Physical exercise, besides improving cognitive and mental health, is known to cause structural changes in the brain. Understanding the structural changes that occur with exercise as well as the neuroanatomical correlates of a predisposition for exercise is important for understanding human health. This study used high-resolution 3D MR imaging, in combination with deformation-based morphometry, to investigate the macroscopic changes in brain structure that occur in healthy adult mice following four weeks of voluntary exercise. We found that exercise induced changes in multiple brain structures that are involved in motor function and learning and memory including the hippocampus, dentate gyrus, stratum granulosum of the dentate gyrus, cingulate cortex, olivary complex, inferior cerebellar peduncle and regions of the cerebellum. In addition, a number of brain structures, including the hippocampus, striatum and pons, when measured on MRI prior to the start of exercise were highly predictive of subsequent exercise activity. Exercise tended to normalize these pre-existing differences between mice.

Choosing one's preferred hypothesis requires multiple brain regions to work in concert as a functionally connected network. We predicted that a stronger network signal would underlie cognitive coherence between a hypothesis and the available evidence. In order to identify such functionally connected networks in magnetoencephalography (MEG) data, we first localized the generators of changes in oscillatory power within three frequency bands, namely alpha (7-13 Hz), beta (18-24 Hz), and theta (3-7 Hz), with a spatial resolution of 5mm and temporal resolution of 50 ms. We then used principal component analysis (PCA) to identify functionally connected networks reflecting co-varying post-stimulus changes in power. As predicted, PCA revealed a functionally connected network with a stronger signal when the evidence supported accepting the hypothesis being judged. This difference was driven by beta-band power decreases in the left dorsolateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex (VMPFC), posterior cingulate cortex (PCC), and midline occipital cortex.

Accurate automated quantification of subcortical structures is a greatly pursued endeavour in neuroimaging. In an effort to establish the validity and reliability of these methods in defining the striatum, globus pallidus, and thalamus, we investigated differences in volumetry between manual delineation and automated segmentations derived by widely used FreeSurfer and FSL packages, and a more recent segmentation method, the MAGeT-Brain algorithm. In a first set of experiments, the basal ganglia and thalamus of thirty subjects (15 first episode psychosis [FEP], 15 controls) were manually defined and compared to the labels generated by the three automated methods. Our results suggest that all methods overestimate volumes compared to the manually derived "gold standard", with the least pronounced differences produced using MAGeT. The least between-method variability was noted for the striatum, whereas marked differences between manual segmentation and MAGeT compared to FreeSurfer and FSL emerged for the globus pallidus and thalamus. Correlations between manual segmentation and automated methods were strongest for MAGeT (range: 0.51 to 0.92; p<0.01, corrected), whereas FreeSurfer and FSL showed moderate to strong Pearson correlations (range 0.44-0.86; p<0.05, corrected), with the exception of FreeSurfer pallidal (r=0.31, p=0.10) and FSL thalamic segmentations (r=0.37, p=0.051). Bland-Altman plots highlighted a tendency for greater volumetric differences between manual labels and automated methods at the lower end of the distribution (i.e. smaller structures), which was most prominent for bilateral thalamus across automated pipelines, and left globus pallidus for FSL. We then went on to examine volume and shape of the basal ganglia structures using automated techniques in 135 FEP patients and 88 controls. The striatum and globus pallidus were significantly larger in FEP patients compared to controls bilaterally, irrespective of the method used. MAGeT-Brain was more sensitive to shape-based group differences, and uncovered widespread surface expansions in the striatum and globus pallidus bilaterally in FEP patients compared to controls, and surface contractions in bilateral thalamus (FDR-corrected). By contrast, after using a recommended cluster-wise thresholding method, FSL only detected differences in the right ventral striatum (FEP>Control) and one cluster of the left thalamus (Control>FEP). These results suggest that different automated pipelines segment subcortical structures with varying degrees of variability compared to manual methods, with particularly pronounced differences found with FreeSurfer and FSL for the globus pallidus and thalamus.

Subtle changes in hippocampal volumes may occur during both physiological and pathophysiological processes in the human brain. Assessing hippocampal volumes manually is a time-consuming procedure, however, creating a need for automated segmentation methods that are both fast and reliable over time. Segmentation algorithms that employ deep convolutional neural networks (CNN) have emerged as a promising solution for large longitudinal neuroimaging studies. However, for these novel algorithms to be useful in clinical studies, the accuracy and reproducibility should be established on independent datasets. Here, we evaluate the performance of a CNN-based hippocampal segmentation algorithm that was developed by Thyreau and colleagues - Hippodeep. We compared its segmentation outputs to manual segmentation and FreeSurfer 6.0 in a sample of 200 healthy participants scanned repeatedly at seven sites across Canada, as part of the Canadian Biomarker Integration Network in Depression consortium. The algorithm demonstrated high levels of stability and reproducibility of volumetric measures across all time points compared to the other two techniques. Although more rigorous testing in clinical populations is necessary, this approach holds promise as a viable option for tracking volumetric changes in longitudinal neuroimaging studies.

Functional connectomes, as measured with functional magnetic resonance imaging (fMRI), are highly individualized, and evidence suggests this individualization may increase across childhood. A connectome can become more individualized either by increasing self-stability or decreasing between-subject-similarity. Here we used a longitudinal early childhood dataset to investigate age associations with connectome self-stability, between-subject-similarity, and developmental individualization, defined as an individual's self-stability across a 12-month interval relative to their between-subject-similarity. fMRI data were collected during an 18-minute passive viewing scan from 73 typically developing children aged 4-7 years, at baseline and 12-month follow-up. We found that young children had highly individualized connectomes, with sufficient self-stability across 12-months for 98% identification accuracy. Linear models showed a significant relationship between age and developmental individualization across the whole brain and in most networks. This association appeared to be largely driven by an increase in self-stability with age, with only weak evidence for relationships between age and similarity across participants. Together our findings suggest that children's connectomes become more individualized across early childhood, and that this effect is driven by increasing self-stability rather than decreasing between-subject-similarity.

Optically pumped magnetometers (OPMs) have been adopted for the measurement of brain activity. Without the need to be cooled to cryogenic temperatures, an array of these sensors can be placed more flexibly, which allows for the recording of neuronal structures other than neocortex. Here we use eight OPM sensors to record human retinal activity following flash stimulation. We compare this magnetoretinographic (MRG) activity to the simultaneously recorded electroretinogram of the eight participants. The MRG shows the familiar flash-evoked potentials (a-wave and b-wave) and shares a highly significant amount of information with the electroretinogram (both in a simultaneous and separate measurement). We conclude that OPM sensors have the potential to become a contactless alternative to fiber electrodes for the measurement of retinal activity. Such a contactless solution can benefit both clinical and neuroscientific settings.

The human visual system is able to extract summary statistics from sets of similar items, but the underlying neural mechanism remains poorly understood. Using functional magnetic resonance imaging (fMRI) and an encoding model, we examined how the neural representation of ensemble coding is constructed by manipulating the task-relevance of ensemble features. We found a gradual increase in orientation-selective responses to the mean orientation of multiple stimuli along the visual hierarchy only when these orientations were task-relevant. Such responses to the ensemble orientation were present in the extrastriate area, V3, even when the mean orientation was not task-relevant, indicating that the ensemble representation can co-exist with the task-relevant individual feature representation. Ensemble orientations were also represented in frontal regions, but those representations were robust only when each mean orientation was linked to a motor response dimension. Together, our findings suggest that the neural representation of the ensemble percept is formed by pooling signals at multiple levels of the visual processing stream.

Studies using resting-state functional magnetic resonance imaging (rsfMRI) are increasingly collecting data at multiple sites in order to speed up recruitment or increase sample size. The main objective of this study was to assess the long-term consistency of rsfMRI connectivity maps derived at multiple sites and vendors using the Canadian Dementia Imaging Protocol (CDIP, www.cdip-pcid.ca). Nine to 10 min of functional BOLD images were acquired from an adult cognitively healthy volunteer scanned repeatedly at 13 Canadian sites on three scanner makes (General Electric, Philips and Siemens) over the course of 2.5 years. The consistency (spatial Pearson's correlation) of rsfMRI connectivity maps for seven canonical networks ranged from 0.3 to 0.8, with a negligible effect of time, but significant site and vendor effects. We noted systematic differences in data quality (i.e. head motion, number of useable time frames, temporal signal-to-noise ratio) across vendors, which may also confound some of these results, and could not be disentangled in this sample. We also pooled the long-term longitudinal data with a single-site, short-term (1 month) data sample acquired on 26 subjects (10 scans per subject), called HNU1. Using randomly selected pairs of scans from each subject, we quantified the ability of a data-driven unsupervised cluster analysis to match two scans of the same subjects. In this "fingerprinting" experiment, we found that scans from the Canadian subject (Csub) could be matched with high accuracy intra-site (>95% for some networks), but that the accuracy decreased substantially for scans drawn from different sites and vendors, even falling outside of the range of accuracies observed in HNU1. Overall, our results demonstrate good multivariate stability of rsfMRI measures over several years, but substantial impact of scanning site and vendors. How detrimental these effects are will depend on the application, yet our results demonstrate that new methods for harmonizing multisite analysis represent an important area for future work.

Divergent thinking tests have been used extensively in neuroscientific studies of creativity. However, output from tests of divergent thinking can be scored in different ways, and those scores can influence assessments of divergent thinking performance and its relationship with brain activation. Here we sought to investigate the relationship between various methods of scoring the Alternate Uses Task (AUT)-a well-known test of divergent thinking-and regional grey matter volume (GMV) using voxel-based morphometry (VBM). We assessed AUT performance based on (a) traditional approaches that involve scoring participants' output on fluency, flexibility, originality, and elaboration, (b) a subjective approach that involves scoring output directly on "snapshot" creativity, and (c) the definitional approach that involves scoring output separately on novelty and usefulness-the two criteria deemed necessary and jointly sufficient to categorize an idea as creative. Correcting for age, sex, intracranial volume, verbal IQ and working memory capacity, we found negative correlations between regional GMV in the left inferior temporal gyrus (ITG) and novelty and usefulness scores, but no correlation involving other scoring approaches. As part of the brain's core semantic system, this region is involved in concept retrieval and integration. We discuss the implications of these findings for our understanding of the neural bases of divergent thinking, and how ITG could be related to the generation of novel and useful responses.

Many magnetic resonance imaging (MRI) measures are being studied longitudinally to explore topics such as biomarker detection and clinical staging. A pertinent concern to longitudinal work is MRI scanner upgrades. When upgrades occur during the course of a longitudinal MRI neuroimaging investigation, there may be an impact on the compatibility of pre- and post-upgrade measures. Similarly, subject motion is another issue that may be detrimental to MRI work and embedding volumetric navigators (vNavs) within acquisition sequences has emerged as a technique that allows for prospective motion correction. Our research group recently underwent an upgrade from a Siemens MAGNETOM 3T Tim Trio system to a Siemens MAGNETOM 3T Prisma Fit system. The goals of the current work were to: 1) investigate the impact of this upgrade on commonly used structural imaging measures and proton magnetic resonance spectroscopy indices ("Prisma Upgrade protocol") and 2) examine structural imaging measures in a sequence with vNavs alongside a standard acquisition sequence ("vNav protocol"). While high reliability was observed for most of the investigated MRI outputs, suboptimal reliability was observed for certain indices. Across the scanner upgrade, increases in frontal, temporal, and cingulate cortical thickness (CT) and thalamus volume, along with decreases in parietal CT and amygdala, globus pallidus, hippocampus, and striatum volumes, were observed. No significant impact of the upgrade was found in 1H-MRS analyses. Further, CT estimates were found to be larger in MPRAGE acquisitions compared to vNav-MPRAGE acquisitions mainly within temporal areas, while the opposite was found mostly in parietal brain regions. The results from this work should be considered in longitudinal study designs and comparable prospective motion correction investigations are warranted in cases of marked head movement.

Although widely used in resting-state fMRI (fMRI) functional connectivity measurement (fcMRI), the BOLD signal is only an indirect measure of neuronal activity, and is inherently modulated by both neuronal activity and vascular physiology. For instance, cerebrovascular reactivity (CVR) varies widely across individuals irrespective of neuronal function, but the implications for fcMRI are currently unknown. This knowledge gap compromises our ability to correctly interpret fcMRI measurements. In this work, we investigate the relationship between CVR and resting fcMRI measurements in healthy young adults, in both the motor and the executive-control networks. We modulate CVR within each individual by subtly increasing and decreasing resting vascular tension through baseline end-tidal CO2 (PETCO2), and measure fcMRI during these hypercapnic, hypocapnic and normocapnic states. Furthermore, we assess the association between CVR and fcMRI within and across individuals. Within individuals, resting PETCO2 is found to significantly influence both CVR and resting fcMRI values. In addition, we find resting fcMRI to be significantly and positively associated with CVR across the group in both networks. This relationship is potentially mediated by concomitant alterations in BOLD signal fluctuation amplitude. This work clearly demonstrates and quantifies a major vascular modulator of resting fcMRI, one that is also subject and regional dependent. We suggest that individualized correction for CVR effects in fcMRI measurements is essential for fcMRI studies of healthy brains, and can be even more important in studying diseased brains.

Interactions between different brain regions can be revealed by dependencies between their neuronal oscillations. We examined the sensitivity of different oscillatory connectivity measures in revealing interhemispheric interactions between primary motor cortices (M1s) during unilateral finger movements. Based on frequency, amplitude, and phase of the oscillations, a number of metrics have been developed to measure connectivity between brain regions, and each metric has its own strengths, weaknesses, and pitfalls. Taking advantage of the well-known movement-related modulations of oscillatory amplitude in M1s, this study compared and contrasted a number of leading connectivity metrics during distinct phases of oscillatory power changes. Between M1s during unilateral movements, we found that phase-based metrics were effective at revealing connectivity during the beta (15-35 Hz) rebound period linked to movement termination, but not during the early period of beta desynchronization occurring during the movement itself. Amplitude correlation metrics revealed robust connectivity during both periods. Techniques for estimating the direction of connectivity had limited success. Granger Causality was not well suited to studying these connections because it was strongly confounded by differences in signal-to-noise ratio linked to modulation of beta amplitude occurring during the task. Phase slope index was suggestive but not conclusive of a unidirectional influence between motor cortices during the beta rebound. Our findings suggest that a combination of amplitude and phase-based metrics is likely required to fully characterize connectivity during task protocols that involve modulation of oscillatory power, and that amplitude-based metrics appear to be more sensitive despite the lack of directional information.

Diffusion MRI tractography processing pipeline requires a large number of steps (typically 20+ steps). If parameters of these steps, number of threads, and random seed generators are not carefully controlled, the resulting tractography can easily be non-reproducible and non-replicable, even in test-test experiments. To handle these issues, we developed TractoFlow. TractoFlow is fully automatic from raw diffusion weighted images to tractography. The pipeline also outputs classical diffusion tensor imaging measures and several fiber orientation distribution function measures. TractoFlow supports the recent Brain Imaging Data Structure (BIDS) format as input and is based on two engines: Nextflow and Singularity. In this work, the TractoFlow pipeline is evaluated on three databases and shown to be efficient and reproducible from 98% to 100%, depending on parameter choices. Moreover, it is easy to use for non-technical users, with little to no installation requirements. TractoFlow is publicly available for academic research and is an important step forward for better structural brain connectivity mapping.

Brain plasticity following focal cerebral ischaemia has been observed in both stroke survivors and in preclinical models of stroke. Endogenous neurovascular adaptation is at present incompletely understood yet its potentiation may improve long-term functional outcome. We employed longitudinal MRI, intracranial array electrophysiology, Montoya Staircase testing, and immunofluorescence to examine function of brain vessels, neurons, and glia in addition to forelimb skilled reaching during the subacute stage of ischemic injury progression. Focal ischemic stroke (~100mm3 or ~20% of the total brain volume) was induced in adult Sprague-Dawley rats via direct injection of endothelin-1 (ET-1) into the right sensori-motor cortex, producing sustained impairment in left forelimb reaching ability. Resting perfusion and vascular reactivity to hypercapnia in the peri-lesional cortex were elevated by approximately 60% and 80% respectively seven days following stroke. At the same time, the normal topological pattern of local field potential (LFP) responses to peripheral somatosensory stimulation was abolished and the average power of spontaneous LFP activity attenuated by approximately 50% relative to the contra-lesional cortex, suggesting initial response attenuation within the peri-infarct zone. By 21 days after stroke, perilesional blood flow resolved, but peri-lesional vascular reactivity remained elevated. Concomitantly, the LFP response amplitudes increased with distance from the site of ET-1 injection, suggesting functional remodelling from the core of the lesion to its periphery. This notion was further buttressed by the lateralization of spontaneous neuronal activity: by day 21, the average ipsi-lesional power of spontaneous LFP activity was almost twice that of the contra-lesional cortex. Over the observation period, the peri-lesional cortex exhibited increased vascular density, along with neuronal loss, astrocytic activation, and recruitment and activation of microglia and macrophages, with neuronal loss and inflammation extending beyond the peri-lesional cortex. These findings highlight the complex relationship between neurophysiological state and behaviour and provide evidence of highly dynamic functional changes in the peri-infarct zone weeks following the ischemic insult, suggesting an extended temporal window for therapeutic interventions.

Syntactically and semantically anomalous words encountered during sentence comprehension are known to elicit dissociable electrophysiological responses, which are thought to reflect distinct aspects of language processing. However, the sources of these responses have not been well characterized. We used beamforming analysis of magnetoencephalography (MEG) data to map generators of electrophysiological responses to linguistic anomalies. Anomalous words occurred in the context of a sentence acceptability judgement task conducted in both visual and auditory modalities. Time-frequency analysis revealed that both kinds of violations elicited event-related synchronization (ERS) in the delta-theta frequency range (1-5 Hz), and desynchronization (ERD) in the alpha-beta range (8-30 Hz). In addition, these responses were differentially modulated by violation type and presentation modality. 1-5 Hz responses were consistently localized within medial prefrontal cortex and did not vary significantly across violation types, but were stronger for visual presentation. In contrast, 8-30 Hz ERD occurred in different regions for different violation types. For semantic violations the distribution was predominantly in the bilateral occipital cortex and left temporal and inferior frontal regions, and these effects did not differ for visual and auditory presentation. In contrast, syntactic responses were strongly affected by presentation modality. Under visual presentation, syntactic violations elicited bilateral 8-30 Hz ERD extending into dorsal parietal and frontal regions, whereas effects were much weaker and mostly statistically insignificant in the auditory modality. These results suggest that delta-theta ERS reflects generalized increases in working memory demands related to linguistic anomaly detection, while alpha-beta ERD reflects specific activation of cortical regions involved in distinct aspects of linguistic processing, such as semantic vs. phonological short-term memory. Beamforming analysis of time-domain average signals (ERFs) revealed an N400m effect for semantic anomalies in both modalities, localized to left superior temporal and posterior frontal regions, and a later P600-like effect for syntactic anomalies in both modalities, widespread over bilateral frontal, posterior temporal, and parietal regions. These results indicate that time-domain averaged responses and induced oscillatory responses have distinct properties, including localization and modality dependence, and likely reflect dissociable and complementary aspects of neural activity related to language comprehension and additional task-related processes.

Lactate is now recognized as an important intermediate in brain metabolism, but its role is still under investigation. In this work we mapped the distribution of lactate and bicarbonate produced from intravenously injected 13C-pyruvate over the whole brain using a new imaging method, hyperpolarized 13C MRI (N = 14, ages 23 to 77). Segmenting the 13C-lactate images into brain atlas regions revealed a pattern of lactate that was preserved across individuals. Higher lactate signal was observed in cortical grey matter compared to white matter and was highest in the precuneus, cuneus and lingual gyrus. Bicarbonate signal, indicating flux of [1-13C]pyruvate into the TCA cycle, also displayed consistent spatial distribution. One-way ANOVA to test for significant differences in lactate among atlas regions gave F = 87.6 and p < 10-6. This report of a "lactate topography" in the human brain and its consistent pattern is evidence of region-specific lactate biology that is preserved across individuals.

Sleep deprivation leads to significant impairments in cognitive performance and changes to the interactions between large scale cortical networks, yet the hierarchical organization of cortical activity across states is still being explored. We used functional magnetic resonance imaging to assess activations and connectivity during cognitive tasks in 20 healthy young adults, during three states: (i) following a normal night of sleep, (ii) following 24hr of total sleep deprivation, and (iii) after a morning recovery nap. Situating cortical activity during cognitive tasks along hierarchical organizing gradients based upon similarity of functional connectivity patterns, we found that regional variations in task-activations were captured by an axis differentiating areas involved in executive control from default mode regions and paralimbic cortex. After global signal regression, the range of functional differentiation along this axis at baseline was significantly related to decline in working memory performance (2-back task) following sleep deprivation, as well as the extent of recovery in performance following a nap. The relative positions of cortical regions within gradients did not significantly change across states, except for a lesser differentiation of the visual system and increased coupling of the posterior cingulate cortex with executive control areas after sleep deprivation. This was despite a widespread increase in the magnitude of functional connectivity across the cortex following sleep deprivation. Cortical gradients of functional differentiation thus appear relatively insensitive to state-dependent changes following sleep deprivation and recovery, suggesting that there are no large-scale changes in cortical functional organization across vigilance states. Certain features of particular gradient axes may be informative for the extent of decline in performance on more complex tasks following sleep deprivation, and could be beneficial over traditional voxel- or parcel-based approaches in identifying realtionships between state-dependent brain activity and behavior.

Movie-watching is becoming a popular acquisition method to increase compliance and enable neuroimaging data collection in challenging populations such as children, with potential to facilitate studying the somatosensory system. However, relatively little is known about the possible crossmodal (audiovisual) influence of movies on cortical somatosensory processing. In this study, we examined the impact of dynamic audiovisual movies on concurrent cortical somatosensory processing using electroencephalography (EEG). Forty healthy young adults (18-25 years) received passive tactile fingertip stimulation while watching an "entertaining" movie and a novel "low-demand" movie called 'Inscapes' compared to eyes-open rest. Watching a movie did not modulate properties of early or late somatosensory-evoked potentials (SEPs). Similarly, no crossmodal influence on somatosensory adaptation, denoted by a reduction in SEP amplitude with repetitive tactile stimulation, was found. The prominent oscillatory responses in the alpha and beta frequency bands following tactile stimulation differed as a function of viewing condition, with stronger alpha/beta event-related desynchronization (ERD) during movie-watching compared to rest. These findings highlight that movie-watching is a valid acquisition method during which SEPs can be measured in basic research and clinical studies, but that the attentional demands of movies need to be taken into account when performing oscillatory analyses.

Cerebrovascular reactivity (CVR) is an important metric of cerebrovascular health. While the BOLD fMRI method in conjunction with carbon-dioxide (CO2) based vascular manipulation has been the most commonly used, the BOLD signal is not a direct measure of vascular changes, and the use of arterial-spin labeling (ASL) cerebral blood flow (CBF) imaging is increasingly advocated. Nonetheless, given the differing dependencies of BOLD and CBF on vascular baseline conditions and the diverse CO2 manipulation types currently used in the literature, knowledge of potential biases introduced by each technique is critical for the interpretation of CVR measurements. In this work, we use simultaneous BOLD-CBF acquisitions during both vasodilatory (hypercapnic) and vasoconstrictive (hypocapnic) stimuli to measure CVR. We further imposed different levels of baseline vascular tension by inducing hypercapnic and hypocapnic baselines, separately from normocapnia by 4mmHg. We saw significant and diverse dependencies on vascular stimulus and baseline condition in both BOLD and CBF CVR measurements: (i) BOLD-based CVR is more sensitive to basal vascular tension than CBF-based CVR; (ii) the use of a combination of vasodilatory and vasoconstrictive stimuli maximizes the sensitivity of CBF-based CVR to vascular tension changes; (iii) the BOLD and CBF vascular response delays are both significantly lengthened at predilated baseline. As vascular tension can often be altered by potential pathology, our findings are important considerations when interpreting CVR measurements in health and disease.

White matter development continues throughout childhood and into early adulthood, but few studies have examined early childhood, and the specific trajectories and regional variation in this age range remain unclear. The aim of this study was to characterize developmental trajectories and sex differences of white matter in typically developing young children. Three hundred and ninety-six diffusion tensor imaging datasets from 120 children (57 male) aged 2-8 years were analyzed using tractography. Fractional anisotropy (FA) increased and mean diffusivity (MD) decreased in all white matter tracts by 5-15% over the 6-year period, likely reflecting increases in myelination and axonal packing. Males showed steeper slopes in a number of brain areas. Overall, early childhood is associated with substantial development of all white matter and appears to be an important period for the development of occipital and limbic connections, which showed the largest changes. This study provides a detailed characterization of age-related white matter changes in early childhood, offering baseline data that can be used to understand cognitive and behavioural development, as well as to identify deviations from normal development in children with various diseases, disorders, or brain injuries.