A multi-site pilot randomized clinical trial of the Treatment and Education Approach for Childhood-onset Lupus (TEACH) program: study design and COVID-19 adaptations.

BACKGROUND: Childhood-onset Systemic Lupus Erythematosus (cSLE) is an autoimmune disease associated with fatigue, mood symptoms, and pain. Fortunately, these symptoms are potentially modifiable with psychological intervention such as cognitive-behavioral therapy (CBT). The Treatment and Education Approach for Childhood-onset Lupus (TEACH) program is a CBT intervention developed to target these symptoms for adolescents and young adults with cSLE. This pilot randomized controlled trial (RCT) aims to determine the feasibility and effect of TEACH for youth with cSLE. Adjustments to the study protocol following the COVID-19 pandemic are also described. METHODS: This two-arm multisite RCT will explore the feasibility (primary outcome) and effect (secondary outcome) of a remotely delivered TEACH protocol. Participants will be randomized to a six-week remotely delivered TEACH program plus medical treatment as usual (TAU) or TAU alone. We will include patients ages 12-22 years presenting to rheumatology clinics from six sites. Validated measures of fatigue, depressive symptoms, and pain will be obtained at baseline and approximately eight and 20 weeks later. Protocol adjustments were also made due to the COVID-19 pandemic, in collaboration with the investigative team, which included patients and caregivers. CONCLUSIONS: Findings from this multi-site RCT aim to document the feasibility of TEACH and provide an estimate of effect of a remotely delivered TEACH protocol on fatigue, depression, and pain symptoms in youth with cSLE as compared to standard medical treatment alone. This findings may positively impact clinical care for patients with cSLE. CLINICAL TRIALS: gov registration: NCT04335643.

Characterising the spatial and oscillatory unfolding of Theory of Mind in adults using fMRI and MEG.

Theory of Mind (ToM) is a core social cognitive skill that refers to the ability to attribute mental states to others. ToM involves understanding that others have beliefs, thoughts and desires that may be different from one's own and from reality. ToM is crucial to predict behaviour and navigate social interactions. This study employed the complementary methodological advantages of both functional MRI (fMRI) and magnetoencephalography (MEG) to examine the neural underpinnings of ToM in adults. Twenty healthy adults were first recruited to rate and describe 28 videos (15s long), each containing three moving shapes designed to depict either social interactions or random motion (control condition). The first sample of adults produced consistent narratives for 6 of those social videos and of those, 4 social videos and 4 control videos were chosen to include in the neuroimaging study. Another sample of twenty-five adults were then recruited to complete the neuroimaging in MEG and fMRI. In fMRI, we found increased activation in frontal-parietal regions in the social compared to the control condition corroborating previous fMRI findings. In MEG, we found recruitment of ToM networks in the social condition in theta, beta and gamma bands. The right supramarginal and angular gyri (right temporal parietal junction), right inferior parietal lobe and right temporal pole were recruited in the first 5s of the videos. Frontal regions such as the superior frontal gyrus were recruited in the second time window (5-10s). Brain regions such as the bilateral amygdalae were also recruited (5-10s), indicating that various social processes were integrated in understanding the social videos. Our study is one of the first to combine multi-modal neuroimaging to examine the neural networks underlying social cognitive processes, combining the strengths of the spatial resolution of fMRI and temporal resolution of MEG. Understanding this information from both modalities helped delineate the mechanism by which ToM processing unfolds over time in healthy adults. This allows us to determine a benchmark against which clinical populations can be compared.

Very preterm brain at rest: longitudinal social-cognitive network connectivity during childhood.

Very preterm (VPT: ≤32 weeks of gestational age) birth poses an increased risk for social and cognitive morbidities that persist throughout life. Resting-state functional network connectivity studies provide information about the intrinsic capacity for cognitive processing. We studied the following four social-cognitive resting-state networks: the default mode, salience, frontal-parietal and language networks. We examined functional connectivity using magnetoencephalography with individual head localization using each participant's MRI at 6 (n = 40) and 8 (n = 40) years of age compared to age- and sex-matched full-term (FT) born children (n = 38 at 6 years and n = 43 at 8 years). VPT children showed increased connectivity compared to FT children in the gamma band (30-80 Hz) at 6 years within the default mode network (DMN), and between the DMN and the salience, frontal-parietal and language networks, pointing to more diffuse, less segregated processing across networks at this age. At 8 years, VPT children had more social and academic difficulties. Increased DMN connectivity at 6 years was associated with social and working memory difficulties at 8 years. Therefore, we suggest that increased DMN connectivity contributes to the observed emerging social and cognitive morbidities in school age.

Do shapes have feelings? Social attribution in children with autism spectrum disorder and attention-deficit/hyperactivity disorder.

Theory of mind (ToM) deficits are common in children with neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which contribute to their social and cognitive difficulties. The social attribution task (SAT) involves geometrical shapes moving in patterns that depict social interactions and is known to recruit brain regions from the classic ToM network. To better understand ToM in ASD and ADHD children, we examined the neural correlates using the SAT and functional magnetic resonance imaging (fMRI) in a cohort of 200 children: ASD (N = 76), ADHD (N = 74) and typically developing (TD; N = 50) (4-19 years). In the scanner, participants were presented with SAT videos corresponding to social help, social threat, and random conditions. Contrasting social vs. random, the ASD compared with TD children showed atypical activation in ToM brain areas-the middle temporal and anterior cingulate gyri. In the social help vs. social threat condition, atypical activation of the bilateral middle cingulate and right supramarginal and superior temporal gyri was shared across the NDD children, with between-diagnosis differences only being observed in the right fusiform. Data-driven subgrouping identified two distinct subgroups spanning all groups that differed in both their clinical characteristics and brain-behaviour relations with ToM ability.

The preterm social brain: altered functional networks for Theory of Mind in very preterm children.

Neurodevelopmental difficulties emerge in very preterm born children (<32-week gestation) in infancy and continue to early adulthood but little is known about their social-cognitive development. This study utilized the complementary methodological advantages of both functional MRI and magnetoencephalography to examine the neural underpinnings of Theory of Mind in very preterm birth. Theory of Mind, one of the core social-cognitive skills, is the ability to attribute mental states to others, and is crucial for predicting others' behaviours in social interactions. Eighty-three children (40 very preterm born, 24 boys, age = 8.7 ± 0.5 years, and 43 full-term born, 22 boys, age = 8.6 ± 0.5 years) completed the study. In functional MRI, both groups recruited classic Theory of Mind areas, without significant group differences. However, reduced Theory of Mind connectivity in the very preterm born group was found in magnetoencephalography in distinct theta, alpha and beta-band networks anchored in a set of brain regions that comprise the social brain. These networks included regions such as the angular gyrus, the medial pre-frontal cortex, the superior temporal gyrus and the temporal poles. Very preterm born children showed increased connectivity compared to controls in a network anchored in the occipital gyri rather than classical social-processing regions. Very preterm born children made significantly more attribution errors and mis-construed the social scenarios. Findings offer novel insight into the neural networks, supporting social cognition in very preterm born children and highlight the importance of multimodal neuroimaging to interrogate the social brain in clinical populations.

Emerging atypical connectivity networks for processing angry and fearful faces in very preterm born children.

Very preterm born (VPT) children are those born before 32/40 weeks' gestational age and comprise 10% of the 15 million babies born prematurely worldwide each year. Due to advancements in neonatal medicine, the survival rate of VPT birth has increased, but few studies have investigated the nonmedical, social-cognitive morbidities that affect these children. In this study, we examined emotional face processing networks in VPT compared to age and sex matched full-term born (FT) children. Magnetoencephalography (MEG) was used to test VPT and FT born children at 6 years (n = 78) and 8 years (n = 83). Children were assessed using an implicit emotion face-processing task. Happy, fearful, and angry faces were presented for 150 ms, but children were asked to respond by button press to the location of a control pixelated image of the face displayed on the side of the screen opposite to the face. Children rated the valence of the images on a five-point scale. Group differences showed that VPT children rated angry faces more positively than their FT peers. VPT children had reduced connectivity for angry and fearful faces at 8 years in networks including regions such as the bilateral amygdala, superior temporal sulci, and anterior cingulate gyrus. Interventions should target both emotion recognition, as well as higher cognitive processes related to emotional control and thinking about one's own emotions.

Mapping the neuroanatomical impact of very preterm birth across childhood.

Those born very preterm (VPT; <32 weeks gestational age) have an increased risk in developing a wide range of cognitive deficits. In early-to-late childhood, brain structure has been shown to be altered in VPT compared to full-term (FT) children; however, the results are inconsistent. The current study examined subcortical volumes, cortical thickness, and surface area in a large cohort of VPT and FT children aged 4-12 years. Structural magnetic resonance imaging (MRI) was obtained on 120 VPT and 146 FT children who returned up to three times, resulting in 176 VPT and 173 FT unique data points. For each participant, Corticometric Iterative Vertex-based Estimation of Thickness was used to obtain global measurements of total brain, cortical grey and cortical white matter volumes, along with surface-based measurements of cortical thickness and surface area, and Multiple Automatically Generated Templates (MAGeT) brain segmentation tool was used to segment the subcortical structures. To examine group differences and group-age interactions, mixed-effects models were used (controlling for whole-brain volume). We found few differences between the two groups in subcortical volumes. The VPT children showed increased cortical thickness in frontal, occipital and fusiform gyri and inferior pre-post-central areas, while thinning occurred in the midcingulate. Cortical thickness in occipital regions showed more rapid decreases with age in the VPT compared to the FT children. VPT children also showed both regional increases, particularly in the temporal lobe, and decreases in surface area. Our results indicate a delayed maturational trajectory in those born VPT.

Disrupted Visual Cortex Neurophysiology Following Very Preterm Birth.

BACKGROUND: Visual regions develop rapidly in utero and throughout early childhood, but very preterm (VPT) birth can disrupt the typical maturation of primary cortices, with VPT children exhibiting mild visual impairments in early life and throughout development. This is thought to be due to dysfunctional maturation of occipital cortices. A way to readily index brain function is to examine neural oscillations; these mechanisms play a central role in the modeling and pruning of connections, providing an intrinsic temporal structure that refines the precise alignment of spiking, processing information in the brain, and coordinating networks. METHODS: Using magnetoencephalography, we examined regional oscillatory patterns and functional coupling in VPT and full-term children. Five minutes of eyes-open resting-state data were acquired from 27 VPT and 32 full-term children at 8 years of age. RESULTS: As hypothesized, the VPT group, when compared with control children, had elevated theta-band power, while alpha amplitude envelope coupling, a marker of connectivity, was found to be decreased. CONCLUSIONS: These results support the hypothesis of spectral slowing in VPT children and more broadly suggest that the developmental arc of visual neurophysiology is disrupted by VPT birth. We conclude that these deficits underlie difficulties in complex visual perceptual processing evident during childhood and beyond.

Spectral slowing is associated with working memory performance in children born very preterm.

Children born very preterm (VPT) often demonstrate selective difficulties in working memory (WM), which may underlie academic difficulties observed in this population. Despite this, few studies have investigated the functional networks underlying WM in young children born VPT, a period when cognitive deficits become apparent. Using magnetoencephalography, we examined the networks underlying the maintenance of visual information in 6-year-old VPT (n = 15) and full-term (FT; n = 20) children. Although task performance was similar, VPT children engaged different oscillatory mechanisms during WM maintenance. Within the FT group, we observed higher mean whole-brain connectivity in the alpha-band during the retention (i.e. maintenance) interval associated with correct compared to incorrect responses. VPT children showed reduced whole-brain alpha synchrony, and a different network organization with fewer connections. In the theta-band, VPT children demonstrated a slight increase in whole-brain connectivity during WM maintenance, and engaged similar network hubs as FT children in the alpha-band, including the left dorsolateral prefrontal cortex and superior temporal gyrus. These findings suggest that VPT children rely on the theta-band to support similar task performance. Altered oscillatory mechanisms may reflect a less mature pattern of functional recruitment underlying WM in VPT children, which may affect the processing in complex ecological situations.

White matter microstructural differences identified using multi-shell diffusion imaging in six-year-old children born very preterm.

INTRODUCTION: The underlying microstructural properties of white matter differences in children born very preterm (<32 weeks gestational age) can be investigated in depth using multi-shell diffusion imaging. The present study compared white matter across the whole brain using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics in children born very preterm and full-term children at six years of age. We also investigated associations between white matter microstructure with early brain injury and developmental outcomes. METHOD: Multi-shell diffusion imaging, T1-weighted anatomical MR images and developmental assessments were acquired in 23 children born very preterm (16 males; mean scan age: 6.57 ±â€¯0.34 years) and 24 full-term controls (10 males, mean scan age: 6.62 ±â€¯0.37 years). DTI metrics were obtained and neurite orientation dispersion index (ODI) and density index (NDI) were estimated using the NODDI diffusion model. FSL's tract-based spatial statistics were performed on traditional DTI metrics and NODDI metrics. Voxel-wise comparisons were performed to test between-group differences and within-group associations with developmental outcomes (intelligence and visual motor abilities) as well as early white matter injury and germinal matrix/intraventricular haemorrhage (GMH/IVH). RESULTS: In comparison to term-born children, the children born very preterm exhibited lower fractional anisotropy (FA) across many white matter regions as well as higher mean diffusivity (MD), radial diffusivity (RD), and ODI. Within-group analyses of the children born very preterm revealed associations between higher FA and NDI with higher IQ and VMI. Lower ODI was found within the corona radiata in those with a history of white matter injury. Within the full-term group, associations were found between higher NDI and ODI with lower IQ. CONCLUSION: Children born very preterm exhibit lower FA and higher ODI than full-term children. NODDI metrics provide more biologically specific information beyond DTI metrics as well as additional information of the impact of prematurity and white matter microstructure on cognitive outcomes at six years of age.

Alpha keeps it together: Alpha oscillatory synchrony underlies working memory maintenance in young children.

Working Memory (WM) supports a wide range of cognitive functions, and is positively associated with academic achievement. Although fMRI studies have revealed WM networks in adults, little is known about how these networks develop to support successful WM performance in children. Using magnetoencephalography, we examined the networks underlying the maintenance of visual information in 6-year-old children. We observed an increase in mean whole-brain connectivity that was specific to the alpha frequency band during the retention interval associated with correct compared to incorrect responses. Additionally, our network analysis revealed elevated alpha synchronization during WM maintenance in a distributed network of frontal, parietal and temporal regions. Central hubs in the network were lateralized to the left hemisphere with dominant fronto-temporal connections, including the dorsolateral prefrontal cortex, middle temporal and superior temporal gyri, as well as other canonical language areas. Local changes in power were also analysed for seeds of interest, including the left inferior parietal lobe, which revealed an increase in alpha power after stimulus onset that was sustained throughout the retention period of WM. Our results therefore implicate sustained fronto-temporal alpha synchrony during the retention interval with subsequent successful WM responses in children, which may be aided by subvocal rehearsal strategies.

Neural correlates of "Theory of Mind" in very preterm born children.

Very preterm (VPT) birth (<32 weeks' gestational age) has been implicated in social-cognitive deficits including Theory of Mind (ToM); the ability to attribute mental states to others and understand that those beliefs can differ from one's own or reality. The neural bases for ToM deficits in VPT born children have not been examined. We used magnetoencephalography (MEG) for its excellent spatial and temporal resolution to determine the neural underpinnings of ToM in 24 VPT and 24 full-term born (FT) children (7-13 years). VPT children performed more poorly on neuropsychological measures of ToM but not inhibition. In the MEG task, both FT children and VPT children recruited regions involved in false belief processing such as the rIFG (VPT: 275-350 ms, FT: 250-375 ms) and left inferior temporal gyrus (VPT: 375-450 ms, FT: 325-375 ms) and right fusiform gyrus (VPT: 150-200 ms, FT: 175-250 ms). The rIPL (included in the temporal-parietal junction) was recruited in FT children (475-575 ms) and the lTPJ in VPT children (500-575 ms). However, activations in all regions were reduced in the VPT compared to the FT group. We suggest that with increasing social-cognitive demands such as varying the type of scenarios in the standardized measure of ToM, reduced activations in the rIFG and TPJ in the VPT group may reflect the decreased performance. With access to both spatial and temporal information, we discuss the role of domain general and specific regions of the ToM network in both groups. Hum Brain Mapp 38:5577-5589, 2017. © 2017 Wiley Periodicals, Inc.

The special status of sad infant faces: age and valence differences in adults' cortical face processing.

Understanding the relative and joint prioritization of age- and valence-related face characteristics in adults' cortical face processing remains elusive because these two characteristics have not been manipulated in a single study of neural face processing. We used electroencephalography to investigate adults' P1, N170, P2 and LPP responses to infant and adult faces with happy and sad facial expressions. Viewing infant vs adult faces was associated with significantly larger P1, N170, P2 and LPP responses, with hemisphere and/or participant gender moderating this effect in select cases. Sad faces were associated with significantly larger N170 responses than happy faces. Sad infant faces were associated with significantly larger N170 responses in the right hemisphere than all other combinations of face age and face valence characteristics. We discuss the relative and joint neural prioritization of infant face characteristics and negative facial affect, and their biological value as distinct caregiving and social cues.

Thinking about the thoughts of others; temporal and spatial neural activation during false belief reasoning.

Theory of Mind (ToM) is the ability to understand the perspectives, mental states and beliefs of others in order to anticipate their behaviour and is therefore crucial to social interactions. Although fMRI has been widely used to establish the neural networks implicated in ToM, little is known about the timing of ToM-related brain activity. We used magnetoencephalography (MEG) to measure the neural processes underlying ToM, as MEG provides very accurate timing and excellent spatial localization of brain processes. We recorded MEG activity during a false belief task, a reliable measure of ToM, in twenty young adults (10 females). MEG data were recorded in a 151 sensor CTF system (MISL, Coquitlam, BC) and data were co-registered to each participant's MRI (Siemens 3T) for source reconstruction. We found stronger right temporoparietal junction (rTPJ) activations in the false belief condition from 150ms to 225ms, in the right precuneus from 275ms to 375ms, in the right inferior frontal gyrus from 200ms to 300ms and the superior frontal gyrus from 300ms to 400ms. Our findings extend the literature by demonstrating the timing and duration of neural activity in the main regions involved in the "mentalizing" network, showing that activations related to false belief in adults are predominantly right lateralized and onset around 100ms. The sensitivity of MEG will allow us to determine spatial and temporal differences in the brain processes in ToM in younger populations or those who demonstrate deficits in this ability.