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Attention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood neurodevelopmental disorder. Given the profound brain changes that occur across childhood and adolescence, it is important to identify functional networks that exhibit differential developmental patterns in children with ADHD. This study sought to examine whether children with ADHD exhibit differential developmental trajectories in functional connectivity compared with typically developing children using a network-based approach.This longitudinal neuroimaging study included 175 participants (91 children with ADHD and 84 control children without ADHD) between ages 9 and 14 and up to 3 waves (173 total resting-state scans in children with ADHD and 197 scans in control children). We adopted network-based statistics to identify connected components with trajectories of development that differed between groups.Children with ADHD exhibited differential developmental trajectories compared with typically developing control children in networks connecting cortical and limbic regions as well as between visual and higher-order cognitive regions. A pattern of reduction in functional connectivity between corticolimbic networks was seen across development in the control group that was not present in the ADHD group. Conversely, the ADHD group showed a significant decrease in connectivity between predominantly visual and higher-order cognitive networks that was not displayed in the control group.Our findings show that the developmental trajectories in children with ADHD are characterized by a subnetwork involving different trajectories predominantly between corticolimbic regions and between visual and higher-order cognitive network connections. These findings highlight the importance of examining the longitudinal maturational course to understand the development of functional connectivity networks in children with ADHD.

Sustained attention is a cognitive function with known links to academic success and mental health disorders such as attention/deficit-hyperactivity disorder (ADHD). Several functional networks are critical to sustained attention, however the association between white matter maturation in tracts linking functional nodes and sustained attention in typical and atypical development is unknown. 309 diffusion-weighted imaging scans were acquired from 161 children and adolescents (80 ADHD, 81 control) at up to three timepoints over ages 9-14. A fixel-based analysis approach was used to calculate mean fiber density and fiber-bundle cross section in tracts of interest. Sustained attention was measured using omission errors and response time variability on the out-of-scanner sustained attention to response task. Linear mixed effects models examined associations of age, group and white matter metrics with sustained attention. Greater fiber density in the bilateral superior longitudinal fasciculus (SLF) I and right SLF II was associated with fewer attention errors in the control group only. In ADHD and control groups, greater fiber density in the left ILF and right thalamo-premotor pathway, as well as greater fiber cross-section in the left SLF I and II and right SLF III, was associated with better sustained attention. Relationships were consistent across the age span. Results suggest that greater axon diameter or number in the dorsal and middle SLF may facilitate sustained attention in neurotypical children but does not assist those with ADHD potentially due to disorder-related alterations in this region. Greater capacity for information transfer across the SLF was associated with attention maintenance in 9-14-year-olds regardless of diagnostic status, suggesting white matter macrostructure may also be important for attention maintenance. White matter and sustained attention associations were consistent across the longitudinal study, according with the stability of structural organization over this time. Future studies can investigate modifiability of white matter properties through ADHD medications.

Irritability has been associated with aberrant patterns of neural activation, yet little is known about structural brain correlates of irritability. As such, we aimed to investigate associations between irritability and gray matter volume (GMV) in a community sample of children enriched for irritability. The sample comprised children (n=162) aged 9-11 years with and without Attention-Deficit/Hyperactivity Disorder (ADHD), participating in a cohort study with magnetic resonance imaging data available. Mixed effects linear regression analyses tested the associations between irritability symptoms and regional GMV (extracted using Freesurfer). Irritability was associated with smaller gray matter volume across multiple brain regions implicated in executive functioning, and emotion and reward processing including frontal regions and the cingulate.

Previous Diffusion Tensor Imaging (DTI) studies in children suggest that developmental improvements in inhibitory control is largely mediated by the degree of white matter organisation within a right-lateralised network of fronto-basal-ganglia regions. Recent advances in diffusion imaging analysis now permit greater biological specificity, both in identifying specific fibre populations within a voxel, as well as in the underlying microstructural properties of that white matter. In the present work, employing a novel fixel-based analysis (FBA) framework, we aimed to comprehensively investigate microstructure within the fronto-basal-ganglia circuit in childhood, and its contribution to inhibition performance. Diffusion MRI data were obtained from 43 healthy children and adolescents aged 9–11 years (10.42 ± .41 years, 18 females). Response inhibition for each participant was assessed using the Stop-signal Task (SST) and quantified as a Stop–Signal Reaction Time (SSRT). All steps relevant to FBA were implemented in MRtrix3Tissue, a fork of the MRtrix3 software library. The fronto-basal-ganglia circuit were delineated using probabilistic tractography to identify the tracts connecting the subthalamic nucleus, pre-supplementary motor area and the inferior frontal gyrus. Connectivity-based fixel enhancement (CFE) was then used to assess the association between fibre density (FD) and fibre cross-section (FC) with inhibitory ability. Significant negative associations were identified for FD in both the right and left fronto-basal-ganglia circuit whereby greater FD was associated with better inhibition performance (e.g., reduced SSRTs). This effect was specifically localised to clusters of fixels within white matter proximal to the right subthalamic nucleus. We did not report any meaningful associations between SSRT and FC. Whilst findings are broadly consistent with prior DTI evidence, current results suggest that SSRT is predominantly facilitated by subcortical microstructure of the connections projecting from the subthalamic nucleus to the cortical regions of the network. Our findings extend current understanding of the role of white matter in childhood response inhibition.

Disruptive mood dysregulation disorder (DMDD) is common in children with ADHD yet it is not known how persistent DMDD is in this population. As such we aimed to investigate the persistence of disruptive mood dysregulation disorder (DMDD) in a community sample of children with ADHD. The sample comprised children (n = 136) participating in a cohort study with data available at age 7 and age 10. DMDD status was ascertained using proxy items from the Diagnostic Interview Schedule for Children, Version IV. Of those with DMDD at age 7 (n = 30), eight (21.1%) had DMDD that persisted at age 10. In the first study investigating the longitudinal course of DMDD in ADHD one in five children with ADHD+DMDD at age 7 continued to meet diagnostic criteria for DMDD three years later.

Vigilant Attention (VA), defined as the ability to maintain attention to cognitively unchallenging activities over a prolonged period of time, is critical to support higher cognitive functions and many behaviours in our everyday life. Evidence has shown that VA rapidly improves throughout childhood and adolescence until young adulthood and tends to decline in older adulthood. Although neuroimaging studies have extensively investigated this cognitive function in adults, the neural correlates of VA in neurotypical children and adolescents remain unclear. The current meta-analysis reviewed and examined functional neuroimaging studies in paediatric populations that used behavioural tasks involving VA. The selected studies (N = 25) were analyzed using the activation likelihood estimation method. Findings showed convergence of activation in mainly right-lateralized brain areas, including dorsomedial frontal cortex and parieto-temporal areas, and are consistent with previous literature on the neural correlates of VA. Results are discussed in terms of their functional and developmental implications for VA in children and adolescents.

Purpose White matter fibre development in childhood involves dynamic changes to microstructural organisation driven by increasing axon diameter, density, and myelination. However, there is a lack of longitudinal studies that have quantified advanced diffusion metrics to identify regions of accelerated fibre maturation, particularly across the early pubertal period. We applied a novel longitudinal fixel-based analysis (FBA) framework, in order to estimate microscopic and macroscopic white matter changes over time. Methods Diffusion-weighted imaging (DWI) data were acquired for 59 typically developing children (27 female) aged 9–13 years at two time-points approximately 16 months apart (time-point 1: 10.4 ± 0.4 years, time-point 2: 11.7 ± 0.5 years). Whole brain FBA was performed using the connectivity-based fixel enhancement method, to assess longitudinal changes in fibre microscopic density and macroscopic morphological measures, and how these changes are related to sex, pubertal stage, and pubertal progression. Follow-up analyses were performed in sub-regions of the corpus callosum to confirm the main findings using a Bayesian repeated measures approach. Results There was a statistically significant increase in fibre density over time localised to medial and posterior commissural and association fibres, including the forceps major and bilateral superior longitudinal fasciculus. Increases in fibre cross-section were substantially more widespread. The rate of fibre development was not associated with age or sex. In addition, there was no significant relationship between pubertal stage or progression and longitudinal fibre development over time. Follow-up Bayesian analyses were performed to confirm the findings, which supported the null effect of the longitudinal pubertal comparison. Conclusion Using a novel longitudinal fixel-based analysis framework, we demonstrate that white matter fibre density and fibre cross-section increased within a 16-month scan rescan period in specific regions. The observed increases might reflect increasing axonal diameter or axon count. Pubertal stage or progression did not influence the rate of fibre development in the early stages of puberty. Future work should focus on quantifying these measures across a wider age range to capture the full spectrum of fibre development across the pubertal period.

Children with attention-deficit/hyperactivity disorder (ADHD) have poor academic functioning compared to typically developing children, with executive dysfunction mediating the relationship between ADHD symptoms and academic outcomes. This study investigated whether differences in prefrontal and frontostriatal structures explain this mediating relationship. 132 children aged 9–11 years (mean 10.4 years) completed a MRI including structural and diffusion acquisitions. Cortical regions were parcellated using Freesurfer. Frontostriatal tracts were generated using constrained spherical deconvolution (CSD) tractography. Executive functioning was assessed using working memory, sustained attention and response inhibition tasks. Academic achievement was measured by direct assessment of reading and mathematics, teacher report of academic competence, and national standardized academic testing. Serial mediation analysis tested whether executive function and frontostriatal structures mediate the poorer academic functioning seen in ADHD. Symptom severity (predominantly inattention) was associated with poorer academic outcomes. Working memory partially mediated the relationship between symptoms and academic outcomes. In a serial mediation model, left DLPFC volume, right orbitofrontal volume, and left striatal structures to DLPFC tract volumes partially mediated academic outcome. This study suggests that variability in frontostriatal structures explain the mediating effect of cognitive performance on the relationship between ADHD symptomatology and academic outcomes.

The development of Vigilant Attention (VA), the ability to focus and maintain our attention to repetitive and cognitively unchallenging tasks over time, has been investigated for more than a decade. The development of this critical executive function across the lifespan has been characterised by a rapid improvement in VA performance throughout childhood and adolescence, a steady improvement in adulthood and a slow decline in older adulthood. However, the development of the neural correlates of VA in children and adolescents remains poorly understood. Using a cross-sectional design, the present study used a meta-analytically defined VA network in children and adolescents to explore the developmental trend of the resting-state functional connectivity (rsFC) within the VA network across two independent cohorts. The results showed a linear and non-linear decrease of rsFC between the left and right VA brain regions across age. However, the results could not be reproduced in the replication cohort, potentially due to a smaller sample size. Based on previous findings from behavioural studies, the present findings suggest that changes in rsFC may underlie a developmental shift in cognitive strategies in neurotypical children and adolescents.

Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organisation. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "fixel-based analysis" (FBA) framework that implements bespoke solutions to this end, and has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to fixel-based analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of current fixel-based analysis studies (until August 2020), categorised across a broad range of neuroscientific domains, listing key design choices and summarising their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the fixel-based analysis framework, and outline some directions and future opportunities.

Background Persistent depressive symptoms in children and adolescents are considered a risk factor for the development of major depressive disorder (MDD) later in life. Previous research has shown alterations in white matter microstructure in pediatric MDD but discrepancies exist as to the specific tracts affected. The current study aimed to improve upon previous methodology and address the question whether previous findings of lower fractional anisotropy (FA) replicate in a sample of children with persistent depressive disorder characterized by mild but more chronic symptoms of depression. Methods White matter microstructure was examined in 25 boys with persistent depressive disorder and 25 typically developing children. Tract specific analysis implemented with the Diffusion Tensor Imaging - ToolKit (DTI-TK) was used to probe fractional anisotropy (FA) in eleven major white matter tracts. Results Clusters within the left uncinate, inferior fronto-occipital and cerebrospinal tracts showed lower FA in the clinical group. FA in the left uncinate showed a negative association with self-reported symptoms of depression. Conclusions The results demonstrate lower FA in several white matter tracts in children with persistent depressive disorder. These findings support the contention that early onset depression is associated with altered white matter microstructure, which may contribute to the maintenance and recurrence of symptoms.

Recent neurodevelopmental research supports the contribution of pubertal stage to local and global grey and white matter remodelling. Little is known, however, about white matter microstructural alterations at pubertal onset. This study investigated differences in white matter properties between pre-pubertal and pubertal children using whole brain fixel-based analysis (FBA) of the microscopic density and macroscopic cross-section of fibre bundles. Diffusion-weighted imaging data were acquired for 74 typically developing children (M=10.4, SD=0.43 years, 31 female) at 3.0T (60 diffusion gradient directions, b-value=2800 s/mm 2 ). Group comparisons of fibre density (FD) and fibre cross-section (FC) were made between age-matched pre-pubertal and pubertal groups, and post-hoc analyses were performed on regions of interest (ROIs) defined in the splenium, body and genu of the corpus callosum. Significant fixel-wise differences in FD were observed between the pubertal groups, where the pubertal group had significantly higher FD compared with age-matched pre-pubertal children, localised to the posterior corpus callosum. Post-hoc analyses on mean FD in the corpus callosum ROIs revealed group differences between the pubertal groups in the splenium, but not body or genu. The observed higher apparent fibre density in the splenium suggests that pubertal onset coincides with white matter differences explained by increasing axon diameter. This may be an important effect to account for over pubertal development, particularly for group studies where age-matched clinical and typical populations may be at various stages of puberty.

Aims Children with attention deficit hyperactivity disorder (ADHD) often present with deficits in fine motor control. The cortico-spinal tract (CST) is critical for voluntary motor control. Although neuroimaging work has identified anomalous microstructural properties in the CST in ADHD, no study to date has attempted to investigate the link between deficits in fine motor performance and microstructural properties of the CST in children with ADHD. This study aimed to address this gap using a novel fixel-based analysis (FBA). Methods Participants were 50 right-handed medication naive children with a history of ADHD and 56 non-ADHD controls aged 9–11 years. Fine motor control was assessed using the Grooved Pegboard task. Children underwent high angular resolution diffusion MRI. Following pre-processing, FBA was performed and the semi-automated deep-learning TractSeg was used to delineate the CST bilaterally. Fibre density (FD), fibre cross-section (FC-log), and fibre density/cross-section (FDC) were extracted for each tract. Results Children with ADHD performed significantly worse than non-ADHD children on the Grooved Pegboard task when using their non-dominant hand. They also demonstrated widespread significantly lower diffusion metrics in both CSTs compared to non-ADHD controls. However, no correlations were observed between Grooved Pegboard performance and diffusion metrics for the CST in either hemisphere. Conclusions While we failed to detect a significant relationship between fine motor skill and FBA metrics in either group, this paper extends previous work by showing that children with ADHD and reduced fine motor competence demonstrate atypical microstructure within the CST relative to non-ADHD controls.

Attention-deficit/hyperactivity disorder (ADHD) has reliably been associated with global grey matter reductions but local alterations are largely inconsistent with perhaps the exception of the caudate nucleus. The aim of this study was to examine local and global brain volume differences between typically developing children (TD) and children with a diagnosis of ADHD. We also addressed whether these parameters would differ between children with the ADHD-combined type (ADHD-C) and those with the ADHD-inattentive type (ADHD-I). Using an ROI approach caudate volume differences were also examined. 79 boys between the ages of 8 and 17 participated in the study. Of those 33 met diagnostic criteria for the ADHD-C and 15 for the ADHD-I subtype. 31 boys were included in the TD group. Structural magnetic resonance imaging data were analysed using voxel-based morphometry. The ADHD group had significantly lower global and local grey matter volumes within clusters in the bilateral frontal, right parietal and right temporal regions compared to TD. A significant group by age interaction was found for right caudate nucleus volume. No differences between the ADHD-C and ADHD-I groups were found. Right caudate nucleus volume and age are more strongly related in ADHD than in TD consistent with previous research.

Although many functional magnetic resonance imaging (fMRI) studies have investigated the neurophysiology of attention deficit hyperactivity disorder (ADHD), the existing studies have not yielded consistent findings. This may be related to the different properties of different frequency bands. To investigate the frequency-specific regional homogeneity (ReHo) of spontaneous neural activities in ADHD, the current study used resting-state fMRI to explore the ReHo properties of five frequency bands, slow-5 (0.01–0.027 Hz), slow-4 (0.027–0.073 Hz), slow-3 (0.073–0.198 Hz), slow-2 (0.198–0.25 Hz) and the extra-low frequency (0–0.01 Hz), in 30 drug-naive boys with ADHD and 30 healthy controls. Compared with controls, the ADHD group showed decreased ReHo in the default mode network (DMN) including the medial prefrontal cortex and precuneus, middle frontal gyrus and angular gyrus. ADHD patients also showed increased ReHo in the posterior cerebellum. Significant interactions between frequency band and group were observed predominantly in the dorsolateral prefrontal and parietal cortices, orbital frontal cortex, supplementary motor area, inferior occipital gyrus, thalamus and anterior cerebellum. In particular, we found that the between-group difference in the extra-low frequency band (0–0.01 Hz) seemed to be greater than that in the other frequency bands for most brain regions. The findings suggest that ADHD children display widespread abnormalities in regional brain activity, particularly in the DMN and attention network, and these abnormalities show frequency specificity.

Purpose Despite the important role of manual dexterity in child development, the neurobiological mechanisms associated with manual dexterity in childhood remain unclear. We leveraged fixel-based analysis (FBA) to examine the longitudinal association between manual dexterity and the development of white matter structural properties in the corticospinal tract (CST). Methods High angular diffusion weighted imaging (HARDI) data were acquired for 44 right-handed typically developing children (22 female) aged 9-13 across two timepoints (timepoint 1: mean age 10.5 years ± 0.5 years, timepoint 2: 11.8 ± 0.5 years). Manual dexterity was assessed using the Grooved Pegboard Test, a widely used measure of manual dexterity. FBA-derived measures of fiber density and morphology were generated for the CST at each timepoint. Connectivity-based fixel enhancement and mixed linear modelling were used to examine the longitudinal association between manual dexterity and white matter structural properties of the CST. Results Longitudinal mixed effects models showed that greater manual dexterity of the dominant hand was associated with increased fiber cross-section in the contralateral CST. Analyses further demonstrated that the rate of improvement in manual dexterity was associated with the rate of increase in fiber cross-section in the contralateral CST between the two timepoints. Conclusion Our longitudinal data suggest that the development of manual dexterity in late childhood is associated with maturation of the CST. These findings significantly enhance our understanding of the neurobiological systems that subserve fine motor development and provide an important step toward mapping normative trajectories of fine motor function against microstructural and morphological development in childhood.

© 2019 Elsevier Inc. Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.

Background Dysthymic disorder (DD) is a depressive disorder characterised by persistent low and/or irritable mood and has been identified as a major risk factor for developing major depressive disorder (MDD). MDD and DD have been associated with executive function difficulties of working memory and attention. Little is known about how executive function networks in the brain are affected in children and adolescents with MDD and even less in DD. This study used fMRI and two spatial working memory paradigms to investigate associated brain function in young people with DD and an age-, gender- and IQ- matched typically developing group. Methods Nineteen male patients with DD (mean age 11.2±1.5 years) diagnosed according to DSM-IV criteria and 16 typically developing boys (mean age 10.5±1.1 years) performed a mental rotation and a delay-match to sample (DMTS) task while undergoing fMRI. All participants were medication-naive at the time of testing. Results Compared to typically developing young people, the DD group showed less activation in left frontal regions including left ventro- and dorsolateral prefrontal cortices (PFC) during mental rotation. Medial frontal regions including dorsomedial PFC, anterior cingulate cortex and frontal pole also showed relatively reduced activation. During the DMTS task patients showed significantly more activation in the right precuneus and posterior cingulate cortex. Limitations This was a cross-sectional study with a small sample limiting the generalizability of the results. Conclusions The results complement previous findings in adults with MDD that have shown differential activation of left PFC regions during working memory tasks. Additionally, altered function of cortical midline structures in young patients with DD was identified. This supports findings in children, adolescents and adults with MDD suggesting that the pathophysiology of depressive disorders extends to DD as a risk factor for MDD and exhibits continuity over the lifespan.

Atypical asymmetries of spatial attention have been reported in children with attention deficit hyperactivity disorder (ADHD) and may be exacerbated by non-spatial factors such as attentional capacity. Although preliminary evidence suggests that asymmetries of attention in ADHD may be modifiable by the psychostimulant, methylphenidate, further placebo-controlled studies are required. This study first aimed to confirm recent evidence that increasing non-spatial processing load at fixation can unmask a spatial gradient of target detection in children with ADHD but not Controls. Second, we used placebo-controlled randomised trial methodology to ask whether 20 mg of methylphenidate (MPH) could remediate any load-dependent asymmetry of spatial attention in adolescents with ADHD. Twelve male adolescents with ADHD were assessed twice in a double-blind, randomized design, under either placebo or an acute dose of methylphenidate. Thirteen typically developing adolescent Controls completed a single session under placebo. Participants completed a computer-based task in which they monitored a centrally presented rapid serial visual presentation stream for a probe stimulus, while also responding to brief peripheral events. The attentional load of the central task was manipulated by varying the target instructions but not the physical stimuli or the frequency of targets. Between-group analyses under placebo conditions indicated that increased attentional load induced a spatial gradient for target detection in the ADHD but not Controls, such that load slowed response times for left, but not, right hemi-field targets. This load-dependent spatial asymmetry in the adolescents with ADHD was abolished by administration of methylphenidate. Methylphenidate may “normalise” target detection between the hemi-fields in ADHD via enhancement of the right-lateralised ventral attention networks that support non-spatial attention.

Obsessive-compulsive disorder (OCD) is a chronic, relapsing anxiety disorder. To date, neuroimaging investigations of OCD have been variable and few studies have examined paediatric populations. Eight children with OCD and 12 typically developing children matched for age, gender, handedness and performance IQ underwent a high resolution T1-weighted structural magnetic resonance imaging (MRI) scan. A voxel-based morphometry (VBM) protocol (using DARTEL) compared the brains of the paediatric OCD children with those of typically developing children. Overall, children with OCD demonstrated significantly lower intra-cranial volume (ICV) and grey- and white-matter volumes. ICV was significantly reduced (∼9%) in the OCD group compared with the typically developing group. The VBM analysis demonstrated lower volumes in widespread grey matter in bilateral frontal, cingulate, temporal-parietal, occipital-frontal and right precuneus regions for OCD. Lower white matter volume was found bilaterally in the cingulate and occipital cortex, right frontal and parietal and left temporal regions, and the corpus callosum. In summary, this study provides further evidence of brain dysmorphology in paediatric OCD patients. In addition to fronto-striatal-thalamic neural networks, abnormalities in other brain regions, such as the parietal lobe and corpus callosum, were demonstrated. These brain regions may play an additional role in the pathophysiology of OCD.

Our ability to remember locations in space (spatial working memory) and our ability to direct attention to those locations (spatial attention) are two fundamental and closely related cognitive processes. A growing body of behavioural evidence suggests that spatial working memory and spatial attention share common resources, while neuroimaging studies show some overlap in the neural regions that mediate these two cognitive functions. The current study used fMRI to directly examine the extent to which spatial working memory and spatial attention rely on common underlying neural mechanisms. Twenty healthy participants underwent functional MRI while performing a dual task of spatial working memory incorporating a visual search task during the working memory retention interval. Working memory and visual search task loads were parametrically modulated. A wide network of prefrontal, premotor, and parietal regions showed increasing activity with increased spatial working memory load. Of these areas, part of the right supramarginal gyrus, lying along the intraparietal sulcus, showed a significant interaction such that the neural activity associated with spatial working memory load was significantly attenuated as visual search load in the dual task was increased. This interaction suggests that this part of the supramarginal gyrus, along the intraparietal sulcus, is critical for mediating both spatial working memory and shifts in spatial attention.