology and has the potential of helping healthcare professionals to define strategies to advise families.

[Mindfulness based interventions for children and adolescents]. / Interventions basées sur la pleine conscience pour les enfants et les adolescents.

Mindfulness based interventions (MBI) are widely available to adults. Programs are also offered to children and adolescents. Interventions in school and clinical settings are increasingly being published in scientific literature. In the school context, the effects are promising on psychological health, such as stress, anxiety, depression or externalized behaviours, and on executive functions, attention, and socio-emotional skills. In the clinical context, MBI has a particular effect on stress/anxiety and depression as well as on the key symptoms of Attention Deficit Hyperactivity Disorder. These results are very encouraging, but all meta-analyses and literature reviews nevertheless emphasize the need for studies with robust methodology before proposing MBI on a large scale for this population.

Les interventions basées sur la pleine conscience (MBI) sont de plus en plus proposées aux enfants et aux adolescents et font l'objet de nombreuses publications scientifiques. Dans le contexte scolaire, les effets sont prometteurs sur la santé psychologique, comme le stress, l'anxiété, la dépression ou les comportements externalisés et sur les fonctions exécutives, l'attention, et les compétences socioémotionnelles. Dans le contexte clinique, les MBI ont un effet en particulier sur le stress/l'anxiété et la dépression ainsi que sur les symptômes clés du trouble du déficit d'attention avec hyperactivité. Ces résultats sont très encourageants mais toutes les méta-analyses et les revues de la littérature soulignent néanmoins la nécessité de faire des études à la méthodologie robuste avant de proposer des MBI à large échelle.

Neural Correlates of Voice Perception in Newborns and the Influence of Preterm Birth.

Maternal voice is a highly relevant stimulus for newborns. Adult voice processing occurs in specific brain regions. Voice-specific brain areas in newborns and the relevance of an early vocal exposure on these networks have not been defined. This study investigates voice perception in newborns and the impact of prematurity on the cerebral processes. Functional magnetic resonance imaging (fMRI) and high-density electroencephalography (EEG) were used to explore the brain responses to maternal and stranger female voices in full-term newborns and preterm infants at term-equivalent age (TEA). fMRI results and the EEG oddball paradigm showed enhanced processing for voices in preterms at TEA than in full-term infants. Preterm infants showed additional cortical regions involved in voice processing in fMRI and a late mismatch response for maternal voice, considered as a first trace of a recognition process based on memory representation. Full-term newborns showed increased cerebral activity to the stranger voice. Results from fMRI, oddball, and standard auditory EEG paradigms highlighted important change detection responses to novelty after birth. These findings suggest that the main components of the adult voice-processing networks emerge early in development. Moreover, an early postnatal exposure to voices in premature infants might enhance their capacity to process voices.

Get real: Orbitofrontal cortex mediates the ability to sense reality in early adolescents.

INTRODUCTION: Orbitofrontal reality filtering (ORFi) is a memory mechanism that distinguishes whether a thought is relevant to present reality or not. In adults, it is mediated by the orbitofrontal cortex (OFC). This region is still not fully developed in preteenagers, but ORFi is already active from age 7. Here, we probe the neural correlates of ORFi in early adolescents, hypothesizing that OFC mediates the sense of reality in this population. METHODS: Functional magnetic resonance images (fMRI) were acquired in 22 early adolescents during a task composed of two runs: run 1 measuring recognition capacity; run 2 measuring ORFi; each containing two types of images (conditions): distractors (D: images seen for the first time in the current run) and targets (T: images seen for the second time in the current run). Group region of interest (ROI) analysis was performed in a flexible factorial design with two factors (run and condition) using SPM12. RESULTS: We found significant main effects for the experimental run and condition. The bilateral OFC activation was higher during ORFi than during the first run. Additionally, the OFC was more active while processing distractors than targets. CONCLUSION: These results confirm, for the first time, the role of OFC in reality filtering in early adolescents.

fMRI-based Neuronal Response to New Odorants in the Newborn Brain.

The sense of smell is one of the oldest and the most primitive senses mammals possess, it helps to evaluate the surrounding environment. From birth, smell is an important sensory modality, highly relevant for neonatal behavioral adaptation. Even though human newborns seem to be able to perceive and react to olfactory stimuli, there is still a lack of knowledge about the ontogeny of smell and the underlying central processing involved in odor perception in newborns. Brain networks involved in chemosensory perception of odorants are well described in adults, however in newborns there is no evidence that central olfaction is functional given the largely unmyelinated neonatal central nervous system. To examine this question, we used functional magnetic resonance imaging (fMRI) in the newborn to characterize cortical response to olfactory and trigeminal odorants. Here we show that brain response to odors can be measured and localized using functional MRI in newborns. Furthermore, we found that the developing brain, only few days after birth, processes new artificial odorants in similar cortical areas than adults, including piriform cortex, orbitofrontal cortex and insula. Our work provides evidence that human olfaction at birth relies on brain functions that involve all levels of the cortical olfactory system.

Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age.

IMPORTANCE: Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies. OBJECTIVE: To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age. DESIGN, SETTING, AND PARTICIPANTS: A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age. INTERVENTIONS: Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. MAIN OUTCOMES AND MEASURES: The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome. RESULTS: At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89). CONCLUSIONS AND RELEVANCE: In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00413946.

Functional brain maturation assessed during early life correlates with anatomical brain maturation at term-equivalent age in preterm infants.

BACKGROUND: Amplitude-integrated electroencephalogram (aEEG) is a reliable monitoring tool for electrocortical activity with good predictive value in preterm infants. Magnetic resonance imaging (MRI) is a good neuroimaging tool to detect brain lesions and to evaluate brain maturation. We hypothesized that early aEEG measures, recorded over the first 3 d of life in very preterm infants, correlate with brain maturation and injury score assessed by conventional MRI at term-equivalent age. METHODS: Thirty-nine infants born at a mean (range) gestational age (GA) of 29.5 (27.0-31.9) wk and birth weight 1,230 (680-2,020) g had continuous aEEG during the first postnatal 72-84 h. aEEG maturity scores and average maximum and minimum amplitudes were evaluated. Conventional brain MRI was performed at 41.2 (37.1-44.1) wk postmenstrual age (PMA) on a 3T GE system and scored qualitatively for injury and maturation. RESULTS: The average aEEG total maturity score and its cycling subscore were positively and significantly associated with the total MRI maturation score after adjustment for GA, morphine sedation, and PMA at MRI examination. No association was found between the aEEG measures and the MRI injury scores. CONCLUSION: Early aEEG maturity seems to relate to structural MRI brain maturation at term-equivalent age in preterm infants.

Impaired neuromotor outcome in school-age children with congenital hypothyroidism receiving early high-dose substitution treatment.

Congenital hypothyroidism (CH) can lead to intellectual deficits despite early high-dose treatment. Our study aimed to determine whether motor impairments can occur despite early high-dose treatment. Sixty-three children with CH and early (median age of onset of treatment 9 d), high-dose treatment (median starting dose of levothyroxine 14.7 µg/kg/d) were tested with the Zurich Neuromotor Assessment (ZNA) at a median age of 13.8 y (range 7.0-14.2 y). Median z-scores in the children with CH were -0.95 in the pure and -0.56 in the adaptive fine motor component, significantly lower than in the ZNA test norms (p < 0.001 and p = 0.01, respectively). The 26 children with athyreosis were more affected than the 33 children with dysgenesis, particularly in the pure motor (-1.55 versus -0.76, p = 0.03), adaptive fine motor (-1.31 versus 0.13, p < 0.01), and static balance task (-0.47 versus 0.67, p = 0.01). Boys performed worse than girls. Older age at onset of treatment was related to poorer adaptive fine motor performance. Movement quality (assessed by associated movements) was not affected. We conclude that severe CH can cause neuromotor deficits persisting into adolescence. These deficits cannot completely be reversed by postnatal treatment, but earlier age at treatment may reduce the degree of impairment.