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 and900 nm, 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.

Cortical responses before 6 months of life associate with later autism.

Autism spectrum disorder (ASD) is a common, highly heritable, developmental disorder and later-born siblings of diagnosed children are at higher risk of developing ASD than the general population. Although the emergence of behavioural symptoms of ASD in toddlerhood is well characterized, far less is known about development during the first months of life of infants at familial risk. In a prospective longitudinal study of infants at familial risk followed to 36 months, we measured functional near-infrared spectroscopy (fNIRS) brain responses to social videos of people (i.e. peek-a-boo) compared to non-social images (vehicles) and human vocalizations compared to non-vocal sounds. At 4-6 months, infants who went on to develop ASD at 3 years (N = 5) evidenced-reduced activation to visual social stimuli relative to low-risk infants (N = 16) across inferior frontal (IFG) and posterior temporal (pSTS-TPJ) regions of the cortex. Furthermore, these infants also showed reduced activation to vocal sounds and enhanced activation to non-vocal sounds within left lateralized temporal (aMTG-STG/pSTS-TPJ) regions compared with low-risk infants and high-risk infants who did not develop ASD (N = 15). The degree of activation to both the visual and auditory stimuli correlated with parent-reported ASD symptomology in toddlerhood. These preliminary findings are consistent with later atypical social brain responses seen in children and adults with ASD, and highlight the need for further work interrogating atypical processing in early infancy and how it may relate to later social interaction and communication difficulties characteristic of ASD.

Changes in Cytochrome-C-Oxidase Account for Changes in Attenuation of Near-Infrared Light in the Healthy Infant Brain.

A novel multi-wavelength broadband near infrared spectroscopy (NIRS) system has been employed to simultaneously measure haemodynamic changes alongside changes in cellular oxygen utilization by measurement of oxidation state of mitochondrial enzyme cytochrome-c-oxidase (oxCCO). The aim of this study was to investigate the role of oxCCO in neural responses to functional activation in infants. Studies were performed using a NIRS broadband system in 33 typically developing infants aged between 4 and 6 months. Responses were recorded over the right temporal lobe while infants were presented with engaging videos containing social and non-social content. Changes in the concentration of oxyhaemoglobin (Δ[HbO2]), deoxyhaemoglobin (Δ[HHb]) and Δ[oxCCO] were calculated using changes in attenuation of light at 120 wavelengths between 780 and 900 nm using the UCLn algorithm. The algorithm was also used to fit (a) HbO2 and HHb spectra (2 component fit) and (b) HbO2, HHb and oxCCO (3 component fit) to the change in attenuation occurring within an experimental block in different participants. Residuals resulting from these two fits were compared with oxidized-minus reduced CCO spectrum, calculated using the CCO specific extinction coefficient. A significant increase in oxCCO was found in response to the social stimuli (maximum increase 0.238 ± 0.13 µM). Residuals analysis showed that the best fits were achieved when oxCCO was included as a tissue chromophore. These results are the first reported significant change in oxCCO to stimulus-evoked activation in infants and may reveal vital information about oxygen metabolism during functional activation in the developing human brain.

A comprehensive pain assessment tool (COMPAT) for chronic pancreatitis: Development, face validation and pilot evaluation.

BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) pain is challenging to treat. Treatment selection is hampered by there being no validated pain assessment tool that accounts for the complexity of CP pain and its underlying mechanisms. This study aims to develop a comprehensive pain assessment tool (COMPAT) specific for CP, evaluate its face validity with experts and patients and test it with a pilot cohort of patients. METHODS: COMPAT was developed from existing pain assessment tools and a literature review. Face validity was conducted by pancreatologists and CP patients using an item-content validity index for importance, relevance and clarity. Subsequent revisions were made to COMPAT. A pilot cohort of CP patients tested COMPAT. RESULTS: COMPAT was developed and covered all important aspects of CP pain. Experts and CP patients reported that 70% of questions were important and relevant to CP pain. Most experts were willing to use COMPAT in clinic, ward/hospital and research settings. The most common location of pain was the epigastrium and food was the most important trigger. Pain Pattern C (constant background pain with pain attacks), had significantly higher frequency of pain attacks, higher opioid use, and affective descriptors of pain than Pattern A (pain attacks with no background pain). CONCLUSIONS: COMPAT has high face validity and met with high acceptance. CP patients successfully self-reported their pain with COMPAT. The results reveal many differences in the CP pain within the pilot cohort, which may reflect different mechanisms of pain. A larger prospective cohort study is planned to further validate COMPAT.

Pain assessment in chronic pancreatitis: A comparative review of methods.

BACKGROUND: Patients with chronic pancreatitis (CP) frequently report chronic abdominal pain that adversely impacts their quality of life. Assessment of pain in CP is required for clinical management and clinical studies. International consensus guidelines recognized a lack of specific and validated pain assessment tools for CP. Therefore, the aim of this systematic review is to identify and compare all clinical studies that assessed pain in the context of a treatment for pain in CP. METHODS: A systematic literature search was performed in PubMed, Cochrane Library and Ovid MEDLINE. The search identified all intervention studies for pain in CP and the pain assessment tools used based on pre-defined inclusion and exclusion criteria. RESULTS: Of 341 articles identified, 137 studies were included. Pain assessment tools were both general and CP-specific. The latter were used in only 22 (16%) studies. Despite recommendations the aspects of pain assessed were limited and variable between tools. Validation of these tools in CP patients was limited to quality of life measures. None of the pain assessment tools evaluated duration of pain and postprandial pain. CONCLUSIONS: There are no published pain assessment tools for CP that includes all relevant aspects of pain. There is the need to develop a comprehensive and validated pain assessment tool for patients with CP to standardised pain assessment, identify likely underlying pain mechanisms, help select appropriate treatments, report outcomes from interventions, improve clinical communication and aid the allocation of patients to clinical trials.

Neural Mechanisms of Body Awareness in Infants.

The ability to differentiate one's body from others is a fundamental aspect of social perception and has been shown to involve the integration of sense modalities attributable to the self. Though behavioral studies in infancy have investigated infants' discrimination of body-related multisensory stimuli, whether they attribute this information as belonging to the self is still unknown. In human adults, neuroimaging studies have demonstrated the recruitment of a specific set of brain regions in response to body-related multisensory integration. To test whether the infant brain integrates this information similarly to adults, in a first functional near-infrared spectroscopy study we investigated the role of visual-proprioceptive feedback when temporal cues are manipulated by showing 5-month-old infants an online video of their own face while the infant was performing movements. To explore the role of body-related contingency further, in a second study we investigated whether cortical activation in response to self-initiated movements and external tactile stimulation was similar to that found in the first study. Our results indicate that infants' specialized cortical activation in response to body-related contingencies is similar to brain activation seen in response to body awareness in adults.

Does kindness matter? Self-compassion buffers the negative impact of diabetes-distress on HbA1c.

BACKGROUND: Higher self-compassion is associated with mental and physical health benefits in both healthy and chronically ill populations. The current study investigated the role of self-compassion in predicting depression, diabetes-specific distress and HbA1c in patients with diabetes. AIMS: To assess the specific operationalization of negative emotionality that best predicted HbA1c and to test whether self-compassion would buffer HbA1c in patients with diabetes against the negative effects of distress. METHODS: Patients with diabetes (n = 110) completed measures assessing trait self-compassion, depression and diabetes-distress. HbA1c results were obtained through medical records. RESULTS: As expected, diabetes-specific distress was a better predictor of HbA1c than depression; self-compassion moderated the relationship between distress and HbA1c such that higher distress predicted higher HbA1c at lower levels of self-compassion, but not at higher levels of self-compassion. CONCLUSIONS: In addition to further demonstrating the link between distress and metabolic outcomes, these findings suggest that self-compassion might buffer patients from the negative metabolic consequences of diabetes-distress.

Atypical development of configural face recognition in children with autism, Down syndrome and Williams syndrome.

BACKGROUND: Configural processing in face recognition is a sensitivity to the spacing between facial features. It has been argued both that its presence represents a high level of expertise in face recognition, and also that it is a developmentally vulnerable process. METHOD: We report a cross-syndrome investigation of the development of configural face recognition in school-aged children with autism, Down syndrome and Williams syndrome compared with a typically developing comparison group. Cross-sectional trajectory analyses were used to compare configural and featural face recognition utilising the 'Jane faces' task. Trajectories were constructed linking featural and configural performance either to chronological age or to different measures of mental age (receptive vocabulary, visuospatial construction), as well as the Benton face recognition task. RESULTS: An emergent inversion effect across age for detecting configural but not featural changes in faces was established as the marker of typical development. Children from clinical groups displayed atypical profiles that differed across all groups. CONCLUSION: We discuss the implications for the nature of face processing within the respective developmental disorders, and how the cross-sectional syndrome comparison informs the constraints that shape the typical development of face recognition.

Reduced neural sensitivity to social stimuli in infants at risk for autism.

In the hope of discovering early markers of autism, attention has recently turned to the study of infants at risk owing to being the younger siblings of children with autism. Because the condition is highly heritable, later-born siblings of diagnosed children are at substantially higher risk for developing autism or the broader autism phenotype than the general population. Currently, there are no strong predictors of autism in early infancy and diagnosis is not reliable until around 3 years of age. Because indicators of brain functioning may be sensitive predictors, and atypical social interactions are characteristic of the syndrome, we examined whether temporal lobe specialization for processing visual and auditory social stimuli during infancy differs in infants at risk. In a functional near-infrared spectroscopy study, infants aged 4-6 months at risk for autism showed less selective neural responses to social stimuli (auditory and visual) than low-risk controls. These group differences could not be attributed to overall levels of attention, developmental stage or chronological age. Our results provide the first demonstration of specific differences in localizable brain function within the first 6 months of life in a group of infants at risk for autism. Further, these differences closely resemble known patterns of neural atypicality in children and adults with autism. Future work will determine whether these differences in infant neural responses to social stimuli predict either later autism or the broader autism phenotype frequently seen in unaffected family members.

Changing expression of chloride channels during preimplantation mouse development.

Plasma membrane chloride channels (ClCs) play important roles in a broad range of cellular processes including cell volume regulation, proliferation, and transepithelial transport, all of which are critical during preimplantation embryonic development. In this study, the molecular and functional expression of voltage-gated ClCs was analyzed throughout preimplantation development of the mouse conceptus. mRNA transcripts for all Clcn genes were detected. Only Clcn1 mRNA showed differential expression in the blastocyst, being detected in the trophectoderm but not in the inner cell mass. CLCN3 protein was detected at low levels in the cytoplasm and plasma membrane in 4-cell embryos and was localized to the apical plasma membrane of the trophoblasts in the blastocyst. Whole-cell patch-clamp recordings demonstrated the presence of a DIDS-sensitive, outwardly rectifying Cl(-) current throughout development, with this conductance being large at the 1-cell, morula and blastocyst stages. A second DIDS-insensitive Cl(-) current, which was inactivated by membrane depolarization, was present in cells differentiating into the trophoblast lineage and during blastocyst expansion. Inhibition of the DIDS-sensitive current and the DIDS-insensitive current, with 9-AC, prevented blastocyst expansion.

Failure to learn from feedback underlies word learning difficulties in toddlers at risk for autism.

Children's assignment of novel words to nameless objects, over objects whose names they know (mutual exclusivity; ME) has been described as a driving force for vocabulary acquisition. Despite their ability to use ME to fast-map words (Preissler & Carey, 2005), children with autism show impaired language acquisition. We aimed to address this puzzle by building on studies showing that correct referent selection using ME does not lead to word learning unless ostensive feedback is provided on the child's object choice (Horst & Samuelson, 2008). We found that although toddlers aged 2;0 at risk for autism can use ME to choose the correct referent of a word, they do not benefit from feedback for long-term retention of the word-object mapping. Further, their difficulty using feedback is associated with their smaller receptive vocabularies. We propose that difficulties learning from social feedback, not lexical principles, limits vocabulary building during development in children at risk for autism.

Parsing eye-tracking data of variable quality to provide accurate fixation duration estimates in infants and adults.

Researchers studying infants' spontaneous allocation of attention have traditionally relied on hand-coding infants' direction of gaze from videos; these techniques have low temporal and spatial resolution and are labor intensive. Eye-tracking technology potentially allows for much more precise measurement of how attention is allocated at the subsecond scale, but a number of technical and methodological issues have given rise to caution about the quality and reliability of high temporal resolution data obtained from infants. We present analyses suggesting that when standard dispersal-based fixation detection algorithms are used to parse eye-tracking data obtained from infants, the results appear to be heavily influenced by interindividual variations in data quality. We discuss the causes of these artifacts, including fragmentary fixations arising from flickery or unreliable contact with the eyetracker and variable degrees of imprecision in reported position of gaze. We also present new algorithms designed to cope with these problems by including a number of new post hoc verification checks to identify and eliminate fixations that may be artifactual. We assess the results of our algorithms by testing their reliability using a variety of methods and on several data sets. We contend that, with appropriate data analysis methods, fixation duration can be a reliable and stable measure in infants. We conclude by discussing ways in which studying fixation durations during unconstrained orienting may offer insights into the relationship between attention and learning in naturalistic settings.

Infant Effortful Control Mediates Relations Between Nondirective Parenting and Internalising-Related Child Behaviours in an Autism-Enriched Infant Cohort.

Internalising problems are common within Autism Spectrum Disorder (ASD); early intervention to support those with emerging signs may be warranted. One promising signal lies in how individual differences in temperament are shaped by parenting. Our longitudinal study of infants with and without an older sibling with ASD investigated how parenting associates with infant behavioural inhibition (8-14 months) and later effortful control (24 months) in relation to 3-year internalising symptoms. Mediation analyses suggest nondirective parenting (8 months) was related to fewer internalising problems through an increase in effortful control. Parenting did not moderate the stable predictive relation of behavioural inhibition on later internalising. We discuss the potential for parenting to strengthen protective factors against internalising in infants from an ASD-enriched cohort.

Parent-child interaction during the first year of life in infants at elevated likelihood of autism spectrum disorder.

Autism spectrum disorder (ASD) likely emerges from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the environment. The interaction with parents forms a key aspect of an infant's social environment, but few prospective studies of infants at elevated likelihood (EL) for ASD (who have an older sibling with ASD) have examined parent-child interactions in the first year of life. As part of a European multisite network, parent-child dyads of free play were observed at 5 months (62 EL infants, 47 infants at typical likelihood (TL)) and 10 months (101 EL siblings, 77 TL siblings). The newly-developed Parent-Infant/Toddler Coding of Interaction (PInTCI) scheme was used, focusing on global characteristics of infant and parent behaviors. Coders were blind to participant information. Linear mixed model analyses showed no significant group differences in infant or parent behaviors at 5 or 10 months of age (all ps≥0.09, d≤0.36), controlling for infant's sex and age, and parental educational level. However, without adjustments, EL infants showed fewer and less clear initiations at 10 months than TL infants (p = 0.02, d = 0.44), but statistical significance was lost after controlling for parental education (p = 0.09, d = 0.36), which tended to be lower in the EL group. Consistent with previous literature focusing on parent-infant dyads, our findings suggest that differences between EL and TL dyads may only be subtle during the first year of life. We discuss possible explanations and implications for future developmental studies.

Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers.

BACKGROUND: The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. METHODS: Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). RESULTS: The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. LIMITATIONS: The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. CONCLUSIONS: Biological motion preference elicits small-to-medium-sized case-control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear.

Infant EEG theta modulation predicts childhood intelligence.

Intellectual functioning is a critical determinant of economic and personal productivity. Identifying early neural predictors of cognitive function in infancy will allow us to map the neurodevelopmental pathways that underpin individual differences in intellect. Here, in three different cohorts we investigate the association between a putative neurophysiological indicator of information encoding (change in frontal theta during a novel video) in infancy and later general cognitive outcome. In a discovery cohort of 12-month-old typically developing infants, we recorded EEG during presentation of dynamic movies of people and objects. Frontal theta power (3-6 Hz) significantly increased during the course of viewing each video. Critically, increase in frontal theta during viewing of a video was associated with a differential response to repetition of that specific video, confirming relation to learning. Further, individual differences in the magnitude of change in frontal theta power were related to concurrent nonverbal cognitive level. We then sought to extend this association in two independent samples enriched for variation in cognitive outcome due to the inclusion of infants at familial risk for autism. We observed similar patterns of theta EEG change at 12 months, and found a predictive relation to verbal and nonverbal cognitive skills measured at 2, 3 and 7 years of age. For the subset of high-risk infants later diagnosed with autism, infant theta EEG explained over 80% of the variance in nonverbal skills at age 3 years. We suggest that EEG theta change in infancy is an excellent candidate predictive biomarker that could yield substantial insight into the mechanisms that underlie individual differences in childhood intelligence, particularly in high risk populations.

Induction of polarity in mouse 8-cell blastomeres: specificity, geometry, and stability.

We studied the cellular mechanisms underlying the induction of polarity in individual blastomeres of the 8-cell mouse embryo. The ability to induce polarity is lacking in the membranes of unfertilized and newly fertilized mouse eggs, then develops during the 2-cell stage, and is present in membranes of cells from 4-, 8-, and 16-cell stages. The axis of polarity takes 3-5 h to become established and thereafter appears to be stable. Multiple cell contacts affect the orientation of the axis of polarity, and no polarity develops in cells which are totally surrounded. Polarized cells show evidence of an limited capacity for slight adjustments in their position relative to other cells. The implications of these results for the mechanisms by which a blastocyst is generated are discussed briefly.