Awake Infants Research Articles

Semiautomated measures of foveal immaturity from handheld swept-source optical coherence tomography are associated with retinopathy of prematurity severity

Background/aimsHandheld swept-source optical coherence tomography (SS-OCT) was previously used to measure foveal maturity through semiautomated methods in awake premature infants. This study assesses the relationship between foveal maturity and retinopathy...

Whole-head high-density diffuse optical tomography to map infant audio-visual responses to social and non-social stimuli

Abstract Infancy is a time of rapid brain development. High-density diffuse optical tomography (HD-DOT) is an optical neuroimaging method that maps changes in cortical haemoglobin concentration, a marker of functional brain activation. Recent years have seen a huge advance in wearable hardware for HD-DOT, however previous headgear has only been capable of sampling specific areas of the cortex. In this work, we aimed to develop headgear capable of sampling across the whole infant scalp surface and to conduct a proof-of-concept demonstration of whole-head HD-DOT in infants aged 5 to 7 months. We developed a whole-head infant implementation of the high-density LUMO design developed by Gowerlabs Ltd. (UK). HD-DOT data were collected from a cohort of infants (N = 16) during the presentation of a screen-based paradigm assessing social processing. Using whole-head HD-DOT, we mapped activity across the entirety of the optically-accessible cortex which far exceeds coverage achieved by previous infant optical neuroimaging methods. We found activity in temporal regions which corroborates previous research. Further, we mapped activity in regions outside those typically sampled in infant research using social processing paradigms, finding activation in regions across the occipital, parietal, and frontal cortices as well as an apparent inverted response in sensorimotor regions. Following this proof-of-concept, we envisage that whole-head HD-DOT will be applied to map the interaction between different regions of the brain, opening new avenues to map activity in the awake infant brain to better understand the trajectory of typical and atypical neurodevelopment.

Single-line macular optic coherence tomography to confirm optic neuropathies in awake infants and young children

BackgroundHandheld optical coherence tomography (HH-OCT) can image awake, young children but lacks integrated segmentation/analysis software. OCT imaging of eyes with optic neuropathies demonstrates ganglion cell layer (GCL) and ganglion cell complex (GCC) thinning, with a normal or thickened inner nuclear layer (INL). We compared pediatric normative data with GCL/INL and GCC/INL ratios from HH-OCT macular scans of awake young children with clinically diagnosed optic neuropathies. MethodsMacular HH-OCT from awake children with optic neuropathies was prospectively obtained using Bioptigen (Leica Microsystems, Wetzlar, Germany). The GCL, GCC, and INL were manually measured by two readers using ImageJ from single-line macular scans at the thickest points nasal and temporal to the fovea, respectively, and the GCL/INL and GCC/INL ratios were calculated and compared with normative data. ResultsHH-OCT images from 17 right eyes of 17 children (mean age, 4.3 ± 2.9 years) with optic neuropathies were analyzed. Mean nasal (17 eyes) and temporal (16 eyes) GCL/INL ratios with optic neuropathies were 0.44 ± 0.38 (95% CI, 0.26-0.62) and 0.26 ± 0.22 (95% CI, 0.15-0.36), respectively. Corresponding normative GCL/INL ratios are 1.26 ± 0.20 (95% CI, 1.19-1.34) and 1.23 ± 0.27 (95% CI, 1.13-1.33), respectively (P < 0.0001). Severe thinning precluded GCL measurements in 2 eyes nasally and 5 eyes temporally, resulting in GCL measurements of zero. Mean nasal (17 eyes) and temporal (16 eyes) GCC/INL ratios were 1.93 ± 0.70 (95% CI,1.60-2.27) and 1.67 ± 0.44 (95% CI,1.46-1.87). Corresponding normative ratios are 2.85 ± 0.38 (95% CI, 2.71-2.99) and 2.87 ± 0.42 (95% CI, 2.70-3.03), respectively (P < 0.0001). ConclusionsGCL/INL and GCC/INL ratios calculated from single-line macular HH-OCT scans in awake young children with optic neuropathies differ significantly from normative values and may thus have utility in helping to establish a diagnosis of optic neuropathy.

Cortical Face-Selective Responses Emerge Early in Human Infancy.

In human adults, multiple cortical regions respond robustly to faces, including the occipital face area (OFA) and fusiform face area (FFA), implicated in face perception, and the superior temporal sulcus (STS) and medial prefrontal cortex (MPFC), implicated in higher-level social functions. When in development, does face selectivity arise in each of these regions? Here, we combined two awake infant functional magnetic resonance imaging (fMRI) datasets to create a sample size twice the size of previous reports (n = 65 infants; 2.6-9.6 months). Infants watched movies of faces, bodies, objects, and scenes, while fMRI data were collected. Despite variable amounts of data from each infant, individual subject whole-brain activation maps revealed responses to faces compared to nonface visual categories in the approximate location of OFA, FFA, STS, and MPFC. To determine the strength and nature of face selectivity in these regions, we used cross-validated functional region of interest analyses. Across this larger sample size, face responses in OFA, FFA, STS, and MPFC were significantly greater than responses to bodies, objects, and scenes. Even the youngest infants (2-5 months) showed significantly face-selective responses in FFA, STS, and MPFC, but not OFA. These results demonstrate that face selectivity is present in multiple cortical regions within months of birth, providing powerful constraints on theories of cortical development.

Socioeconomic Inequalities Affect Brain Responses of Infants Growing Up in Germany.

Developmental changes in functional neural networks are sensitive to environmental influences. This EEG study investigated how infant brain responses relate to the social context that their families live in. Event-related potentials of 255 healthy, awake infants between six and fourteen months were measured during a passive auditory oddball paradigm. Infants were presented with 200 standard tones and 48 randomly distributed deviants. All infants are part of a longitudinal study focusing on families with socioeconomic and/or cultural challenges (Bremen Initiative to Foster Early Childhood Development; BRISE; Germany). As part of their familial socioeconomic status (SES), parental level of education and infant's migration background were assessed with questionnaires. For 30.6% of the infants both parents had a low level of education (≤10 years of schooling) and for 43.1% of the infants at least one parent was born abroad. The N2-P3a complex is associated with unintentional directing of attention to deviant stimuli and was analysed in frontocentral brain regions. Age was utilised as a control variable. Our results show that tone deviations in infants trigger an immature N2-P3a complex. Contrary to studies with older children or adults, the N2 amplitude was more positive for deviants than for standards. This may be related to an immature superposition of the N2 with the P3a. For infants whose parents had no high-school degree and were born abroad, this tendency was increased, indicating that facing multiple challenges as a young family impacts on the infant's early neural development. As such, attending to unexpected stimulus changes may be important for early learning processes. Variations of the infant N2-P3a complex may, thus, relate to early changes in attentional capacity and learning experiences due to familial challenges. This points towards the importance of early prevention programs.

Neurodevelopment of children exposed to prolonged anesthesia in infancy: GABA study interim analysis of resting-state brain networks at 2, 4, and 10-months old

BackgroundPrevious studies have raised concerns regarding neurodevelopmental impacts of early exposures to general anesthesia and surgery. Electroencephalography (EEG) can be used to study ontogeny of brain networks during infancy. As a substudy of an ongoing study, we examined measures of functional connectivity in awake infants with prior early and prolonged anesthetic exposures and in control infants. MethodsEEG functional connectivity was assessed using debiased weighted phase lag index at source and sensor levels and graph theoretical measures for resting state activity in awake infants in the early anesthesia (n = 26 at 10 month visit, median duration of anesthesia = 4 [2, 7 h]) and control (n = 38 at 10 month visit) groups at ages approximately 2, 4 and 10 months. Theta and low alpha frequency bands were of primary interest. Linear mixed models incorporated impact of age and cumulative hours of general anesthesia exposure. ResultsModels showed no significant impact of cumulative hours of general anesthesia exposure on debiased weighted phase lag index, characteristic path length, clustering coefficient or small-worldness (conditional R2 0.05–0.34). An effect of age was apparent in many of these measures. ConclusionsWe could not demonstrate significant impact of general anesthesia in the first months of life on early development of resting state brain networks over the first postnatal year. Future studies will explore these networks as these infants grow older.

Using multi-modal neuroimaging to characterise social brain specialisation in infants.

The specialised regional functionality of the mature human cortex partly emerges through experience-dependent specialisation during early development. Our existing understanding of functional specialisation in the infant brain is based on evidence from unitary imaging modalities and has thus focused on isolated estimates of spatial or temporal selectivity of neural or haemodynamic activation, giving an incomplete picture. We speculate that functional specialisation will be underpinned by better coordinated haemodynamic and metabolic changes in a broadly orchestrated physiological response. To enable researchers to track this process through development, we develop new tools that allow the simultaneous measurement of coordinated neural activity (EEG), metabolic rate, and oxygenated blood supply (broadband near-infrared spectroscopy) in the awake infant. In 4- to 7-month-old infants, we use these new tools to show that social processing is accompanied by spatially and temporally specific increases in coupled activation in the temporal-parietal junction, a core hub region of the adult social brain. During non-social processing, coupled activation decreased in the same region, indicating specificity to social processing. Coupling was strongest with high-frequency brain activity (beta and gamma), consistent with the greater energetic requirements and more localised action of high-frequency brain activity. The development of simultaneous multimodal neural measures will enable future researchers to open new vistas in understanding functional specialisation of the brain.

Neural processing of auditory temporal modulations in awake infants.

The amplitude modulation following response (AMFR) is the steady-state auditory response signaling phase-locking to slow variations in the amplitude (AM) of auditory stimuli that provide fundamental acoustic information. From a developmental perspective, the AMFR has been recorded in sleeping infants, compared to sleeping or awake adults. The lack of AMFR recordings in awake infants limits conclusions on the development of phase-locking to AM. Moreover, previous studies assessing phase-locking to AM using non-speech carriers have not included slow AM rates (<20 Hz), which are particularly important for speech processing. This study aimed at disentangling these issues by recording the AMFR with electroencephalography: in awake infants (3- and 10-month-olds) and awake young adults and for both slow and faster modulation rates (8 and 40 Hz). The AMFR was observable at 8 Hz at all ages (40%, 60%, and 33% of significant AMFR at 3 months, 10 months, and adults, respectively), but only adults showed reliable responses at 40 Hz (6% of significant AMFR at both 3 and 10 months, 100% in adults), thus, ruling out the possibility that sleep has a suppressing effect on the response. This pattern might be explained by developmental differences in the sources of neural processing of faster AM rates.

Third trimester fetal lung volume, thoracic circumference, and early infant lung function.

We aimed to investigate the relationship between fetal third trimester lung volume (LV), thoracic circumference (TC), fetal weight, as well as fetal thoracic and weight growth, and early infant lung function. Fetal LV, TC and estimated weight were measured with ultrasound at 30 gestational weeks in 257 fetuses from the general population-based prospective cohort study Preventing Atopic Dermatitis and ALLergies in Children (PreventADALL). Fetal thoracic growth rate and weight increase were calculated using TC and estimated fetal weight measured by ultrasound during pregnancy, and TC and birthweight of the newborn. Lung function was assessed by tidal flow-volume measurement in awake infants at 3 months of age. The associations between fetal size (LV, TC, and estimated weight) and growth (thoracic growth rate and fetal weight increase) measures and the time to peak tidal expiratory flow to expiratory time ratio (tPTEF /tE ) as well as tidal volume standardized for body weight (VT /kg) were analyzed using linear and logistic regression models. We observed no associations between fetal LV, TC or estimated fetal weight and tPTEF /tE as a continuous variable, tPTEF /tE < 25th percentile, or VT /kg. Similarly, fetal thoracic growth and weight increase were not associated with infant lung function. Analyses stratified for sex showed a significant inverse association between fetal weight increase and VT /kg (p = 0.02) in girls. Overall, fetal third trimester LV, TC, estimated fetal weight, thoracic growth rate and weight increase were not associated with infant lung function at 3 months of age.

Maturation of cortical responses to sound in the first year of life

Infants show sophisticated sound discrimination from the time they are born but the neural mechanisms that support infant auditory perception are not well understood. A central question is the discrepancy between the early onset of auditory skills and the protracted and extended maturation of the auditory cortex. To investigate the cortical processing of sound, we have been employing magnetoencephalography (MEG) with recent advancements in movement compensation to obtain functional neural measures of sound processing in awake infants. MEG responses from an Elekta Neuromag 306-channel system were recorded longitudinally at 3 (n = 27), 6 (n = 19), and 11 (n = 14) months to an ecologically salient bi-syllabic word and an amplitude-modulated complex tone pair in typically hearing infants. The neural generators of the MEG signals were determined using an equivalent current dipole (ECD) model. Our preliminary analyses have focused on two measures: cortical responses to acoustic change and the development of hemispheric lateralization to speech. Our preliminary analyses show that high quality MEG data with good signal-to-noise ratios can be obtained by 3 months and dipole modeling of MEG signals in combination with advanced movement compensation offers a temporally precise method of investigating the maturation of auditory cortical networks in infants.

Automated and manual segmentation of the hippocampus in human infants

The hippocampus, critical for learning and memory, undergoes substantial changes early in life. Investigating the developmental trajectory of hippocampal structure and function requires an accurate method for segmenting this region from anatomical MRI scans. Although manual segmentation is regarded as the “gold standard” approach, it is laborious and subjective. This has fueled the pursuit of automated segmentation methods in adults. However, little is known about the reliability of these automated protocols in infants, particularly when anatomical scan quality is degraded by head motion or the use of shorter and quieter infant-friendly sequences. During a task-based fMRI protocol, we collected quiet T1-weighted anatomical scans from 42 sessions with awake infants aged 4–23 months. Two expert tracers first segmented the hippocampus in both hemispheres manually. The resulting inter-rater reliability (IRR) was only moderate, reflecting the difficulty of infant segmentation. We then used four protocols to predict these manual segmentations: average adult template, average infant template, FreeSurfer software, and Automated Segmentation of Hippocampal Subfields (ASHS) software. ASHS generated the most reliable hippocampal segmentations in infants, exceeding the manual IRR of experts. Automated methods thus provide robust hippocampal segmentations of noisy T1-weighted infant scans, opening new possibilities for interrogating early hippocampal development.

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.

Infant lung function: criteria for selecting tidal flow-volume loops.

BackgroundTidal flow–volume (TFV) loops are commonly recorded in infants during sleep, due to the more regular breathing patterns compared to the awake state. Standardised deselection of loops outside pre-specified ranges are based on periods of regular breathing, while criteria and available software for visual evaluation of TFV loops are lacking. We aimed to determine the reliability of standardised criteria for manual selection of infant TFV loops.MethodsUsing a pre-defined set of criteria, three independent raters manually evaluated TFV loops among 57 randomly selected awake healthy 3-month-old infants with available TFV measurements in the Scandinavian Preventing Atopic Dermatitis and ALLergies in children (PreventADALL) study. The TFV loops were sampled using the Eco Medics Exhalyzer D. Criteria for selecting TFV loops included reproducible shape and volume with only one peak in tidal expiratory flow (PTEF), excluding loops with no clear or uneven flow towards PTEF. By intraclass coefficient (ICC), the reliability of agreement between raters was determined for the time to PTEF (tPTEF) to expiratory time (tE) and other TFV loop parameters.ResultsFive infants had unsuccessful tests. Among the remaining 52 infants, the raters selected a median of 25, 26 and 15 loops per test. The ICCs (95% CI) were 0.97 (0.92–0.98) for tPTEF/tE, 0.99 (0.99–1.00) for respiratory rate, 0.98 (0.97–0.99) for tidal volume per kg and 0.98 (0.97–0.99) for expiratory volume, reflecting excellent agreement in all categories.ConclusionManual TFV loop selection using standardised criteria provides a reliable alternative for lung function measures in awake infants with interrupted breathing cycles in a real-life setting.

Biphasic change in retinal nerve fibre layer thickness from 30 to 60 weeks postmenstrual age in preterm infants

Background/AimsThe optic nerve development during the critical postnatal weeks of preterm infants is unclear. We aimed to investigate the change of retinal nerve fibre layer (RNFL) in preterm infants.MethodsWe used...

Semi-automated analysis of foveal maturity in premature and full-term infants using handheld swept-source optical coherence tomography

Semi-automated foveal analysis using an investigational handheld swept source-optical coherence tomography (SS-OCT) may identify foveal immaturity in awake infants.

A comparative study of mother-infant co-regulation of distance at home in Japan and Scotland

Mothers and infants co-regulate their distance from one another at home. Continuous, naturalistic home observations of the changes in mother-infant distance were carried out in Japan and Scotland during infant ages of 0–1, 6–7, and 12–13 months. This study examined mutual distance-increasing and distance-reducing behaviours, referred to as parent-infant ‘centrifugalism’ and ‘centripetalism’. Cultural differences emerged in the modes of mother-infant distance co-regulation. Scottish mothers were more active in initiating contact and leaving infants alone to sleep, whereas Japanese mothers showed stronger infant-centredness by maintaining physical contact with infants when they fell asleep and reacting to their crying when they woke up. Age differences were found relating to decrease in sleep and increase in object play in the middle of the first year, which resulted in more separation within a 0.5 m distance at 6–7 months, a compromise between closeness and distancing between mothers and awake infants. Cultural and age differences in the co-regulation of mother-infant distance were discussed in relation to the development of locomotion, object play, and intention-reading.

Infant brain imaging using magnetoencephalography: Challenges, solutions, and best practices.

The excellent temporal resolution and advanced spatial resolution of magnetoencephalography (MEG) makes it an excellent tool to study the neural dynamics underlying cognitive processes in the developing brain. Nonetheless, a number of challenges exist when using MEG to image infant populations. There is a persistent belief that collecting MEG data with infants presents a number of limitations and challenges that are difficult to overcome. Due to this notion, many researchers either avoid conducting infant MEG research or believe that, in order to collect high‐quality data, they must impose limiting restrictions on the infant or the experimental paradigm. In this article, we discuss the various challenges unique to imaging awake infants and young children with MEG, and share general best‐practice guidelines and recommendations for data collection, acquisition, preprocessing, and analysis. The current article is focused on methodology that allows investigators to test the sensory, perceptual, and cognitive capacities of awake and moving infants. We believe that such methodology opens the pathway for using MEG to provide mechanistic explanations for the complex behavior observed in awake, sentient, and dynamically interacting infants, thus addressing core topics in developmental cognitive neuroscience.

Regional Haemodynamic and Metabolic Coupling in Infants.

Metabolic pathways underlying brain function remain largely unexplored during neurodevelopment, predominantly due to the lack of feasible techniques for use with awake infants. Broadband near-infrared spectroscopy (bNIRS) provides the opportunity to explore the relationship between cerebral energy metabolism and blood oxygenation/haemodynamics through the measurement of changes in the oxidation state of mitochondrial respiratory chain enzyme cytochrome-c-oxidase (ΔoxCCO) alongside haemodynamic changes. We used a bNIRS system to measure ΔoxCCO and haemodynamics during functional activation in a group of 42 typically developing infants aged between 4 and 7 months. bNIRS measurements were made over the right hemisphere over temporal, parietal and central cortical regions, in response to social and non-social visual and auditory stimuli. Both ΔoxCCO and Δ[HbO2] displayed larger activation for the social condition in comparison to the non-social condition. Integration of haemodynamic and metabolic signals revealed networks of stimulus-selective cortical regions that were not apparent from analysis of the individual bNIRS signals. These results provide the first spatially resolved measures of cerebral metabolic activity alongside haemodynamics during functional activation in infants. Measuring synchronised changes in metabolism and haemodynamics have the potential for uncovering the development of cortical specialisation in early infancy.

Imaging Cerebral Energy Metabolism in Healthy Infants.

Broadband near-infrared spectroscopy (bNIRS) has the potential to provide non-invasive measures of cerebral haemodynamic changes alongside changes in cellular oxygen utilisation through the measurement of mitochondrial enzyme cytochrome-c-oxidase (oxCCO). It therefore provides the opportunity to explore brain function and specialisation, which remains largely unexplored in infancy. We used bNIRS to measure changes in haemodynamics and changes in oxCCO in 4-to-7-month-old infants over the occipital and right temporal and parietal cortices in response to social and non-social visual and auditory stimuli. Changes in concentration of oxygenated-haemoglobin (Δ[HbO2]), deoxygenated haemoglobin (Δ[HHb]) and change in the oxidation state of oxCCO (Δ[oxCCO]) were calculated using changes in attenuation of light at 120 wavelengths between 780 and900nm, using the UCLn algorithm. For 4 infants, the attenuation changes in a subset of wavelengths were used to perform image reconstruction, in an age-matched infant model, for channels over the right parietal and temporal cortices, using a multispectral approach which allows direct reconstruction of concentration change data. The volumetric reconstructed images were mapped onto the cortical surface to visualise the reconstructed changes in concentration of HbO2 and HHb and changes in metabolism for both social and non-social stimuli. Spatially localised activation was observed for Δ[oxCCO] and Δ[HbO2] over the temporo-parietal region, in response to the social stimulus. This study provides the first reconstructed images of changes in metabolism in healthy, awake infants.

The neural processing of sound in infants

Early auditory abilities play an important role in infants’ ability to acquire language, appreciate music, and navigate the complex acoustic environments around them. However, the neural mechanisms that support infant sound processing are not well understood. This study used magnetoencephalography (MEG) with recent advancements in movement compensation to obtain functional measures of auditory processing in awake infants. MEG responses were recorded longitudinally at 3, 6, and 11 months of age to an English bi-syllabic word and an amplitude-modulated complex tone as a non-speech but spectro-temporally complex control stimulus. MEG recordings were made with an Elekta Neuromag® whole-head 306-channel MEG system. The neural generators of the MEG signals were determined using an equivalent current dipole (ECD) model. High quality MEG data with good signal-to-noise ratios were recorded in infants as young as 3 months of age in both conditions. ECD field maps showed focal sources in the brain confirming the ECD model is a robust source localization approach that can fit auditory neural sources in infants. Our results show that dipole modeling of MEG signals in combination with advanced movement compensation offers a temporally precise method of investigating how the cortical processing of sound changes across the first year of life.