Visual attention and dietary supplementation in children with perinatal brain injury.

AIM: To investigate whether children with perinatal brain injury have impairments in specific components of visual attention, and whether early dietary supplementation can reduce any deficits. METHOD: Children participating in the Dolphin neonatal trial of dietary supplementation were tested at age 6 months with the Infant Fixation Shift Attention Test, and at 4 to 5 years with four subtests of the Early Childhood Attention Battery (ECAB) assessing different components of attention (selective, sustained, and executive function), and the Fluid Crystallized Intelligence Index of the Kaufman Assessment Battery for Children, Second Edition (KABC-II). From 59 children originally assigned to trial groups, 33 were available for testing at 4 to 5 years (18 treatment group of whom seven, six, and five showed mild, moderate, or severe neonatal brain injury; 15 controls with one, seven, and seven in the neonatal brain injury categories respectively). Given the imbalance in numbers with mild brain injury, analysis of trial group differences is restricted to moderate and severe brain injury severities (n=25). RESULTS: Children with perinatal brain injury showed poorer attention across all components relative to age norms (mean standard scores 75-87; p<0.001 for three of the four subtests), with the greatest impairment in sustained attention. These impairments remained when compared with cognitive age assessed using the Fluid Crystallized Intelligence Index. Impairment was reduced in the treatment compared to the control group (p=0.04 for flanker test, p=0.002 for counterpointing, and p=0.027 for the overall ECAB score). INTERPRETATION: Perinatal brain injury is associated with later impaired attention, beyond that predicted from any general cognitive disability. Impairment varies across attention components, being most severe for sustained attention. The effects on flanker and counterpointing suggest that dietary supplementation from 0 to 2 years of age may reduce attention problems. Measuring the different components of attention is important when considering assessment and interventions for children with perinatal brain injury.

Development of the spatial contrast sensitivity function (CSF) during childhood: Analysis of previous findings and new psychophysical data.

Although the contrast sensitivity function (CSF) changes markedly during infancy, there is no consensus regarding whether, how, and why it continues to develop in later childhood. Here, we analyzed previously published data (N = 1928 CSFs), and present new psychophysical findings from 98 children (4.7-14.8 years) and 50 adults (18.1-29.7 years), in order to answer the following questions: (1) Does the CSF change during childhood? (2) How large is the developmental effect size? (3) Are any changes uniform across the CSF, or frequency-specific? and (4) Can some or all of the changes be explained by "non-visual" (i.e. procedural/cognitive) factors, such as boredom or inattentiveness? The new data were collected using a four-alternative forced-choice (4AFC) Gabor-detection task, with two different psychophysical procedures (Weighted Staircase; QUEST+), and suprathreshold (false-negative) catch trials to quantify lapse rates. It is shown that from ages 4 to 18 years, the CSF improves (at an exponentially decaying rate) by approximately 0.3 log10 units (a doubling of contrast sensitivity [CS]), with 90% of this change complete by 12 years of age. The size of the effect was small relative to individual variability, with age alone explaining less than one sixth of variability (16%), and most children performing as well as some adults (i.e. falling within the 90% population limits for adults). Development was frequency-specific, with changes occurring primarily around or below the CSF peak (≤ 4 cpd). At least half - and potentially all - of the changes observed could be explained by non-visual factors (e.g. lapses in concentration), although possible biological mechanisms are discussed.

Neural mechanisms of attention become more specialised during infancy: Insights from combined eye tracking and EEG.

The Fixation Shift Paradigm (FSP) measures infants' ability to shift gaze from a central fixation stimulus to a peripheral target (e.g. Hood & Atkinson, 1993: Infant Behavior and Development, 16(4), 405-422). Cortical maturation has been suggested as crucial for the developing ability to shift attention. This study investigated the development of neural mechanisms by combining EEG with simultaneous eye tracking during FSP testing, in typically developing infants aged between 1 and 8 months. The most prominent neural response was a frontal positivity which occurred only in the hemisphere contralateral to the target in the youngest infants but became more ipsilateral with age. This changing lateralisation was associated with improving ability to shift attention (decreasing saccade latencies and fewer 'sticky fixations'-failures to disengage attention from the central target). These findings suggest that the lateralisation of neural responses develops during infancy, possibly due to developing intracortical connections, allowing infants to shift attention more efficiently. RESEARCH HIGHLIGHTS: Successful use of combined simultaneous remote eye tracking and EEG to measure infant attention shifts. Neural responses involved in attention shifts change in the first year of life. The lateralisation of EEG responses changes with age in the first year of life. Frontal cortex is involved in attention shifts from around 2 months of age.

The Davida Teller Award Lecture, 2016: Visual Brain Development: A review of "Dorsal Stream Vulnerability"-motion, mathematics, amblyopia, actions, and attention.

Research in the Visual Development Unit on "dorsal stream vulnerability' (DSV) arose from research in two somewhat different areas. In the first, using cortical milestones for local and global processing from our neurobiological model, we identified cerebral visual impairment in infants in the first year of life. In the second, using photo/videorefraction in population refractive screening programs, we showed that infant spectacle wear could reduce the incidence of strabismus and amblyopia, but many preschool children, who had been significantly hyperopic earlier, showed visuo-motor and attentional deficits. This led us to compare developing dorsal and ventral streams, using sensitivity to global motion and form as signatures, finding deficits in motion sensitivity relative to form in children with Williams syndrome, or perinatal brain injury in hemiplegia or preterm birth. Later research showed that this "DSV" was common across many disorders, both genetic and acquired, from autism to amblyopia. Here, we extend DSV to be a cluster of problems, common to many disorders, including poor motion sensitivity, visuo-motor spatial integration for planning actions, attention, and number skills. In current research, we find that individual differences in motion coherence sensitivity in typically developing children are correlated with MRI measures of area variations in parietal lobe, fractional anisotropy (from TBSS) of the superior longitudinal fasciculus, and performance on tasks of mathematics and visuo-motor integration. These findings suggest that individual differences in motion sensitivity reflect decision making and attentional control rather than integration in MT/V5 or V3A. Its neural underpinnings may be related to Duncan's "multiple-demand" (MD) system.

Global Visual Motion Sensitivity: Associations with Parietal Area and Children's Mathematical Cognition.

Sensitivity to global visual motion has been proposed as a signature of brain development, related to the dorsal rather than ventral cortical stream. Thresholds for global motion have been found to be elevated more than for global static form in many developmental disorders, leading to the idea of "dorsal stream vulnerability." Here we explore the association of global motion thresholds with individual differences in children's brain development, in a group of typically developing 5- to 12-year-olds. Good performance was associated with a relative increase in parietal lobe surface area, most strongly around the intraparietal sulcus and decrease in occipital area. In line with the involvement of intraparietal sulcus, areas in visuospatial and numerical cognition, we also found that global motion performance was correlated with tests of visuomotor integration and numerical skills. Individual differences in global form detection showed none of these anatomical or cognitive correlations. This suggests that the correlations with motion sensitivity are unlikely to reflect general perceptual or attentional abilities required for both form and motion. We conclude that individual developmental variations in global motion processing are not linked to greater area in the extrastriate visual areas, which initially process such motion, but in the parietal systems that make decisions based on this information. The overlap with visuospatial and numerical abilities may indicate the anatomical substrate of the "dorsal stream vulnerability" proposed as characterizing neurodevelopmental disorders.

Optimizing the rapid measurement of detection thresholds in infants.

Accurate measures of perceptual threshold are difficult to obtain in infants. In a clinical context, the challenges are particularly acute because the methods must yield meaningful results quickly and within a single individual. The present work considers how best to maximize speed, accuracy, and reliability when testing infants behaviorally and suggests some simple principles for improving test efficiency. Monte Carlo simulations, together with empirical (visual acuity) data from 65 infants, are used to demonstrate how psychophysical methods developed with adults can produce misleading results when applied to infants. The statistical properties of an effective clinical infant test are characterized, and based on these, it is shown that (a) a reduced (false-positive) guessing rate can greatly increase test efficiency, (b) the ideal threshold to target is often below 50% correct, and (c) simply taking the max correct response can often provide the best measure of an infant's perceptual sensitivity.

The effect of blur on cortical responses to global form and motion.

Global form and motion sensitivity undergo long development in childhood with motion sensitivity rather than form being impaired in a number of childhood disorders and both impaired in adult clinical populations. This suggests extended development and vulnerability of extrastriate cortical areas associated with global processing. However, in some developmental and clinical populations, it remains unclear to what extent impairments might reflect deficits at earlier stages of visual processing, such as reduced visual acuity and contrast sensitivity. To address this, we investigated the impact of degraded spatial vision on cortical global form and motion processing in healthy adults. Loss of high spatial frequencies was simulated using a diffuser to blur the stimuli. Participants completed behavioral and EEG tests of global form and motion perception under three levels of blur. For the behavioral tests, participants' form and motion coherence thresholds were measured using a two-alternative, forced-choice procedure. Steady-state visual evoked potentials were used to measure cortical responses to changes in the coherence of global form and motion stimuli. Both global form and global motion perception were impaired with increasing blur as measured by elevated behavioral thresholds and reduced cortical responses. However, form thresholds showed greater impairment in both behavioral and EEG measures than motion thresholds at the highest levels of blur. The results suggest that high spatial frequencies play an important role in the perception of both global form and motion but are especially significant for global form. Overall, the results reveal complex interactions between low-level factors and global visual processing, highlighting the importance of taking these factors into account when investigating extrastriate function in low vision populations.

Construction and validation of an infant chest phantom for paediatric computed tomography.

Paediatric imaging protocols should be carefully optimised to maintain the desired image quality while minimising the delivered patient dose. A paediatric chest phantom was designed, constructed and evaluated to optimise chest CT examinations for infants. The phantom was designed to enable dosimetry and image quality measurements within the anthropomorphic structure. It was constructed using tissue equivalent materials to mimic thoracic structures of infants, aged 0-6 months. The phantom materials were validated across a range of diagnostic tube voltages with resulting CT numbers found equivalent to paediatric tissues observed via a survey of clinical paediatric chest studies. The phantom has been successfully used to measure radiation dose and evaluate various image quality parameters for paediatric specific protocols.

An Automated Radiosynthesis of [68Ga]Ga-FAPI-46 for Routine Clinical Use.

[68Ga]Ga-FAPI-46 is a promising new tracer for the imaging of fibroblast activation protein (FAP) by positron emission tomography (PET). Labeled FAP inhibitors (FAPIs) have demonstrated uptake in various types of cancers, including breast, lung, prostate, pancreatic and colorectal cancer. FAPI-PET also possesses a practical advantage over FDG-PET as fasting and resting are not required. [68Ga]Ga-FAPI-46 exhibits enhanced pharmacokinetic properties, improved tumor retention, and higher contrast images than the earlier presented [68Ga]Ga-FAPI-02 and [68Ga]Ga-FAPI-04. Although a manual synthesis protocol for [68Ga]Ga-FAPI-46 was initially described, in recent years, automated methods using different commercial synthesizers have been reported. In this work, we describe the development of the automated synthesis of [68Ga]Ga-FAPI-46 using the iPHASE MultiSyn synthesizer for clinical applications. Initially, optimization of the reaction time and comparison of the performance of four different solid phase extraction (SPE) cartridges for final product purification were investigated. Then, the development and validation of the production of 0.6-1.7 GBq of [68Ga]Ga-FAPI-46 were conducted using these optimized parameters. The product was synthesized in 89.8 ± 4.8% decay corrected yield (n = 6) over 25 min. The final product met all recommended quality control specifications and was stable up to 3 h post synthesis.

Inferences about infants' visual brain mechanisms.

We discuss hypotheses that link the measurements we can make with infants to inferences about their developing neural mechanisms. First, we examine evidence from the sensitivity to visual stimulus properties seen in infants' responses, using both electrophysiological measures (transient and steady-state recordings of visual evoked potentials/visual event-related potentials) and behavioral measures and compare this with the sensitivity of brain processes, known from data on mammalian neurophysiology and human neuroimaging. The evidence for multiple behavioral systems with different patterns of visual sensitivity is discussed. Second, we consider the analogies which can be made between infants' behavior and that of adults with identified brain damage, and extend these links to hypothesize about the brain basis of visual deficits in infants and children with developmental disorders. Last, we consider how these lines of data might allow us to form "inverse linking hypotheses" about infants' visual experience.

Visual control of manual actions: brain mechanisms in typical development and developmental disorders.

Some key stages in the development of manual actions have been discussed in this supplement based on the idea of the dorsal cortical stream as the pathway for translating visual information into action control. We argue that visual information, transmitted through specialized visuomotor dorsal-stream modules, is required in the control of manual actions for selecting and attending to the target object of the action, translating visual spatial information into motor programmes and planning a coordinated sequence of actions so as to reach an optimal end-state. In typical development, we illustrate dorsal-stream processing through results on the use of stereoscopic information to guide infants' reaches, and changes in target selection and detailed kinematics of reaches depending on age, object size, and reaching in darkness (when dorsal-stream information rapidly decays). We hypothesize 'dorsal-stream vulnerability' as a widespread feature of neurodevelopmental disorders, such as autism, Williams syndrome, and children born very preterm. Such deficits, identified as abnormal visuomanual actions, are seen in bimanual coordination, visual guidance of action in the 'postbox' task, and failures in motor planning for end-state comfort. We discuss the possible application of these approaches to a wider range of disorders including developmental coordination disorder.

Development of visual motion processing: phase and peak latencies of direction-specific visual evoked potential.

The direction-reversal visual evoked potential (DR-VEP) latency is a key measure of the development of motion processing in infancy. However, the latency of this response has not been previously investigated. For other stimuli, both the latency of an initial peak and a latency measure calculated from steady-state phase as a function of frequency have been shown to be important and distinctive indicators of development. The latter measure is hypothesized to reflect the time course of cortical processing beyond the initial response that generates the first positive peak. DR-VEP was tested in 61 adults at 1-16 reversals per second (r/s) and 76 infants (age 7.7-79.0 weeks) at 2-8 r/s. In addition to measuring the transient peak latency at 1-3 r/s, latencies from the gradient of phase against reversal rates were also calculated from steady-state recordings at 1-16 r/s. For both adults and infants, peak latencies were similar for 1-3 r/s, while the calculated latency was substantially longer. Thirty-nine percent of adults and 17% of infants showed additional early transient peaks. We suggest that this early peak may reflect activation of extrastriate areas by motion, by a route that bypasses V1. While both transient latencies were similar to adult values around the onset of DR responses at 10 weeks of age, the latency calculated from phase values did not asymptote to the adult value of 207 ms until around 30 weeks. The overall time course of the response to direction reversal is prolonged compared with the transmission delay that generates the initial transient peak, presumably reflecting feed-forward, lateral, and recurrent connections that refine and elaborate the directional response of cortical neurons. While the peak latencies stay relatively unchanged throughout development, the dynamics of further motion processing are not mature until after 8 months of age. These measures may prove important indicators of motion development in future clinical evaluations.

The organization of attention in typical development: a new preschool attention test battery.

This article introduces a new battery of attention tests for typically developing and atypically developing children with a mental age of 3-6 years. In the light of adult and child studies supporting a model of distinct networks for specific attentional operations, tests in the current battery were selected with the aim of measuring functions of selective attention, sustained attention and attentional control (executive function). Normative data were collected from 154 typically developing children aged 3-6 years and examined using exploratory factor analysis to determine latent constructs underlying test performance. This analysis suggested increasing differentiation of attention functions over the age range, with support for the hypothesized three-factor model only after 4½ years of age. Additional analyses supported the validity of the new attention battery with respect to (1) parent/teacher report measures of everyday attention behaviour and (2) later performance on the Test of Everyday Attention for Children (TEA-Ch), a battery designed for children aged 6-16 years. The results show the developing differentiation of attention functions and support the ecological and predictive validity of the battery as providing early performance-based measures of attention and an attention 'profile' for each individual child, which may aid characterization and remediation of neurodevelopmental disorders.

Attention in Williams syndrome and Down's syndrome: performance on the new early childhood attention battery.

Attentional problems are commonly reported as a feature of the behavioural profile in both Williams syndrome (WS) and Down's syndrome (DS). Recent studies have begun to investigate these impairments empirically, acknowledging the need for an approach that considers cross-syndrome comparisons and developmental changes across the different component functions of attention. The present study assessed children with WS and DS using a new preschool attention battery (ECAB: early childhood attention battery), designed to be suitable for mental age 3-6 years including groups with developmental disorders. The ECAB has the advantage of giving an individual profile of attentional abilities for each child, covering different components of attention. In relation to test norms for their mental age, both groups showed a profile of strengths and weaknesses in the attention domain. Both syndrome groups performed relatively well on tests of sustained attention and poorly on aspects of selective attention and attentional control (executive function). The DS group showed a specific strength in auditory sustained attention, whilst the WS group showed a particular deficit in visuo-spatial response control. There was also evidence for considerable differences in the developmental trajectory of these abilities across the two groups. The results provide evidence for syndrome-specific patterns of impairment, and distinct profiles of strengths and weaknesses that may be useful in understanding the nature of everyday attention difficulties in these groups and tailoring interventions to meet these needs.

Infants and adults reaching in the dark.

It has been shown that infants over the age of 6 months will reach for an object in complete darkness. This experiment measured the reaching movements of 9- to 16-month-old infants and adults under several different conditions of illumination to investigate the role of vision and stored visual representations in reach control. In one condition, participants reached for an object with the lights on. In a second condition, participants reached for an object glowing in the dark (glowing condition). This allowed us to measure the effects of vision of the arm and vision of the reach space. We also looked at the effect of removing vision of the object on reach control: in the final two conditions, participants reached for an object in complete darkness (0-s dark) and in complete darkness after a 4-s delay (4-s dark). We compared the kinematics of a reach (e.g. average speed, reach straightness) between the four illumination conditions. The results showed that infants reached faster and decelerated for a shorter period of time in the dark (0- and 4-s dark) than in the light. By comparison, adults reached slower and decelerated for a longer period of time in the dark (0- and 4-s dark) than in the light. We did not find any effect of the glowing condition compared to full vision on infant reaching movements. These results suggest that infant reaching movements only become compromised when the target is not visible, whereas vision of the hand and the reach space are less significant. Without online visual feedback, an infant reach in the dark appears to be driven by feedforward mechanisms and control may be affected by an immature ability to form and/or retain visual spatial memory.

The effect of removing visual information on reach control in young children.

Visual information about the hand, the reach space, and a target can all contribute to the control of a reaching movement. When visual information is removed, both feedforward mechanisms (involved in planning the movement) and feedback mechanisms (involved in correcting errors) may be affected. This study looks at how 4- to 5-year-old children use visual information to guide reaching movements. Children reached for a toy object in four conditions--in the light, in the dark while the toy was glowing, and in complete darkness after a 0-s delay and a 4-s delay. When a reach in the glowing condition was compared with a reach in the light, reaches were more curved, had a longer duration, and earlier time-to-peak-velocity than a reach in the light but the number of grasping responses were comparable to in the light condition. When a reach in the two dark conditions (0- and 4-s) was compared with a reach in the light, the number of grasping responses decreased and 14 and 31 % of reaches resulted in a miss, that is, no contact was made with the object. While we did not find any significant kinematic differences between the 0- and 4-s dark conditions, there was a significantly larger number of misses in the 4-s dark condition, suggesting that memory of target position may decay over time. Overall, removing vision of the hand and reach space in the glowing condition appears to affect the planning of a reach (as vision of the hand was not available at reach initiation) and feedback control, while removing vision of the object in the dark conditions has an effect on endpoint response as we found that children experience difficulty retrieving the object in the dark. While young children demonstrate more adult-like reach control (i.e., relatively longer deceleration time, increased reach duration) under reduced feedback conditions, they have difficulty retrieving the object in the dark, particularly after a 4-s delay, and it is possible that mechanisms guiding predictive control and visual memory are still developing.

Visually guided step descent in children with Williams syndrome.

Individuals with Williams syndrome (WS) have impairments in visuospatial tasks and in manual visuomotor control, consistent with parietal and cerebellar abnormalities. Here we examined whether individuals with WS also have difficulties in visually controlling whole-body movements. We investigated visual control of stepping down at a change of level in children with WS (5-16-year-olds), who descended a single step while their movement was kinematically recorded. On each trial step height was set unpredictably, so that visual information was necessary to perceive the step depth and position the legs appropriately before landing. Kinematic measures established that children with WS did not use visual information to slow the leg at an appropriate point during the step. This pattern contrasts with that observed in typically developing 3- and 4-year-old children, implying severe impairment in whole-body visuomotor control in WS. For children with WS, performance was not significantly predicted by low-level visual or balance problems, but improved significantly with verbal age. The results suggest some plasticity and development in WS whole-body control. These data clearly show that visuospatial and visuomotor deficits in WS extend to the locomotor domain. Taken together with evidence for parietal and cerebellar abnormalities in WS, these results also provide new evidence for the role of these circuits in the visual control of whole-body movement.

Visual attention in the first years: typical development and developmental disorders.

The development of attention is critical for the young child's competence in dealing with the demands of everyday life. Here we review evidence from infants and preschool children regarding the development of three neural subsystems of attention: selective attention, sustained attention, and attentional (executive) control. These systems overlap with dorsal cortical visual streams and their disorders are related to the general hypothesis of 'dorsal stream vulnerability'. Infants' ability to control spatial selective attention can be measured using the 'Fixation Shift' task. From around 4 months of age, infants start to show cortical control in disengaging to switch between competing targets. Fixation shifts have proved to be an effective early indicator of attentional disorders associated with perinatal brain damage. Executive function emerges slowly, starting around 1 year of age. The new Early Childhood Attention Battery has identified the three attention subsystems as distinct before 5 years of age in typical development and allows assessment of individual attention profiles across these subsystems. The Early Childhood Attention Battery is now being used to identify specific profiles associated with developmental syndromes such as Williams, Down, and fragile X. These new methods offer the possibility of very early identification of attention disorders, raising the challenge of effective remediation and treatment at an early age.