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.

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.

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.

Dorsal and Ventral Stream Function in Children With Developmental Coordination Disorder.

Dorsal stream cortical networks underpin a cluster of visuomotor, visuospatial, and visual attention functions. Sensitivity to global coherence of motion and static form is considered a signature of visual cortical processing in the dorsal stream (motion) relative to the ventral stream (form). Poorer sensitivity to global motion compared to global static form has been found across a diverse range of neurodevelopmental disorders, suggesting a "dorsal stream vulnerability." However, previous studies of global coherence sensitivity in Developmental Coordination Disorder (DCD) have shown conflicting findings. We examined two groups totalling 102 children with DCD (age 5-12 years), using the "Ball in the Grass" psychophysical test to compare sensitivity to global motion and global static form. Motor impairment was measured using the Movement-ABC (M-ABC). Global coherence sensitivity was compared with a typically developing control group (N = 69) in the same age range. Children with DCD showed impaired sensitivity to global motion (p = 0.002), but not global form (p = 0.695), compared to controls. Within the DCD group, motor impairment showed a significant linear relationship with global form sensitivity (p < 0.001). There was also a significant quadratic relationship between motor impairment and global motion sensitivity (p = 0.046), where poorer global motion sensitivity was only apparent with greater motor impairment. We suggest that two distinct visually related components, associated with global form and global motion sensitivity, contribute to DCD differentially over the range of severity of the disorder. Possible neural circuitry underlying these relationships is discussed.

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.

Visual development.

The developing visual brain is an integrated system, linking analysis of the visual input to visuomotor control, visual cognition, and attention. Major points in human visual development are the presence of rudimentary pathways present at birth which can control fixation behavior, with subsequent development of specific functions. These functions include the emergence of cortical selectivity; the integration of local signals to provide global representations of motion, shape, and space; the development of visuomotor modules for eye movements, manual reaching, and locomotion; and the development of distinct attentional systems. Measures of these processes in infancy and early childhood can provide indicators of broader brain development in the at-risk child. A key system in development is the dorsal cortical stream. Measures of global motion processing, visuomotor actions, and attention suggest that this system is particularly vulnerable in children with a wide range of neurodevelopmental disorders. Early disorders of the eye (strabismus, cataract) reveal the level of plasticity in the developing visual system and the ways in which early experience can affect the course of functional development.

Early Childhood Attention Battery: Italian adaptation and new expanded normative data.

BACKGROUND: The Early Childhood Attention Battery (ECAB) has been used to assess three different components of attention in preschool children, namely, selective, sustained and attentional control. AIM: The aim of the study was: I) to adapt the ECAB to the Italian language; II) to collect Italian reference data using the translated version and III) to expand the available reference data using 6-month age intervals. STUDY DESIGN: The adaptation of the ECAB to Italian language and the collection of Italian reference data was performed in four phases: translation and identification of the manual and subtests that needed adaptation; interobserver reliability and feasibility of the Italian version; application of the Italian ECAB; statistical analysis. SUBJECTS: The ECAB was performed on a low risk population between 3 and 5 years, 11 months. RESULTS: Statistical analysis was conducted subdividing the cohort in 6-month age groups. The final cohort included 300 low-risk typically developing children. The assessment was well accepted and enjoyed by most of the children except for some in the youngest group who refused to complete all of the tests. Our data showed a progressive improvement in attention across age in seven of the eight subtests of the ECAB. CONCLUSION: The ECAB is a feasible battery in Italian as in the English version, for the assessment of early attention in preschool children, allowing the assessment of the different components of attention and a specific maturation follow up with increasing age.

Different trajectories of decline for global form and global motion processing in aging, mild cognitive impairment and Alzheimer's disease.

The visual processing of complex motion is impaired in Alzheimer's disease (AD). However, it is unclear whether these impairments are biased toward the motion stream or part of a general disruption of global visual processing, given some reports of impaired static form processing in AD. Here, for the first time, we directly compared the relative preservation of motion and form systems in AD, mild cognitive impairment, and healthy aging, by measuring coherence thresholds for well-established global rotational motion and static form stimuli known to be of equivalent complexity. Our data confirm a marked motion-processing deficit specific to some AD patients, and greater than any form-processing deficit for this group. In parallel, we identified a more gradual decline in static form recognition, with thresholds raised in mild cognitive impairment patients and slightly further in the AD group compared with controls. We conclude that complex motion processing is more vulnerable to decline in dementia than complex form processing, perhaps owing to greater reliance on long-range neural connections heavily targeted by AD pathology.

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.

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.

Individual differences in children's global motion sensitivity correlate with TBSS-based measures of the superior longitudinal fasciculus.

Reduced global motion sensitivity, relative to global static form sensitivity, has been found in children with many neurodevelopmental disorders, leading to the "dorsal stream vulnerability" hypothesis (Braddick et al., 2003). Individual differences in typically developing children's global motion thresholds have been shown to be associated with variations in specific parietal cortical areas (Braddick et al., 2016). Here, in 125 children aged 5-12years, we relate individual differences in global motion and form coherence thresholds to fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF), a major fibre tract communicating between parietal lobe and anterior cortical areas. We find a positive correlation between FA of the right SLF and individual children's sensitivity to global motion coherence, while FA of the left SLF shows a negative correlation. Further analysis of parietal cortical area data shows that this is also asymmetrical, showing a stronger association with global motion sensitivity in the left hemisphere. None of these associations hold for an analogous measure of global form sensitivity. We conclude that a complex pattern of structural asymmetry, including the parietal lobe and the superior longitudinal fasciculus, is specifically linked to the development of sensitivity to global visual motion. This pattern suggests that individual differences in motion sensitivity are primarily linked to parietal brain areas interacting with frontal systems in making decisions on integrated motion signals, rather than in the extra-striate visual areas that perform the initial integration. The basis of motion processing deficits in neurodevelopmental disorders may depend on these same structures.

Neural Differences between Covert and Overt Attention Studied using EEG with Simultaneous Remote Eye Tracking.

Research on neural mechanisms of attention has generally instructed subjects to direct attention covertly while maintaining a fixed gaze. This study combined simultaneous eye tracking and electroencephalogram (EEG) to measure neural attention responses during exogenous cueing in overt attention shifts (with saccadic eye movements to a target) and compared these with covert attention shifts (responding manually while maintaining central fixation). EEG analysis of the period preceding the saccade latency showed similar occipital response amplitudes for overt and covert shifts, although response latencies differed. However, a frontal positivity was greater during covert attention shifts, possibly reflecting saccade inhibition to maintain fixation. The results show that combined EEG and eye tracking can be successfully used to study natural overt shifts of attention (applicable to non-verbal infants) and that requiring inhibition of saccades can lead to additional frontal responses. Such data can be used to refine current neural models of attention that have been mainly based on covert shifts.

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.

Dissociations in Coherence Sensitivity Reveal Atypical Development of Cortical Visual Processing in Congenital Achromatopsia.

PURPOSE: While basic visual functions have been described in subjects with congenital achromatopsia (ACHM), little is known about their mid- or high-level cortical visual processing. We compared midlevel cortical visual processing in ACHM subjects (n = 11) and controls (n = 20). METHODS: Abilities to detect global form, global motion, and biological motion embedded in noise were tested across a range of light levels, including scotopic, in which both ACHM subjects and controls must rely on rods. Contrast sensitivity functions (CSFs) were also measured. RESULTS: Achromatopsia subjects showed differential impairments across tests. In scotopic conditions, global form was most impaired, while biological motion was normal. In a subset of three ACHM subjects with normal scotopic CSFs, two of the three showed global form perception worse than controls; all showed global motion comparable to controls; and strikingly, two of the three showed biological motion perception superior to controls. CONCLUSIONS: The cone signal appears to play a crucial role in the development of perception of global form, as in ACHM this is impaired even in scotopic conditions, in which controls also have to rely on rods, and even in ACHM subjects with no scotopic spatial vision loss. In contrast, the rod signal appears sufficient for the development of normal (or even superior) extrastriate biological motion perception. These results suggest that ACHM leads to atypical development of cortical vision, highlighting the need to better understand the potential for further reorganization of cortical visual processing following new therapies aimed at restoring cone function.

Cortical processing of global form, motion and biological motion under low light levels.

Advances in potential treatments for rod and cone dystrophies have increased the need to understand the contributions of rods and cones to higher-level cortical vision. We measured form, motion and biological motion coherence thresholds and EEG steady-state visual evoked potentials (SSVEP) responses under light conditions ranging from photopic to scotopic. Low light increased thresholds for all three kinds of stimuli; however, global form thresholds were relatively more impaired than those for global motion or biological motion. SSVEP responses to coherent global form and motion were reduced in low light, and motion responses showed a shift in topography from the midline to more lateral locations. Contrast sensitivity measures confirmed that basic visual processing was also affected by low light. However, comparison with contrast sensitivity function (CSF) reductions achieved by optical blur indicated that these were insufficient to explain the pattern of results, although the temporal properties of the rod system may also play a role. Overall, mid-level processing in extra-striate areas is differentially affected by light level, in ways that cannot be explained in terms of low-level spatiotemporal sensitivity. A topographical shift in scotopic motion SSVEP responses may reflect either changes to inhibitory feedback mechanisms between V1 and extra-striate regions or a reduction of input to the visual cortex. These results provide insight into how higher-level cortical vision is normally organised in absence of cone input, and provide a basis for comparison with patients with cone dystrophies, before and after treatments aiming to restore cone function.

Automatic Detection of Attention Shifts in Infancy: Eye Tracking in the Fixation Shift Paradigm.

This study measured changes in switches of attention between 1 and 9 months of age in 67 typically developing infants. Remote eye-tracking (Tobii X120) was used to measure saccadic latencies, related to switches of fixation, as a measure of shifts of attention, from a central stimulus to a peripheral visual target, measured in the Fixation Shift Paradigm. Fixation shifts occur later if the central fixation stimulus stays visible when the peripheral target appears (competition condition), than if the central stimulus disappears as the peripheral target appears (non-competition condition). This difference decreases with age. Our results show significantly faster disengagement in infants over 4 months than in the younger group, and provide more precise measures of fixation shifts, than behavioural observation with the same paradigm. Reduced saccadic latencies in the course of a test session indicate a novel learning effect. The Fixation Shift Paradigm combined with remote eye-tracking measures showed improved temporal and spatial accuracy compared to direct observation by a trained observer, and allowed an increased number of trials in a short testing time. This makes it an infant-friendly non-invasive procedure, involving minimal observational training, suitable for use in future studies of clinical populations to detect early attentional abnormalities in the first few months of life.

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.

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.