Circulating Blood Prognostic Biomarker Signatures for Hemorrhagic Cerebral Cavernous Malformations (CCMs).

Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to hemorrhagic strokes, a major cause of death and disability worldwide. The limited treatment options for CCMs underscore the importance of prognostic biomarkers to predict the likelihood of hemorrhagic events, aiding in treatment decisions and identifying potential pharmacological targets. This study aimed to identify blood biomarkers capable of diagnosing and predicting the risk of hemorrhage in CCM1 patients, establishing an initial set of circulating biomarker signatures. By analyzing proteomic profiles from both human and mouse CCM models and conducting pathway enrichment analyses, we compared groups to identify potential blood biomarkers with statistical significance. Specific candidate biomarkers primarily associated with metabolism and blood clotting pathways were identified. These biomarkers show promise as prognostic indicators for CCM1 deficiency and the risk of hemorrhagic stroke, strongly correlating with the likelihood of hemorrhagic cerebral cavernous malformations (CCMs). This lays the groundwork for further investigation into blood biomarkers to assess the risk of hemorrhagic CCMs.

Functional networks in the infant brain during sleep and wake states.

Functional brain networks are assessed differently earlier versus later in development: infants are almost universally scanned asleep, whereas adults are typically scanned awake. Observed differences between infant and adult functional networks may thus reflect differing states of consciousness rather than or in addition to developmental changes. We explore this question by comparing functional networks in functional magnetic resonance imaging (fMRI) scans of infants during natural sleep and awake movie-watching. As a reference, we also scanned adults during awake rest and movie-watching. Whole-brain functional connectivity was more similar within the same state (sleep and movie in infants; rest and movie in adults) compared with across states. Indeed, a classifier trained on patterns of functional connectivity robustly decoded infant state and even generalized to adults; interestingly, a classifier trained on adult state did not generalize as well to infants. Moreover, overall similarity between infant and adult functional connectivity was modulated by adult state (stronger for movie than rest) but not infant state (same for sleep and movie). Nevertheless, the connections that drove this similarity, particularly in the frontoparietal control network, were modulated by infant state. In sum, infant functional connectivity differs between sleep and movie states, highlighting the value of awake fMRI for studying functional networks over development.

Fatty acid elongases 1-3 have distinct roles in mitochondrial function, growth, and lipid homeostasis in Trypanosoma cruzi.

Trypanosomatids are a diverse group of uniflagellate protozoan parasites that include globally relevant pathogens such as Trypanosoma cruzi, the causative agent of Chagas disease. Trypanosomes lack the fatty acid synthase system typically used for de novo fatty acid (FA) synthesis in other eukaryotes. Instead, these microbes have evolved a modular FA elongase (ELO) system comprised of individual ELO enzymes (ELO1-4) that can operate processively to generate long chain- and very long chain-FAs. The importance of ELO's for maintaining lipid homeostasis in trypanosomatids is currently unclear, given their ability to take up and utilize exogenous FAs for lipid synthesis. To assess ELO function in T. cruzi, we generated individual KO lines, Δelo1, Δelo2, and Δelo3, in which the genes encoding ELO1-3 were functionally disrupted in the parasite insect stage (epimastigote). Using unbiased lipidomic and metabolomic analyses, in combination with metabolic tracing and biochemical approaches, we demonstrate that ELO2 and ELO3 are required for global lipid homeostasis, whereas ELO1 is dispensable for this function. Instead, ELO1 activity is needed to sustain mitochondrial activity and normal growth in T. cruzi epimastigotes. The cross-talk between microsomal ELO1 and the mitochondrion is a novel finding that, we propose, merits further examination of the trypanosomatid ELO pathway as critical for central metabolism.

Missense and nonsense mutations of the zebrafish hcfc1a gene result in contrasting mTor and radial glial phenotypes.

Mutations in the HCFC1 transcriptional co-factor protein are the cause of cblX syndrome and X-linked intellectual disability (XLID). cblX is the more severe disorder associated with intractable epilepsy, abnormal cobalamin metabolism, facial dysmorphia, cortical gyral malformations, and intellectual disability. In vitro, murine Hcfc1 regulates neural precursor (NPCs) proliferation and number, which has been validated in zebrafish. However, conditional deletion of mouse Hcfc1 in Nkx2.1 + cells increased cell death, reduced Gfap expression, and reduced numbers of GABAergic neurons. Thus, the role of this gene in brain development is not completely understood. Recently, knock-in of both a cblX (HCFC1) and cblX-like (THAP11) allele were created in mice. Knock-in of the cblX-like allele was associated with increased expression of proteins required for ribosome biogenesis. However, the brain phenotypes were not comprehensively studied due to sub-viability. Therefore, a mechanism underlying increased ribosome biogenesis was not described. We used a missense, a nonsense, and two conditional zebrafish alleles to further elucidate this mechanism during brain development. We observed contrasting phenotypes at the level of Akt/mTor activation, the number of radial glial cells, and the expression of two downstream target genes of HCFC1, asxl1 and ywhab. Despite these divergent phenotypes, each allele studied demonstrates with a high degree of face validity when compared to the phenotypes reported in the literature. Collectively, these data suggest that individual mutations in the HCFC1 protein result in differential mTOR activity which may be associated with contrasting cellular phenotypes.

Characterization of the zebrafish gabra1sa43718/sa43718 germline loss of function allele confirms a function for Gabra1 in motility and nervous system development.

Mutation of the GABRA1 gene is associated with neurodevelopmental defects and epilepsy. GABRA1 encodes for the α1 subunit of the gamma-aminobutyric acid type A receptor (GABAAR), which regulates the fast inhibitory impulses of the nervous system. Multiple model systems have previously been developed to understand the function of GABRA1 during development, but these models have produced complex and at times incongruent data. Thus, additional model systems are required to validate and substantiate previously published results. We investigated the behavioral swim patterns associated with a nonsense mutation of the zebrafish gabra1 (sa43718 allele) gene. The sa43718 allele causes a decrease in gabra1 mRNA expression, which is associated with light induced hypermotility, one phenotype associated with seizure like behavior in zebrafish. Mutation of gabra1 was accompanied by decreased mRNA expression of gabra2, gabra3, and gabra5, indicating a reduction in the expression of additional alpha sub-units of the GABAAR. Although multiple sub-units were decreased in total expression, larvae continued to respond to pentylenetetrazole (PTZ) indicating that a residual GABAAR exists in the sa43718 allele. Proteomics analysis demonstrated that nonsense mutation of gabra1 is associated with abnormal expression of proteins that regulate proton transport, ion homeostasis, vesicle transport, and mitochondrial protein complexes. These data support previous studies performed in a zebrafish nonsense allele created by CRISPR/Cas9 and validate that loss of function mutations in the gabra1 gene result in seizure like phenotypes with abnormal function of inhibitory synapses.

Face processing in the infant brain after pandemic lockdown.

The role of visual experience in the development of face processing has long been debated. We present a new angle on this question through a serendipitous study that cannot easily be repeated. Infants viewed short blocks of faces during fMRI in a repetition suppression task. The same identity was presented multiple times in half of the blocks (repeat condition) and different identities were presented once each in the other half (novel condition). In adults, the fusiform face area (FFA) tends to show greater neural activity for novel versus repeat blocks in such designs, suggesting that it can distinguish same versus different face identities. As part of an ongoing study, we collected data before the COVID-19 pandemic and after an initial local lockdown was lifted. The resulting sample of 12 infants (9-24 months) divided equally into pre- and post-lockdown groups with matching ages and data quantity/quality. The groups had strikingly different FFA responses: pre-lockdown infants showed repetition suppression (novel > repeat), whereas post-lockdown infants showed the opposite (repeat > novel), often referred to as repetition enhancement. These findings provide speculative evidence that altered visual experience during the lockdown, or other correlated environmental changes, may have affected face processing in the infant brain.

Neural effects of controllability as a key dimension of stress exposure.

Cross-species evidence suggests that the ability to exert control over a stressor is a key dimension of stress exposure that may sensitize frontostriatal-amygdala circuitry to promote more adaptive responses to subsequent stressors. The present study examined neural correlates of stressor controllability in young adults. Participants (N = 56; Mage = 23.74, range = 18-30 years) completed either the controllable or uncontrollable stress condition of the first of two novel stressor controllability tasks during functional magnetic resonance imaging (fMRI) acquisition. Participants in the uncontrollable stress condition were yoked to age- and sex-matched participants in the controllable stress condition. All participants were subsequently exposed to uncontrollable stress in the second task, which is the focus of fMRI analyses reported here. A whole-brain searchlight classification analysis revealed that patterns of activity in the right dorsal anterior insula (dAI) during subsequent exposure to uncontrollable stress could be used to classify participants' initial exposure to either controllable or uncontrollable stress with a peak of 73% accuracy. Previous experience of exerting control over a stressor may change the computations performed within the right dAI during subsequent stress exposure, shedding further light on the neural underpinnings of stressor controllability.

Neural event segmentation of continuous experience in human infants.

How infants experience the world is fundamental to understanding their cognition and development. A key principle of adult experience is that, despite receiving continuous sensory input, we perceive this input as discrete events. Here we investigate such event segmentation in infants and how it differs from adults. Research on event cognition in infants often uses simplified tasks in which (adult) experimenters help solve the segmentation problem for infants by defining event boundaries or presenting discrete actions/vignettes. This presupposes which events are experienced by infants and leaves open questions about the principles governing infant segmentation. We take a different, data-driven approach by studying infant event segmentation of continuous input. We collected whole-brain functional MRI (fMRI) data from awake infants (and adults, for comparison) watching a cartoon and used a hidden Markov model to identify event states in the brain. We quantified the existence, timescale, and organization of multiple-event representations across brain regions. The adult brain exhibited a known hierarchical gradient of event timescales, from shorter events in early visual regions to longer events in later visual and associative regions. In contrast, the infant brain represented only longer events, even in early visual regions, with no timescale hierarchy. The boundaries defining these infant events only partially overlapped with boundaries defined from adult brain activity and behavioral judgments. These findings suggest that events are organized differently in infants, with longer timescales and more stable neural patterns, even in sensory regions. This may indicate greater temporal integration and reduced temporal precision during dynamic, naturalistic perception.

Giardial lipid rafts share virulence factors with secreted vesicles and participate in parasitic infection in mice.

Giardia lamblia, a protozoan parasite, is a major cause of waterborne infection, worldwide. While the trophozoite form of this parasite induces pathological symptoms in the gut, the cyst form transmits the infection. Since Giardia is a noninvasive parasite, the actual mechanism by which it causes disease remains elusive. We have previously reported that Giardia assembles cholesterol and GM1 glycosphingolipid-enriched lipid rafts (LRs) that participate in encystation and cyst production. To further delineate the role of LRs in pathogenesis, we isolated LRs from Giardia and subjected them to proteomic analysis. Various cellular proteins including potential virulence factors-e.g., giardins, variant surface proteins, arginine deaminases, elongation factors, ornithine carbomyltransferases, and high cysteine-rich membrane proteins-were found to be present in LRs. Since Giardia secretes virulence factors encapsulated in extracellular vesicles (EVs) that induce proinflammatory responses in hosts, EVs released by the parasite were isolated and subjected to nanoparticle tracking and proteomic analysis. Two types of EV-i.e., small vesicles (SVs; <100 nm, exosome-like particles) and large vesicles (LVs; 100-400 nm, microvesicle-like particles)-were identified and found to contain a diverse group of proteins including above potential virulence factors. Although pretreatment of the parasite with two giardial lipid raft (gLR) disruptors, nystatin (27 µM) and oseltamivir (20 µM), altered the expression profiles of virulence factors in LVs and SVs, the effects were more robust in the case of SVs. To examine the potential role of rafts and vesicles in pathogenicity, Giardia-infected mice were treated with oseltamivir (1.5 and 3.0 mg/kg), and the shedding of cysts were monitored. We observed that this drug significantly reduced the parasite load in mice. Taken together, our results suggest that virulence factors partitioning in gLRs, released into the extracellular milieu via SVs and LVs, participate in spread of giardiasis and could be targeted for future drug development.

A Branched and Double Alpha-Gal-Bearing Synthetic Neoglycoprotein as a Biomarker for Chagas Disease.

Chagas disease (CD) is caused by the parasite Trypanosoma cruzi and affects 6-7 million people worldwide. The diagnosis is still challenging, due to extensive parasite diversity encompassing seven genotypes (TcI-VI and Tcbat) with diverse ecoepidemiological, biological, and pathological traits. Chemotherapeutic intervention is usually effective but associated with severe adverse events. The development of safer, more effective therapies is hampered by the lack of biomarker(s) (BMKs) for the early assessment of therapeutic outcomes. The mammal-dwelling trypomastigote parasite stage expresses glycosylphosphatidylinositol-anchored mucins (tGPI-MUC), whose O-glycans are mostly branched with terminal, nonreducing α-galactopyranosyl (α-Gal) glycotopes. These are absent in humans, and thus highly immunogenic and inducers of specific CD anti-α-Gal antibodies. In search for α-Gal-based BMKs, here we describe the synthesis of neoglycoprotein NGP11b, comprised of a carrier protein decorated with the branched trisaccharide Galα(1,2)[Galα(1,6)]Galß. By chemiluminescent immunoassay using sera/plasma from chronic CD (CCD) patients from Venezuela and Mexico and healthy controls, NGP11b exhibited sensitivity and specificity similar to that of tGPI-MUC from genotype TcI, predominant in those countries. Preliminary evaluation of CCD patients subjected to chemotherapy showed a significant reduction in anti-α-Gal antibody reactivity to NGP11b. Our data indicated that NGP11b is a potential BMK for diagnosis and treatment assessment in CCD patients.

CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling.

BACKGROUND: Breast cancer, the most diagnosed cancer, remains the second leading cause of cancer death in the United States, and excessive Progesterone (PRG) or Mifepristone (MIF) exposure may be at an increased risk for developing breast cancer. PRG exerts its cellular responses through signaling cascades involving classic, non-classic, or combined responses by binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Currently, the intricate balance and switch mechanisms between these two signaling cascades remain elusive. Three genes, CCM1-3, form the CCM signaling complex (CSC) which mediates multiple signaling cascades. METHODS: Utilizing molecular, cellular, Omics, and systems biology approaches, we analyzed the relationship among the CSC, PRG, and nPRs/mPRs during breast cancer tumorigenesis. RESULTS: We discovered that the CSC plays an essential role in coupling both classic and non-classic PRG signaling pathways by mediating crosstalk between them, forming the CmPn (CSC-mPRs-PRG-nPRs) signaling network. We found that mPR-specific PRG actions (PRG + MIF) play an essential role in this CmPn network during breast cancer tumorigenesis. Additionally, we have identified 4 categories of candidate biomarkers (9 intrinsic, 2 PRG-inducible, 1 PRG-repressive, 1 mPR-specific PRG-repressive, and 2 mPR-responsive) for Luminal-A breast cancers during tumorigenesis and have confirmed the prognostic application of RPL13 and RPL38 as intrinsic biomarkers using a dual validation method. CONCLUSIONS: We have discovered that the CSC plays an essential role in the CmPn signaling network for Luminal-A breast cancers with identification of two intrinsic biomarkers. Video Abstract.

Medical cannabis and automobile accidents: Evidence from auto insurance.

While many states have legalized medical cannabis, many unintended consequences remain under-studied. We focus on one potential detriment-the effect of cannabis legalization on automobile safety. We examine this relationship through auto insurance premiums. Employing a modern difference-in-differences framework and zip code-level premium data from 2014 to 2019, we find that premiums declined, on average, by $22 per year following medical cannabis legalization. The effect is more substantial in areas near a dispensary and in areas with a higher prevalence of drunk driving before legalization. We estimate that existing legalization has reduced health expenditures related to auto accidents by almost $820 million per year with the potential for a further $350 million reduction if legalized nationally.

A comparative proteomics study of Arabidopsis thaliana responding to the coexistence of BPA and TiO2-NPs at environmentally relevant concentrations.

Through the applications of recycling sewage sludge to soils as nutrients, bisphenol A (BPA) and titanium dioxide nanoparticles (TiO2-NPs) are commonly found in the agricultural environment. Previous studies have reported that BPA and nanoparticles are harmful to the environment. However, the combined toxicity of both compounds is not yet understood. This work presented an in-depth proteomic analysis of Arabidopsis thaliana exposed to BPA and TiO2-NPs concurrently at environmentally relevant levels. Seeds were simultaneously treated with varying concentrations of BPA (0, 10, 100, and 1000 µg·kg-1) and TiO2-NPs (0, 1, 10 and 100 mg·kg-1). In treatment of 1000 µg·kg-1 BPA and 100 mg·kg-1 TiO2-NPs, highest seed germination rate (87.97%, p < 0.05) was observed. Shorter primary roots but more branched roots were obtained in treatments of high BPA and NPs concentrations (100, 1000 µg·kg-1 BPA and 10, 100 mg·kg-1 TiO2-NPs) while no significant effects on plant height and biomass were found. In the comparative analysis, both concentration related positive and negative effects were observed, such as regulation of cell proliferation (positive), root hair elongation (positive), cellular response to oxidative stress (negative), and cell wall organization (negative). In response to the stress caused by BPA and TiO2-NPs, some proteins related to plant root development, such as CD48E, DNAJ2 and GL24, were up-regulated explaining the shorter primary root length and more branched roots. Moreover, Arabidopsis may have stimulated its ability of resource transportation and energy metabolism to overcome the stress and maintain or somehow enhance their growth by up-regulating proteins like TBB6, CALM1, RAA2A, G3PP2 and KASC1. Our comparative proteomics analysis also highlighted multiple biological processes that consequently lead to the stability of plant growth and its stress adaptation. The results demonstrated that applying biosolids to soil as a fertilizer may be considered as a sustainable practice.

Extracellular Vesicles Regulate Biofilm Formation and Yeast-to-Hypha Differentiation in Candida albicans.

In this study, we investigated the influence of fungal extracellular vesicles (EVs) during biofilm formation and morphogenesis in Candida albicans. Using crystal violet staining and scanning electron microscopy (SEM), we demonstrated that C. albicans EVs inhibited biofilm formation in vitro. By time-lapse microscopy and SEM, we showed that C. albicans EV treatment stopped filamentation and promoted pseudohyphae formation with multiple budding sites. The ability of C. albicans EVs to regulate dimorphism was further compared to EVs isolated from different C. albicans strains, Saccharomyces cerevisiae, and Histoplasma capsulatum. C. albicans EVs from distinct strains inhibited yeast-to-hyphae differentiation with morphological changes occurring in less than 4 h. EVs from S. cerevisiae and H. capsulatum modestly reduced morphogenesis, and the effect was evident after 24 h of incubation. The inhibitory activity of C. albicans EVs on phase transition was promoted by a combination of lipid compounds, which were identified by gas chromatography-tandem mass spectrometry analysis as sesquiterpenes, diterpenes, and fatty acids. Remarkably, C. albicans EVs were also able to reverse filamentation. Finally, C. albicans cells treated with C. albicans EVs for 24 h lost their capacity to penetrate agar and were avirulent when inoculated into Galleria mellonella. Our results indicate that fungal EVs can regulate yeast-to-hypha differentiation, thereby inhibiting biofilm formation and attenuating virulence. IMPORTANCE The ability to undergo morphological changes during adaptation to distinct environments is exploited by Candida albicans and has a direct impact on biofilm formation and virulence. Morphogenesis is controlled by a diversity of stimuli, including osmotic stress, pH, starvation, presence of serum, and microbial components, among others. Apart from external inducers, C. albicans also produces autoregulatory substances. Farnesol and tyrosol are examples of quorum-sensing molecules (QSM) released by C. albicans to regulate yeast-to-hypha conversion. Here, we demonstrate that fungal EVs are messengers impacting biofilm formation, morphogenesis, and virulence in C. albicans. The major players exported in C. albicans EVs included sesquiterpenes, diterpenes, and fatty acids. The understanding of how C. albicans cells communicate to regulate physiology and pathogenesis can lead to novel therapeutic tools to combat candidiasis.

Context Matters: Recovering Human Semantic Structure from Machine Learning Analysis of Large-Scale Text Corpora.

Applying machine learning algorithms to automatically infer relationships between concepts from large-scale collections of documents presents a unique opportunity to investigate at scale how human semantic knowledge is organized, how people use it to make fundamental judgments ("How similar are cats and bears?"), and how these judgments depend on the features that describe concepts (e.g., size, furriness). However, efforts to date have exhibited a substantial discrepancy between algorithm predictions and human empirical judgments. Here, we introduce a novel approach to generating embeddings for this purpose motivated by the idea that semantic context plays a critical role in human judgment. We leverage this idea by constraining the topic or domain from which documents used for generating embeddings are drawn (e.g., referring to the natural world vs. transportation apparatus). Specifically, we trained state-of-the-art machine learning algorithms using contextually-constrained text corpora (domain-specific subsets of Wikipedia articles, 50+ million words each) and showed that this procedure greatly improved predictions of empirical similarity judgments and feature ratings of contextually relevant concepts. Furthermore, we describe a novel, computationally tractable method for improving predictions of contextually-unconstrained embedding models based on dimensionality reduction of their internal representation to a small number of contextually relevant semantic features. By improving the correspondence between predictions derived automatically by machine learning methods using vast amounts of data and more limited, but direct empirical measurements of human judgments, our approach may help leverage the availability of online corpora to better understand the structure of human semantic representations and how people make judgments based on those.

Specific Recognition of ß-Galactofuranose-Containing Glycans of Synthetic Neoglycoproteins by Sera of Chronic Chagas Disease Patients.

Chagas disease (CD) can be accurately diagnosed by detecting Trypanosoma cruzi in patients' blood using polymerase chain reaction (PCR). However, parasite-derived biomarkers are of great interest for the serological diagnosis and early evaluation of chemotherapeutic efficacy when PCR may fail, owing to a blood parasite load below the method's limit of detection. Previously, we focused on the detection of specific anti-α-galactopyranosyl (α-Gal) antibodies in chronic CD (CCD) patients elicited by α-Gal glycotopes copiously expressed on insect-derived and mammal-dwelling infective parasite stages. Nevertheless, these stages also abundantly express cell surface glycosylphosphatidylinositol (GPI)-anchored glycoproteins and glycoinositolphospholipids (GIPLs) bearing nonreducing terminal ß-galactofuranosyl (ß-Galf) residues, which are equally foreign to humans and, therefore, highly immunogenic. Here we report that CCD patients' sera react specifically with synthetic ß-Galf-containing glycans. We took a reversed immunoglycomics approach that entailed: (a) Synthesis of T. cruzi GIPL-derived Galfß1,3Manpα-(CH2)3SH (glycan G29SH) and Galfß1,3Manpα1,2-[Galfß1,3]Manpα-(CH2)3SH (glycan G32SH); and (b) preparation of neoglycoproteins NGP29b and NGP32b, and their evaluation in a chemiluminescent immunoassay. Receiver-operating characteristic analysis revealed that NGP32b can distinguish CCD sera from sera of healthy individuals with 85.3% sensitivity and 100% specificity. This suggests that Galfß1,3Manpα1,2-[Galfß1,3]Manpα is an immunodominant glycotope and that NGP32b could potentially be used as a novel CCD biomarker.

Crowd-Out and Emergency Department Utilization.

When consumers gain Medicaid, their cost of healthcare changes. The direction of this change determines how utilization changes. The previously uninsured see a stark decrease in the price of primary care after gaining public insurance. Due to charity care, they may face an increase in the price of emergency department care. The previously insured see a reduction in emergency department prices and decreased access to primary care. We examine the impact of the prior insurance status of the newly publicly insured on substitution between healthcare. We base our identification on California's LIHP and ACA Medicaid expansions. One challenge we face is estimating crowd-out. We use machine learning techniques to predict prior insurance status based on observable covariates in cross-sectional data. We find an increase in emergency department utilization caused entirely by those crowded-out whose access to primary care has decreased. We find the opposite utilization patterns for the previously uninsured.

Retinotopic organization of visual cortex in human infants.

Vision develops rapidly during infancy, yet how visual cortex is organized during this period is unclear. In particular, it is unknown whether functional maps that organize the mature adult visual cortex are present in the infant striate and extrastriate cortex. Here, we test the functional maturity of infant visual cortex by performing retinotopic mapping with functional magnetic resonance imaging (fMRI). Infants aged 5-23 months had retinotopic maps, with alternating preferences for vertical and horizontal meridians indicating the boundaries of visual areas V1 to V4 and an orthogonal gradient of preferences from high to low spatial frequencies. The presence of multiple visual maps throughout visual cortex in infants indicates a greater maturity of extrastriate cortex than previously appreciated. The areas showed subtle age-related fine-tuning, suggesting that early maturation undergoes continued refinement. This early maturation of area boundaries and tuning may scaffold subsequent developmental changes.

Evidence of hippocampal learning in human infants.

The hippocampus is essential for human memory.1 The protracted maturation of memory capacities from infancy through early childhood2-4 is thus often attributed to hippocampal immaturity.5-7 The hippocampus of human infants has been characterized in terms of anatomy,8,9 but its function has never been tested directly because of technical challenges.10,11 Here, we use recently developed methods for task-based fMRI in awake human infants12 to test the hypothesis that the infant hippocampus supports statistical learning.13-15 Hippocampal activity increased with exposure to visual sequences of objects when the temporal order contained regularities to be learned, compared to when the order was random. Despite the hippocampus doubling in anatomical volume across infancy, learning-related functional activity bore no relationship to age. This suggests that the hippocampus is recruited for statistical learning at the youngest ages in our sample, around 3 months. Within the hippocampus, statistical learning was clearer in anterior than posterior divisions. This is consistent with the theory that statistical learning occurs in the monosynaptic pathway,16 which is more strongly represented in the anterior hippocampus.17,18 The monosynaptic pathway develops earlier than the trisynaptic pathway, which is linked to episodic memory,19,20 raising the possibility that the infant hippocampus participates in statistical learning before it forms durable memories. Beyond the hippocampus, the medial prefrontal cortex showed statistical learning, consistent with its role in adult memory integration21 and generalization.22 These results suggest that the hippocampus supports the vital ability of infants to extract the structure of their environment through experience.

Attention recruits frontal cortex in human infants.

Young infants learn about the world by overtly shifting their attention to perceptually salient events. In adults, attention recruits several brain regions spanning the frontal and parietal lobes. However, it is unclear whether these regions are sufficiently mature in infancy to support attention and, more generally, how infant attention is supported by the brain. We used event-related functional magnetic resonance imaging (fMRI) in 24 sessions from 20 awake behaving infants 3 mo to 12 mo old while they performed a child-friendly attentional cuing task. A target was presented to either the left or right of the infant's fixation, and offline gaze coding was used to measure the latency with which they saccaded to the target. To manipulate attention, a brief cue was presented before the target in three conditions: on the same side as the upcoming target (valid), on the other side (invalid), or on both sides (neutral). All infants were faster to look at the target on valid versus invalid trials, with valid faster than neutral and invalid slower than neutral, indicating that the cues effectively captured attention. We then compared the fMRI activity evoked by these trial types. Regions of adult attention networks activated more strongly for invalid than valid trials, particularly frontal regions. Neither behavioral nor neural effects varied by infant age within the first year, suggesting that these regions may function early in development to support the orienting of attention. Together, this furthers our mechanistic understanding of how the infant brain controls the allocation of attention.