Study protocol of the Hungarian Longitudinal Study of Healthy Brain Aging (HuBA).

Background and purpose:

Neuro­cog­nitive aging and the associated brain diseases impose a major social and economic burden. Therefore, substantial efforts have been put into revealing the lifestyle, the neurobiological and the genetic underpinnings of healthy neurocognitive aging. However, these studies take place almost exclusively in a limited number of highly-developed countries. Thus, it is an important open question to what extent their findings may generalize to neurocognitive aging in other, not yet investigated regions. The purpose of the Hungarian Longitudinal Study of Healthy Brain Aging (HuBA) is to collect multi-modal longitudinal data on healthy neurocognitive aging to address the data gap in this field in Central and Eastern Europe.

We adapted the Australian Ima­ging, Biomarkers and Lifestyle (AIBL) study of aging study protocol to local circumstances and collected demographic, lifestyle, men­tal and physical health, medication and medical history related information as well as re­cor­ded a series of magnetic resonance imaging (MRI) data. In addition, participants were al­so offered to participate in the collection of blood samples to assess circulating in­flam­matory biomarkers as well as a sleep study aimed at evaluating the general sleep quality based on multi-day collection of subjective sleep questionnaires and whole-night elec­troencephalographic (EEG) data.

Baseline data collection has al­ready been accomplished for more than a hundred participants and data collection in the se­cond
session is on the way. The collected data might reveal specific local trends or could also indicate the generalizability of previous findings. Moreover, as the HuBA protocol al­so offers a sleep study designed for tho­rough characterization of participants’ sleep quality and related factors, our extended multi-modal dataset might provide a base for incorporating these measures into healthy and clinical aging research. 

Besides its straightforward na­tional benefits in terms of health ex­pen­di­ture, we hope that this Hungarian initiative could provide results valid for the whole Cent­ral and Eastern European region and could also promote aging and Alzheimer’s disease research in these countries.

Automatic brain MRI motion artifact detection based on end-to-end deep learning is similarly effective as traditional machine learning trained on image quality metrics.

Head motion artifacts in magnetic resonance imaging (MRI) are an important confounding factor concerning brain research as well as clinical practice. For this reason, several machine learning-based methods have been developed for the automatic quality control of structural MRI scans. Deep learning offers a promising solution to this problem, however, given its data-hungry nature and the scarcity of expert-annotated datasets, its advantage over traditional machine learning methods in identifying motion-corrupted brain scans is yet to be determined. In the present study, we investigated the relative advantage of the two methods in structural MRI quality control. To this end, we collected publicly available T1-weighted images and scanned subjects in our own lab under conventional and active head motion conditions. The quality of the images was rated by a team of radiologists from the point of view of clinical diagnostic use. We present a relatively simple, lightweight 3D convolutional neural network trained in an end-to-end manner that achieved a test set (N = 411) balanced accuracy of 94.41% in classifying brain scans into clinically usable or unusable categories. A support vector machine trained on image quality metrics achieved a balanced accuracy of 88.44% on the same test set. Statistical comparison of the two models yielded no significant difference in terms of confusion matrices, error rates, or receiver operating characteristic curves. Our results suggest that these machine learning methods are similarly effective in identifying severe motion artifacts in brain MRI scans, and underline the efficacy of end-to-end deep learning-based systems in brain MRI quality control, allowing the rapid evaluation of diagnostic utility without the need for elaborate image pre-processing.

Preverbal infants produce more protophones with artificial objects compared to natural objects.

Protophones are considered to be precursors of speech. These vocalizations have been notably discussed in relation to toys and their importance for developing language skills. However, little is known about how natural objects, compared to artificial objects, may affect protophone production, an approach that could additionally help reconstruct how language evolved. In the current study, we examined protophone production in 58 infants (4-18 months) while interacting with their caregivers when using natural objects, household items, and toys. The infants were recorded in their home environment, in a rural area in Zambia. The results showed that the infants produced significantly fewer protophones when using natural objects than when using household items or toys. Importantly, this pattern was found only for the younger preverbal infants, and there was no indication in the data that the level of caregiver responsiveness differed with regard to the object type. Furthermore, the infants of the present work selected primarily the household items when exposed to both natural objects and household items. These findings suggest that natural objects are less likely to promote protophone production and, consequently, language skill development than artificial objects in preverbal infants, who seem to favor the latter, perhaps due to their features designed for specific functional purposes. Furthermore, these findings provide empirical evidence that the use of complex tools in social interactions may have helped to promote the evolution of language among hominins.

T cell immunity ameliorates COVID-19 disease severity and provides post-exposure prophylaxis after peptide-vaccination, in Syrian hamsters.

Background: The emergence of novel SARS-CoV-2 variants that resist neutralizing antibodies drew the attention to cellular immunity and calls for the development of alternative vaccination strategies to combat the pandemic. Here, we have assessed the kinetics of T cell responses and protective efficacy against severe COVID-19 in pre- and post-exposure settings, elicited by PolyPEPI-SCoV-2, a peptide based T cell vaccine. Methods: 75 Syrian hamsters were immunized subcutaneously with PolyPEPI-SCoV-2 on D0 and D14. On D42, hamsters were intranasally challenged with 102 TCID50 of the virus. To analyze immunogenicity by IFN-γ ELISPOT and antibody secretion, lymphoid tissues were collected both before (D0, D14, D28, D42) and after challenge (D44, D46, D49). To measure vaccine efficacy, lung tissue, throat swabs and nasal turbinate samples were assessed for viral load and histopathological changes. Further, body weight was monitored on D0, D28, D42 and every day after challenge. Results: The vaccine induced robust activation of T cells against all SARS-CoV-2 structural proteins that were rapidly boosted after virus challenge compared to control animals (~4-fold, p<0.05). A single dose of PolyPEPI-SCoV-2 administered one day after challenge also resulted in elevated T cell response (p<0.01). The vaccination did not induce virus-specific antibodies and viral load reduction. Still, peptide vaccination significantly reduced body weight loss (p<0.001), relative lung weight (p<0.05) and lung lesions (p<0.05), in both settings. Conclusion: Our study provides first proof of concept data on the contribution of T cell immunity on disease course and provide rationale for the use of T cell-based peptide vaccines against both novel SARS-CoV-2 variants and supports post-exposure prophylaxis as alternative vaccination strategy against COVID-19.

Tactile training facilitates infants' ability to reach to targets on the body.

This longitudinal study investigated the effect of experience with tactile stimulation on infants' ability to reach to targets on the body, an important adaptive skill. Infants were provided weekly tactile stimulation on eight body locations from 4 to 8 months of age (N = 11), comparing their ability to reach to the body to infants in a control group who did not receive stimulation (N = 10). Infants who received stimulation were more likely to successfully reach targets on the body than controls by 7 months of age. These findings indicate that tactile stimulation facilitates the development of reaching to the body by allowing infants to explore the sensorimotor correlations emerging from the stimulation.

Movement-related artefacts (MR-ART) dataset of matched motion-corrupted and clean structural MRI brain scans.

Magnetic Resonance Imaging (MRI) provides a unique opportunity to investigate neural changes in healthy and clinical conditions. Its large inherent susceptibility to motion, however, often confounds the measurement. Approaches assessing, correcting, or preventing motion corruption of MRI measurements are under active development, and such efforts can greatly benefit from carefully controlled datasets. We present a unique dataset of structural brain MRI images collected from 148 healthy adults which includes both motion-free and motion-affected data acquired from the same participants. This matched dataset allows direct evaluation of motion artefacts, their impact on derived data, and testing approaches to correct for them. Our dataset further stands out by containing images with different levels of motion artefacts from the same participants, is enriched with expert scoring characterizing the image quality from a clinical point of view and is also complemented with standard image quality metrics obtained from MRIQC. The goal of the dataset is to raise awareness of the issue and provide a useful resource to assess and improve current motion correction approaches.

Effects of screen exposure on young children's cognitive development: A review.

The past decade has witnessed a rapid increase in the use of screen media in families, and infants are exposed to screens at younger ages than ever before. The objective of this review is twofold: (1) to understand the correlates and demographic factors determining exposure to screens, including interactive screens, when available, and (2) to study the effects of watching screens and using touchscreens on cognitive development, during the first 3 years of life. We argue that the effects of screen viewing depend mostly on contextual aspects of the viewing rather than on the quantity of viewing. That context includes the behavior of adult caregivers during viewing, the watched content in relation to the child's age, the interactivity of the screen and whether the screen is in the background or not. Depending on the context, screen viewing can have positive, neutral or negative effects on infants' cognition.

Effect of head motion-induced artefacts on the reliability of deep learning-based whole-brain segmentation.

Due to their robustness and speed, recently developed deep learning-based methods have the potential to provide a faster and hence more scalable alternative to more conventional neuroimaging analysis pipelines in terms of whole-brain segmentation based on magnetic resonance (MR) images. These methods were also shown to have higher test-retest reliability, raising the possibility that they could also exhibit superior head motion tolerance. We investigated this by comparing the effect of head motion-induced artifacts in structural MR images on the consistency of segmentation performed by FreeSurfer and recently developed deep learning-based methods to a similar extent. We used state-of-the art neural network models (FastSurferCNN and Kwyk) and developed a new whole-brain segmentation pipeline (ReSeg) to examine whether reliability depends on choice of deep learning method. Structural MRI scans were collected from 110 participants under rest and active head motion and were evaluated for image quality by radiologists. Compared to FreeSurfer, deep learning-based methods provided more consistent segmentations across different levels of image quality, suggesting that they also have the advantage of providing more reliable whole-brain segmentations of MR images corrupted by motion-induced artifacts, and provide evidence for their practical applicability in the study of brain structural alterations in health and disease.

In Silico Model Estimates the Clinical Trial Outcome of Cancer Vaccines.

Over 30 years after the first cancer vaccine clinical trial (CT), scientists still search the missing link between immunogenicity and clinical responses. A predictor able to estimate the outcome of cancer vaccine CTs would greatly benefit vaccine development. Published results of 94 CTs with 64 therapeutic vaccines were collected. We found that preselection of CT subjects based on a single matching HLA allele does not increase immune response rates (IRR) compared with non-preselected CTs (median 60% vs. 57%, p = 0.4490). A representative in silico model population (MP) comprising HLA-genotyped subjects was used to retrospectively calculate in silico IRRs of CTs based on the percentage of MP-subjects having epitope(s) predicted to bind ≥ 1-4 autologous HLA allele(s). We found that in vitro measured IRRs correlated with the frequency of predicted multiple autologous allele-binding epitopes (AUC 0.63-0.79). Subgroup analysis of multi-antigen targeting vaccine CTs revealed correlation between clinical response rates (CRRs) and predicted multi-epitope IRRs when HLA threshold was ≥ 3 (r = 0.7463, p = 0.0004) but not for single HLA allele-binding epitopes (r = 0.2865, p = 0.2491). Our results suggest that CRR depends on the induction of broad T-cell responses and both IRR and CRR can be predicted when epitopes binding to multiple autologous HLAs are considered.

A Peptide Vaccine Candidate Tailored to Individuals' Genetics Mimics the Multi-Targeted T Cell Immunity of COVID-19 Convalescent Subjects.

Long-term immunity to coronaviruses likely stems from T cell activity. We present here a novel approach for the selection of immunoprevalent SARS-CoV-2-derived T cell epitopes using an in silico cohort of HLA-genotyped individuals with different ethnicities. Nine 30-mer peptides derived from the four major structural proteins of SARS-CoV-2 were selected and included in a peptide vaccine candidate to recapitulate the broad virus-specific T cell responses observed in natural infection. PolyPEPI-SCoV-2-specific, polyfunctional CD8+ and CD4+ T cells were detected in each of the 17 asymptomatic/mild COVID-19 convalescents' blood against on average seven different vaccine peptides. Furthermore, convalescents' complete HLA-genotype predicted their T cell responses to SARS-CoV-2-derived peptides with 84% accuracy. Computational extrapolation of this relationship to a cohort of 16,000 HLA-genotyped individuals with 16 different ethnicities suggest that PolyPEPI-SCoV-2 vaccination will likely elicit multi-antigenic T cell responses in 98% of individuals, independent of ethnicity. PolyPEPI-SCoV-2 administered with Montanide ISA 51 VG generated robust, Th1-biased CD8+, and CD4+ T cell responses against all represented proteins, as well as binding antibodies upon subcutaneous injection into BALB/c and hCD34+ transgenic mice modeling human immune system. These results have implications for the development of global, highly immunogenic, T cell-focused vaccines against various pathogens and diseases.

The effect of language on prosocial behaviors in preschool children.

The present study investigated how linguistic group membership influences prosocial behaviors, namely helpfulness and cooperation, in preschool children. Whilst research indicates that children preferentially direct their prosocial behavior towards members of their own groups, the influence of perceived linguistic group membership on actual helpfulness and cooperation has not been investigated. We presented an experimenter to 4- and 5-year-olds either as a foreigner, who did not speak the local language or as a native person. Children were then given the opportunity to help or cooperate with this experimenter in a series of nonverbal playful tasks. Whilst 4-year-olds helped and cooperated equally with the foreign and the native experimenter, 5-year-olds required significantly more cues and prompts in order to help or cooperate in the foreign condition. We also found that children were overall more reluctant to respond prosocially in the cooperation tasks than in the helping tasks. We tested children in two European countries (France and Hungary) and found the same pattern of responses in the two locations, suggesting that our findings are not specific to the local culture. Our results extend the findings of earlier research that showed selectivity according to the language spoken by the partner for sharing and imitation. Studies that looked at helpfulness or cooperation used the minimal group paradigm to induce group membership (based on arbitrary cues) and used indirect measures of prosociality, such as different forms of reasoning about the partner. In our study, we used language, a natural cue for group membership (versus arbitrary cues or cues based on social conventions) and directly observed children's helpful and cooperative behaviors toward the experimenter. Our results also confirm previous results indicating that with age, children become selective in their prosocial behaviors as they acquire new means of social evaluation and categorization. We conclude that the language associated with a potential social partner is not only a cue for affiliation and shared knowledge but also a cue mediating children's prosocial acts.

Right-handed one day, right-handed the next day?

Although a population bias toward right-hand preference is observed at the early stage of grasping, hand preference fluctuates in infancy. Given these fluctuations, one can wonder whether testing a young infant on a single occasion gives reliable results of its handedness. Very few studies have evaluated short-term test-retest reliability. This was the goal of this study in which 21 infants aged 9-15 months were tested for handedness every day for a total of 5 sessions. The infants were given a classical handedness baby test. Their handedness index (HI) and their category of handedness were compared across sessions. The results show that at the group level the distribution of handedness does not differ significantly across the five sessions. At the individual level, only 19% of infants were categorized as right-handed at all five sessions while 52.4% were consistent in using more one hand than the other across the five sessions (right hand: 47.6%). Most of the fluctuations across sessions occurred between being lateralized and non-lateralized rather than between being right-handed and left-handed. These figures indicate that testing handedness at that age gives fairly reliable results in terms of direction of hand preference, but less so in terms of degree.

Know Your Body Through Intrinsic Goals.

The first "object" that newborn children play with is their own body. This activity allows them to autonomously form a sensorimotor map of their own body and a repertoire of actions supporting future cognitive and motor development. Here we propose the theoretical hypothesis, operationalized as a computational model, that this acquisition of body knowledge is not guided by random motor-babbling, but rather by autonomously generated goals formed on the basis of intrinsic motivations. Motor exploration leads the agent to discover and form representations of the possible sensory events it can cause with its own actions. When the agent realizes the possibility of improving the competence to re-activate those representations, it is intrinsically motivated to select and pursue them as goals. The model is based on four components: (1) a self-organizing neural network, modulated by competence-based intrinsic motivations, that acquires abstract representations of experienced sensory (touch) changes; (2) a selector that selects the goal to pursue, and the motor resources to train to pursue it, on the basis of competence improvement; (3) an echo-state neural network that controls and learns, through goal-accomplishment and competence, the agent's motor skills; (4) a predictor of the accomplishment of the selected goals generating the competence-based intrinsic motivation signals. The model is tested as the controller of a simulated simple planar robot composed of a torso and two kinematic 3-DoF 2D arms. The robot explores its body covered by touch sensors by moving its arms. The results, which might be used to guide future empirical experiments, show how the system converges to goals and motor skills allowing it to touch the different parts of own body and how the morphology of the body affects the formed goals. The convergence is strongly dependent on competence-based intrinsic motivations affecting not only skill learning and the selection of formed goals, but also the formation of the goal representations themselves.

Fetal Origin of Sensorimotor Behavior.

The aim of this article is to track the fetal origin of infants' sensorimotor behavior. We consider development as the self-organizing emergence of complex forms from spontaneously generated activity, governed by the innate capacity to detect and memorize the consequences of spontaneous activity (contingencies), and constrained by the sensory and motor maturation of the body. In support of this view, we show how observations on fetuses and also several fetal experiments suggest that the fetus's first motor activity allows it to feel the space around it and to feel its body and the consequences of its movements on its body. This primitive motor babbling gives way progressively to sensorimotor behavior which already possesses most of the characteristics of infants' later behavior: repetition of actions leading to sensations, intentionality, some motor control and oriented reactions to sensory stimulation. In this way the fetus can start developing a body map and acquiring knowledge of its limited physical and social environment.

Which limb is it? Responses to vibrotactile stimulation in early infancy.

This study focuses on how the body schema develops during the first months of life, by investigating infants' motor responses to localized vibrotactile stimulation on their limbs. Vibrotactile stimulation was provided by small buzzers that were attached to the infants' four limbs one at a time. Four age groups were compared cross-sectionally (3-, 4-, 5-, and 6-month-olds). We show that before they actually reach for the buzzer, which, according to previous studies, occurs around 7-8 months of age, infants demonstrate emerging knowledge about their body's configuration by producing specific movement patterns associated with the stimulated body area. At 3 months, infants responded with an increase in general activity when the buzzer was placed on the body, independently of the vibrator's location. Differentiated topographical awareness of the body seemed to appear around 5 months, with specific responses resulting from stimulation of the hands emerging first, followed by the differentiation of movement patterns associated with the stimulation of the feet. Qualitative analyses revealed specific movement types reliably associated with each stimulated location by 6 months of age, possibly preparing infants' ability to actually reach for the vibrating target. We discuss this result in relation to newborns' ability to learn specific movement patterns through intersensory contingency. Statement of contribution what is already known on infants' sensorimotor knowledge about their own bodies 3-month-olds readily learn to produce specific limb movements to obtain a desired effect (movement of a mobile). infants detect temporal and spatial correspondences between events involving their own body and visual events. what the present study adds until 4-5 months of age, infants mostly produce general motor responses to localized touch. this is because in the present study, infants could not rely on immediate contingent feedback. we propose a cephalocaudal developmental trend of topographic differentiation of body areas.

The Relative Importance of Language in Guiding Social Preferences Through Development.

In this paper, we review evidence from infants, toddlers, and preschoolers to tackle the question of how individuals orient preferences and actions toward social partners and how these preferences change over development. We aim at emphasizing the importance of language in guiding categorization relatively to other cues such as age, race and gender. We discuss the importance of language as part of a communication system that orients infants and older children's attention toward relevant information in their environment and toward affiliated social partners who are potential sources of knowledge. We argue that other cues (visually perceptible features) are less reliable in informing individuals whether others share a common knowledge and whether they can be source of information.

What Does It Take for an Infant to Learn How to Use a Tool by Observation?

Observational learning is probably one of the most powerful factors determining progress during child development. When learning a new skill, infants rely on their own exploration; but they also frequently benefit from an adult's verbal support or from demonstration by an adult modeling the action. At what age and under what conditions does adult demonstration really help the infant to learn a novel behavior? In this review, we summarize recently published work we have conducted on the acquisition of tool use during the second year of life. In particular, we consider under what conditions and to what extent seeing a demonstration from an adult advances an infant's understanding of how to use a tool to obtain an out-of-reach object. Our results show that classic demonstration starts being helpful at 18 months of age. When adults explicitly show their intention prior to demonstration, even 16-month-old infants learn from the demonstration. On the other hand, providing an explicit demonstration ("look at how I do it") is not very useful before infants are ready to succeed by themselves anyway. In contrast, repeated observations of the required action in a social context, without explicit reference to this action, considerably advances the age of success and the usefulness of providing a demonstration. We also show that the effect of demonstration can be enhanced if the demonstration makes the baby laugh. Taken together, the results from this series of studies on observational learning of tool use in infants suggest, first, that when observing a demonstration, infants do not know what to pay attention to: demonstration must be accompanied by rich social cues to be effective; second, infants' attention is inhibited rather than enhanced by an explicit demand of "look at what I do"; and finally a humorous situation considerably helps infants understand the demonstration.

Humour production may enhance observational learning of a new tool-use action in 18-month-old infants.

Many studies have shown that making children laugh enhances certain cognitive capacities such as attention, motivation, perception and/or memory, which in turn enhance learning. However, no study thus far has investigated whether laughing has an effect on learning earlier in infancy. The goal of this study was to see whether using humour with young infants in a demonstration of a complex tool-use task can enhance their learning. Fifty-three 18-month-old infants participated in this study and were included either in a humorous or a control demonstration group. In both groups infants observed an adult using a tool to retrieve an out-of-reach toy. What differed between groups was that in the humorous demonstration group, instead of playing with the toy, the adult threw it on the floor immediately after retrieval. The results show that infants who laughed at the demonstration in the humorous demonstration group reproduced significantly more frequent target actions than infants who did not laugh and those in the control group. This effect is discussed with regard to individual differences in terms of temperament and social capacities as well as positive emotion and dopamine release.

Working Memory Integration Processes in Benign Childhood Epilepsy with Centrotemporal Spikes.

OBJECTIVE AND BACKGROUND: Benign epilepsy of childhood with centrotemporal spikes (BECTS) is the most frequent focal epilepsy in children; however, the pattern of affected memory processes remains controversial. Previous studies in BECTS imply deficits in complex working memory tasks, but not in simple modality-specific tasks. We studied working memory processes in children with BECTS by comparing performance in memory binding tasks of different complexities. METHODS: We compared 17 children with BECTS (aged 6 to 13 years) to 17 healthy children matched for age, sex, and intelligence quotient. We measured spatial and verbal memory components separately and jointly on three single-binding tasks (binding of what and where; what and when; and where and when) and a combined-binding task (integration of what, where, and when). We also evaluated basic visuospatial memory functions with subtests of the Children's Memory Scale, and intellectual abilities with verbal tasks of the Wechsler Intelligence Scale for Children-Fourth Edition and the Raven Progressive Matrices. RESULTS: We found no difference between the BECTS and control groups in single-binding tasks; however, the children with BECTS performed significantly worse on the combined task, which included integration of spatial, verbal, and temporal information. We found no deficits in their intellectual abilities or basic visuospatial memory functions. CONCLUSIONS: Children with BECTS may have intact simple maintenance processes of working memory, but difficulty with high-level functions requiring attentional and executive resources. Our findings imply no specific memory dysfunction in BECTS, but suggest difficulties in integrating information within working memory, and possible frontal lobe disturbances.