Growth in early infancy drives optimal brain functional connectivity which predicts cognitive flexibility in later childhood.

Functional brain network organization, measured by functional connectivity (FC), reflects key neurodevelopmental processes for healthy development. Early exposure to adversity, e.g. undernutrition, affects neurodevelopment, observable via disrupted FC, and leads to poorer outcomes from preschool age onward. We assessed longitudinally the impact of early growth trajectories on developmental FC in a rural Gambian population from age 5 to 24 months. To investigate how these early trajectories relate to later childhood outcomes, we assessed cognitive flexibility at 3-5 years. We observed that early physical growth before the fifth month of life drove optimal developmental trajectories of FC that in turn predicted cognitive flexibility at pre-school age. In contrast to previously studied developmental populations, this Gambian sample exhibited long-range interhemispheric FC that decreased with age. Our results highlight the measurable effects that poor growth in early infancy has on brain development and the subsequent impact on pre-school age cognitive development, underscoring the need for early life interventions throughout global settings of adversity.

The typical and atypical development of empathy: How big is the gap from lab to field?

Background: Empathy-understanding and sharing someone else's feelings-is crucial for social bonds. Studies on empathy development are limited and mainly performed with behavioural assessments. This is in contrast to the extensive literature on cognitive and affective empathy in adults. However, understanding the mechanisms behind empathy development is critical to developing early interventions to support children with limited empathy. This is particularly key in toddlerhood, as children transition from highly scaffolded interactions with their parents and towards interactions with their peers. However, we know little about toddlers' empathy, in part due to the methodological constraints of testing this population in traditional lab settings. Methods: Here, we combine naturalistic observations with a targeted review of the literature to provide an assessment of our current understanding of the development of empathy in toddlerhood as it is expressed in real-world settings. We went into toddlers' typical habitat, a nursery, and we performed 21 h of naturalistic observations of 2-to-4-year-olds. We then reviewed the literature to evaluate our current understanding of the mechanisms that underpin observed behaviours. Results: We observed that (i) emotional contagion, possibly a primitive form of empathy, was observed at the nursery, but rarely; (ii) older toddlers often stared when someone cried, but there was no clear evidence of shared feelings; (iii) teacher and parent scaffolding might be paramount for empathy development; (iv) as some atypical empathic reactions can be observed from toddlerhood, early interventions could be developed. Several competing theoretical frameworks could account for current findings. Conclusions: Targeted studies of toddlers and their interaction partners in both controlled and naturalistic contexts are required to distinguish different mechanistic explanations for empathic behaviour in toddlerhood. We recommend the use of new cutting-edge methodologies to embed neurocognitively-informed frameworks into toddlers' natural social world.

Combining wearable fNIRS and immersive virtual reality to study preschoolers' social development: a proof-of-principle study on preschoolers' social preference.

A child's social world is complex and rich, but has traditionally been assessed with conventional experiments where children are presented with repeated stimuli on a screen. These assessments are impoverished relative to the dynamics of social interactions in real life, and can be challenging to implement with preschoolers, who struggle to comply with strict lab rules. The current work meets the need to develop new platforms to assess preschoolers' social development, by presenting a unique virtual-reality set-up combined with wearable functional near-infrared spectroscopy (fNIRS). As a proof-of-principle, we validated this platform by measuring brain activity during self-guided social interaction in 3-to-5-year-olds, which is under-investigated, yet crucial to understand the basis of social interactions in preschoolers. 37 preschoolers chose an interaction partner from one of 4 human-like avatars of different gender and age. We recorded spontaneous brain fluctuations from the frontal and temporoparietal regions (notably engaged in social-categorization and preference) while children played a bubble-popping game with a preferred and an assigned avatar. 60% of the participants chose to play with the same-gender and same-age avatar. However, this result was driven by females (>80% vs. 50% in males). Different fronto-temporoparietal connectivity patterns when playing with the two avatars were observed, especially in females. We showed the feasibility of using a novel set-up to naturalistically assess social preference in preschoolers, which was assessed at the behavioural and functional connectivity level. This work provides a first proof-of-principle for using cutting-edge technologies and naturalistic experiments to study social development, opening new avenues of research.

Association of psychosocial adversity and social information processing in children raised in a low-resource setting: an fNIRS study.

Social cognition skills and socioemotional development are compromised in children growing up in low SES contexts, however, the mechanisms underlying this association remain unknown. Exposure to psychosocial risk factors early in life alters the child's social milieu and in turn, could lead to atypical processing of social stimuli. In this study, we used functional Near Infrared Spectroscopy (fNIRS) to measure cortical responses to a social discrimination task in children raised in a low-resource setting at 6, 24, and 36 months. In addition, we assessed the relation between cortical responses to social and non-social information with psychosocial risk factors assessed using the Childhood Psychosocial Adversity Scale (CPAS). In line with previous findings, we observed specialization to social stimuli in cortical regions in all age groups. In addition, we found that risk factors were associated with social discrimination at 24 months (intimate partner violence and verbal abuse and family conflict) and 36 months (verbal abuse and family conflict and maternal depression) but not at 6 months. Overall, the results show that exposure to psychosocial adversity has more impact on social information processing in toddlerhood than earlier in infancy.

Longitudinal infant fNIRS channel-space analyses are robust to variability parameters at the group-level: An image reconstruction investigation.

The first 1000 days from conception to two-years of age are a critical period in brain development, and there is an increasing drive for developing technologies to help advance our understanding of neurodevelopmental processes during this time. Functional near-infrared spectroscopy (fNIRS) has enabled longitudinal infant brain function to be studied in a multitude of settings. Conventional fNIRS analyses tend to occur in the channel-space, where data from equivalent channels across individuals are combined, which implicitly assumes that head size and source-detector positions (i.e. array position) on the scalp are constant across individuals. The validity of such assumptions in longitudinal infant fNIRS analyses, where head growth is most rapid, has not previously been investigated. We employed an image reconstruction approach to analyse fNIRS data collected from a longitudinal cohort of infants in The Gambia aged 5- to 12-months. This enabled us to investigate the effect of variability in both head size and array position on the anatomical and statistical inferences drawn from the data at both the group- and the individual-level. We also sought to investigate the impact of group size on inferences drawn from the data. We found that variability in array position was the driving factor between differing inferences drawn from the data at both the individual- and group-level, but its effect was weakened as group size increased towards the full cohort size (N = 53 at 5-months, N = 40 at 8-months and N = 45 at 12-months). We conclude that, at the group sizes in our dataset, group-level channel-space analysis of longitudinal infant fNIRS data is robust to assumptions about head size and array position given the variability in these parameters in our dataset. These findings support a more widespread use of image reconstruction techniques in longitudinal infant fNIRS studies.

Opportunities and Limitations of Mobile Neuroimaging Technologies in Educational Neuroscience.

As the field of educational neuroscience continues to grow, questions have emerged regarding the ecological validity and applicability of this research to educational practice. Recent advances in mobile neuroimaging technologies have made it possible to conduct neuroscientific studies directly in naturalistic learning environments. We propose that embedding mobile neuroimaging research in a cycle (Matusz, Dikker, Huth, & Perrodin, 2019), involving lab-based, seminaturalistic, and fully naturalistic experiments, is well suited for addressing educational questions. With this review, we take a cautious approach, by discussing the valuable insights that can be gained from mobile neuroimaging technology, including electroencephalography and functional near-infrared spectroscopy, as well as the challenges posed by bringing neuroscientific methods into the classroom. Research paradigms used alongside mobile neuroimaging technology vary considerably. To illustrate this point, studies are discussed with increasingly naturalistic designs. We conclude with several ethical considerations that should be taken into account in this unique area of research.

Observing third-party ostracism enhances facial mimicry in 30-month-olds.

Mimicry is suggested to be one of the strategies via which we enhance social affiliation. Although recent studies have shown that, like adults, young children selectively mimic the facial actions of in-group over out-group members, it is unknown whether this early mimicry behavior is driven by affiliative motivations. Here we investigated the functional role of facial mimicry in early childhood by testing whether observing third-party ostracism, which has previously been shown to enhance children's affiliative behaviors, enhances facial mimicry in 30-month-olds. Toddlers were presented with videos in which one shape was ostracized by other shapes or with control videos that did not show any ostracism. Before and after this, the toddlers observed videos of models performing facial actions (e.g., eyebrow raising, mouth opening) while we measured activation over their corresponding facial muscles using electromyography (EMG) to obtain an index of facial mimicry. We also coded the videos of the sessions for overt imitation. We found that toddlers in the ostracism condition showed greater facial mimicry at posttest than toddlers in the control condition, as indicated by both EMG and behavioral coding measures. Although the exact mechanism underlying this result needs to be investigated in future studies, this finding is consistent with social affiliation accounts of mimicry and suggests that mimicry may play a key role in maintaining affiliative bonds when toddlers perceive the risk of social exclusion.

The developmental trajectory of fronto-temporoparietal connectivity as a proxy of the default mode network: a longitudinal fNIRS investigation.

The default mode network (DMN) is a network of brain regions that is activated while we are not engaged in any particular task. While there is a large volume of research documenting functional connectivity within the DMN in adults, knowledge of the development of this network is still limited. There is some evidence for a gradual increase in the functional connections within the DMN during the first 2 years of life, in contrast to other functional resting-state networks that support primary sensorimotor functions, which are online from very early in life. Previous studies that investigated the development of the DMN acquired data from sleeping infants using fMRI. However, sleep stages are known to affect functional connectivity. In the current longitudinal study, fNIRS was used to measure spontaneous fluctuations in connectivity within fronto-temporoparietal areas-as a proxy for the DMN-in awake participants every 6 months from 11 months till 36 months. This study validates a method for recording resting-state data from awake infants, and presents a data analysis pipeline for the investigation of functional connections with infant fNIRS data, which will be beneficial for researchers in this field. A gradual development of fronto-temporoparietal connectivity was found, supporting the idea that the DMN develops over the first years of life. Functional connectivity reached its maximum peak at about 24 months, which is consistent with previous findings showing that, by 2 years of age, DMN connectivity is similar to that observed in adults.

Fronto-temporoparietal connectivity and self-awareness in 18-month-olds: A resting state fNIRS study.

How and when a concept of the 'self' emerges has been the topic of much interest in developmental psychology. Self-awareness has been proposed to emerge at around 18 months, when toddlers start to show evidence of physical self-recognition. However, to what extent physical self-recognition is a valid indicator of being able to think about oneself, is debated. Research in adult cognitive neuroscience has suggested that a common network of brain regions called Default Mode Network (DMN), including the temporo-parietal junction (TPJ) and the medial prefrontal cortex (mPFC), is recruited when we are reflecting on the self. We hypothesized that if mirror self-recognition involves self-awareness, toddlers who exhibit mirror self-recognition might show increased functional connectivity between frontal and temporoparietal regions of the brain, relative to those toddlers who do not yet show mirror self-recognition. Using fNIRS, we collected resting-state data from 18 Recognizers and 22 Non-Recognizers at 18 months of age. We found significantly stronger fronto-temporoparietal connectivity in Recognizers compared to Non-Recognizers, a finding which might support the hypothesized relationship between mirror-self recognition and self-awareness in infancy.

Recommendations for motion correction of infant fNIRS data applicable to multiple data sets and acquisition systems.

Despite motion artifacts are a major source of noise in fNIRS infant data, how to approach motion correction in this population has only recently started to be investigated. Homer2 offers a wide range of motion correction methods and previous work on simulated and adult data suggested the use of Spline interpolation and Wavelet filtering as optimal methods for the recovery of trials affected by motion. However, motion artifacts in infant data differ from those in adults' both in amplitude and frequency of occurrence. Therefore, artifact correction recommendations derived from adult data might not be optimal for infant data. We hypothesized that the combined use of Spline and Wavelet would outperform their individual use on data with complex profiles of motion artifacts. To demonstrate this, we first compared, on infant semi-simulated data, the performance of several motion correction techniques on their own and of the novel combined approach; then, we investigated the performance of Spline and Wavelet alone and in combination on real cognitive data from three datasets collected with infants of different ages (5, 7 and 10 months), with different tasks (auditory, visual and tactile) and with different NIRS systems. To quantitatively estimate and compare the efficacy of these techniques, we adopted four metrics: hemodynamic response recovery error, within-subject standard deviation, between-subjects standard deviation and number of trials that survived each correction method. Our results demonstrated that (i) it is always better correcting for motion artifacts than rejecting the corrupted trials; (ii) Wavelet filtering on its own and in combination with Spline interpolation seems to be the most effective approach in reducing the between- and the within-subject standard deviations. Importantly, the combination of Spline and Wavelet was the approach providing the best performance in semi-simulation both at low and high levels of noise, also recovering most of the trials affected by motion artifacts across all datasets, a crucial result when working with infant data.

Selective facial mimicry of native over foreign speakers in preverbal infants.

Mimicry, the spontaneous copying of others' behaviors, plays an important role in social affiliation, with adults selectively mimicking in-group members over out-group members. Despite infants' early documented sensitivity to cues to group membership, previous work suggests that it is not until 4 years of age that spontaneous mimicry is modulated by group status. Here we demonstrate that mimicry is sensitive to cues to group membership at a much earlier age if the cues presented are more relevant to infants. 11-month-old infants observed videos of facial actions (e.g., mouth opening, eyebrow raising) performed by models who either spoke the infants' native language or an unfamiliar foreign language while we measured activation of the infants' mouth and eyebrow muscle regions using electromyography to obtain an index of mimicry. We simultaneously used functional near-infrared spectroscopy to investigate the neural mechanisms underlying differential mimicry responses. We found that infants showed greater facial mimicry of the native speaker compared to the foreign speaker and that the left temporal parietal cortex was activated more strongly during the observation of facial actions performed by the native speaker compared to the foreign speaker. Although the exact mechanisms underlying this selective mimicry response will need to be investigated in future research, these findings provide the first demonstration of the modulation of facial mimicry by cues to group status in preverbal infants and suggest that the foundations for the role that mimicry plays in facilitating social bonds seem to be present during the first year of life.

Dynamic causal modelling on infant fNIRS data: A validation study on a simultaneously recorded fNIRS-fMRI dataset.

Tracking the connectivity of the developing brain from infancy through childhood is an area of increasing research interest, and fNIRS provides an ideal method for studying the infant brain as it is compact, safe and robust to motion. However, data analysis methods for fNIRS are still underdeveloped compared to those available for fMRI. Dynamic causal modelling (DCM) is an advanced connectivity technique developed for fMRI data, that aims to estimate the coupling between brain regions and how this might be modulated by changes in experimental conditions. DCM has recently been applied to adult fNIRS, but not to infants. The present paper provides a proof-of-principle for the application of this method to infant fNIRS data and a demonstration of the robustness of this method using a simultaneously recorded fMRI-fNIRS single case study, thereby allowing the use of this technique in future infant studies. fMRI and fNIRS were simultaneously recorded from a 6-month-old sleeping infant, who was presented with auditory stimuli in a block design. Both fMRI and fNIRS data were preprocessed using SPM, and analysed using a general linear model approach. The main challenges that adapting DCM for fNIRS infant data posed included: (i) the import of the structural image of the participant for spatial pre-processing, (ii) the spatial registration of the optodes on the structural image of the infant, (iii) calculation of an accurate 3-layer segmentation of the structural image, (iv) creation of a high-density mesh as well as (v) the estimation of the NIRS optical sensitivity functions. To assess our results, we compared the values obtained for variational Free Energy (F), Bayesian Model Selection (BMS) and Bayesian Model Average (BMA) with the same set of possible models applied to both the fMRI and fNIRS datasets. We found high correspondence in F, BMS, and BMA between fMRI and fNIRS data, therefore showing for the first time high reliability of DCM applied to infant fNIRS data. This work opens new avenues for future research on effective connectivity in infancy by contributing a data analysis pipeline and guidance for applying DCM to infant fNIRS data.

Fluent Speakers of a Second Language Process Graspable Nouns Expressed in L2 Like in Their Native Language.

According to embodied cognition, language processing relies on the same neural structures involved when individuals experience the content of language material. If so, processing nouns expressing a motor content presented in a second language should modulate the motor system as if presented in the mother tongue. We tested this hypothesis using a go-no go paradigm. Stimuli included English nouns and pictures depicting either graspable or non-graspable objects. Pseudo-words and scrambled images served as controls. Italian participants, fluent speakers of English as a second language, had to respond when the stimulus was sensitive and refrain from responding when it was not. As foreseen by embodiment, motor responses were selectively modulated by graspable items (images or nouns) as in a previous experiment where nouns in the same category were presented in the native language.

Corticolimbic Connectivity Mediates the Relationship between Adverse Childhood Experiences and Symptom Severity in Borderline Personality Disorder.

The interaction between biological and environmental factors (especially adverse childhood experiences, ACEs) plays a crucial role in the development and maintenance of borderline personality disorder (BPD). These factors act influencing BPD core features such as pervasive instability in affect regulation, impulse control, social cognition, and interpersonal relationships. In line with this perspective, abnormalities in social cognition and related neurobiological underpinnings could mediate the relationship between ACEs and psychopathological manifestations in adulthood. In a sample of 14 females, functional connectivity (FC) analyses were performed modeling the interaction between ACEs and corticolimbic dysregulation during emotional processing and its relationship with BPD symptom severity. ACEs were associated with a dampening of the negative FC between (1) the right amygdala (Amy) and right dorsolateral prefrontal cortex (DLPFC) and between (2) the left Amy and bilateral DLPFC, right precuneus, left cerebellum and left dorsomedial prefrontal cortex during emotional processing. The connectivity between right Amy and DLPFC mediates the relationship between childhood adversities and BPD symptomatology. Furthermore, the negative FC between Amy and DLPFC, postcentral gyrus, the vermis of cerebellum and precuneus was also associated with BPD symptom severity, with a weaker negative coupling between Amy and these regions being related to a worse BPD psychopathology. Our results confirm the role of ACEs in contributing to social cognition impairments in BPD and related symptomatology from a neurobiological perspective.

Fronto-limbic effective connectivity as possible predictor of antidepressant response to SSRI administration.

The timely selection of the optimal treatment for depressed patients is critical to improve remission rates. The detection of pre-treatment variables able to predict differential treatment response may provide novel approaches for treatment selection. Selective serotonin reuptake inhibitors (SSRIs) modulate the fronto-limbic functional response and connectivity, an effect preceding the overt clinical antidepressant effects. Here we investigated whether the cortico-limbic connectivity associated with emotional bias measured before SSRI administration predicts the efficacy of antidepressant treatment in MDD patients. fMRI and Dynamic Causal Modeling (DCM) were combined to study if effective connectivity might differentiate healthy controls (HC) and patients affected by major depression who later responded (RMDD, n=21), or failed to respond (nRMDD, n=12), to 6 weeks of escitalopram administration. Sixteen DCMs exploring connectivity between anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC), Amygdala (Amy), and fusiform gyrus (FG) were constructed. Analyses revealed that nRMDD had reduced endogenous connectivity from Amy to VLPFC and to ACC, with an increased connectivity and modulation of the ACC to Amy connectivity when processing of fearful emotional stimuli compared to HC. RMDD and HC did not significantly differ among themselves. Pre-treatment effective connectivity in fronto-limbic circuitry could be an important factor affecting antidepressant response, and highlight the mechanisms which may be involved in recovery from depression. These results suggest that fronto-limbic connectivity might provide a neural biomarker to predict the clinical outcome to SSRIs administration in major depression.

Stem Cell Factor (SCF) is a putative biomarker of antidepressant response.

Growth factors involved in neurogenesis and neuroplasticity could play a role in biological processes that drive depression recovery. Combined total sleep deprivation and morning light therapy (TSD + LT) can acutely reverse depressive symptoms, thus allowing to investigate the neurobiological correlates of antidepressant response. We tested if changes on plasma levels of Brain Derived Neurotrophic Factor (BDNF), S100 calcium binding protein B (S100-B), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor-BB (PDGF-BB), and Vascular Endothelial Growth Factor (VEGF) are associated with response to TSD + LT in 26 inpatients affected by a major depressive episode in the course of bipolar disorder. Regional grey matter (GM) volumes were assessed at baseline, and BOLD fMRI neural responses to a moral valence decision task were recorded before and after treatment. 61.5 % of patients responded to treatment. SCF plasma levels increased significantly more in responders, and correlated with GM volumes in frontal and parietal cortical areas. The pattern of change of SCF also associated with both GM volumes and changes of BOLD fMRI neural responses in the anterior cingulate and medial prefrontal cortex. SCF is both a hematopoietic growth factor and a neurotrophic factor, involved in neuron-neuron and neuron-(micro) glia interactions, fostering neuronal growth and an anti-inflammatory milieu. We correlated SCF levels with antidepressant response and with functional and structural MRI measures in cortical areas that are involved in the cognitive generation and control of affect. SCF may be a candidate growth factor that contributes to neurotrophic and immune effects that are involved in the process of remission/recovery from depression.

Successful antidepressant chronotherapeutics enhance fronto-limbic neural responses and connectivity in bipolar depression.

The identification of antidepressant response predictors in bipolar disorder (BD) may provide new potential enhancements in treatment selection. Repeated total sleep deprivation combined with light therapy (TSD+LT) can acutely reverse depressive symptoms and has been proposed as a model antidepressant treatment. This study aims at investigating the effect of TSD+LT on effective connectivity and neural response in cortico-limbic circuitries during implicit processing of fearful and angry faces in patients with BD. fMRI and Dynamic Causal Modeling (DCM) were combined to study the effect of chronotherapeutics on neural responses in healthy controls (HC, n = 35) and BD patients either responder (RBD, n = 26) or non responder (nRBD, n = 11) to 3 consecutive TSD+LT sessions. Twenty-four DCMs exploring connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), Amygdala (Amy), fusiform gyrus and visual cortex were constructed. After treatment, patients significantly increased their neural responses in DLPFC, ACC and insula. nRBD showed lower baseline and endpoint neural responses than RBD. The increased activity in ACC and in medial prefrontal cortex, associated with antidepressant treatment, was positively associated with the improvement of depressive symptomatology. Only RBD patients increased intrinsic connectivity from DLPFC to ACC and reduced the modulatory effect of the task on Amy-DLPFC connection. A successful antidepressant treatment was associated with an increased functional activity and connectivity within cortico-limbic networks, suggesting the possible role of these measures in providing possible biomarkers for treatment efficacy.