NeuroImage: Reports

Very preterm (VPT) young adolescents are at high risk of executive, behavioural and socio-emotional difficulties. Previous research has shown significant evidence of the benefits of mindfulness-based intervention (MBI) on these abilities. This study aims to assess the association between the effects of MBI on neurobehavioral functioning and changes in white-matter microstructure in VPT young adolescents who completed an 8-week MBI program. Neurobehavioural assessments and multi-shell diffusion MRI were performed before and after MBI in 32 VPT young adolescents. Combined diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) measures were extracted on well-defined white matter tracts (TractSeg). A multivariate data-driven approach (partial least squares correlation) was used to explore associations between MBI-related changes on neurobehavioural measures and microstructural changes. Our finding showed an enhancement of global executive functioning after MBI that was associated with a general pattern of significant increase in fractional anisotropy (FA) and decrease in axonal dispersion (ODI) in white-matter tracts involved in executive processes. Young VPT adolescents with lower gestational age at birth showed the greatest gain in white-matter microstructural changes after MBI. HighlightsO_LIVery preterm adolescents (VPT) completed an 8-week mindfulness-based intervention (MBI) C_LIO_LIImprovement in overall executive functioning was observed after MBI C_LIO_LIExecutive gain was associate with white-matter microstructural changes C_LIO_LIThe increase in microstructural properties was in tracts involved in executive processes C_LIO_LIVPT with lower gestational age show bigger gains in microstructural changes C_LI CRediT rolesVanessa Siffredi: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Software; Visualization; Writing - original draft; Writing - review & editing - Maria Chiara Liverani: Conceptualization; Data curation; Investigation; Methodology; Project administration; Writing - review & editing. - Dimitri Van De Ville: Methodology; Resources; Software; Supervision; Writing - review & editing. - Lorena Freitas: Data curation; Investigation; Writing - review & editing. - Cristina Borradori Tolsa: Conceptualization; Funding acquisition; Investigation; Project administration; Resources; Supervision; Validation; Writing - review & editing. - Petra Susan Huppi: Conceptualization; Funding acquisition; Methodology; Project administration; Resources; Supervision; Validation; Writing - review & editing. -Russia Ha-Vinh Leuchter: Conceptualization; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Writing - review & editing.

The FMR1 gene is inactive in Fragile X syndrome (FXS), resulting in low levels of FMRP and consequent neurochemical, synaptic and local circuit neurophysiological alterations in the fmr1 KO mouse. In FXS patients, electrophysiological studies of have demonstrated a marked reduction in global alpha activity and regional increases in gamma oscillations that have been associated with intellectual disability and sensory hypersensitivity. Since alpha activity is associated with thalamocortical function that has widely distributed modulatory effects on neocortical excitability, insight into alpha physiology may provide insight into systems-level disease mechanisms. Herein, we took a data driven approach to clarify the temporal and spatial properties of alpha and theta activity in participants with FXS. High-resolution resting-state EEG data was collected from participants affected by FXS (n=65) and matched controls (n=70). We used a multivariate technique to empirically classify neural oscillatory bands based on their coherent spatiotemporal patterns. Participants with FXS demonstrated: 1) a redistribution of lower-frequency boundaries indicating a "slower" dominant alpha rhythm, 2) an anteriorization of alpha frequency activity, and 3) a correlation of increased individualized alpha power measurements with auditory neurosensory dysfunction. These findings suggest an important role for alterations in thalamocortical physiology for the well-established neocortical hyper-excitability in FXS, and thus a role for neural systems level disruption to cortical hyperexcitability that has been studied primarily at the local circuit level in mouse model research.

BackgroundThe Cambridge Centre for Ageing and Neuroscience (Cam-CAN) started in 2010 to study the effect of healthy adult ageing on cognition and the brain in a population-derived sample. The study design and protocol for Phases 1-3 of Cam-CAN were detailed in Shafto et al. (2014); this paper outlines the design and protocol of Phases 4-5, which enable longitudinal investigation of cognitive and brain ageing over approximately 12 years. More details about the Cam-CAN project can be found here: www.cam-can.org. Methods/DesignPhase 4 was an at-home assessment of cognition, demographics and lifestyle, performed approximately 6 years after Phase 1 (baseline assessment), for which all people from Phase 1 were invited. Phase 5 combined repeated online cognitive, demographics and lifestyle assessment, followed by in-lab attendance for MRI and MEG brain scanning, approximately 12 years after Phase 1, for which all people from Phase 2 (baseline brain assessment) were invited. Demographics, lifestyle and cognitive data are therefore now available for three timepoints, and MRI and MEG brain data for two timepoints. DiscussionThe Cam-CAN study offers deep and wide phenotyping of neurocognitive health across the adult lifespan (18-96). These rich data will allow researchers to address questions like: why do some people maintain their cognitive abilities better than others, in terms of their brain structure or function, their lifestyle and/or their genetics? Given the shifting demographics towards old age in most countries, this knowledge will be important to help people function independently for longer, reducing both individual and societal burden.

IntroductionSustained attention and inhibition processes are fundamental components of attention that mature during adolescence, a transitive period between childhood and adulthood characterized by a rapid behavioral and cognitive development. The current study aimed to provide a better understanding of sustained attention and inhibition processes in typically developing adolescents (n = 26) aged 11-18. MethodsFunctional magnetic resonance images (fMRI) were acquired during two different modalities (the face and the scene) from a previously validated gradual{square}onset continuous (gradCPT) paradigm to evaluate sustained attention performances. In addition, we performed linear regression analyses to investigate how cerebral activation varied as a function of covariates of interest. ResultsWe showed a bilateral fronto-parieto-occipito brain activation during response inhibition regardless the type of task. Participants demonstrated better behavioral performances during the scene gradCPT. We observed a mainly left-lateralized pattern of activation in a fronto-cingulo-cerebellum area during the face gradCPT and an extended bilateral fronto-temporo-parieto-occipital activation during the scene gradCPT. Finally, we found associations between brain activity and behavioral attentional responses. ConclusionThis study gives a better understanding of the neural correlates of sustained attention and inhibition in a typically developing adolescent population.

Children born very preterm (VPT; < 32 completed weeks of gestation) are at high risk of neurodevelopmental and neurobehavioral difficulties associated with atypical brain maturation. The analysis of large-scale brain network dynamics during rest allows to investigate brain functional connectivity and their association with behavioural outcomes. Of interest, prematurity has been associated with atypical socio-emotional development with significant implications for the forming of peer relationships, adaptive functioning, academic achievement and mental health. In this study, we extracted dynamic functional connectivity by using the innovation-driven co-activation patterns (iCAPs) framework in preterm and full-term children aged 6 to 9 to explore changes in spatial organisation, laterality and temporal dynamics of spontaneous large-scale brain activity. Multivariate pattern analysis was used to explore potential biomarkers for socio-emotional difficulties in preterm children. Results show a spatial organisation of 13 networks retrieved comparable to full-term controls. Dynamic features and lateralisation of network brain activity were also comparable across groups for all large-scale brain networks. Despite apparent similarities in terms of dynamical functional connectivity parameters, multivariate pattern analysis unveiled group differences in their associations with socio-emotional abilities. While a pattern of decreased engagement in certain brain networks were associated with better socio-emotional abilities in full-term controls; in the VPT group, better socio-emotional abilities were associated with coordination of activity across different networks, i.e., coupling duration between different pairs of networks. It is possible that group differences reflect reduced degree of maturation of functional architecture in the VPT group for socio-emotional abilities.

This multimodal brain imaging study investigated functional MRI (fMRI) neural processing of cardiac interoceptive signals in 38 patients with functional neurological disorder (FND) compared to 38 healthy controls (HCs). Additionally, we characterized how brain fMRI responses during heartbeat counting (interoception) vs. tone counting (exteroception) or rest related to grey matter volume, interoceptive awareness, and psychopathology scores. For both interoception vs. rest and interoception vs. exteroception contrasts, principal component analyses showed that principal component 1 (PC1) as derived from all study participants was comprised primarily of salience, ventral attention and sensorimotor network co-activations, along with default mode and visual processing network co-deactivations. Compared to HCs, patients with FND showed reduced contribution to these PC1 co-activation/co-deactivations patterns in both interoception vs. exteroception and interoception vs. rest contrasts; only the interoception vs. exteroception between-group fMRI findings held adjusting for depression/anxiety scores, antidepressant use and FND subtype. For the interoception vs. rest contrast, increasingly negative PC1 contribution scores positively correlated with decreased cingulate gyrus volumes and increased psychopathology scores. This multimodal brain imaging study underscores a role for salience and default-mode networks in the pathophysiology of FND, and sets the stage for comprehensive research efforts further contextualizing the mechanistic importance of altered interoception in patients with FND.

A cardinal feature of the encephalopathy of prematurity is dysmaturation of developing white matter and subsequent hypomyelination. Magnetisation transfer imaging (MTI) offers surrogate markers for myelination including magnetisation transfer ratio (MTR) and magnetisation transfer saturation (MTsat). Using data from 105 neonates, we characterise MTR and MTsat in the developing brain and investigate how these markers are affected by gestational age at scan and preterm birth. We explore correlations of the two measures with fractional anisotropy (FA), radial diffusivity (RD) and T1w/T2w ratio which are commonly used markers of white matter integrity in early life. We used two complementary analysis methods: voxel-wise analysis across the white matter skeleton, and tract-of-interest analysis across 16 major white matter tracts. We found that MTR and MTsat positively correlate with gestational age at scan. Preterm infants at term-equivalent age had lower values of MTsat in the genu and splenium of the corpus callosum, while MTR was higher in central white matter regions, the corticospinal tract and the uncinate fasciculus. Correlations of MTI metrics with other MRI parameters revealed that there were moderate positive correlations between T1w/T2w and MTsat and MTR at voxel-level, but at tract-level FA had stronger positive correlations with these metrics. RD had the strongest correlations with MTI metrics, particularly with MTsat in major white matter tracts. The observed changes in MTI metrics are consistent with an increase in myelin density during early postnatal life, and lower myelination and cellular/axonal density in preterm infants at term-equivalent age compared to term controls. Furthermore, correlations between MTI-derived features and conventional measures from dMRI provide new understanding about the contribution of myelination to non-specific imaging metrics that are often used to characterise early brain development.

Concurrent transcranial direct current stimulation (tDCS) and proton Magnetic Resonance Spectroscopy (1H MRS) experiments have shown up- or downregulation of neurotransmitter concentration. However, effects have been modest applying mostly lower current doses and not all studies found significant effects. Dose of stimulation might be an important variable in eliciting a consistent response. To investigate dose effects of tDCS on neurometabolites, we placed an electrode over the left supraorbital region (with a return electrode over the right mastoid bone) and utilized an MRS voxel (3x3x3cm) that was centered over the anterior cingulate/inferior mesial prefrontal region which is in the path of the current distribution. We conducted 5 epochs of acquisition, each one with a 9:18min acquisition time, and applied tDCS in the third epoch. We observed significant dose and polarity dependent modulation of GABA and to a lesser degree of Glutamine/Glutamate (GLX) with the highest and reliable changes seen with the highest current dose, 5mA (current density 0.39 mA/cm2), during and after the stimulation epoch compared with pre-stimulation baselines. The strong effect on GABA concentration (achieving a mean change of 63% from baseline, more than twice as much as reported with lower doses of stimulation) establishes tDCS-dose as an important parameter in eliciting a regional brain engagement and response. Furthermore, our experimental design in examining tDCS parameters and effects using shorter epochs of acquisitions might constitute a framework to explore the tDCS parameter space further and establish measures of regional engagement by non-invasive brain-stimulation.

AIMChildren born preterm (PT) experience perinatal white matter injury and later reading deficits at school age. We used two complementary neuroimaging modalities to determine if reading skills would be associated with contemporaneous white matter properties in school-aged PT children. METHODIn 8-year-old PT children (N=29), we measured diffusivity (fractional anisotropy, FA), from diffusion MRI, and myelin content (relaxation rate, R1) from quantitative relaxometry. We assessed reading (Grays Oral Reading Test, Fifth Edition) in each child. Whole-brain deterministic tractography coupled with automatic segmentation and quantification were applied to extract FA and R1 along four tracts and assess their statistical association with reading scores. RESULTSReading-FA correlations were not significant along the four analyzed tracts. Reading-R1 correlations were significantly positive in portions of the left superior longitudinal fasciculus, right uncinate fasciculus, and left inferior longitudinal fasciculus. FA positively correlated with R1 in limited areas of reading-R1 associations, but did not contribute to the variance in reading scores. INTERPRETATIONCombining complementary neuroimaging approaches identified relations between reading and white matter properties not found using a single MRI measure. Associations of reading skills and white matter properties may vary across white matter tracts and metrics in PT children. What this paper adds{blacksquare} Preterm childrens reading was associated with white matter myelin content. {blacksquare}Preterm childrens reading was not associated with white matter diffusivity.

Transcranial direct current stimulation (tDCS) over the prefrontal cortex has the potential to enhance working memory by means of a weak direct current applied to the scalp. However, its effects are highly variable and possibly dependent on individual variability in cortical architecture and head anatomy. Unveiling sources of heterogeneity might improve fundamental and clinical application of tDCS in the field. Therefore, we investigated sources of tDCS variability of prefrontal 1.5mA tDCS, 3mA tDCS and sham tDCS in 40 participants (67.5% women, mean age 24.7 years) by associating simulated electric field (E-field) magnitude in brain regions of interest (dorsolateral prefrontal cortex, anterior cingulate cortex (ACC) and subgenual ACC) and working memory performance. Emotional and non-emotional 3-back paradigms were used. In the tDCS protocol analysis, effects were only significant for the 3mA group, and only for the emotional tasks. In the individual E-field magnitude analysis, faster responses in non-emotional, but not in the emotional task, were associated with stronger E-fields in all brain regions of interest. A follow-up analysis showed that people with higher (vs. lower) E-fields magnitude in the left DLPFC were faster in the both tasks, and more accurate in the emotional task. Concluding, individual E-field distribution might explain part of the variability of prefrontal tDCS effects on working memory performance and in clinical samples. Our results suggest that tDCS effects can be more consistent or improved by applying personalizing current intensity, although this hypothesis should be confirmed by further studies.

Children with attention deficit/hyperactivity disorder (ADHD) frequently display impairments in selective attention. Prior research has identified the dorsolateral prefrontal cortex (dlPFC) as a critical region contributing to these deficits. In this study, we examined the effects of transcranial light stimulation (tLS) over the right dlPFC on selective attention in children with ADHD. In Experiment 1, we modeled photon propagation pathways and attenuation patterns within pediatric cranial structures to determine the optimal stimulation dose, estimating that the effective tLS dosage in children should be approximately 40% of the adult level. In Experiment 2, we applied these parameters in a triple-blind, randomized, crossover clinical trial involving 40 children with ADHD. Active tLS significantly increased the amplitude of the event-related potential (ERP) markers of selective attention and strengthened spatial Selective cortical tuning function (CTF) modulation. These neural changes predicted measurable improvements in attention symptoms over the subsequent following week. In Experiment 3, we further included typically developing (TD) children as a control group and found that the selective attention performance in children with ADHD following active tLS approached the levels observed in TD children. Our findings demonstrate that right dlPFC-targeted tLS enhances selective attention in children with ADHD and produces clinically meaningful improvements in inattention. This study provides novel evidence supporting the potential of tLS as a therapeutic intervention for ADHD.

BackgroundThe left inferior frontal gyrus (IFG) has been shown to be involved in sentence comprehension in many studies through its involvement in both semantic and syntactic computations. However, causal evidence for its involvement in sentence comprehension is scarce. We used transcranial direct current stimulation (tDCS) to test the causal involvement of the left IFG in sentence comprehension in a group of individuals with primary progressive aphasia (PPA). These individuals participated in a tDCS study targeting lexical retrieval only, not sentence comprehension, therefore in the present study we report on far-transfer effects of tDCS in sentence comprehension. ObjectiveWe sought to determine whether tDCS over the left inferior frontal gyrus (IFG) coupled with lexical retrieval treatment may improve sentence comprehension in PPA. MethodWithin a sham-controlled, double-blind design, we tested whether 15 daily sessions of anodal tDCS over the left IFG may improve sentence comprehension in 27 people with PPA, and whether the tDCS effects were sustained up to two months post-treatment. ResultsWe found that immediately post-treatment, and up to 2-months post-treatment, there was significantly larger improvement of sentence comprehension in the tDCS condition compared to sham. There were, however, differential effects of tDCS in each PPA variant and sentence-type. Importantly, participants with the epicenter of atrophy over the stimulated area (non-fluent PPA) benefited most from tDCS. ConclusionTDCS over the left IFG induces far-transfer effects and may improve sentence comprehension in PPA. We provide causal evidence that left IFG is a critical area for sentence comprehension.

IntroductionFunctional magnetic resonance imaging (fMRI) is widely used to study neural processes of behavior, but evaluations of test-retest reliability (TRR) of task-related blood-oxygen-level-dependent (BOLD) responses are scarce for many cognitive tasks. Such information is particularly important for longitudinal and intervention research. The ability to learn associations between choices and outcomes across decision stages is crucial for daily behavior. We assessed the measurement reliability of behavioral performance and fMRI BOLD signals during value-based sequential decision making to evaluate the TRR of task-relevant regions for future research on non-invasive brain stimulations. MethodsTwenty healthy adults (22 to 40 years) completed two task-fMRI sessions that were at least 2 weeks apart. During scanning, participants performed two variants of a three-stage Markov decision task with conditions varied in temporal contingency (immediate vs. delayed) and magnitude of choice outcomes (high vs. low). Both sessions were conducted under sham tDCS via a focal 3 x 1 montage targeting left dorsolateral prefrontal cortex (DLPFC). The TRR was assessed using intraclass correlation coefficients (ICC) with a two-way mixed-effects consistency model for decision performance and task-related fMRI signals at voxel-wise level and summarized in key regions defined by the extended Human Connectome Project atlas (HCPex). ResultsDecision performance was lower with delayed than immediate outcomes (p < 0.001). Higher outcome magnitude improved performance (p < 0.001). Decision performance increased across learning bins (p < 0.001). The behavioral TRR was in the moderate to good level (ICC(3,1) = 0.742 for accuracy; ICC(3,1) = 0.801 for reaction time). At the whole-brain level, contrasting brain activities in delayed with immediate condition revealed suprathreshold cluster peaks in several frontal-parietal (e.g., bilateral orbitofrontal, bilateral dorsolateral prefrontal, and medial parietal cortices) and striatal regions (e.g., bilateral putamen). Voxel-wise ICCs revealed variable but partly good-to-excellent TRR across task-relevant regions, with stronger reliability in several striatal, orbitofrontal, and left dorsolateral prefrontal parcels, and more variable reliability across anterior cingulate and medial prefrontal parcels. ConclusionThese results from a 2-session tDCS sham-sham stimulation study establish the validity of using the three-stage Markov decision task in future studies about intervention effects on the frontal-parietal-striatal network.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSFragile X syndrome (FXS) is the most prevalent form of inherited intellectual disability and is the most common monogenetic cause of autism. Previous studies have linked the structural and functional alterations in FXS with impaired sensory processing and sensory hypersensitivity, which may hinder the early development of cognitive functions such as language comprehension. In this study, we compared the P1 response in event-related potential (ERP) and its habituation to repeated auditory stimuli in male children (2-7 years old) with and without FXS, and examined their association with clinical measures in these two groups. MethodsWe collected high-density electroencephalography (EEG) data in an auditory oddball paradigm from 12 children with FXS and 11 age- and sex-matched typically developing (TD) children. After standardized EEG pre-processing, we conducted a spatial principal component (PC) analysis and identified two major PCs -- a frontal PC and a temporal PC. Within each PC, we compared the P1 amplitude and inter-trial phase coherence (ITPC) between the two groups, and performed a series of linear regression analysis to study the association between these EEG measures and several clinical measures, including assessment scores for language development, non-verbal skills, and sensory hypersensitivity. ResultsAt the temporal PC, both early and late standard stimuli evoked a larger P1 response (p = 0.0037, p<0.0001, respectively) and higher ITPC (p = 0.0402, p = 0.0027) in FXS than in TD. We observed habituation of ITPC in both groups at the frontal PC (p = 0.0149 for FXS; p = 0.0244 for TD). Linear regression analysis showed that within the FXS group reduced frontal P1 response to late standard stimuli and increased habituation were associated with better languages scores. No associations were observed with non-verbal skills or sensory hypersensitivity. ConclusionWe identified P1 amplitude and ITPC in the temporal region as a contrasting EEG phenotype between the FXS and the TD groups. P1 response and habituation in the frontal region may be reflective of the language outcome in male children with FXS. These EEG measures are potential biomarkers for early diagnosis and future language development in patients with FXS.

ObjectiveThe aim of this pilot study was to assess associations of prenatal alcohol exposure (PAE), prenatal tobacco exposure (PTE), and their interaction and quantity on subsequent cortical and subcortical measures at age 6 years. MethodsMothers with varying levels of alcohol and tobacco exposure at different trimesters during pregnancy were approached when their children (born participating in the Safe Passage Study) were approximately 6 years old. 72 mothers agreed to participate, and 51 children completed brain magnetic resonance imaging (MRI). Brain regions of interest (ROIs) that were significantly associated prior to multiple comparison testing, were examined for associations related to exposure quantity, frequency, and timing (QFT), to explore how patterns of PAE and PTE influence brain outcomes in children. Linear regression was used to identify associations between PAE, PTE, and their interaction with cortical (n = 68 ROIs) and subcortical (n = 40 ROIs) measures. ResultsPrior to correction for multiple comparison testing, both PAE and PTE, as well as their interaction, were associated with a range of cortical and subcortical measures. However, none of these findings survived correction for multiple comparisons. Nevertheless, when exploring quantity of PAE, the total amount of standard drinks consumed during pregnancy and the average number of drinks per drinking day were positively associated with cortical volume in the right fusiform gyrus. ConclusionThese trend results in this pilot study provide preliminary evidence that PAE impacts brain development in unique ways from PTE, and their interactive co-exposure is not a straight forward synergistic or additive effect on the brain.

BackgroundUnderstanding the neurobiology behind Fragile X syndrome (FXS) is critical in identifying effective therapeutics and improving care for affected individuals. Electroencephalography (EEG) provides an opportunity to investigate the biological foundations of this disorder. We aimed to characterize the visual evoked potential (VEP) in young children with FXS, and to understand how measures of the VEP are associated with verbal and nonverbal development within FXS. MethodsVEPs were collected in children between 2-7 years old with FXS (n = 9) as well as corresponding age-(n = 10) and cognitive-matched (n = 9) typically developing children. Additionally, the Mullen Scales of Early Learning and Preschool Language Scales were administered to collect measures of verbal and nonverbal development. Differences in component amplitudes and latencies of the VEP were assessed using ANCOVAs, and associations of VEP measures and verbal and nonverbal development were evaluated using linear regression with age as a covariate. ResultsNo differences between groups were observed in N1, P1, or N2 VEP components. However, a consistent and prominent P2 component (latency = 177ms {+/-} 13.7), was observed in children with FXS. The P2 amplitude was significantly increased in FXS children compared to the cognitive-matched group (p = 0.004). For children with FXS, the amplitude of several VEP components were associated with verbal and nonverbal development; larger N1 amplitude and smaller P1 and P2 amplitudes were all associated with better receptive language (all p<0.05) and larger N1 amplitude was also associated with better fine motor skills (p<0.05). ConclusionsThe observed increase in P2 amplitude and its negative association with language development within the FXS group supports the P2 component as a potential biomarker for FXS as a disorder, as well as a pathophysiological marker of verbal impairment that could be used in clinical trials.

Auditory processing disorder (APD) is a listening impairment that some school-aged children may experience as difficulty understanding speech in background noise despite having normal peripheral hearing. Recent resting-state functional magnetic resonance imaging (MRI) has revealed an alteration in regional, but not global, functional brain topology in children with APD. However, little is known about the brain structural organization in APD. We used diffusion MRI data to investigate the structural white matter connectome of 58 children from 8 to 14 years old diagnosed with APD (n=29) and children without hearing complaints (healthy controls, HC; n=29). We investigated the rich-club organization and structural connection differences between APD and HC groups using the network science approach. The APD group showed neither edge-based connectivity differences nor any differences in rich-club organization and connectivity strength (i.e., rich, feeder, local connections) compared to HCs. However, at the regional network level, we observed increased average path length (APL) and betweenness centrality in the right inferior parietal lobule and inferior precentral gyrus, respectively, in children with APD. HCs demonstrated a positive association between APL in the left orbital gyrus and the listening-in-spatialized-noise-sentences task, a measure of auditory processing ability. This correlation was not observed in the APD group. In line with previous functional connectome findings, the current results provide evidence for altered structural networks at a regional level in children with APD, and an association with listening performance, suggesting the involvement of multimodal deficits and a role for structure-function alteration in listening difficulties of children with APD.

In recent years, there has been debate about the effectiveness of treatments from different fields, such as neurostimulation, neurofeedback, brain training, and pharmacotherapy. This debate has been fuelled by contradictory and nuanced experimental findings. Notably, the effectiveness of a given treatment is commonly evaluated by comparing the effect of the active treatment versus the placebo on human health and/or behaviour. However, this approach neglects the individuals subjective experience of the type of treatment s/he received in establishing treatment efficacy. Here, we show that individual differences in subjective treatment--the thought of receiving the active or placebo condition during an experiment--can explain variability in outcomes better than the actual treatment. We analysed four independent datasets (N=387 participants), including clinical patients and healthy adults from different age groups who were exposed to different neurostimulation treatments (transcranial magnetic stimulation: Study 1 & 2; transcranial direct current stimulation: Study 3 & 4). Our findings show that the inclusion of subjective treatment can provide a better model fit, either alone or in interaction with objective treatment (defined as the condition to which participants are assigned in the experiment). These results demonstrate the significant contribution of subjective experience in explaining the variability of clinical, cognitive and behavioural outcomes. We advocate for existing and future studies in clinical and non-clinical research to start accounting for participants subjective beliefs and their interplay with objective treatment when assessing the efficacy of treatments. This approach will be crucial in providing a more accurate estimation of the treatment effect and its source, allowing the development of effective and reproducible interventions. Significance statementWe demonstrate that individual differences in subjective treatment--the belief of receiving the active or placebo condition during an experiment--can explain variability in research outcomes better than objective treatment, the actual treatment to which participants are assigned. Even though it is a standard practice for intervention studies to collect data on subjective treatment, its contribution to research outcomes has been overlooked. By demonstrating the explanatory power of subjective treatment beyond objective treatment in four independent datasets, we show its potential to provide further insights into the effectiveness of different interventions. We, therefore, encourage researchers to adopt our approach in existing and new studies, to improve experimental design and ultimately increase the rigour and robustness of clinical and non-clinical interventions.

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder involving nutritional, endocrine /metabolic, emotional and behavior dimensions. There is evidence for impaired hypothalamic development and function in PWS, involving oxytocin and ghrelin, which can account for the typical PWS phenotype. Hyperphagia with addiction-like behavior is one of the common features of PWS and is a consequence of the hypothalamic dysfunction. In this study, we hypothesized that brain regions associated with compulsive eating behavior would be abnormally activated by food-related odors in PWS, as these can stimulate the appetite and induce hunger-related behavior. MethodsWe used a classic olfactory discrimination test to verify that olfaction was normal in patients with PWS. In an fMRI scanner, we presented two odors, a tulip and a caramel odor, which have a different hedonic valence and a different capacity to arouse hunger-related behavior. ResultsThere was a five-fold higher activation in the right amygdala for the caramel odor compared with the tulip odor in patients with PWS (n=14). No such hyperactivation was found in age-matched controls (n=11). Cluster analysis of clinical hyperphagia scores in patients with PWS revealed a link with the right amygdala hyperactivation. ConclusionsOur study provides evidence for functional alteration of the right amygdala in PWS, which is part of the brain reward network involved in food addiction. This finding may relate to dysfunction of the ghrelin and oxytocin systems in PWS, as these are involved in addictive behavior, appetite, and olfactory bulb regulation.

BackgroundNeurofibromatosis-1 (NF1) is an autosomal dominant neurodevelopmental condition commonly characterised by learning difficulties, with co-occurring autism spectrum conditions in 30% and attention deficit hyperactivity disorder in about 50% of affected school-age children. The structural brain phenotype characteristically shows T2-white matter hyperintensities, particularly in the thalamus and basal ganglia, and previous diffusion MRI studies have demonstrated widespread white matter microstructural differences, suggesting aberrant myelination in NF1. However, no previous studies have investigated quantitative myelin in NF1. The aim of this study is to compare quantitative myelination in NF1 compared to neurotypical controls, and examine the relationship between myelin and working memory performance in children with NF1. Methods and materialsThe T1-weighted and T2-weighted structural MRI images were acquired from 48 children and adolescents with NF1 aged 11-18 years. These were compared to data from 168 age- and gender-matched neurotypical controls drawn from the Human Connectome Project. Visuospatial n-back tasks were used to measure the working memory performance in the NF1 cohort. Pituitary depth was used as a covariate to control for pubertal differences. ResultsCompared to neurotypicals, children with NF1 showed significantly reduced grey matter/white matter myelin ratios both throughout the brain and within each of the four major cerebral lobes. The stratified age-related whole-brain myelin differences were reduced in NF1 relative to controls. The sex-related whole-brain myelin differences were found to be greater in females than in males. However, no significant correlation was found between myelin and working memory performance in NF1. Pituitary depth was reduced in NF1 relative to controls. ConclusionThe reduced grey matter/white matter (GM/WM) myelin ratios in the whole brain and the frontal, temporal, parietal and occipital lobes suggests a widespread disruption of cerebral myelination in NF1. The age and sex-related myelin differences, and associated differences in developmental trajectories, may occur due to the effects of gonadal hormones but needs to be examined in future studies.