Brain Growth Trajectories Research Articles

Brain Volumes in Opsoclonus-Myoclonus Ataxia Syndrome: A Longitudinal Study.

Little is known about the longitudinal trajectory of brain growth in children with opsoclonus-myoclonus ataxia syndrome. We performed a longitudinal evaluation of brain volumes in pediatric opsoclonus-myoclonus ataxia syndrome patients compared with age- and sex-matched healthy children. This longitudinal case-control study included brain magnetic resonance imaging (MRI) scans from consecutive pediatric opsoclonus-myoclonus ataxia syndrome patients (2009-2020) and age- and sex-matched healthy control children. FreeSurfer analysis provided automatic volumetry of the brain. Paired t tests were performed on the curvature of growth trajectories, with Bonferroni correction. A total of 14 opsoclonus-myoclonus ataxia syndrome patients (12 female) and 474 healthy control children (406 female) were included. Curvature of the growth trajectories of the cerebral white and gray matter, cerebellar white and gray matter, and brainstem differed significantly between opsoclonus-myoclonus ataxia syndrome patients and healthy control children (cerebral white matter, P = .01; cerebral gray matter, P = .01; cerebellar white matter, P < .001; cerebellar gray matter, P = .049; brainstem, P < .01). We found abnormal brain maturation in the supratentorial brain, brainstem, and cerebellum in children with opsoclonus-myoclonus ataxia syndrome.

The giant leap to humankind

Penny (2009) urges that biologists stress more strongly the biological continuity between great apes and humans. Besides stressing genetic similarities, he suggests that great apes also share psychological capacities, including language and tool use. I argue that he underestimates the psychological differences. There is no evidence that great apes have anything approaching human language, or human technological capacity. A main ingredient of human cognition is recursion, which lifted communication to true combinatorial language and simple tool use to advanced combinatorial technology. Recursion may also explain the combinatorial structure of human memory, imagination, and theory of mind. Part of the key, as Penny recognises, may lie in the trajectory of human brain growth, but there is still much to understand in how micro-tweaking of the genome achieved such dramatic differences between ape and human.

Neurodevelopment among children exposed to HIV and uninfected in sub-Saharan Africa.

The population of 16 million children exposed to HIV and uninfected (CHEU) under 15 years of age continues to expand rapidly, and the estimated prevalence of CHEU exceeds 20% in several countries in sub-Saharan Africa with high HIV prevalence. Some evidence suggests that CHEU experience suboptimal neurodevelopmental outcomes compared to children born to women without HIV. In this commentary, we discuss the latest research on biologic and socio-behavioural factors associated with neurodevelopmental outcomes among CHEU. Some but not all studies have noted that CHEU are at risk of poorer neurodevelopment across multiple cognitive domains, most notably in language and motor skills, in diverse settings, ages and using varied assessment tools. Foetal HIV exposure can adversely influence infant immune function, structural brain integrity and growth trajectories. Foetal exposure to antiretrovirals may also influence outcomes. Moreover, general, non-CHEU-specific risk factors for poor neurodevelopment, such as preterm birth, food insecurity, growth faltering and household violence, are amplified among CHEU; addressing these factors will require multi-factorial solutions. There is a need for rigorous harmonised approaches to identify children at the highest risk of delay. In high-burden HIV settings, existing maternal child health programmes serving the general population could adopt structured early child development programmes that educate healthcare workers on CHEU-specific risk factors and train them to conduct rapid neurodevelopmental screening tests. Community-based interventions targeting parent knowledge of optimal caregiving practices have shown to be successful in improving neurodevelopmental outcomes in children and should be adapted for CHEU. CHEU in sub-Saharan Africa have biologic and socio-behavioural factors that may influence their neurodevelopment, brain maturation, immune system and overall health and wellbeing. Multidisciplinary research is needed to disentangle complex interactions between contributing factors. Common environmental and social risk factors for suboptimal neurodevelopment in the general population are disproportionately magnified within the CHEU population, and it is, therefore, important to draw on existing knowledge when considering the socio-behavioural pathways through which HIV exposure could impact CHEU neurodevelopment. Approaches to identify children at greatest risk for poor outcomes and multisectoral interventions are needed to ensure optimal outcomes for CHEU in sub-Saharan Africa.

Relationship of early brain growth pattern measured by ultrasound with neurological outcome at two years of age in very low birth weight infants

The purpose of this study is to define the impact of early brain growth trajectory in very low birth weight infants (VLBWI) on neurological prognosis at 2 years, assessed using sequential ultrasound (US) scans. This is a prospective cohort study with consecutive inclusion of VLBWI ≤ 32 weeks gestational age and ≤ 1500 g at birth. Total brain volume (TBV) was assessed using sequential 3D-US from birth to discharge. Prognosis at 2 years (corrected age) was assessed using the Bayley Scales of Infant and Toddler Development Third Edition. TBV showed slower growth with postmenstrual age (PMA) in those VLBWI who had an adverse cognitive prognosis compared to those with good cognitive prognosis (mean difference in TBV between prognostic groups from 4.56 cm3 at 28 weeks to 42.58 cm3 at 43 weeks) as well as in those with adverse language prognosis (mean difference in TBV from 2.21 cm3 at 28 weeks to 26.98 cm3 at 43 weeks) although other variables showed more impact than TBV on language prognosis (gestational age at birth, brain injury at term, and socioeconomic status). No association was found between TBV and motor prognosis. Brain growth rate was also significantly higher in those VLBWI who presented good cognitive scores (18.78 + (0.33 × (PMA-33)) cm3/week) compared to those with adverse cognitive outcome (13.73 + (0.64 × (PMA-33)) cm3/week). Conclusion: Early altered brain growth is associated with poor cognitive prognosis at 2 years of age. Using sequential US monitoring, we can detect early brain growth deviation in patients who will have adverse cognitive outcomes.What is known:• The prediction of neurodevelopmental outcome of VLBWI is mostly based on the presence of brain injury in US and structural magnetic resonance imaging (MRI) at term. • Some studies have related brain volume measured on MRI at term with neurodevelopment outcome.What is new:• VLBWI with adverse cognitive prognosis at two years of age present smaller brain volumes detectable by sequential US during NICU admission.• Brain volume can be estimated from 2D and 3D US and has prognostic value in VLBWI.

Individual Assessment of Perioperative Brain Growth Trajectories in Infants With Congenital Heart Disease: Correlation With Clinical and Surgical Risk Factors.

Background Infants with congenital heart disease (CHD) are at risk of neurodevelopmental impairments, which may be associated with impaired brain growth. We characterized how perioperative brain growth in infants with CHD deviates from typical trajectories and assessed the relationship between individualized perioperative brain growth and clinical risk factors. Methods and Results A total of 36 infants with CHD underwent preoperative and postoperative brain magnetic resonance imaging. Regional brain volumes were extracted. Normative volumetric development curves were generated using data from 219 healthy infants. Z-scores, representing the degree of positive or negative deviation from the normative mean for age and sex, were calculated for regional brain volumes from each infant with CHD before and after surgery. The degree of Z-score change was correlated with clinical risk factors. Perioperative growth was impaired across the brain, and it was associated with longer postoperative intensive care stay (false discovery rate P<0.05). Higher preoperative creatinine levels were associated with impaired brainstem, caudate nuclei, and right thalamus growth (all false discovery rate P=0.033). Older postnatal age at surgery was associated with impaired brainstem and right lentiform growth (both false discovery rate P=0.042). Longer cardiopulmonary bypass duration was associated with impaired brainstem and right caudate growth (false discovery rate P<0.027). Conclusions Infants with CHD can have impaired brain growth in the immediate postoperative period, the degree of which associates with postoperative intensive care duration. Brainstem growth appears particularly vulnerable to perioperative clinical course, whereas impaired deep gray matter growth was associated with multiple clinical risk factors, possibly reflecting vulnerability of these regions to short- and long-term hypoxic injury.

Deviation From Normative Whole Brain and Deep Gray Matter Growth in Children With MOGAD, MS, and Monophasic Seronegative Demyelination.

Pediatric-acquired demyelination of the CNS associated with antibodies directed against myelin oligodendrocyte glycoprotein (MOG; MOG antibody-associated disease [MOGAD]) occurs as a monophasic or relapsing disease and with variable but often extensive T2 lesions in the brain. The impact of MOGAD on brain growth during maturation is unknown. We quantified the effect of pediatric MOGAD on brain growth trajectories and compared this with the growth trajectories of age-matched and sex-matched healthy children and children with multiple sclerosis (MS, a chronic relapsing disease known to lead to failure of normal brain growth and to loss of brain volume) and monophasic seronegative demyelination. We included children enrolled at incident attack in the prospective longitudinal Canadian Pediatric Demyelinating Disease Study who were recruited at the 3 largest enrollment sites, underwent research brain MRI scans, and were tested for serum MOG-IgG. Children seropositive for MOG-IgG were diagnosed with MOGAD. MS was diagnosed per the 2017 McDonald criteria. Monophasic seronegative demyelination was confirmed in children with no clinical or MRI evidence of recurrent demyelination and negative results for MOG-IgG and aquaporin-4-IgG. Whole and regional brain volumes were computed through symmetric nonlinear registration to templates. We computed age-normalized and sex-normalized z scores for brain volume using a normative dataset of 813 brain MRI scans obtained from typically developing children and used mixed-effect models to assess potential deviation from brain growth trajectories. We assessed brain volumes of 46 children with MOGAD, 26 with MS, and 51 with monophasic seronegative demyelinating syndrome. Children with MOGAD exhibited delayed (p < 0.001) age-expected and sex-expected growth of thalamus, caudate, and globus pallidus, normalized for the whole brain volume. Divergence from expected growth was particularly pronounced in the first year postonset and was detected even in children with monophasic MOGAD. Thalamic volume abnormalities were less pronounced in children with MOGAD compared with those in children with MS. The onset of MOGAD during childhood adversely affects the expected trajectory of growth of deep gray matter structures, with accelerated changes in the months after an acute attack. Further studies are required to better determine the relative impact of monophasic vs relapsing MOGAD and whether relapsing MOGAD with attacks isolated to the optic nerves or spinal cord affects brain volume over time.

Brain growth in fetuses with congenital diaphragmatic hernia.

To perform a volumetric evaluation of the brain in fetuses with right or left congenital diaphragmatic hernia (CDH), and to compare brain growth trajectories to normal fetuses. We identified fetal MRIs performed between 2015 and 2020 in fetuses with a diagnosis of CDH. Gestational age (GA) range was 19-40 weeks. Control subjects consisted of normally developing fetuses between 19 and 40weeks recruited for a separate prospective study. All images were acquired at 3 Tesla and were processed with retrospective motion correction and slice-to-volume reconstruction to generate super-resolution 3-dimensional volumes. These volumes were registered to a common atlas space and segmented in 29 anatomic parcellations. A total of 174 fetal MRIs in 149 fetuses were analyzed (99 controls [mean GA: 29.2±5.2weeks], 34 fetuses left-sided CDH [mean GA: 28.4±5.3weeks], and 16 fetuses right-sided CDH [mean GA: 27±5.4weeks]). In fetuses with left-sided CDH, brain parenchymal volume was -8.0% (95% confidence interval [CI] [-13.1, -2.5]; p=.005) lower than normal controls. Differences ranged from -11.4% (95% CI [-18, -4.3]; p<.001) in the corpus callosum to -4.6% (95% CI [-8.9, -0.1]; p=.044) in the hippocampus. In fetuses with right-sided CDH, brain parenchymal volume was -10.1% (95% CI [-16.8, -2.7]; p=.008) lower than controls. Differences ranged from -14.1% (95% CI [-21, -6.5]; p<.001) in the ventricular zone to -5.6% (95% CI [-9.3, -1.8]; p=.025) in the brainstem. Left and right CDH are associated with lower fetal brain volumes.

Modelling of factors underlying the evolution of human language

A central question in the evolution of human language is how it emerged. Based on recent research across disciplines, we identified three processes proposed as potential driving factors behind the evolution of ‘modern’ language phenotype: i) a reduction in reactive aggression entailing a boost in prosociality and cooperation, ii) a change in early brain growth trajectory that impacted structures like the cerebellum and striatum, and thus likely impacted the (procedural) memory circuits these regions support, and iii) a demographic expansion of H. sapiens during the Middle Pleistocene. While extensively researched on their own, the interaction between these three processes has yet to be investigated systematically. We develop an abstract agent-based model to interrogate the relationship between these three factors and how they influence transmission of information within a population, which we take to be the essence of language. The model abstracts linguistic capacity to an ‘array of skills’ and investigates under what conditions the number of skills increases. The results demonstrate that there is an optimal degree of cooperation and memory capacity at which the amount of transmitted information is the highest. Our model also shows that separate linguistic communities arise under circumstances where individuals have high levels of memory capacity and there is at least a certain degree of non-cooperation. In contrast, we find no significant direct effects for population size in the process of linguistic community formation. Taken together, these results highlight the explanatory benefits of combining insights from cognitive science, archaeology, and computational modelling.

Ultrasonographic evaluation of the early brain growth pattern in very low birth weight infants.

Preterm infants develop smaller brain volumes compared to term newborns. Our aim is to study early brain growth related to perinatal factors in very low birth weight infants (VLBWI). Manual segmentation of total brain volume (TBV) was performed in weekly 3D-ultrasonographies in our cohort of VLBWI. We studied the brain growth pattern related to term magnetic resonance image (term-MRI). We found different brain growth trajectories, with smaller brain volumes and a decrease in brain growth rate in those VLBWI who would later have an abnormal term-MRI (mean TBV 190.68 vs. 213.9 cm3; P = 0.0001 and mean TBV growth rate 14.35 (±1.27) vs. 16.94 (±2.29) cm3/week; P = 0.0001). TBV in those with normal term-MRI was related to gestational age (GA), being small for gestational age (SGA), sex, and duration of parenteral nutrition (TPN) while in those with abnormal term-MRI findings it was related to GA, SGA, TPN, and comorbidities. We found a deceleration in brain growth rate in those with ≥3 comorbidities. An altered brain growth pattern in VLBWI who subsequently present worst scores on term-MRI is related to GA, being SGA and comorbidities. Early ultrasonographic monitoring of TBV could be useful to detect deviated patterns of brain growth. We describe the brain growth pattern in very low birth weight infants during their first postnatal weeks. Brain growth may be affected in the presence of certain perinatal factors and comorbidities, conditioning a deviation of the normal growth pattern. The serial ultrasound follow-up of these at-risk patients allows identifying these brain growth patterns early, which offers a window of opportunity for implementing earlier interventions.

Sexual dimorphism of the fetal brain biometry: an MRI-based study.

Fetal growth assessment is a key component of prenatal care. Sex-specific fetal brain nomograms on ultrasound are available and are clinically used. In recent years, the use of fetal MRI has been increasing; however, there are no sex-specific fetal CNS nomograms on MRI. The study aimed to assess the differences in fetal brain biometry and growth trajectories and to create population-based standards of the fetal brain on MRI. In this cross-sectional study, brain structures of singleton fetuses with normal brain MRI scans were analyzed: biparietal diameter, occipitofrontal diameter, trans-cerebellar diameter, and the corpus callosum were measured and converted into centiles. Sex-specific nomograms were created. A total of 3848 MRI scans were performed in one tertiary medical center between 2011 and 2019; of them, 598 fetuses met the inclusion criteria, 300 males and 298 females between 28- and 37-weeks' gestation. Males had significantly larger occipitofrontal diameter than females (median 75%, IQR 54-88%; median 61%, IQR 40-77%) and biparietal diameter (median 63%, IQR 42-82%; median 50%, IQR 25-73%), respectively (p < 0.001). The cerebellum had the greatest growth rate, with a 1.5-fold increase in diameter between 28 and 37weeks' gestation, with no measurement difference between the sexes (p = 0.239). No significant difference was found in the corpus callosum (p = 0.074). Measuring both sexes on the same nomograms may result in over-estimation of male fetuses and under-estimation of females. We provide fetal sex-specific nomograms on two-dimensional MRI.

Alcohol's effects on the mouse brain are modulated by age and sex.

Binge alcohol consumption is common among adolescents and may impair normal brain development. Emerging, longitudinal studies in adolescents suggest that the effects of binge alcohol exposure on brain structure differ between sexes. To test the hypothesis that the effects of binge alcohol exposure on developmental brain growth trajectories are influenced by age of exposure and sex, adolescent and adult, male and female C57Bl/6 mice (n = 32), were exposed to a binge‐like ethanol (EtOH) exposure paradigm (i.e., 5 cycles of 2 on/2 off days of 5 g/kg EtOH intraperitoneal) or served as saline controls. Longitudinal structural magnetic resonance imaging was acquired at baseline, following binge EtOH exposure, and after 2 weeks of recovery. Alcohol treatment showed interactions with age and sex in altering whole brain volume: adolescents of both sexes demonstrated inhibited whole brain growth relative to their control counterparts, although significance was only attained in female mice which showed a larger magnitude response to EtOH compared to male mice. In region of interest analyses, the somatosensory cortex and cerebellum showed inhibited growth in male and female adolescent mice exposed to EtOH, but the difference relative to controls did not reach multiple comparison‐corrected statistical significance. These data suggest that in mice exposed to binge EtOH treatment, adolescent age of exposure and female sex may confer a higher risk to the detrimental effects of EtOH on brain structure and reinforce the need for direct testing of both sexes.

Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring.

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are conducted in rodents, the nonhuman primate provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a nonhuman primate MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.

Grey and White Matter Volume Changes after Preterm Birth: A Meta-Analytic Approach.

Cross-sectional studies have reported lower brain grey matter volumes (GMV) and white matter volumes (WMV) in preterm (PT) born individuals. While large MRI studies in the normative population have led to a better understanding of brain growth trajectories across the lifespan, such results remain elusive for PT born individuals since large, aggregated datasets of PT born individuals do not exist. To close this gap, we investigated GMV and WMV in PT born individuals as reported in the literature and contrasted it against individual volumetric data and trajectories from the general population. Systematic database search of PubMed and Web of Science in March 2021, and extraction of outcome measures were conducted by two independent reviewers. Individual data on full-term (FT) controls was extracted from freely available databases. Mean GMV, WMV, total intracranial volume (TIV), and mean age at scan were the main outcome measures. Of 532 identified records, nine studies were included with 538 PT born subjects between 1.1 and 28.5 years of age. Reference data was generated from 880 FT controls between 1 and 30 years of age. GMV was consistently lower in PT born individuals from infancy to early adulthood with no evidence for catch-up growth. While GMV changes followed a similar trajectory as FT controls, WMV was particularly low in adolescence after PT birth. Results demonstrate altered brain volumes after PT birth across the first half of lifespan. Future studies should address this issue in large aggregated datasets of PT born individuals.

Rearing Environment and Longitudinal Brain Development in the Pig

ObjectivesArtificial rearing of pigs provides a number of advantages over conventional rearing (i.e., true maternal care), including careful control of nutrient intake and environment conditions. Yet there remains a gap in knowledge when comparing brain development between sow-reared and artificially-reared domestic pigs. Thus, our research sought to model brain development and assess recognition memory in a longitudinal manner by directly comparing rearing environments. MethodsForty-four intact (i.e., not castrated) male pigs were artificially-reared or sow-reared from postnatal day 2 until postnatal week 4. After postnatal week 4, all pigs were housed in a group setting within the same environment until postnatal week 24. Magnetic resonance imaging was conducted on pigs at 8 longitudinal time-points to model developmental trajectories of brain macrostrutural and microstructural outcomes. Additionally, pigs behavior were tested using the novel object recognition task at postnatal weeks 4 and 8. ResultsThroughout the 24-week study, no differences between rearing groups were noted in weekly body weights, average growth and feed intake patterns, or feed efficiency. Whole brain, grey matter, white matter, and cerebrospinal fluid growth patterns also did not differ between pigs assigned to different early-life rearing environments. Moreover, minimal differences in regional absolute volumes and fractional anisotropy developmental trajectories were identified, though artificially-reared pigs exhibited higher initial rates of myelination in multiple brain regions compared with sow-reared pigs. Furthermore, behavioral assessment at both PNW 4 and 8 suggested little influence of rearing environment on recognition memory, however, an age-dependent increase in object recognition memory was observed in the sow-reared group. ConclusionsOur findings suggest that early-life rearing environment has little influence on brain growth trajectories and behavior in the domestic pig. Artificial rearing may promote maturation in certain brain areas but does not appear to elicit long-term effects in outcomes including brain structure or behavior. Funding SourcesThe study was funded by Société des Produits Nestlé SA.

A voxel-wise assessment of growth differences in infants developing autism spectrum disorder

Autism Spectrum Disorder (ASD) is a phenotypically and etiologically heterogeneous developmental disorder typically diagnosed around 4 years of age. The development of biomarkers to help in earlier, presymptomatic diagnosis could facilitate earlier identification and therefore earlier intervention and may lead to better outcomes, as well as providing information to help better understand the underlying mechanisms of ASD. In this study, magnetic resonance imaging (MRI) scans of infants at high familial risk, from the Infant Brain Imaging Study (IBIS), at 6, 12 and 24 months of age were included in a morphological analysis, fitting a mixed-effects model to Tensor Based Morphometry (TBM) results to obtain voxel-wise growth trajectories. Subjects were grouped by familial risk and clinical diagnosis at 2 years of age. Several regions, including the posterior cingulate gyrus, the cingulum, the fusiform gyrus, and the precentral gyrus, showed a significant effect for the interaction of group and age associated with ASD, either as an increased or a decreased growth rate of the cerebrum. In general, our results showed increased growth rate within white matter with decreased growth rate found mostly in grey matter. Overall, the regions showing increased growth rate were larger and more numerous than those with decreased growth rate. These results detail, at the voxel level, differences in brain growth trajectories in ASD during the first years of life, previously reported in terms of overall brain volume and surface area.

Abstract 17303: Longitudinal Cerebral Oxygen Metabolism in Congenital Heart Disease

Background: Brain growth differences are apparent between different types of cyanotic congenital heart disease, but the underlying mechanism remains unclear. Here, we explored and characterized longitudinal cerebral hemodynamic and oxygen metabolism profiles and their relationships to brain growth patterns in infants with single ventricle physiologies (SV) and transposition of the great arteries (TGA). We hypothesized that there are marked differences in cerebral oxygen metabolism in those with SV compared with TGA. Methods: Cerebral blood flow (CBF), oxygen delivery (CDO2) and consumption (CVO2) and brain growth were measured in 103 term newborns with SV and TGA using MRI at pre- and post-surgery and at follow-up. We measured whole brain size by segmenting a 3D steady state free precession acquisition. Cerebral blood flow was measured using phase contrast imaging of the neck vessels and cerebral venous blood oxygen saturation was derived from T2 oximetry of the superior sagittal sinus. TGAs were divided into those with and without ventricular septums. Results: CBF profiles were similar between the 3 lesion groups. Cerebral oxygen delivery trends increased but were not significantly different between cardiac groups. We observed that this may be mediated by different mechanisms: an increase in arterial saturation in TGAs, and an increase in hemoglobin concentration in SVs. Cerebral oxygen consumption in SV infants remained low (p = 0.54) while that of TGA increased over time (TGA IVS p &lt; 0.001; TGA VSD p &lt;0.001) (Fig. 1), mediated by an unchanging oxygen extraction fraction in SVs (p = 0.59). The SV cerebral oxygen consumption profile aligned with their declining brain weight z-score trajectory. Conclusions: In conclusion, there are characteristic differences in hemodynamic adaptations between SVs and TGAs. Changes in oxygen metabolism may be facilitating brain growth trajectories. This informs us of possible mechanisms involved during a time of critical brain development.

Regional Brain Growth Trajectories in Fetuses with Congenital Heart Disease.

Congenital heart disease (CHD) is associated with abnormal brain development in utero. We applied innovative fetal magnetic resonance imaging (MRI) techniques to determine whether reduced fetal cerebral substrate delivery impacts the brain globally, or in a region-specific pattern. Our novel design included two control groups, one with and the other without a family history of CHD, to explore the contribution of shared genes and/or fetal environment to brain development. From 2014 to 2018, we enrolled 179 pregnant women into 4 groups: "HLHS/TGA" fetuses with hypoplastic left heart syndrome (HLHS) or transposition of the great arteries (TGA), diagnoses with lowest fetal cerebral substrate delivery; "CHD-other," with other CHD diagnoses; "CHD-related," healthy with a CHD family history; and "optimal control," healthy without a family history. Two MRIs were obtained between 18 and 40 weeks gestation. Random effect regression models assessed group differences in brain volumes and relationships to hemodynamic variables. HLHS/TGA (n = 24), CHD-other (50), and CHD-related (34) groups each had generally smaller brain volumes than the optimal controls (71). Compared with CHD-related, the HLHS/TGA group had smaller subplate (-13.3% [standard error = 4.3%], p < 0.01) and intermediate (-13.7% [4.3%], p < 0.01) zones, with a similar trend in ventricular zone (-7.1% [1.9%], p = 0.07). These volumetric reductions were associated with lower cerebral substrate delivery. Fetuses with CHD, especially those with lowest cerebral substrate delivery, show a region-specific pattern of small brain volumes and impaired brain growth before 32 weeks gestation. The brains of fetuses with CHD were more similar to those of CHD-related than optimal controls, suggesting genetic or environmental factors also contribute. ANN NEUROL 2021;89:143-157.

Growth trajectories of the human fetal brain in healthy and complicated pregnancies and associations with neurodevelopmental outcome in the early life course

BackgroundThere is a need for non-invasive prenatal markers of the brain to assess fetuses at risk for poor postnatal neurodevelopmental outcome. Periconceptional maternal conditions and pregnancy complications impact prenatal brain development. AimsTo investigate associations between growth trajectories of fetal brain structures and neurodevelopmental outcome in children in the early life course. Study designPericonceptional prospective observational cohort. SubjectsSingleton pregnancies were included in the Rotterdam periconception cohort. Two- and three-dimensional ultrasound scans at 22, 26 and 32 weeks gestational age were analysed. Outcome measuresHead circumference (HC), cerebellum, corpus callosum (CC), Sylvian fissure, insula and parieto-occipital fissure (POF) were measured. Neurodevelopment was evaluated using the Age-and-Stages-questionnaire-3 (ASQ-3) and the Child-Behaviour-Checklist (CBCL) at 2 years of age. Linear mixed models, used to estimate the prenatal brain growth trajectories, and linear regression models, used to evaluate the associations between prenatal brain structures and neurodevelopmental outcomes, were applied in the total study population, and in subgroups: fetal growth restriction (FGR), preterm birth (PTB), fetal congenital heart disease (CHD), and uncomplicated controls. ResultsConsent for participation was received from parents on behalf of their child 138/203 (68%). ASQ-3 was completed in 128/203 children (63%) and CBCL in 93/203 children (46%). Significant smaller subject-specific growth trajectories (growth rate of CC, HC, left insula, left POF and right POF and the baseline size of CC, HC, left POF and right POF) were found in the FGR subgroup, compared to the other subgroups (all p-values <0.05). In the total group (n = 138), the growth rate of the left insula was associated with poorer ASQ-3 score (β = −869.51; p < 0.05). Healthy controls (n = 106) showed a comparable association (β = −1209.87; p < 0.01). FGR (n = 10) showed a larger baseline size of the right Sylvian fissure in association with poorer CBCL-score (β = 4.13; p < 0.01). In CHD (n = 12) the baseline size of the left Sylvian fissure and its growth rate were associated with respectively poorer and better CBCL-scores (β = 3.11; p < 0.01); (β = −171.99; p < 0.01). In PTB (n = 10) no associations were found. ConclusionsThis explorative study suggests associations between ultrasound measurements of fetal brain growth and neurodevelopmental outcome at 2 years of age. In future, this non-invasive technique may improve early identification of fetuses at risk for neurodevelopmental outcome and follow-up postnatal clinical care.

Motion corrected MRI differentiates male and female human brain growth trajectories from mid-gestation

It is of considerable scientific, medical, and societal interest to understand the developmental origins of differences between male and female brains. Here we report the use of advances in MR imaging and analysis to accurately measure global, lobe and millimetre scale growth trajectory patterns over 18 gestational weeks in normal pregnancies with repeated measures. Statistical modelling of absolute growth trajectories revealed underlying differences in many measures, potentially reflecting overall body size differences. However, models of relative growth accounting for global measures revealed a complex temporal form, with strikingly similar cortical development in males and females at lobe scales. In contrast, local cortical growth patterns and larger scale white matter volume and surface measures differed significantly between male and female. Many proportional differences were maintained during neurogenesis and over 18 weeks of growth. These indicate sex related sculpting of neuroanatomy begins early in development, before cortical folding, potentially influencing postnatal development.

Predation drives the evolution of brain cell proliferation and brain allometry in male Trinidadian killifish, Rivulus hartii.

The external environment influences brain cell proliferation, and this might contribute to brain plasticity underlying adaptive behavioural changes. Additionally, internal genetic factors influence the brain cell proliferation rate. However, to date, researchers have not examined the importance of environmental versus genetic factors in causing natural variation in brain cell proliferation. Here, we examine brain cell proliferation and brain growth trajectories in free-living populations of Trinidadian killifish, Rivulus hartii, exposed to contrasting predation environments. Compared to populations without predators, populations in high predation (HP) environments exhibited higher rates of brain cell proliferation and a steeper brain growth trajectory (relative to body size). To test whether these differences in the wild persist in a common garden environment, we reared first-generation fish originating from both predation environments in uniform laboratory conditions. Just as in the wild, brain cell proliferation and brain growth in the common garden were greater in HP populations than in no predation populations. The differences in cell proliferation observed across the brain in both the field and common garden studies indicate that the differences are probably genetically based and are mediated by evolutionary shifts in overall brain growth and life-history traits.