Functional imaging of the developing brain with wearable high-density diffuse optical tomography: A new benchmark for infant neuroimaging outside the scanner environment.

Studies of cortical function in the awake infant are extremely challenging to undertake with traditional neuroimaging approaches. Partly in response to this challenge, functional near-infrared spectroscopy (fNIRS) has become increasingly common in developmental neuroscience, but has significant limitations including resolution, spatial specificity and ergonomics. In adults, high-density arrays of near-infrared sources and detectors have recently been shown to yield dramatic improvements in spatial resolution and specificity when compared to typical fNIRS approaches. However, most existing fNIRS devices only permit the acquisition of ~20-100 sparsely distributed fNIRS channels, and increasing the number of optodes presents significant mechanical challenges, particularly for infant applications. A new generation of wearable, modular, high-density diffuse optical tomography (HD-DOT) technologies has recently emerged that overcomes many of the limitations of traditional, fibre-based and low-density fNIRS measurements. Driven by the development of this new technology, we have undertaken the first study of the infant brain using wearable HD-DOT. Using a well-established social stimulus paradigm, and combining this new imaging technology with advances in cap design and spatial registration, we show that it is now possible to obtain high-quality, functional images of the infant brain with minimal constraints on either the environment or on the infant participants. Our results are consistent with prior low-density fNIRS measures based on similar paradigms, but demonstrate superior spatial localization, improved depth specificity, higher SNR and a dramatic improvement in the consistency of the responses across participants. Our data retention rates also demonstrate that this new generation of wearable technology is well tolerated by the infant population.

Association between caregiver and infant visual neurocognition.

Previous work has shown that caregiver attention shapes visual cognition in infants through dyadic interactions. Is this association measurable when visual cognition is objectively measured in caregivers and infants using comparable experimental paradigms? In the current study, we presented infants (N = 86) and caregivers (N = 78) with age-specific variants of the same preferential looking visual cognition task to investigate whether caregiver visual cognition was associated with their infants' visual cognition. In each trial of the task, two side-by-side flashing displays of coloured shapes were presented. On the 'unchanging' side, the colours of the shapes remained the same. On the 'changing' side, the colour of one shape changed after each flash. Load was varied by changing the number of shapes across trials (low, medium, and high loads). We extracted looking dynamics using video recordings and brain function using functional near-infrared spectroscopy as both infants and caregivers engaged with the task. Change preference (CP) score, which represented the amount of time spent looking at the changing side divided by the total looking duration, showed a load-dependent modulation for both infants and caregivers. Both groups showed the highest CP scores at the low load. Further, higher caregiver CP scores was associated with higher infant CP scores at the low load. Both infants and caregivers engaged canonical regions of the fronto-parietal network involved in visual cognition. Critically, higher caregiver CP scores were associated with greater activation in the left superior parietal lobule in younger infants, a region involved in allocating visuo-spatial attention and working memory maintenance. Further, there was spatial overlap between performance-dependent regions in the right parietal cortex in caregivers and younger infants. Our findings provide first evidence of a heritability-related visual neurocognitive association between caregivers and their children in the first year of life.

Early Infant Prefrontal Cortical Microstructure Predicts Present and Future Emotionality.

BACKGROUND: High levels of infant negative emotionality (NE) and low positive emotionality (PE) predict future emotional and behavioral problems. The prefrontal cortex (PFC) supports emotional regulation, with each PFC subregion specializing in specific emotional processes. Neurite orientation dispersion and density imaging estimates microstructural integrity and myelination via the neurite density index (NDI) and dispersion via the orientation dispersion index (ODI), with potential to more accurately evaluate microstructural alterations in the developing brain. Yet, no study has used these indices to examine associations between PFC microstructure and concurrent or developing infant emotionality. METHODS: We modeled PFC subregional NDI and ODI at 3 months with caregiver-reported infant NE and PE at 3 months (n = 61) and at 9 months (n = 50), using multivariable and subsequent bivariate regression models. RESULTS: The most robust statistically significant findings were positive associations among 3-month rostral anterior cingulate cortex (ACC) ODI and caudal ACC NDI and concurrent NE, a positive association between 3-month lateral orbitofrontal cortex ODI and prospective NE, and a negative association between 3-month dorsolateral PFC ODI and concurrent PE. Multivariate models also revealed that other PFC subregional microstructure measures, as well as infant and caregiver sociodemographic and clinical factors, predicted infant 3- and 9-month NE and PE. CONCLUSIONS: Greater NDI and ODI, reflecting greater microstructural complexity, in PFC regions supporting salience perception (rostral ACC), decision making (lateral orbitofrontal cortex), action selection (caudal ACC), and attentional processes (dorsolateral PFC) might result in greater integration of these subregions with other neural networks and greater attention to salient negative external cues, thus higher NE and/or lower PE. These findings provide potential infant cortical markers of future psychopathology risk.

Maternal childhood maltreatment: associations to offspring brain volume and white matter connectivity.

The deleterious effects of adversity are likely intergenerational, such that one generation's adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children's behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

ID-Seg: an infant deep learning-based segmentation framework to improve limbic structure estimates.

Infant brain magnetic resonance imaging (MRI) is a promising approach for studying early neurodevelopment. However, segmenting small regions such as limbic structures is challenging due to their low inter-regional contrast and high curvature. MRI studies of the adult brain have successfully applied deep learning techniques to segment limbic structures, and similar deep learning models are being leveraged for infant studies. However, these deep learning-based infant MRI segmentation models have generally been derived from small datasets, and may suffer from generalization problems. Moreover, the accuracy of segmentations derived from these deep learning models relative to more standard Expectation-Maximization approaches has not been characterized. To address these challenges, we leveraged a large, public infant MRI dataset (n = 473) and the transfer-learning technique to first pre-train a deep convolutional neural network model on two limbic structures: amygdala and hippocampus. Then we used a leave-one-out cross-validation strategy to fine-tune the pre-trained model and evaluated it separately on two independent datasets with manual labels. We term this new approach the Infant Deep learning SEGmentation Framework (ID-Seg). ID-Seg performed well on both datasets with a mean dice similarity score (DSC) of 0.87, a mean intra-class correlation (ICC) of 0.93, and a mean average surface distance (ASD) of 0.31 mm. Compared to the Developmental Human Connectome pipeline (dHCP) pipeline, ID-Seg significantly improved segmentation accuracy. In a third infant MRI dataset (n = 50), we used ID-Seg and dHCP separately to estimate amygdala and hippocampus volumes and shapes. The estimates derived from ID-seg, relative to those from the dHCP, showed stronger associations with behavioral problems assessed in these infants at age 2. In sum, ID-Seg consistently performed well on two different datasets with an 0.87 DSC, however, multi-site testing and extension for brain regions beyond the amygdala and hippocampus are still needed.

An ode to fetal, infant, and toddler neuroimaging: Chronicling early clinical to research applications with MRI, and an introduction to an academic society connecting the field.

Fetal, infant, and toddler neuroimaging is commonly thought of as a development of modern times (last two decades). Yet, this field mobilized shortly after the discovery and implementation of MRI technology. Here, we provide a review of the parallel advancements in the fields of fetal, infant, and toddler neuroimaging, noting the shifts from clinical to research use, and the ongoing challenges in this fast-growing field. We chronicle the pioneering science of fetal, infant, and toddler neuroimaging, highlighting the early studies that set the stage for modern advances in imaging during this developmental period, and the large-scale multi-site efforts which ultimately led to the explosion of interest in the field today. Lastly, we consider the growing pains of the community and the need for an academic society that bridges expertise in developmental neuroscience, clinical science, as well as computational and biomedical engineering, to ensure special consideration of the vulnerable mother-offspring dyad (especially during pregnancy), data quality, and image processing tools that are created, rather than adapted, for the young brain.

Prenatal stress exposure and multimodal assessment of amygdala-medial prefrontal cortex connectivity in infants.

Stressful experiences are linked to neurodevelopment. There is growing interest in the role of stress in the connectivity between the amygdala and medial prefrontal cortex (mPFC), a circuit that subserves automatic emotion regulation. However, the specific timing and mechanisms that underlie the association between stress and amygdala-mPFC connectivity are unclear. Many factors, including variations in fetal exposure to maternal stress, appear to affect early developing brain circuitry. However, few studies have examined the associations of stress and amygdala-mPFC connectivity in early life, when the brain is most plastic and sensitive to environmental influence. In this longitudinal pilot study, we characterized the association between prenatal stress and amygdala-mPFC connectivity in young infants (approximately age 5 weeks). A final sample of 33 women who provided data on preconception and prenatal stress during their pregnancy returned with their offspring for a magnetic resonance imaging scan session, which enabled us to characterize amygdala-mPFC structural and functional connectivity as a function of prenatal stress. Increased prenatal stress was associated with decreased functional connectivity and increased structural connectivity between the amygdala and mPFC. These results provide insight into the influence of prenatal maternal stress on the early development of this critical regulatory circuitry.

Video-based motion-resilient reconstruction of three-dimensional position for functional near-infrared spectroscopy and electroencephalography head mounted probes.

Significance: We propose a video-based, motion-resilient, and fast method for estimating the position of optodes on the scalp. Aim: Measuring the exact placement of probes (e.g., electrodes and optodes) on a participant's head is a notoriously difficult step in acquiring neuroimaging data from methods that rely on scalp recordings (e.g., electroencephalography and functional near-infrared spectroscopy) and is particularly difficult for any clinical or developmental population. Existing methods of head measurements require the participant to remain still for a lengthy period of time, are laborious, and require extensive training. Therefore, a fast and motion-resilient method is required for estimating the scalp location of probes. Approach: We propose an innovative video-based method for estimating the probes' positions relative to the participant's head, which is fast, motion-resilient, and automatic. Our method builds on capitalizing the advantages and understanding the limitations of cutting-edge computer vision and machine learning tools. We validate our method on 10 adult subjects and provide proof of feasibility with infant subjects. Results: We show that our method is both reliable and valid compared to existing state-of-the-art methods by estimating probe positions in a single measurement and by tracking their translation and consistency across sessions. Finally, we show that our automatic method is able to estimate the position of probes on an infant head without lengthy offline procedures, a task that has been considered challenging until now. Conclusions: Our proposed method allows, for the first time, the use of automated spatial co-registration methods on developmental and clinical populations, where lengthy, motion-sensitive measurement methods routinely fail.