The longitudinal relationship between BOLD signal variability changes and white matter maturation during early childhood.

Intra-individual transient temporal fluctuations in brain signal, as measured by fMRI blood oxygenation level dependent (BOLD) variability, is increasingly considered an important signal rather than measurement noise. Evidence from computational and cognitive neuroscience suggests that signal variability is a good proxy-measure of brain functional integrity and information processing capacity. Here, we sought to explore across-participant and longitudinal relationships between BOLD variability, age, and white matter structure in early childhood. We measured standard deviation of BOLD signal, total white matter volume, global fractional anisotropy (FA) and mean diffusivity (MD) during passive movie viewing in a sample of healthy children (aged 2-8 years; N = 83). We investigated how age and white matter development related to changes in BOLD variability both across- and within-participants. Our across-participant analyses using behavioural partial least squares (bPLS) revealed that the influence of age and white matter maturation on BOLD variability was highly interrelated. BOLD variability increased in widespread frontal, temporal and parietal regions, and decreased in the hippocampus and parahippocampal gyrus with age and white matter development. Our longitudinal analyses using linear mixed effects modelling revealed significant associations between BOLD variability, age and white matter microstructure. Analyses using artificial neural networks demonstrated that BOLD variability and white matter micro and macro-structure at earlier ages were strong predictors of BOLD variability at later ages. By characterizing the across-participant and longitudinal features of the association between BOLD variability and white matter micro- and macrostructure in early childhood, our results provide a novel perspective to understand structure-function relationships in the developing brain.

Beyond the average brain: individual differences in social brain development are associated with friendship quality.

We tested whether adolescents differ from each other in the structural development of the social brain and whether individual differences in social brain development predicted variability in friendship quality development. Adolescents (N = 299, Mage T1 = 13.98 years) were followed across three biannual waves. We analysed self-reported friendship quality with the best friend at T1 and T3, and bilateral measures of surface area and cortical thickness of the medial prefrontal cortex (mPFC), posterior superior temporal sulcus (pSTS), temporoparietal junction (TPJ) and precuneus across all waves. At the group level, growth curve models confirmed non-linear decreases of surface area and cortical thickness in social brain regions. We identified substantial individual differences in levels and change rates of social brain regions, especially for surface area of the mPFC, pSTS and TPJ. Change rates of cortical thickness varied less between persons. Higher levels of mPFC surface area and cortical thickness predicted stronger increases in friendship quality over time. Moreover, faster cortical thinning of mPFC surface area predicted a stronger increase in friendship quality. Higher levels of TPJ cortical thickness predicted lower friendship quality. Together, our results indicate heterogeneity in social brain development and how this variability uniquely predicts friendship quality development.

Postnatal Development of Glutamate and GABA Transcript Expression in Monkey Visual, Parietal, and Prefrontal Cortices.

Visuospatial working memory (vsWM) requires information transfer among multiple cortical regions, from primary visual (V1) to prefrontal (PFC) cortices. This information is conveyed via layer 3 glutamatergic neurons whose activity is regulated by gamma-aminobutyric acid (GABA)ergic interneurons. In layer 3 of adult human neocortex, molecular markers of glutamate neurotransmission were lowest in V1 and highest in PFC, whereas GABA markers had the reverse pattern. Here, we asked if these opposite V1-visual association cortex (V2)-posterior parietal cortex (PPC)-PFC gradients across the vsWM network are present in layer 3 of monkey neocortex, when they are established during postnatal development, and if they are specific to this layer. We quantified transcript levels of glutamate and GABA markers in layers 3 and 6 of four vsWM cortical regions in a postnatal developmental series of 30 macaque monkeys. In adult monkeys, glutamate transcript levels in layer 3 increased across V1-V2-PPC-PFC regions, whereas GABA transcripts showed the opposite V1-V2-PPC-PFC gradient. Glutamate transcripts established adult-like expression patterns earlier during postnatal development than GABA transcripts. These V1-V2-PPC-PFC gradients and developmental patterns were less evident in layer 6. These findings demonstrate that expression of glutamate and GABA transcripts differs across cortical regions and layers during postnatal development, revealing potential molecular substrates for vsWM functional maturation.

Preterm birth leads to impaired rich-club organization and fronto-paralimbic/limbic structural connectivity in newborns.

Prematurity disrupts brain development during a critical period of brain growth and organization and is known to be associated with an increased risk of neurodevelopmental impairments. Investigating whole-brain structural connectivity alterations accompanying preterm birth may provide a better comprehension of the neurobiological mechanisms related to the later neurocognitive deficits observed in this population. Using a connectome approach, we aimed to study the impact of prematurity on neonatal whole-brain structural network organization at term-equivalent age. In this cohort study, twenty-four very preterm infants at term-equivalent age (VPT-TEA) and fourteen full-term (FT) newborns underwent a brain MRI exam at term age, comprising T2-weighted imaging and diffusion MRI, used to reconstruct brain connectomes by applying probabilistic constrained spherical deconvolution whole-brain tractography. The topological properties of brain networks were quantified through a graph-theoretical approach. Furthermore, edge-wise connectivity strength was compared between groups. Overall, VPT-TEA infants' brain networks evidenced increased segregation and decreased integration capacity, revealed by an increased clustering coefficient, increased modularity, increased characteristic path length, decreased global efficiency and diminished rich-club coefficient. Furthermore, in comparison to FT, VPT-TEA infants had decreased connectivity strength in various cortico-cortical, cortico-subcortical and intra-subcortical networks, the majority of them being intra-hemispheric fronto-paralimbic and fronto-limbic. Inter-hemispheric connectivity was also decreased in VPT-TEA infants, namely through connections linking to the left precuneus or left dorsal cingulate gyrus - two regions that were found to be hubs in FT but not in VPT-TEA infants. Moreover, posterior regions from Default-Mode-Network (DMN), namely precuneus and posterior cingulate gyrus, had decreased structural connectivity in VPT-TEA group. Our finding that VPT-TEA infants' brain networks displayed increased modularity, weakened rich-club connectivity and diminished global efficiency compared to FT infants suggests a delayed transition from a local architecture, focused on short-range connections, to a more distributed architecture with efficient long-range connections in those infants. The disruption of connectivity in fronto-paralimbic/limbic and posterior DMN regions might underlie the behavioral and social cognition difficulties previously reported in the preterm population.

A Longitudinal Study of Changes in Resting-State Functional Magnetic Resonance Imaging Functional Connectivity Networks During Healthy Aging.

Background: Vast increases in life expectancy over the last century have led to shifts in population demographics and the emergence of a largely aged population, globally. This has led to a need to understand neurobiological changes associated with healthy aging. Studies on age-related changes in functional connectivity networks have largely been cross-sectional and focused on the default mode network (DMN). The current study investigated longitudinal changes in functional connectivity in multiple resting-state networks over 4 years of aging in cognitively normal older adults. Methods: Resting-state functional magnetic resonance imaging scans from older adults (n = 16) who maintained "cognitive normal" status over 4 years were retrieved at baseline and follow-up from the Alzheimer's Disease Neuroimaging Initiative database. A seed-based approach was executed in Functional MRI of the Brain Software Library (FSL) to examine significant changes in functional connectivity within the DMN, frontoparietal network (FPN), and salience network (SN) within subjects over time. Results: Results indicated significantly (p < 0.05, corrected) reduced functional connectivity in the FPN and SN, but not in the DMN at year 4 compared with baseline in older adults who were cognitively stable. Conclusions: The current study highlights the importance of a longitudinal approach for understanding changes in functional connectivity. The findings also underscore the need to examine multiple networks within the same participants, given that changes were apparent in the FPN and SN but not in the DMN. Future studies should also examine changes in internetwork connectivity as well as shifts in structural connectivity over time. Impact statement Investigations of age-related changes in functional connectivity have largely been cross-sectional and focused on the default mode network (DMN). The current study examined the DMN as well as the frontoparietal network (FN) and salience network (SN), in a group of healthy aging adults over four years. The results revealed decreased functional connectivity over time, in the FN and SN, but not the DMN. These findings provide insights about the healthy aging brain. They also underscore the need to broaden the scope of functional connectivity analyses beyond the DMN and highlight the use of longitudinal methods.

Neuron-derived VEGF contributes to cortical and hippocampal development independently of VEGFR1/2-mediated neurotrophism.

Vascular endothelial growth factor (VEGF) is a potent mitogen critical for angiogenesis and organogenesis. Deletion or inhibition of VEGF during development not only profoundly suppresses vascular outgrowth, but significantly affects the development and function of various organs. In the brain, VEGF is thought to not only promote vascular growth, but also directly act on neurons as a neurotrophic factor by activating VEGF receptors. In the present study, we demonstrated that deletion of VEGF using hGfap-Cre line, which recombines genes specifically in cortical and hippocampal neurons, severely impaired brain organization and vascularization of these regions. The mutant mice had motor deficits, with lethality around the time of weaning. Multiple reporter lines indicated that VEGF was highly expressed in neurons, but that its cognate receptors, VEGFR1 and 2 were exclusive to endothelial cells in the brain. In accordance, mice lacking neuronal VEGFR1 and VEGFR2 did not exhibit neuronal deformities or lethality. Taken together, our data suggest that neuron-derived VEGF contributes to cortical and hippocampal development likely through angiogenesis independently of direct neurotrophic effects mediated by VEGFR1 and 2.

Modular segregation of task-dependent brain networks contributes to the development of executive function in children.

Executive function (EF) refers as to a set of high-level cognitive abilities that are critical to many aspects of daily life. Despite its importance in human daily life, the neural networks responsible for the development of EF in childhood are not well understood. The present study thus aimed to examine the development of task-dependent brain network organization and its relationship to age-related improvements in EF. To address this issue, we recruited eighty-eight Chinese children ranging in age from 7 to 12 years old, and collected their functional magnetic resonance imaging (fMRI) data when they performed an EF task. By utilizing graph theory, we found that the task-dependent brain network modules became increasingly segregated with age. Specifically, the intra-module connections within the default-mode network (DMN), frontal-parietal network (FPN) and sensorimotor network (SMN) increased significantly with age. In contrast, the inter-module connections of the visual network to both the FPN/SMN decreased significantly with age. Most importantly, modular segregation of the FPN significantly mediated the relationship between age and EF performance. These findings add to our growing understanding of how development changes in task-dependent brain network organization support vast behavioral improvements in EF observed during childhood.

A genome-wide association study identifies genetic loci associated with specific lobar brain volumes.

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.

Absence of neural speech discrimination in preterm infants at term-equivalent age.

Children born preterm are at higher risk to develop language deficits. Auditory speech discrimination deficits may be early signs for language developmental problems. The present study used functional near-infrared spectroscopy to investigate neural speech discrimination in 15 preterm infants at term-equivalent age compared to 15 full term neonates. The full term group revealed a significantly greater hemodynamic response to forward compared to backward speech within the left hemisphere extending from superior temporal to inferior parietal and middle and inferior frontal areas. In contrast, the preterm group did not show differences in their hemodynamic responses during forward versus backward speech, thus, they did not discriminate speech from non-speech. Groups differed significantly in their responses to forward speech, whereas they did not differ in their responses to backward speech. The significant differences between groups point to an altered development of the functional network underlying language acquisition in preterm infants as early as in term-equivalent age.

Charting shared developmental trajectories of cortical thickness and structural connectivity in childhood and adolescence.

The cortex is organised into broadly hierarchical functional systems with distinct neuroanatomical characteristics reflected by macroscopic measures of cortical morphology. Diffusion-weighted magnetic resonance imaging allows the delineation of areal connectivity, changes to which reflect the ongoing maturation of white matter tracts. These developmental processes are intrinsically linked with timing coincident with the development of cognitive function. In this study, we use a data-driven multivariate approach, nonnegative matrix factorisation, to define cortical regions that co-vary together across a large paediatric cohort (n = 456) and are associated with specific subnetworks of cortical connectivity. We find that age between 3 and 21 years is associated with accelerated cortical thinning in frontoparietal regions, whereas relative thinning of primary motor and sensory regions is slower. Together, the subject-specific weights of the derived set of cortical components can be combined to predict chronological age. Structural connectivity networks reveal a relative increase in strength in connection within, as opposed to between hemispheres that vary in line with cortical changes. We confirm our findings in an independent sample.

Immediate and Delayed Effects of Food Restriction on Some Parameters of Brain Development in Rats.

The effects of 15-day restriction diet (from 1 to 1.5 months of age) on some parameters of brain development were studied in rats. The immediate and delayed (15 days after transfer to normal ration) effects were evaluated. The immediate effects included a significant decrease of the absolute weights of the brain and hemispheres. The relative weight of the brain was significantly higher. The thickness of the cortex of the parietal lobe proper and its layer I decreased. The absolute weights of the brain and hemispheres were less than in the control 15 days after the rats were transferred to ad libitum feeding, while the relative weight of the brain was higher than in controls. The thickness of the parietal and anterior parietal cortex and the numerical density of neurons in layers II and V did not differ from the control. In the neurons of layers II and V of the anterior parietal and parietal lobe proper the nuclei were larger, while the nucleoli were enlarged in the neurons of these locations and the hippocampus, the shifts being significant in the anterior parietal layer V. The concentrations of RNA in the parietal, anterior parietal, and hippocampal lobe neurons in different groups were similar directly and 15 days after the diet. Changes in the gravimetric and morphometric parameters of the brain were paralleled by the development of oxidative stress.

Developmental Maturation of the Precuneus as a Functional Core of the Default Mode Network.

Efforts to map the functional architecture of the developing human brain have shown that connectivity between and within functional neural networks changes from childhood to adulthood. Although prior work has established that the adult precuneus distinctively modifies its connectivity during task versus rest states [Utevsky, A. V., Smith, D. V., & Huettel, S. A. Precuneus is a functional core of the default-mode network. Journal of Neuroscience, 34, 932-940, 2014], it remains unknown how these connectivity patterns emerge over development. Here, we use fMRI data collected at two longitudinal time points from over 250 participants between the ages of 8 and 26 years engaging in two cognitive tasks and a resting-state scan. By applying independent component analysis to both task and rest data, we identified three canonical networks of interest-the rest-based default mode network and the task-based left and right frontoparietal networks (LFPN and RFPN, respectively)-which we explored for developmental changes using dual regression analyses. We found systematic state-dependent functional connectivity in the precuneus, such that engaging in a task (compared with rest) resulted in greater precuneus-LFPN and precuneus-RFPN connectivity, whereas being at rest (compared with task) resulted in greater precuneus-default mode network connectivity. These cross-sectional results replicated across both tasks and at both developmental time points. Finally, we used longitudinal mixed models to show that the degree to which precuneus distinguishes between task and rest states increases with age, due to age-related increasing segregation between precuneus and LFPN at rest. Our results highlight the distinct role of the precuneus in tracking processing state, in a manner that is both present throughout and strengthened across development.

The relationship between biological and psychosocial risk factors and resting-state functional connectivity in 2-month-old Bangladeshi infants: A feasibility and pilot study.

Childhood poverty has been associated with structural and functional alterations in the developing brain. However, poverty does not alter brain development directly, but acts through associated biological or psychosocial risk factors (e.g. malnutrition, family conflict). Yet few studies have investigated risk factors in the context of infant neurodevelopment, and none have done so in low-resource settings such as Bangladesh, where children are exposed to multiple, severe biological and psychosocial hazards. In this feasibility and pilot study, usable resting-state fMRI data were acquired in infants from extremely poor (n = 16) and (relatively) more affluent (n = 16) families in Dhaka, Bangladesh. Whole-brain intrinsic functional connectivity (iFC) was estimated using bilateral seeds in the amygdala, where iFC has shown susceptibility to early life stress, and in sensory areas, which have exhibited less susceptibility to early life hazards. Biological and psychosocial risk factors were examined for associations with iFC. Three resting-state networks were identified in within-group brain maps: medial temporal/striatal, visual, and auditory networks. Infants from extremely poor families compared with those from more affluent families exhibited greater (i.e. less negative) iFC in precuneus for amygdala seeds; however, no group differences in iFC were observed for sensory area seeds. Height-for-age, a proxy for malnutrition/infection, was not associated with amygdala/precuneus iFC, whereas prenatal family conflict was positively correlated. Findings suggest that it is feasible to conduct infant fMRI studies in low-resource settings. Challenges and practical steps for successful implementations are discussed.

Connectivity between the visual word form area and the parietal lobe improves after the first year of reading instruction: a longitudinal MRI study in children.

Shortly after reading instruction, a region in the ventral occipital temporal cortex (vOTC) of the left hemisphere, the Visual Word Form Area (VWFA), becomes specialized for written words. Its reproducible location across scripts suggests important anatomical constraints, such as specific patterns of connectivity, notably to spoken language areas. Here, we explored the structural connectivity of the emerging VWFA in terms of its specificity relative to other ventral visual regions and its stability throughout the process of reading instruction in ten children studied longitudinally over 2 years. Category-specific regions for words, houses, faces, and tools were identified in the left vOTC of each subject with functional MRI. With diffusion MRI and tractography, we reconstructed the connections of these regions at two time points (mean age ± standard deviation: 6.2 ± 0.3, 7.2 ± 0.4 years). We first showed that the regions for each visual category harbor their own specific connectivity, all of which precede reading instruction and remain stable throughout development. The most specific connections of the VWFA were to the dorsal posterior parietal cortex. We then showed that microstructural changes in these connections correlated with improvements in reading scores over the first year of instruction but not 1 year later in a subsample of eight children (age: 8.4 ± 0.3 years). These results suggest that the VWFA location depends on its connectivity to distant regions, in particular, the left inferior parietal region which may play a crucial role in visual field maps and eye movement dynamics in addition to attentional control in letter-by-letter reading and disambiguation of mirror-letters during the first stages of learning to read.

Fronto-parietal numerical networks in relation with early numeracy in young children.

Early numeracy provides the foundation of acquiring mathematical skills that is essential for future academic success. This study examined numerical functional networks in relation to counting and number relational skills in preschoolers at 4 and 6 years of age. The counting and number relational skills were assessed using school readiness test (SRT). Resting-state fMRI (rs-fMRI) was acquired in 123 4-year-olds and 146 6-year-olds. Among them, 61 were scanned twice over the course of 2 years. Meta-analysis on existing task-based numeracy fMRI studies identified the left parietal-dominant network for both counting and number relational skills and the right parietal-dominant network only for number relational skills in adults. We showed that the fronto-parietal numerical networks, observed in adults, already exist in 4-year and 6-year-olds. The counting skills were associated with the bilateral fronto-parietal network in 4-year-olds and with the right parietal-dominant network in 6-year-olds. Moreover, the number relational skills were related to the bilateral fronto-parietal and right parietal-dominant networks in 4-year-olds and had a trend of the significant relationship with the right parietal-dominant network in 6-year-olds. Our findings suggested that neural fine-tuning of the fronto-parietal numerical networks may subserve the maturation of numeracy in early childhood.

Altered brain cortical maturation is found in adolescents with a family history of alcoholism.

Substance-naïve offspring from high-density alcohol use disorder (AUD) families exhibit altered subcortical brain volumes structurally and altered executive-functioning and emotion-processing functionally, compared with their peers. However, there is a dearth of literature exploring alterations of cortical thickness (CTh) in this population. T1-weighted structural brain MRI was acquired in 75 substance-naïve male offspring of treatment-seeking early onset (<25 years) AUD patients with high familial loading of AUDs (≥2 affected relatives) (FHP) and 65 age-matched substance-naïve male controls with negative family history from the community. Surface-based CTh reconstruction was done using FreeSurfer. Univariate general linear models were implemented at each vertex using SurfStat, controlling for age (linear and quadratic effects), and head size, to examine the main effect of familial AUD risk on CTh and its relationship with externalizing symptom score (ESS). A Johnson-Neyman procedure revealed that the main effect of familial AUD risk on CTh was seen during adolescence, where the FHP group had thicker cortices involving bilateral precentral gyri, left caudal middle frontal gyrus (MFG), bilateral temporo-parietal junction, left inferior-frontal gyrus and right inferior-temporal gyrus. Thicker cortices in left MFG and inferior-parietal lobule were also associated with greater ESS within both groups. More importantly, these group differences diminished with age by young adulthood. Familial AUD risk is associated with age-related differences in maturation of several higher order association cortices that are critical to ongoing development in executive function, emotion regulation and social cognition during adolescence. Early supportive intervention for a delay in alcohol initiation during this critical phase may be crucial for this at-risk population.

The developmental neural substrates of item and serial order components of verbal working memory.

Behavioral and developmental studies have made a critical distinction between item and serial order processing components of verbal working memory (WM). This functional magnetic resonance imaging (fMRI) study determined the extent to which item and serial order WM components are characterized by specialized neural networks already in young children or whether this specialization emerges at a later developmental stage. Total of 59 children aged 7-12 years performed item and serial order short-term probe recognition tasks in an fMRI experiment. While a left frontoparietal network was recruited in both item and serial order WM conditions, the right intraparietal sulcus was selectively involved in the serial order WM condition. This neural segregation was modulated by age, with both networks becoming increasingly separated in older children. Our results indicate a progressive specialization of networks involved in item and order WM processes during cognitive development.

Aspects of excitatory/inhibitory synapses in multiple brain regions are correlated with levels of brain-derived neurotrophic factor/neurotrophin-3.

Appropriate synapse formation during development is necessary for normal brain function, and synapse impairment is often associated with brain dysfunction. Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are key factors in regulating synaptic development. We previously reported that BDNF/NT-3 secretion was enhanced by calcium-dependent activator protein for secretion 2 (CADPS2). Although BDNF/NT-3 and CADPS2 are co-expressed in various brain regions, the effect of Cadps2-deficiency on brain region-specific BDNF/NT-3 levels and synaptic development remains elusive. Here, we show developmental changes of BDNF/NT-3 levels and we assess disruption of excitatory/inhibitory synapses in multiple brain regions (cerebellum, hypothalamus, striatum, hippocampus, parietal cortex and prefrontal cortex) of Cadps2 knockout (KO) mice compared with wild-type (WT) mice. Compared with WT, BDNF levels in KO mice were reduced in young/adult hippocampus, but increased in young hypothalamus, while NT-3 levels were reduced in adult cerebellum and young hippocampus, but increased in adult parietal cortex. Immunofluorescence of vGluT1, an excitatory synapse marker, and vGAT, an inhibitory synapse marker, in adult KO showed that vGluT1 was higher in the cerebellum and parietal cortex but lower in the hippocampus, whereas vGAT was lower in the hippocampus and parietal cortex compared with WT. Immunolabeling for both vGluT1 and vGAT was increased in the parietal cortex but vGAT was decreased in the cerebellum in adult KO compared with WT. These data suggest that CADPS2-mediated secretion of BDNF/NT-3 may be involved in development and maturation of synapses and in the balance between inhibitory and excitatory synapses.

Impaired neural processing of transitive relations in children with math learning difficulty.

Math learning difficulty (i.e., MLD) is common in children and can have far-reaching consequences in personal and professional life. Converging evidence suggests that MLD is associated with impairments in the intraparietal sulcus (IPS). However, the role that these impairments play in MLD remains unclear. Although it is often assumed that IPS deficits affect core numerical abilities, the IPS is also involved in several non-numerical processes that may contribute to math skills. For instance, the IPS supports transitive reasoning (i.e., the ability to integrate relations such as A > B and B > C to infer that A > C), a skill that is central to many aspects of math learning in children. Here we measured fMRI activity of 8- to 12-year-olds with MLD and typically developing (TD) peers while they listened to stories that included transitive relations. Children also answered questions evaluating whether transitive inferences were made during story comprehension. Compared to non-transitive relations (e.g., A > B and C > D), listening to transitive relations (e.g., A > B and B > C) was associated with enhanced activity in the IPS in TD children. In children with MLD, the difference in activity between transitive and non-transitive relations in the IPS was (i) non-reliable and (ii) smaller than in TD children. Finally, children with MLD were less accurate than TD peers when making transitive inferences based on transitive relations. Thus, a deficit in the online processing of transitive relations in the IPS might contribute to math difficulties in children with MLD.

When less is more: Thinner fronto-parietal cortices are associated with better forward digit span performance during early childhood.

Although research shows that working memory improves during early childhood, it remains unclear how the fronto-parietal network of cortical regions, known to support this ability in adults, relates to changes in young children. Measures of cortical thickness may be useful in investigating this association as they reflect age-related differences in gray matter and have been proposed to support age-related improvements in other cognitive abilities, but have only sparingly been tested empirically in early childhood. The present study sought to investigate relations between cortical thickness and performance on a digit span task in 200 4- to 8-year-old children using both a priori defined regions of interest related to working memory (superior frontal cortex, middle frontal cortex, anterior cingulate cortex, superior parietal cortex) and whole brain analyses. Results indicated a significant association between cortical thickness in each a priori defined fronto-parietal region and performance on digit span, such that those with a thinner cortex recalled more items than those with a thicker cortex. Similar regions emerged from the whole brain analyses, as did several other regions not typically included in the fronto-parietal network. Results of a mediation analysis indicated that age-related differences in behavior were partially explained by variations in thickness of anterior cingulate cortex, suggesting a potentially important role for this structure during early childhood. Overall, these results suggest that in children as young as 4 years of age there are associations between working memory abilities and thickness in cortical areas known to support working memory in adults.