Depressive symptoms during the transition to adolescence: Left hippocampal volume as a marker of social context sensitivity.

The transition to adolescence is a critical period for mental health development. Socio-experiential environments play an important role in the emergence of depressive symptoms with some adolescents showing more sensitivity to social contexts than others. Drawing on recent developmental neuroscience advances, we examined whether hippocampal volume amplifies social context effects in the transition to adolescence. We analyzed 2-y longitudinal data from the Adolescent Brain Cognitive Development (ABCD®) study in a diverse sample of 11,832 youth (mean age: 9.914 y; range: 8.917 to 11.083 y; 47.8% girls) from 21 sites across the United States. Socio-experiential environments (i.e., family conflict, primary caregiver's depressive symptoms, parental warmth, peer victimization, and prosocial school environment), hippocampal volume, and a wide range of demographic characteristics were measured at baseline. Youth's symptoms of major depressive disorder were assessed at both baseline and 2 y later. Multilevel mixed-effects linear regression analyses showed that negative social environments (i.e., family conflict, primary caregiver's depressive symptoms, and peer victimization) and the absence of positive social environments (i.e., parental warmth and prosocial school environment) predicted greater increases in youth's depressive symptoms over 2 y. Importantly, left hippocampal volume amplified social context effects such that youth with larger left hippocampal volume experienced greater increases in depressive symptoms in more negative and less positive social environments. Consistent with brain-environment interaction models of mental health, these findings underscore the importance of families, peers, and schools in the development of depression during the transition to adolescence and show how neural structure amplifies social context sensitivity.

Love on the developing brain: Maternal sensitivity and infants' neural responses to emotion in the dorsolateral prefrontal cortex.

Infancy is a sensitive period of development, during which experiences of parental care are particularly important for shaping the developing brain. In a longitudinal study of N = 95 mothers and infants, we examined links between caregiving behavior (maternal sensitivity observed during a mother-infant free-play) and infants' neural response to emotion (happy, angry, and fearful faces) at 5 and 7 months of age. Neural activity was assessed using functional Near-Infrared Spectroscopy (fNIRS) in the dorsolateral prefrontal cortex (dlPFC), a region involved in cognitive control and emotion regulation. Maternal sensitivity was positively correlated with infants' neural responses to happy faces in the bilateral dlPFC and was associated with relative increases in such responses from 5 to 7 months. Multilevel analyses revealed caregiving-related individual differences in infants' neural responses to happy compared to fearful faces in the bilateral dlPFC, as well as other brain regions. We suggest that variability in dlPFC responses to emotion in the developing brain may be one correlate of early experiences of caregiving, with implications for social-emotional functioning and self-regulation.

The extraordinary "ordinary magic" of resilience.

In this essay, I will briefly sample different instances of the utilization of the concept of resilience, attempting to complement a comprehensive representation of the field in the special issue of Development and Psychopathology inspired by the 42nd Minnesota Symposium on Child Psychology, hosted by the Institute of Child Development at the University of Minnesota and held in October of 2022. Having established the general context of the field, I will zoom in on some of its features, which I consider "low-hanging fruit" and which can be harvested in a systematic way to advance the study of resilience in the context of the future of developmental psychopathology.

The future of neuroscience in developmental psychopathology.

Developmental psychopathology started as an intersection of fields and is now a field itself. As we contemplate the future of this field, we consider the ways in which a newer, interdisciplinary field - human developmental neuroscience - can inform, and be informed by, developmental psychopathology. To do so, we outline principles of developmental psychopathology and how they are and/or can be implemented in developmental neuroscience. In turn, we highlight how the collaboration between these fields can lead to richer models and more impactful translation. In doing so, we describe the ways in which models from developmental psychopathology can enrich developmental neuroscience and future directions for developmental psychopathology.

Infants' sex affects neural responses to affective touch in early infancy.

Social touch is closely related to the establishment and maintenance of social bonds in humans, and the sensory brain circuit for gentle brushing is already active soon after birth. Brain development is known to be sexually dimorphic, but the potential effect of sex on brain activation to gentle touch remains unknown. Here, we examined brain activation to gentle skin stroking, a tactile stimulation that resembles affective or social touch, in term-born neonates. Eighteen infants aged 11-36 days, recruited from the FinnBrain Birth Cohort Study, were included in the study. During natural sleep, soft brush strokes were applied to the skin of the right leg during functional magnetic resonance imaging (fMRI) at 3 cm/s velocity. We examined potential differences in brain activation between males (n = 10) and females (n = 8) and found that females had larger blood oxygenation level dependent (BOLD) responses (brushing vs. rest) in bilateral orbitofrontal cortex (OFC), right ventral striatum and bilateral inferior striatum, pons, and cerebellum compared to males. Moreover, the psychophysiological interactions (PPI) analysis, setting the left and right OFC as seed regions, revealed significant differences between males and females. Females exhibited stronger PPI connectivity between the left OFC and posterior cingulate or cuneus. Our work suggests that social touch neural responses are different in male and female neonates, which may have major ramifications for later brain, cognitive, and social development. Finally, many of the sexually dimorphic brain responses were subcortical, not captured by surface-based neuroimaging, indicating that fMRI will be a relevant technique for future studies.

[Developing Knowledge Together: Participatory Methods in Psychological and Neuroscientific Research with Children and Adolescents]. / Wissen gemeinsam erarbeiten: Partizipative Methoden in der psychologischen und neurowissenschaftlichen Forschung mit Kindern und Jugendlichen.

Developing Knowledge Together: Participatory Methods in Psychological and Neuroscientific Research with Children and Adolescents Abstract: Participatory action research understands the implementation of research as a cooperation or coproduction of researchers with nonscientific individuals. However, the general knowledge about the participatory approach as well as participatory methods and their implementation is still limited. Especially the active involvement and empowerment of children and adolescents require special measures and a creative and flexible application of various methods. In addition, the use of participatory methods in neurodevelopmental research first demands prior explanation of complex techniques to successfully implement the cooperation and coproduction between researchers and children and adolescents. In this contribution, we emphasize the relevance of the participatory approach for scientific work, present different methods that allow an introduction of complex techniques in neurodevelopmental research, and illustrate how to systematically apply this approach to research in children and adolescents.

Emergence and organization of adult brain function throughout child development.

Adult cognitive neuroscience has guided the study of human brain development by identifying regions associated with cognitive functions at maturity. The activity, connectivity, and structure of a region can be compared across ages to characterize the developmental trajectory of the corresponding function. However, developmental differences may reflect both the maturation of the function and also its organization across the brain. That is, a function may be present in children but supported by different brain regions, leading its maturity to be underestimated. Here we test the presence, maturity, and localization of adult functions in children using shared response modeling, a machine learning approach for functional alignment. After learning a lower-dimensional feature space from fMRI activity as adults watched a movie, we translated these shared features into the anatomical brain space of children 3-12 years old. To evaluate functional maturity, we correlated this reconstructed activity with children's actual fMRI activity as they watched the same movie. We found reliable correlations throughout cortex, even in the youngest children. The strength of the correlation in the precuneus, inferior frontal gyrus, and lateral occipital cortex predicted chronological age. These age-related changes were driven by three types of developmental trajectories: emergence from absence to presence, consistency in anatomical expression, and reorganization from one anatomical region to another. We also found evidence that the processing of pain-related events in the movie underwent reorganization across childhood. This data-driven, naturalistic approach provides a new perspective on the development of functional neuroanatomy throughout childhood.

Déficits précoces de l'empathie et psychopathologie Early empathy deficits and psychopathology.

Empathy is a complex social-cognitive ability that is best understood by distinguishing its emotional, cognitive and motivational dimensions, which from early childhood interact between the child and her/his social environment. To date, among the many factors that are acknowledged to influence the development of empathy, children's temperament and parenting behaviors have been identified as interacting in predicting the extent to which children demonstrate empathic responses. Recent studies in developmental social neuroscience cast light on the neural networks engaged in the development of each of the dimensions that constitute empathy, which are needed to navigate social interaction and establishing positive social relationships. Indeed, early deficits in empathic processes can lead to difficulties in socialization, particularly associated with reduced attention to others' emotions, especially when they are suffering, a lesser degree of remorse and guilt, and a greater tendency to ignore social norms or break the rules. Difficulties in socialization are particularly visible in two well-known developmental disorders: children with autism spectrum disorders (ASD) and children with conduct disorder and callous unemotional traits (CU). This paper provides a critical and selective review of recent empirical studies in psychopathology and developmental neuroscience by addressing the dimensions underlying empathy, specifically emotional sharing and caring for others. For children with ASD, some studies report that they pay less attention to another person in distress. However, functional neuroimaging studies conducted with ASD adolescents indicate that the emotional dimension appears to be preserved, but a lack of emotional self-regulation may impair them from experiencing empathic concern. Children with conduct disorder and CU traits clearly manifest a reduced autonomic nervous system response to others' distress or suffering. This may account for their disregard or contempt for others' well-being and social norms. Functional neuroimaging studies show that atypical patterns of brain activity at 15 months of age can predict later severe conduct disorder. Neural regions engaged in emotional processing such as the anterior cingulate cortex, insula and amygdala shown reduced activation to empathy-eliciting stimuli in children with CU. Finally, the genetic nature of CU traits is highlighted in several studies. We conclude by proposing several avenues for developmental research to identify biomarkers from an early age and by inviting to focus on psychological interventions with those populations accordingly.

L'empathie est un phénomène complexe dont la compréhension est améliorée par la distinction de ses dimensions émotionnelle, cognitive et motivationnelle, qui interagissent entre I'individu et son l'environnement dès le plus jeune âge. Des déficits précoces dans les processus empathiques peuvent conduire à des difficultés de socialisation qui se manifestent particulièrement chez les enfants présentant des troubles du spectre de l'autisme et le trouble des conduites. Cette revue critique des connaissances en psychopathologie et neuroscience développementale aborde les dimensions sous-jacentes à l'empathie que sont le partage affectif et le souci de l'autre. L'article conclut en proposant des pistes de recherche pour identifier des biomarqueurs précoces.

Personalized connectome fingerprints: Their importance in cognition from childhood to adult years.

Structural neural network architecture patterns in the human brain could be related to individual differences in phenotype, behavior, genetic determinants, and clinical outcomes from neuropsychiatric disorders. Recent studies have indicated that a personalized neural (brain) fingerprint can be identified from structural brain connectomes. However, the accuracy, reproducibility and translational potential of personalized fingerprints in terms of cognition is not yet fully determined. In this study, we introduce a dynamic connectome modeling approach to identify a critical set of white matter subnetworks that can be used as a personalized fingerprint. Several individual variable assessments were performed that demonstrate the accuracy and practicality of personalized fingerprint, specifically predicting the identity and IQ of middle age adults, and the developmental quotient in toddlers. Our findings suggest the fingerprint found by our dynamic modeling approach is sufficient for differentiation between individuals, and is also capable of predicting general intellectual ability across human development.

Spatial migration of human reward processing with functional development: Evidence from quantitative meta-analyses.

Functional magnetic resonance imaging (fMRI) studies have shown notable age-dependent differences in reward processing. We analyzed data from a total of 554 children, 1,059 adolescents, and 1,831 adults from 70 articles. Quantitative meta-analyses results show that adults engage an extended set of regions that include anterior and posterior cingulate gyri, insula, basal ganglia, and thalamus. Adolescents engage the posterior cingulate and middle frontal gyri as well as the insula and amygdala, whereas children show concordance in right insula and striatal regions almost exclusively. Our data support the notion of reorganization of function over childhood and adolescence and may inform current hypotheses relating to decision-making across age.

Quantifying the individual auditory and visual brain response in 7-month-old infants watching a brief cartoon movie.

Electroencephalography (EEG) continues to be the most popular method to investigate cognitive brain mechanisms in young children and infants. Most infant studies rely on the well-established and easy-to-use event-related brain potential (ERP). As a severe disadvantage, ERP computation requires a large number of repetitions of items from the same stimulus-category, compromising both ERPs' reliability and their ecological validity in infant research. We here explore a way to investigate infant continuous EEG responses to an ongoing, engaging signal (i.e., "neural tracking") by using multivariate temporal response functions (mTRFs), an approach increasingly popular in adult EEG research. N = 52 infants watched a 5-min episode of an age-appropriate cartoon while the EEG signal was recorded. We estimated and validated forward encoding models of auditory-envelope and visual-motion features. We compared individual and group-based ('generic') models of the infant brain response to comparison data from N = 28 adults. The generic model yielded clearly defined response functions for both, the auditory and the motion regressor. Importantly, this response profile was present also on an individual level, albeit with lower precision of the estimate but above-chance predictive accuracy for the modelled individual brain responses. In sum, we demonstrate that mTRFs are a feasible way of analyzing continuous EEG responses in infants. We observe robust response estimates both across and within participants from only 5 min of recorded EEG signal. Our results open ways for incorporating more engaging and more ecologically valid stimulus materials when probing cognitive, perceptual, and affective processes in infants and young children.

New tools for studying microglia in the mouse and human CNS.

The specific function of microglia, the tissue resident macrophages of the brain and spinal cord, has been difficult to ascertain because of a lack of tools to distinguish microglia from other immune cells, thereby limiting specific immunostaining, purification, and manipulation. Because of their unique developmental origins and predicted functions, the distinction of microglia from other myeloid cells is critically important for understanding brain development and disease; better tools would greatly facilitate studies of microglia function in the developing, adult, and injured CNS. Here, we identify transmembrane protein 119 (Tmem119), a cell-surface protein of unknown function, as a highly expressed microglia-specific marker in both mouse and human. We developed monoclonal antibodies to its intracellular and extracellular domains that enable the immunostaining of microglia in histological sections in healthy and diseased brains, as well as isolation of pure nonactivated microglia by FACS. Using our antibodies, we provide, to our knowledge, the first RNAseq profiles of highly pure mouse microglia during development and after an immune challenge. We used these to demonstrate that mouse microglia mature by the second postnatal week and to predict novel microglial functions. Together, we anticipate these resources will be valuable for the future study and understanding of microglia in health and disease.

Paediatric population neuroimaging and the Generation R Study: the second wave.

Paediatric population neuroimaging is an emerging field that falls at the intersection between developmental neuroscience and epidemiology. A key feature of population neuroimaging studies involves large-scale recruitment that is representative of the general population. One successful approach for population neuroimaging is to embed neuroimaging studies within large epidemiological cohorts. The Generation R Study is a large, prospective population-based birth-cohort in which nearly 10,000 pregnant mothers were recruited between 2002 and 2006 with repeated measurements in the children and their parents over time. Magnetic resonance imaging was included in 2009 with the scanning of 1070 6-to-9-year-old children. The second neuroimaging wave was initiated in April 2013 with a total of 4245 visiting the MRI suite and 4087 9-to-11-year-old children being scanned. The sequences included high-resolution structural MRI, 35-direction diffusion weighted imaging, and a 6 min and 2 s resting-state functional MRI scan. The goal of this paper is to provide an overview of the imaging protocol and the overlap between the neuroimaging data and metadata. We conclude by providing a brief overview of results from our first wave of neuroimaging, which highlights a diverse array of questions that can be addressed by merging the fields of developmental neuroscience and epidemiology.

Nogo-A is a negative regulator of CNS angiogenesis.

Nogo-A is an important axonal growth inhibitor in the adult and developing CNS. In vitro, Nogo-A has been shown to inhibit migration and cell spreading of neuronal and nonneuronal cell types. Here, we studied in vivo and in vitro effects of Nogo-A on vascular endothelial cells during angiogenesis of the early postnatal brain and retina in which Nogo-A is expressed by many types of neurons. Genetic ablation or virus-mediated knock down of Nogo-A or neutralization of Nogo-A with an antibody caused a marked increase in the blood vessel density in vivo. In culture, Nogo-A inhibited spreading, migration, and sprouting of primary brain microvascular endothelial cells (MVECs) in a dose-dependent manner and induced the retraction of MVEC lamellipodia and filopodia. Mechanistically, we show that only the Nogo-A-specific Delta 20 domain exerts inhibitory effects on MVECs, but the Nogo-66 fragment, an inhibitory domain common to Nogo-A, -B, and -C, does not. Furthermore, the action of Nogo-A Delta 20 on MVECs required the intracellular activation of the Ras homolog gene family, member A (Rho-A)-associated, coiled-coil containing protein kinase (ROCK)-Myosin II pathway. The inhibitory effects of early postnatal brain membranes or cultured neurons on MVECs were relieved significantly by anti-Nogo-A antibodies. These findings identify Nogo-A as an important negative regulator of developmental angiogenesis in the CNS. They may have important implications in CNS pathologies involving angiogenesis such as stroke, brain tumors, and retinopathies.

Mea6/cTAGE5 cooperates with TRAPPC12 to regulate PTN secretion and white matter development.

Mutations of TRAPPC12 are associated with progressive childhood encephalopathy including abnormal white matter. However, the underlying pathogenesis is still unclear. Here, we found that Trappc12 deficiency in CG4 and oligodendrocyte progenitor cells (OPCs) affects their differentiation and maturation. In addition, TRAPPC12 interacts with Mea6/cTAGE5, and Mea6/cTAGE5 ablation in OPCs affects their proliferation and differentiation, leading to marked hypomyelination, compromised synaptic functionality, and aberrant behaviors in mice. We reveal that TRAPPC12 is associated with COPII components at ER exit site, and Mea6/cTAGE5 cKO disrupts the trafficking pathway by affecting the distribution and/or expression of TRAPPC12, SEC13, SEC31A, and SAR1. Moreover, we observed marked disturbances in the secretion of pleiotrophin (PTN) in Mea6-deficient OPCs. Notably, exogenous PTN supplementation ameliorated the differentiation deficits of these OPCs. Collectively, our findings indicate that the association between TRAPPC12 and MEA6 is important for cargo trafficking and white matter development.

Perceptual reorganization from prior knowledge emerges late in childhood.

Human vision relies heavily on prior knowledge. Here, we show for the first time that prior-knowledge-induced reshaping of visual inputs emerges gradually in late childhood. To isolate the effects of prior knowledge on perception, we presented 4- to 12-year-olds and adults with two-tone images - hard-to-recognize degraded photos. In adults, seeing the original photo triggers perceptual reorganization, causing mandatory recognition of the two-tone version. This involves top-down signaling from higher-order brain areas to early visual cortex. We show that children younger than 7-9 years do not experience this knowledge-guided shift, despite viewing the original photo immediately before each two-tone. To assess computations underlying this development, we compared human performance to three neural networks with varying architectures. The best-performing model behaved much like 4- to 5-year-olds, displaying feature-based rather than holistic processing strategies. The reconciliation of prior knowledge with sensory input undergoes a striking age-related shift, which may underpin the development of many perceptual abilities.

Sustained generation of neurons destined for neocortex with oxidative metabolic upregulation upon filamin abrogation.

Neurons in the neocortex are generated during embryonic development. While the adult ventricular-subventricular zone (V-SVZ) contains cells with neural stem/progenitors' characteristics, it remains unclear whether it has the capacity of producing neocortical neurons. Here, we show that generating neurons with transcriptomic resemblance to upper layer neocortical neurons continues in the V-SVZ of mouse models of a human condition known as periventricular heterotopia by abrogating Flna and Flnb. We found such surplus neurogenesis was associated with V-SVZ's upregulation of oxidative phosphorylation, mitochondrial biogenesis, and vascular abundance. Additionally, spatial transcriptomics analyses showed V-SVZ's neurogenic activation was coupled with transcriptional enrichment of genes in diverse pathways for energy metabolism, angiogenesis, cell signaling, synaptic transmission, and turnovers of nucleic acids and proteins in upper cortical layers. These findings support the potential of generating neocortical neurons in adulthood through boosting brain-wide vascular circulation, aerobic adenosine triphosphate synthesis, metabolic turnover, and neuronal activity.

Development of sensorimotor-visual connectome gradient at birth predicts neurocognitive outcomes at 2 years of age.

Functional connectome gradients represent fundamental organizing principles of the brain. Here, we report the development of the connectome gradients in preterm and term babies aged 31-42 postmenstrual weeks using task-free functional MRI and its association with postnatal cognitive growth. We show that the principal sensorimotor-to-visual gradient is present during the late preterm period and continuously evolves toward a term-like pattern. The global measurements of this gradient, characterized by explanation ratio, gradient range, and gradient variation, increased with age (p < 0.05, corrected). Focal gradient development mainly occurs in the sensorimotor, lateral, and medial parietal regions, and visual regions (p < 0.05, corrected). The connectome gradient at birth predicts cognitive and language outcomes at 2-year follow-up (p < 0.005). These results are replicated using an independent dataset from the Developing Human Connectome Project. Our findings highlight early emergent rules of the brain connectome gradient and their implications for later cognitive growth.

Microbiota-dependent early-life programming of gastrointestinal motility.

Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNA sequencing (RNA-seq) of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later-or not at all-showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early-life microbiome in later-life dysmotility.

Sirt6 regulates the proliferation of neural precursor cells and cortical neurogenesis in mice.

Sirt6, a member of the class III histone deacetylases (HDACs), functions in the regulation of genomic stability, DNA repair, cancer, metabolism and aging. Sirt6 deficiency is lethal, and newborn SIRT6-null cynomolgus monkeys show unfinished brain development. After the generation of a cortex-specific Sirt6 conditional knockout mouse model, we investigated the specific deletion of Sirt6 in NPCs at E10.5. This study found that Sirt6 deficiency causes excessive proliferation of neural precursor cells (NPCs) and retards differentiation. The results suggest that endogenous Sirt6 in NPCs regulates histone acetylation and limits stemness-related genes, including Notch1, in order to participate in NPC fate determination. These findings help elucidate Sirt6's role in brain development and in NPC fate determination while providing data on species generality and differentiation.