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Funder: Evelyn Trust; doi: https://doi.org/10.13039/501100004282, Funder: James S. McDonnell Foundation (McDonnell Foundation); doi: https://doi.org/10.13039/100000913, Funder: Canadian Institute for Advanced Research (L'Institut Canadien de Recherches Avancées), The human brain entertains rich spatiotemporal dynamics, which are drastically reconfigured when consciousness is lost due to anaesthesia or disorders of consciousness (DOC). Here, we sought to identify the neurobiological mechanisms that explain how transient pharmacological intervention and chronic neuroanatomical injury can lead to common reconfigurations of neural activity. We developed and systematically perturbed a neurobiologically realistic model of whole-brain haemodynamic signals. By incorporating PET data about the cortical distribution of GABA receptors, our computational model reveals a key role of spatially-specific local inhibition for reproducing the functional MRI activity observed during anaesthesia with the GABA-ergic agent propofol. Additionally, incorporating diffusion MRI data obtained from DOC patients reveals that the dynamics that characterise loss of consciousness can also emerge from randomised neuroanatomical connectivity. Our results generalise between anaesthesia and DOC datasets, demonstrating how increased inhibition and connectome perturbation represent distinct neurobiological paths towards the characteristic activity of the unconscious brain.

Small world topologies are thought to provide a valuable insight into human brain organisation and consciousness. However, functional magnetic resonance imaging studies in consciousness have not yielded consistent results. Given the importance of dynamics for both consciousness and cognition, here we investigate how the diversity of brain dynamics pertaining to small world topology (quantified by sample entropy; dSW-E) scales with decreasing levels of awareness (i.e., sedation and disorders of consciousness). Paying particular attention to result reproducibility, we show that dSW-E is a consistent predictor of levels of awareness even when controlling for the underlying functional connectivity dynamics. We find that dSW-E of subcortical and cortical areas are predictive, with the former showing higher and more robust effect sizes across analyses. Consequently, we propose that the dynamic reorganisation of the functional information architecture, in particular of the subcortex, is a characteristic that emerges with awareness and has explanatory power beyond that of the complexity of dynamic functional connectivity.

Acknowledgements: We thank the volunteers who participated in the travelling heads study and the radiography staff who collected data at all four sites. We thank Fraunhofer MEVIS, Bremen, Germany, for provision of the Siemens 3D-GRASE ASL sequence., Funder: National Institute for Health Research; funder-id: http://dx.doi.org/10.13039/501100000272, Funder: Addenbrooke’s Charitable Trust, Cambridge University Hospitals; funder-id: http://dx.doi.org/10.13039/501100002927, Funder: NIHR Oxford Biomedical Research Centre; funder-id: http://dx.doi.org/10.13039/501100013373, INTRODUCTION: Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV-2 infection on the brain by diverse potentially pathogenic mechanisms, and with high reliability across multiple sites and scanner manufacturers. Here we describe the development of such a protocol, based upon the UK Biobank, and its validation with a travelling heads study. A multi-modal brain MRI protocol comprising sequences for T1-weighted MRI, T2-FLAIR, diffusion MRI (dMRI), resting-state functional MRI (fMRI), susceptibility-weighted imaging (swMRI), and arterial spin labelling (ASL), was defined in close approximation to prior UK Biobank (UKB) and C-MORE protocols for Siemens 3T systems. We iteratively defined a comparable set of sequences for General Electric (GE) 3T systems. To assess multi-site feasibility and between-site variability of this protocol, N = 8 healthy participants were each scanned at 4 UK sites: 3 using Siemens PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (King's College London). Over 2,000 Imaging Derived Phenotypes (IDPs), measuring both data quality and regional image properties of interest, were automatically estimated by customised UKB image processing pipelines (S2 File). Components of variance and intra-class correlations (ICCs) were estimated for each IDP by linear mixed effects models and benchmarked by comparison to repeated measurements of the same IDPs from UKB participants. Intra-class correlations for many IDPs indicated good-to-excellent between-site reliability. Considering only data from the Siemens sites, between-site reliability generally matched the high levels of test-retest reliability of the same IDPs estimated in repeated, within-site, within-subject scans from UK Biobank. Inclusion of the GE site resulted in good-to-excellent reliability for many IDPs, although there were significant between-site differences in mean and scaling, and reduced ICCs, for some classes of IDP, especially T1 contrast and some dMRI-derived measures. We also identified high reliability of quantitative susceptibility mapping (QSM) IDPs derived from swMRI images, multi-network ICA-based IDPs from resting-state fMRI, and olfactory bulb structure IDPs from T1, T2-FLAIR and dMRI data. CONCLUSION: These results give confidence that large, multi-site MRI datasets can be collected reliably at different sites across the diverse range of MRI modalities and IDPs that could be mechanistically informative in COVID brain research. We discuss limitations of the study and strategies for further harmonisation of data collected from sites using scanners supplied by different manufacturers. These acquisition and analysis protocols are now in use for MRI assessments of post-COVID patients (N = 700) as part of the ongoing COVID-CNS study.

Alzheimer's disease (AD) pathology is frequently observed as a comorbidity in people with dementia with Lewy bodies (DLB). Here, we evaluated the in vivo distribution of tau burden and its influence on the clinical phenotype of DLB. Tau deposition was quantified using [18F]-AV1451 positron emission tomography in people with DLB (n = 10), AD (n = 27), and healthy controls (n = 14). A subset of patients with Lewy body diseases (n = 4) also underwent [11C]-PK11195 positron emission tomography to estimate microglial activation. [18F]-AV1451 BPND was lower in DLB than AD across widespread regions. The medial temporal lobe [18F]-AV1451 BPND distinguished people with DLB from AD (AUC = 0.87), and negatively correlated with Addenbrooke's Cognitive Examination-Revised and Mini-Mental State Examination. There was a high degree of colocalization between [18F]-AV1451 and [11C]-PK11195 binding (p < 0.001). Our findings of minimal tau burden in DLB confirm previous studies. Nevertheless, the associations of [18F]-AV1451 binding with cognitive impairment suggest that tau may interact synergistically with other pathologic processes to aggravate disease severity in DLB., Highlights • We evaluated [18F]-AV1451 uptake in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). • There is minimal tau deposition in DLB compared to healthy controls. • Tau imaging may be useful for differential diagnosis of DLB and AD. • Tau deposition was correlated with cognitive impairment in DLB.

Chronic drug use negatively impacts ageing, resulting in diminished health and quality of life. However, little is known about biomarkers of abnormal ageing in stimulant drug users. Using morphometric similarity network mapping, a novel approach to structural connectomics, we first mapped cross-sectional morphometric similarity trajectories of ageing in the publicly available Rockland Sample (20-80 years of age, n = 665). We then compared morphometric similarity and neuropsychological function between non-treatment-seeking, actively using patients with stimulant use disorder (n = 183, mean age: 35.6 years) and healthy control participants (n = 148, mean age: 36.0 years). The significantly altered mean regional morphometric similarity was found in 43 cortical regions including the inferior and orbital frontal gyri, pre/postcentral gyri and anterior temporal, superior parietal and occipital areas. Deviations from normative morphometric similarity trajectories in patients with stimulant use disorder suggested abnormal brain ageing. Furthermore, deficits in paired associates learning were consistent with neuropathology associated with both ageing and stimulant use disorder. Morphometric similarity mapping provides a promising biomarker for ageing in health and disease and may complement existing neuropsychological markers of age-related cognitive decline. Neuropathological ageing mechanisms in stimulant use disorder warrant further investigation to develop more age-appropriate treatments for older people addicted to stimulant drugs., Sponsor: University of Cambridge Funding: Medical Research Council (G0701497 and MR/J012084/1)

Small world topologies are thought to provide a valuable insight into human brain organisation and consciousness. However, functional magnetic resonance imaging studies in consciousness have not yielded consistent results. Given the importance of dynamics for both consciousness and cognition, here we investigate how the diversity of small world dynamics (quantified by sample entropy; dSW-E1) scales with decreasing levels of awareness (i.e., sedation and disorders of consciousness). Paying particular attention to result reproducibility, we show that dSW-E is a consistent predictor of levels of awareness even when controlling for the underlying functional connectivity dynamics. We find that dSW-E of subcortical, and cortical areas are predictive, with the former showing higher and more robust effect sizes across analyses. We find that the network dynamics of intermodular communication in the cerebellum also have unique predictive power for levels of awareness. Consequently, we propose that the dynamic reorganisation of the functional information architecture, in particular of the subcortex, is a characteristic that emerges with awareness and has explanatory power beyond that of the complexity of dynamic functional connectivity.

Background Macrostructural brain alterations in the form of brain atrophy or cortical thinning typically occur during the prodromal Alzheimer’s disease stage. Mixed findings largely dependent on the age of the examined cohorts have been reported during the preclinical, asymptomatic disease stage. In the present study, our aim was to examine the association of midlife dementia risk with brain macrostructural alterations. Methods Structural 3T MRI scans were acquired for 647 cognitively normal middle-aged (40–59 years old) participants in the PREVENT-Dementia study. Cortical thickness, volumes of subcortical structures, the hippocampus and hippocampal subfields were quantified using Freesurfer version 7.1. The clarity of the hippocampal molecular layer was evaluated based on T2-weighted hippocampal scans. Associations of structural measures with apolipoprotein ε4 (APOE4) genotype and dementia family history (FHD), were investigated using linear regression. Correlations between the CAIDE dementia risk score (incorporating information about blood pressure, cholesterol, physical activity, body mass index, education, age and sex) and structural measures were further investigated. Results A higher CAIDE score was associated with thinner cortex and a larger hippocampal fissure. APOE4 genotype was associated with reduced molecular layer clarity. Conclusions Our findings suggest that a higher CAIDE score is associated with widespread cortical thinning. Conversely, APOE4 carriers and participants with FHD do not demonstrate prominent macrostructural alterations at this age range. These findings indicate that cardiovascular and not inherited risk factors for dementia are associated with macrostructural brain alterations at midlife.

Background The balance between goal-directed behavior and habits has been hypothesized to be biased toward the latter in individuals with cocaine use disorder (CUD), suggesting possible neurochemical changes in the putamen, which may contribute to their compulsive behavior. Methods We assessed habitual behavior in 48 patients with CUD and 42 healthy control participants using a contingency degradation paradigm and the Creature of Habit Scale. In a subgroup of this sample (CUD: n = 21; control participants: n = 22), we also measured glutamate and glutamine concentrations in the left putamen using ultra-high-field (7T) magnetic resonance spectroscopy. We hypothesized that increased habitual tendencies in patients with CUD would be associated with abnormal glutamatergic metabolites in the putamen. Results Compared with their non–drug-using peers, patients with CUD exhibited greater habitual tendencies during contingency degradation, which correlated with increased levels of self-reported daily habits. We further identified a significant reduction in glutamate concentration and glutamate turnover (glutamate-to-glutamine ratio) in the putamen in patients with CUD, which was significantly related to the level of self-reported daily habits. Conclusions Patients with CUD exhibit enhanced habitual behavior, as assessed both by questionnaire and by a laboratory paradigm of contingency degradation. This automatic habitual tendency is related to a reduced glutamate turnover in the putamen, suggesting a dysregulation of habits caused by chronic cocaine use.

Highlights • Dendritic complexity and presynaptic density are reduced in the 4R-tauopathies of PSP and CBD. • The reduction in ODI and UCB-J binding is coupled across the cortical mantle as well as subcortically. • The relationship between ODI and UCB-J binding is not attributed to atrophy. • ODI may be a useful biomarker of synaptic pathology in neurodegenerative diseases., Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborization are characteristic and can be quantified in vivo, with [11C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of progressive supranuclear palsy – Richardson's Syndrome (PSP-RS; n = 22) and amyloid-negative (determined by [11C]PiB PET) Corticobasal Syndrome (Cortiobasal degeneration, CBD; n =14), as neurodegenerative disease models, in this proof-of-concept study. Compared to controls (n = 27), PSP-RS and CBD patients had widespread reductions in cortical ODI, and [11C]UCB-J non-displaceable binding potential (BPND) in excess of atrophy. In PSP-RS and CBD separately, regional cortical ODI was significantly associated with [11C]UCB-J BPND in disease-associated regions (p < 0.05, FDR corrected). Our findings indicate that reductions in synaptic density and dendritic complexity in PSP-RS and CBD are more severe and extensive than atrophy. Furthermore, both measures are tightly coupled in vivo, furthering our understanding of the pathophysiology of neurodegeneration, and applicable to studies of early neurodegeneration with a safe and widely available MRI platform.

Importance: Persistent symptoms after mild traumatic brain injury (mTBI) represent a major public health problem. Objective: To identify neuroanatomical substrates of mTBI and the optimal timing for magnetic resonance imaging (

The human brain generates a rich repertoire of spatiotemporal dynamics during normal wakefulness, supporting a wide variety of conscious experiences and cognitive functions. However, neural dynamics are reconfigured, in comparable ways, when consciousness is lost either due to anaesthesia or disorders of consciousness (DOC). Here, leveraging a neurobiologically realistic whole-brain computational model informed by functional MRI, diffusion MRI, and PET, we sought to identify the neurobiological mechanisms that explain the common reconfiguration of neural dynamics observed both for transient pharmacological intervention and chronic neuroanatomical injury. Our results show that, by incorporating local inhibitory action through a PET-based GABA receptor density map, our model can reproduce the brain dynamics of subjects undergoing propofol anaesthesia, and that this effect depends specifically on the spatial distribution of GABA receptors across cortical regions. Additionally, using a structural connectome obtained from DOC patients, we demonstrate how the dynamics that characterise loss of consciousness can emerge from changes in neuroanatomical connectivity. Crucially, we find that each of these two interventions generalises across datasets: a model with increased GABA-mediated inhibition can reproduce the dynamics of DOC patients’ brains, and a model with a DOC connectome is also compatible with brain dynamics observed during propofol anaesthesia. These results demonstrate how increased inhibition and connectome randomisation represent different neurobiological paths towards the characteristic dynamics of the unconscious brain. Overall, the present findings begin to disentangle the neurobiological mechanisms by which highly dissimilar perturbations of the brain’s neurodynamics can lead to unconsciousness.

Functional magnetic resonance imaging (fMRI) can be seriously impaired by patient motion. The purpose of this study was to characterize the typical motion in a clinical population of patients in disorders of consciousness and compare the performance of retrospective correction with rigid-body realignment as implemented in widely used software packages. 63 subjects were scanned with an fMRI visual checkerboard paradigm using a 3 T scanner. Time series were corrected for motion, and the resulting transformations were used to calculate a motion score. SPM, FSL, AFNI and AIR were evaluated by comparing the motion obtained by re-running the tool on the corrected data. A publicly available sample fMRI dataset was modified with the motion detected in each patient with each tool. The performance of each tool was measured by comparing the number of supra-threshold voxels after standard fMRI analysis, both in the sample dataset and in simulated fMRI data. We assessed the effect of user-changeable parameters on motion correction in SPM. We found the equivalent motion in the patient population to be 1.4 mm on average. There was no significant difference in performance between SPM, FSL and AFNI. AIR was considerably worse, and took more time to run. We found that in SPM the quality factor and interpolation method have no effect on the cluster size, while higher separation and smoothing reduce it. We showed that the main packages SPM, FSL and AFNI are equally suitable for retrospective motion correction of fMRI time series. We show that typically only 80% of activated voxels are recovered by retrospective motion correction.

Self-similarity is ubiquitous throughout natural phenomena, including the human brain. Recent evidence indicates that fractal dimension of functional brain networks, a measure of self-similarity, is diminished in patients diagnosed with disorders of consciousness arising from severe brain injury. Here, we set out to investigate whether loss of self-similarity is observed in the structural connectome of patients with disorders of consciousness. Using diffusion MRI tractography from N = 11 patients in a minimally conscious state (MCS), N = 10 patients diagnosed with unresponsive wakefulness syndrome (UWS), and N = 20 healthy controls, we show that fractal dimension of structural brain networks is diminished in DOC patients. Remarkably, we also show that fractal dimension of structural brain networks is preserved in patients who exhibit evidence of covert consciousness by performing mental imagery tasks during functional MRI scanning. These results demonstrate that differences in fractal dimension of structural brain networks are quantitatively associated with chronic loss of consciousness induced by severe brain injury, highlighting the close connection between structural organisation of the human brain and its ability to support cognitive function.

BACKGROUND: First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate "estimated years to onset of dementia" (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. METHODS: 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER) was performed on voxelwise statistical maps. RESULTS: There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCEFWERp < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. CONCLUSIONS: Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings.

Early and profound pathological changes are evident in the locus coeruleus (LC) in dementia and Parkinson's disease, with effects on arousal, attention, cognitive and motor control. The LC can be identified in vivo using non-invasive magnetic resonance imaging techniques which have potential as biomarkers for detecting and monitoring disease progression. Technical limitations of existing imaging protocols have impaired the sensitivity to regional contrast variance or the spatial variability on the rostrocaudal extent of the LC, with spatial mapping consistent with post mortem findings. The current study employs a sensitive magnetisation transfer sequence using ultrahigh field 7T MRI to investigate the LC structure in vivo at high-resolution (0.4 × 0.4 × 0.5 mm). Magnetisation transfer images from 53 healthy older volunteers (52 - 84 years) clearly revealed the spatial features of the LC and were used to create a probabilistic LC atlas for older adults. This atlas may be especially relevant for studying disorders associated with older age. To use the atlas does not require use of the same MT sequence of 7T MRI, provided good co-registration and normalisation is achieved. Consistent rostrocaudal gradients of slice-wise volume, contrast and variance along the LC were observed, mirroring distinctive ex vivo spatial distributions of LC cells in its subregions. The contrast-to-noise ratios were calculated for the peak voxels, and for the averaged signals within the atlas, to accommodate the volumetric differences in estimated contrast. The probabilistic atlas is freely available, and the MRI dataset will be made available for non-commercial research, for replication or to facilitate accurate LC localisation and unbiased contrast extraction in future studies.

Introduction The deposition of neurofibrillary tangles in neurodegenerative disorders is associated with neuronal loss on autopsy; however, their in vivo associations with atrophy across the continuum of Alzheimer's disease (AD) remain unclear. Methods We estimated cortical thickness, tau ([18F]‐AV‐1451), and amyloid β (Aβ) status ([11C]‐PiB) in 47 subjects who were stratified into Aβ− (14 healthy controls and six mild cognitive impairment–Aβ−) and Aβ+ (14 mild cognitive impairment–Aβ+ and 13 AD) groups. Results Compared with the Aβ− group, tau was increased in widespread regions whereas cortical thinning was restricted to the temporal cortices. Increased tau binding was associated with cortical thinning in each Aβ group. Locally, regional tau was associated with temporoparietal atrophy. Discussion These findings position tau as a promising therapeutic target. Further studies are needed to elucidate the casual relationships between tau pathology and trajectories of atrophy in AD.

We investigated whole-brain atrophy and ventricular enlargement over 18 months in nondemented Parkinson's disease (PD) and examined their associations with clinical measures and baseline CSF markers. PD subjects (n = 100) were classified at baseline into those with mild cognitive impairment (MCI; PD-MCI, n = 36) and no cognitive impairment (PD-NC, n = 64). Percentage of whole-brain volume change (PBVC) and ventricular expansion over 18 months were assessed with FSL-SIENA and ventricular enlargement (VIENA) respectively. PD-MCI showed increased global atrophy (-1.1% ± 0.8%) and ventricular enlargement (6.9 % ± 5.2%) compared with both PD-NC (PBVC: -0.4 ± 0.5, p < 0.01; VIENA: 2.1% ± 4.3%, p < 0.01) and healthy controls. In a subset of 35 PD subjects, CSF levels of tau, and Aβ42/Aβ40 ratio were correlated with PBVC and ventricular enlargement respectively. The sample size required to demonstrate a 20% reduction in PBVC and VIENA was approximately 1/15th of that required to detect equivalent changes in cognitive decline. These findings suggest that longitudinal MRI measurements have potential to serve as surrogate markers to complement clinical assessments for future disease-modifying trials in PD.

Highlights • Increased microglial activation is documented in dementias. • Dementia with Lewy bodies also exhibit altered white matter (WM) tracts. • An increased parietal microglial activation was associated with WM preservation. • A preserved cognition was also associated with higher microglial activation. • This study suggests neuroinflammation acts as an early marker of degeneration., Dementia with Lewy bodies (DLB) is characterized by alpha-synuclein protein deposition with variable degree of concurrent Alzheimer's pathology. Neuroinflammation is also increasingly recognized as a significant contributor to degeneration. We aimed to examine the relationship between microglial activation as measured with [11C]-PK11195 brain PET, MR diffusion tensor imaging (DTI) and grey matter atrophy in DLB. Nineteen clinically probable DLB and 20 similarly aged controls underwent 3T structural MRI (T1-weighted) and diffusion-weighted imaging. Eighteen DLB subjects also underwent [11C]-PK11195 PET imaging and 15 had [11C]-Pittsburgh compound B amyloid PET, resulting in 9/15 being amyloid-positive. We used Computational Anatomy Toolbox (CAT12) for volume-based morphometry (VBM) and Tract-Based Spatial Statistics (TBSS) for DTI to assess group comparisons between DLB and controls and to identify associations of [11C]-PK11195 binding with grey/white matter changes and cognitive score in DLB patients. VBM analyses showed that DLB had extensive reduction of grey matter volume in superior frontal, temporal, parietal and occipital cortices (family-wise error (FWE)-corrected p

Neuroinflammation is increasingly recognized as playing a key pathogenetic role in Alzheimer's disease (AD). We examined the relationship between in vivo neuroinflammation and gray matter (GM) changes. Twenty-eight subjects with clinically probable AD (n = 14) and amyloid-positive mild cognitive impairment (n = 14) (age 71.9 ± 8.4 years, 46% female) and 24 healthy controls underwent structural 3T brain MRI. AD/mild cognitive impairment participants exhibited GM atrophy and cortical thinning in AD-related temporoparietal regions (false discovery rate–corrected p < 0.05). Patients also showed increased microglial activation in temporal cortices. Higher 11C-PK11195 binding in these regions was associated with reduced volume and cortical thickness in parietal, occipital, and cingulate areas (false discovery rate p < 0.05). Hippocampal GM atrophy and parahippocampal cortical thinning were related to worse cognition (p < 0.05), but these effects were not mediated by microglial activation. This study demonstrates an association between in vivo microglial activation and markers of GM damage in AD, positioning neuroinflammation as a potential target for immunotherapeutic strategies., Highlights • Neuroinflammation is a key player in Alzheimer's disease pathophysiology. • Microglial activation with 11C-PK11195 PET was assessed in patients with Alzheimer's disease. • Increased microglial activation was observed in temporal cortices. • Microglial activation was related to parieto-occipital atrophy and cortical thinning. • It did not mediate the effects of structural damage on cognitive decline.

This work addresses a central topic in Magnetic Resonance Imaging (MRI) which is the motion-correction problem in a joint reconstruction and registration framework. From a set of multiple MR acquisitions corrupted by motion, we aim at - jointly - reconstructing a single motion-free corrected image and retrieving the physiological dynamics through the deformation maps. To this purpose, we propose a novel variational model. First, we introduce an $L^2$ fidelity term, which intertwines reconstruction and registration along with the weighted total variation. Second, we introduce an additional regulariser which is based on the hyperelasticity principles to allow large and smooth deformations. We demonstrate through numerical results that this combination creates synergies in our complex variational approach resulting in higher quality reconstructions and a good estimate of the breathing dynamics. We also show that our joint model outperforms in terms of contrast, detail and blurring artefacts, a sequential approach., 12 pages, 3 figure, accepted for publication in Scale Space and Variational Methods in Computer Vision conference proceedings

Summary Ultra-high field (UHF) neuroimaging affords the sub-millimeter resolution that allows researchers to interrogate brain computations at a finer scale than that afforded by standard fMRI techniques. Here, we present a step-by-step protocol for using UHF imaging (Siemens Terra 7T scanner) to measure activity in the human brain. We outline how to preprocess the data using a pipeline that combines tools from SPM, FreeSurfer, ITK-SNAP, and BrainVoyager and correct for vasculature-related confounders to improve the spatial accuracy of the fMRI signal. For complete details on the use and execution of this protocol, please refer to Jia et al. (2020) and Zamboni et al. (2020)., Graphical abstract, Highlights • Protocol for using ultra-high field imaging to measure activity in the human brain • Defining cortical layers using high-resolution anatomical scans • Preprocessing functional brain imaging data across cortical depth • Correcting for vasculature-related confounds to improve spatial specificity, Ultra-high field (UHF) neuroimaging affords the sub-millimeter resolution that allows researchers to interrogate brain computations at a finer scale than that afforded by standard fMRI techniques. Here, we present a step-by-step protocol for using UHF imaging (Siemens Terra 7T scanner) to measure activity in the human brain. We outline how to preprocess the data using a pipeline that combines tools from SPM, FreeSurfer, ITK-SNAP, and BrainVoyager and correct for vasculature-related confounders to improve the spatial accuracy of the fMRI signal.

$\textbf{BACKGROUND}$: Volumetric atrophy and microstructural alterations in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in people with Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, no study to date has jointly investigated concomitant microstructural and volumetric changes of the hippocampus in dementia with Lewy bodies (DLB). $\textbf{METHODS}$: A total of 84 subjects (23 MCI, 17 DLB, 14 AD, and 30 healthy controls) were recruited for a multi-modal imaging (3T MRI and DTI) study that included neuropsychological evaluation. Freesurfer was used to segment the total hippocampus and delineate its subfields. The hippocampal segmentations were co-registered to the mean diffusivity (MD) and fractional anisotropy (FA) maps obtained from the DTI images. $\textbf{RESULTS}$: Both AD and MCI groups showed significantly smaller hippocampal volumes compared to DLB and controls, predominantly in the CA1 and subiculum subfields. Compared to controls, hippocampal MD was elevated in AD, but not in MCI. DLB was characterized by both volumetric and microstructural preservation of the hippocampus. In MCI, higher hippocampal MD was associated with greater atrophy of the hippocampus and CA1 region. Hippocampal volume was a stronger predictor of memory scores compared to MD within the MCI group. $\textbf{CONCLUSIONS}$: Through a multi-modal integration, we report novel evidence that the hippocampus in DLB is characterized by both macrostructural and microstructural preservation. Contrary to recent suggestions, our findings do not support the view that DTI measurements of the hippocampus are superior to volumetric changes in characterizing group differences, particularly between MCI and controls.

Introduction: We present the reliability of ultra-high field T2* MRI at 7T, as part of the UK7T Network's “Travelling Heads” study. T2*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R2* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R2* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5–3T). We aimed to determine the inter-subject and inter-site reproducibility of QSM and R2* mapping at 7T, in readiness for future multi-site clinical studies. Methods: Ten healthy volunteers were scanned with harmonised single- and multi-echo T2*-weighted gradient echo pulse sequences. Participants were scanned five times at each “home” site and once at each of four other sites. The five sites had 1× Philips, 2× Siemens Magnetom, and 2× Siemens Terra scanners. QSM and R2* maps were computed with the Multi-Scale Dipole Inversion (MSDI) algorithm (https://github.com/fil-physics/Publication-Code). Results were assessed in relevant subcortical and cortical regions of interest (ROIs) defined manually or by the MNI152 standard space. Results and Discussion: Mean susceptibility (χ) and R2* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001–0.005 ppm (χ) and 0.0005–0.001 ms−1 (R2*). For χ this is 2.1–4.8 fold better than 3T reports, and 1.1–3.4 fold better for R2*. The median ICC from within- and cross-site R2* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B0 inhomogeneity such as the inferior frontal cortex. Across sites, R2* values were more consistent than QSM in subcortical structures due to differences in B0-shimming. On a between-subject level, our measured χ and R2* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol. Conclusion: The harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R2* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T.

Background: Alzheimer’s disease (AD) is associated with atrophy in entorhinal cortex (ERC), the hippocampus, and its subfields Cornu Ammonis 1 (CA1) and subiculum, which predict conversion from Mild Cognitive Impairment (MCI) to clinical AD. The stratum radiatum, lacunosum and moleculare (SRLM) are also important gateways involving ERC and CA1, which are affected by early AD pathology. Objective: To assess whether the SRLM is affected in MCI and AD. Methods: In this proof-of-concept study, 27 controls, 13 subjects with AD and 22 with MCI underwent 3T MRI. T1 maps were used for whole-hippocampal volumetry, T2 maps were segmented for hippocampal subfield areas, entorhinal cortex and subiculum thickness, and evaluated for SRLM integrity. Results: Significant CA1 atrophy and subiculum thinning were found in both AD and MCI compared to similarly aged controls. However, SRLM integrity was only significantly reduced in AD but not in MCI compared to controls. There were no significant differences in other hippocampal subfields (CA2, CA3/Dentate Gyrus) or ERC thickness between the groups. Finally, CA1 and CA3/DG areas and SRLM clarity were correlated with clinical and cognitive measurements of disease severity. Conclusion: Although this study was cross sectional, it suggests a progression of specific subfield changes from MCI to established AD that is associated with the reduced integrity of SRLM, which may reflect more widespread hippocampal involvement as the disease progresses and the relative preservation of SRLM in MCI. These results provide new MRI biomarkers for disease staging and understanding of the neurobiology in AD.

We have previously shown that normobaric hyperoxia may benefit peri-lesional brain and white matter following traumatic brain injury (TBI). This study examined the impact of brief exposure to hyperoxia using diffusion tensor imaging (DTI) to identify axonal injury distant from contusions. Fourteen patients with acute moderate/severe TBI underwent baseline DTI and following one hour of 80% oxygen. Thirty-two controls underwent DTI, with 6 undergoing imaging following graded exposure to oxygen. Visible lesions were excluded and data compared with controls. We used the 99% prediction interval (PI) for zero change from historical control reproducibility measurements to demonstrate significant change following hyperoxia. Following hyperoxia DTI was unchanged in controls. In patients following hyperoxia, mean diffusivity (MD) was unchanged despite baseline values lower than controls (p

It is well established that the neurodegenerative process of Alzheimer's disease (AD) begins many years before symptom onset. This preclinical phase provides a crucial time-window for therapeutic intervention, though this requires biomarkers that could evaluate the efficacy of future disease-modification treatments in asymptomatic individuals. The last decade has witnessed a proliferation of studies characterizing the temporal sequence of the earliest functional and structural brain imaging changes in AD. These efforts have focused on studying individuals who are highly vulnerable to develop AD, such as those with familial genetic mutations, susceptibility genes (i.e. apolipoprotein epsilon-4 allele), and/or a positive family history of AD. In this paper, we review the rapidly growing literature of functional imaging changes in cognitively intact individuals who are middle-aged: positron emission tomography (PET) studies of amyloid deposition, glucose metabolism, as well as arterial spin labeling (ASL), task-dependent, resting-state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) studies. The prevailing evidence points to early brain functional changes in the relative absence of cognitive impairment and structural atrophy, although there is marked variability in the directionality of the changes, which could, in turn, be related to antagonistic pleiotropy early in life. A common theme across studies relates to the spatial extent of these changes, most of which overlap with brain regions that are implicated in established AD. Notwithstanding several methodological caveats, functional imaging techniques could be preferentially sensitive to the earliest events of AD pathology prior to macroscopic grey matter loss and clinical manifestations of AD. We conclude that while these techniques have great potential to serve as biomarkers to identify at-risk individuals, more longitudinal studies with greater sample size and robust correction for multiple comparisons are still warranted to establish their utility.

The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer's disease (AD), where both widespread atrophy and 'signature' brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.

Summary Learning and experience are critical for translating ambiguous sensory information from our environments to perceptual decisions. Yet evidence on how training molds the adult human brain remains controversial, as fMRI at standard resolution does not allow us to discern the finer scale mechanisms that underlie sensory plasticity. Here, we combine ultra-high-field (7T) functional imaging at sub-millimeter resolution with orientation discrimination training to interrogate experience-dependent plasticity across cortical depths that are known to support dissociable brain computations. We demonstrate that learning alters orientation-specific representations in superficial rather than middle or deeper V1 layers, consistent with recurrent plasticity mechanisms via horizontal connections. Further, learning increases feedforward rather than feedback layer-to-layer connectivity in occipito-parietal regions, suggesting that sensory plasticity gates perceptual decisions. Our findings reveal finer scale plasticity mechanisms that re-weight sensory signals to inform improved decisions, bridging the gap between micro- and macro-circuits of experience-dependent plasticity., Highlights • Discrimination training alters orientation representations in superficial V1 layers • Orientation-specific V1 plasticity is independent of task context • Discrimination training alters orientation representations in middle IPS layers • Learning enhances feedforward connectivity from visual to parietal cortex, Using high-field laminar fMRI, Jia et al. show that learning alters orientation-specific representations in superficial V1 layers and enhances connectivity from visual to parietal cortex, suggesting that recurrent visual plasticity and feedforward connectivity gate perceptual decision making.

Stimulant drugs acutely increase dopamine neurotransmission in the brain, and chronic use leads to neuroadaptive changes in the mesolimbic dopamine system and morphological changes in basal ganglia structures. Little is known about the mechanisms underlying these changes but preclinical evidence suggests that iron, a coenzyme in dopamine synthesis and storage, may be a candidate mediator. Iron is present in high concentrations in the basal ganglia and stimulant drugs may interfere with iron homeostasis. We hypothesised that morphological brain changes in cocaine addiction relate to abnormal iron regulation in the brain and periphery. We determined iron concentration in the brain, using quantitative susceptibility mapping, and in the periphery, using iron markers in circulating blood, in 44 patients with cocaine addiction and 44 healthy controls. Cocaine-addicted individuals showed excess iron accumulation in the globus pallidus, which strongly correlated with duration of cocaine use, and mild iron deficiency in the periphery, which was associated with low iron levels in the red nucleus. Our findings show that iron dysregulation occurs in cocaine addiction and suggest that it arises consequent to chronic cocaine use. Putamen enlargement in these individuals was unrelated to iron concentrations, suggesting that these are co-occurring morphological changes that may respectively reflect predisposition to, and consequences of cocaine addiction. Understanding the mechanisms by which cocaine affects iron metabolism may reveal novel therapeutic targets, and determine the value of iron levels in the brain and periphery as biomarkers of vulnerability to, as well as progression and response to treatment of cocaine addiction.

$\textit{Introduction}$ Inflammation of the central nervous system is increasingly regarded as having a role in cognitive disorders such as dementia and depression, but it is not clear how such neuroinflammation relates to other aspects of neuropathology (e.g., tau and amyloid pathology) as well as to structural and functional changes in the brain and symptoms (as assessed via MRI and clinical and neuropsychological assessment). This study will explore these pathophysiological mechanisms using positron emission tomography (PET) which allows $\textit{in vivo}$ imaging of inflammation, amyloid and tau deposition, together with neuropsychological profiling, magnetic resonance imaging (MRI) and peripheral biomarker analysis. $\textit{Methods & analysis}$ Using PET imaging of the ligand [11C]PK11195 we will test for increased neuroinflammation $\textit{in vivo}$ in patients with Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, late onset depression and mild cognitive impairment, when compared to healthy controls. We will assess whether areas of inflammatory change are associated with amyloid and tau deposition (assessed using $^{11}$C-labelled Pittsburgh Compound B ([$^{11}$C]PiB) and $^{18}$F-labelled AV-1451 respectively), as well as structural and functional connectivity changes found on MRI. Inflammatory biomarker analysis and immune-phenotyping of peripheral blood monocytes will determine the correlation between central (i.e., neural) and peripheral inflammation. Finally, we will examine whether neuroinflammatory changes seen on PET imaging are associated with global and domain specific cognitive impairments, or predict cognitive decline over 12 months. $\textit{Ethics & dissemination}$ The study protocol was approved by the local ethics committee, East of England - Cambridge Central Research Ethics Committee (reference: 13/EE/0104). The study is also ARSAC approved as part of this process. Data will be disseminated by presentation at national and international conferences and by publication, predominantly in journals of neuroscience as well as clinical neurology and psychiatry. $\textit{Strengths}$ Multimodal deep phenotyping Comparisons between diseases as well as with controls Longitudinal neuropsychology data Comparison of central and peripheral inflammation $\textit{Weaknesses}$ Lack of longitudinal neuroimaging Not a prospective study, unable to assess causation

Fundamental criticisms have been made over the use of (31)P magnetic resonance spectroscopy (MRS) magnetization transfer estimates of inorganic phosphate (Pi)→ATP flux (VPi-ATP) in human resting skeletal muscle for assessing mitochondrial function. Although the discrepancy in the magnitude of VPi-ATP is now acknowledged, little is known about its metabolic determinants. Here we use a novel protocol to measure VPi-ATP in human exercising muscle for the first time. Steady-state VPi-ATP was measured at rest and over a range of exercise intensities and compared with suprabasal oxidative ATP synthesis rates estimated from the initial rates of postexercise phosphocreatine resynthesis (VATP). We define a surplus Pi→ATP flux as the difference between VPi-ATP and VATP. The coupled reactions catalyzed by the glycolytic enzymes GAPDH and phosphoglycerate kinase (PGK) have been shown to catalyze measurable exchange between ATP and Pi in some systems and have been suggested to be responsible for this surplus flux. Surplus VPi-ATP did not change between rest and exercise, even though the concentrations of Pi and ADP, which are substrates for GAPDH and PGK, respectively, increased as expected. However, involvement of these enzymes is suggested by correlations between absolute and surplus Pi→ATP flux, both at rest and during exercise, and the intensity of the phosphomonoester peak in the (31)P NMR spectrum. This peak includes contributions from sugar phosphates in the glycolytic pathway, and changes in its intensity may indicate changes in downstream glycolytic intermediates, including 3-phosphoglycerate, which has been shown to influence the exchange between ATP and Pi catalyzed by GAPDH and PGK.

Objective. Traumatic brain injury (TBI) is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We aimed to assess patient trajectories over the entire disease narrative, from ictus to late outcome. Methods. Twelve patients with moderate-to-severe TBI underwent magnetic resonance imaging in the acute phase (within 1 week of injury) and twice in the chronic phase of injury (median 7 and 21 months), with some undergoing imaging at up to 2 additional time points. Longitudinal imaging changes were assessed using structural volumetry, deterministic tractography, voxel-based diffusion tensor analysis, and region of interest analyses (including corpus callosum, parasagittal white matter, and thalamus). Imaging changes were related to behavior. Results. Changes in structural volumes, fractional anisotropy, and mean diffusivity continued for months to years postictus. Changes in diffusion tensor imaging were driven by increases in both axial and radial diffusivity except for the earliest time point, and were associated with changes in reaction time and performance in a visual memory and learning task (paired associates learning). Dynamic structural changes after TBI can be detected using diffusion tensor imaging and could explain changes in behavior. Conclusions. These data can provide further insight into early and late pathophysiology, and begin to provide a framework that allows magnetic resonance imaging to be used as an imaging biomarker of therapy response. Knowledge of the temporal pattern of changes in TBI patient populations also provides a contextual framework for assessing imaging changes in individuals at any given time point.

Mild cognitive impairment in Parkinson’s disease (PDMCI) is associated with progression to dementia in a majority of patients. Mak et al. reveal accelerated cortical thinning in patients with PDMCI compared to non-cognitively impaired patients and healthy controls. Patterns of cortical thinning may constitute biomarkers for increased dementia risk., Mild cognitive impairment in Parkinson’s disease is associated with progression to dementia (Parkinson’s disease dementia) in a majority of patients. Determining structural imaging biomarkers associated with prodromal Parkinson’s disease dementia may allow for the earlier identification of those at risk, and allow for targeted disease modifying therapies. One hundred and five non-demented subjects with newly diagnosed idiopathic Parkinson’s disease and 37 healthy matched controls had serial 3 T structural magnetic resonance imaging scans with clinical and neuropsychological assessments at baseline, which were repeated after 18 months. The Movement Disorder Society Task Force criteria were used to classify the Parkinson’s disease subjects into Parkinson’s disease with mild cognitive impairment (n = 39) and Parkinson’s disease with no cognitive impairment (n = 66). Freesurfer image processing software was used to measure cortical thickness and subcortical volumes at baseline and follow-up. We compared regional percentage change of cortical thinning and subcortical atrophy over 18 months. At baseline, cases with Parkinson’s disease with mild cognitive impairment demonstrated widespread cortical thinning relative to controls and atrophy of the nucleus accumbens compared to both controls and subjects with Parkinson’s disease with no cognitive impairment. Regional cortical thickness at baseline was correlated with global cognition in the combined Parkinson’s disease cohort. Over 18 months, patients with Parkinson’s disease with mild cognitive impairment demonstrated more severe cortical thinning in frontal and temporo-parietal cortices, including hippocampal atrophy, relative to those with Parkinson’s disease and no cognitive impairment and healthy controls, whereas subjects with Parkinson’s disease and no cognitive impairment showed more severe frontal cortical thinning compared to healthy controls. At baseline, Parkinson’s disease with no cognitive impairment converters showed bilateral temporal cortex thinning relative to the Parkinson’s disease with no cognitive impairment stable subjects. Although loss of both cortical and subcortical volume occurs in non-demented Parkinson’s disease, our longitudinal analyses revealed that Parkinson’s disease with mild cognitive impairment shows more extensive atrophy and greater percentage of cortical thinning compared to Parkinson’s disease with no cognitive impairment. In particular, an extension of cortical thinning in the temporo-parietal regions in addition to frontal atrophy could be a biomarker in therapeutic studies of mild cognitive impairment in Parkinson’s disease for progression towards dementia.

The ability to recognize facial expressions of emotion in others is a cornerstone of human interaction. Selective impairments in the recognition of facial expressions of fear have frequently been reported in chronic cocaine users, but the nature of these impairments remains poorly understood. We used the multivariate method of partial least squares and structural magnetic resonance imaging to identify gray matter brain networks that underlie facial affect processing in both cocaine-dependent (n = 29) and healthy male volunteers (n = 29). We hypothesized that disruptions in neuroendocrine function in cocaine-dependent individuals would explain their impairments in fear recognition by modulating the relationship with the underlying gray matter networks. We found that cocaine-dependent individuals not only exhibited significant impairments in the recognition of fear, but also for facial expressions of anger. Although recognition accuracy of threatening expressions co-varied in all participants with distinctive gray matter networks implicated in fear and anger processing, in cocaine users it was less well predicted by these networks than in controls. The weaker brain-behavior relationships for threat processing were also mediated by distinctly different factors. Fear recognition impairments were influenced by variations in intelligence levels, whereas anger recognition impairments were associated with comorbid opiate dependence and related reduction in testosterone levels. We also observed an inverse relationship between testosterone levels and the duration of crack and opiate use. Our data provide novel insight into the neurobiological basis of abnormal threat processing in cocaine dependence, which may shed light on new opportunities facilitating the psychosocial integration of these patients.

Patterns of progressive cortical thinning in dementia with Lewy bodies (DLB) remain poorly understood. We examined spatiotemporal patterns of cortical thinning and subcortical atrophy over 12 months in DLB (n = 13), compared with Alzheimer's disease (AD) (n = 23) and healthy control subjects (HC) (n = 33). Rates of temporal thinning in DLB were relatively preserved compared with AD. Volumetric analyses subcortical changes revealed that the AD group demonstrated significantly increased hippocampal atrophy (-5.8%) relative to the HC (-1.7%; p < 0.001) and DLB groups (-2.5%, p = 0.006). Significant lateral ventricular expansion was also observed in AD (8.9%) compared with HC (4.3%; p < 0.001) and DLB (4.7%; p = 0.008) at trend level. There was no significant difference in subcortical atrophy and ventricular expansion between DLB and HC. In the DLB group, increased rates of cortical thinning in the frontal and parietal regions were significantly correlated with decline in global cognition (Mini-Mental State Examination) and motor deterioration (Unified Parkinson's Disease Rating Scale 3), respectively. Overall, AD and DLB are characterized by different spatiotemporal patterns of cortical thinning over time. Our findings warrant further consideration of longitudinal cortical thinning as a potential imaging marker to differentiate DLB from AD.

There has been a gradual shift in the definition of Parkinson's disease, from a movement disorder to a neurodegenerative condition affecting multiple cognitive domains. Mild cognitive impairment (PD-MCI) is a frequent comorbidity in PD that is associated with progression to dementia (PDD) and debilitating consequences for patients and caregivers. At present, the pathophysiology underpinning cognitive impairment in PD is not established, although emerging evidence has suggested that multi-modal imaging biomarkers could be useful in the early diagnosis of PD-MCI and PDD, thereby identifying at-risk patients to enable treatment at the earliest stage possible. Structural MRI studies have revealed prominent grey matter atrophy and disruptions of white matter tracts in PDD, although findings in non-demented PD have been more variable. There is a need for further longitudinal studies to clarify the spatial and temporal progression of morphological changes in PD, as well as to assess their underlying involvement in the evolution of cognitive deficits. In this review, we discuss the aetiology and neuropsychological profiles of PD-MCI and PDD, summarize the putative imaging substrates in light of evidence from multi-modal neuroimaging studies, highlight limitations in the present literature, and suggest recommendations for future research.

Theoretical advances in the science of consciousness have proposed that it is concomitant with balanced cortical integration and differentiation, enabled by efficient networks of information transfer across multiple scales. Here, we apply graph theory to compare key signatures of such networks in high-density electroencephalographic data from 32 patients with chronic disorders of consciousness, against normative data from healthy controls. Based on connectivity within canonical frequency bands, we found that patient networks had reduced local and global efficiency, and fewer hubs in the alpha band. We devised a novel topographical metric, termed modular span, which showed that the alpha network modules in patients were also spatially circumscribed, lacking the structured long-distance interactions commonly observed in the healthy controls. Importantly however, these differences between graph-theoretic metrics were partially reversed in delta and theta band networks, which were also significantly more similar to each other in patients than controls. Going further, we found that metrics of alpha network efficiency also correlated with the degree of behavioural awareness. Intriguingly, some patients in behaviourally unresponsive vegetative states who demonstrated evidence of covert awareness with functional neuroimaging stood out from this trend: they had alpha networks that were remarkably well preserved and similar to those observed in the controls. Taken together, our findings inform current understanding of disorders of consciousness by highlighting the distinctive brain networks that characterise them. In the significant minority of vegetative patients who follow commands in neuroimaging tests, they point to putative network mechanisms that could support cognitive function and consciousness despite profound behavioural impairment., Author Summary What are the neural signatures of consciousness? This is an elusive yet fascinating challenge to current cognitive neuroscience, but it takes on an immediate clinical and societal significance in patients diagnosed as vegetative and minimally conscious. In these patients, it leads us to ask whether we can test for the presence of these signatures in the absence of any external signs of awareness. Recent conceptual advances suggest that consciousness requires a dynamic balance between integrated and differentiated networks of information exchange between brain regions. Here we apply this insight to study such networks in patients and compare them to healthy adults. Using the science of graph theory, we show that the rich and diversely connected networks that support awareness are characteristically impaired in patients, lacking the ability to efficiently integrate information across disparate regions via well-connected hubs. We find that the quality of patients' networks also correlates well with their degree of behavioural responsiveness, and some vegetative patients who show signs of hidden awareness have remarkably well-preserved networks similar to healthy adults. Overall, our research highlights distinctive network signatures of pathological unconsciousness, which could improve clinical assessment and help identify patients who are aware despite being uncommunicative.

Ischemia and metabolic dysfunction remain important causes of neuronal loss after head injury, and we have shown that normobaric hyperoxia may rescue such metabolic compromise. This study examines the impact of hyperoxia within injured brain using diffusion tensor imaging (DTI). Fourteen patients underwent DTI at baseline and after 1 hour of 80% oxygen. Using the apparent diffusion coefficient (ADC) we assessed the impact of hyperoxia within contusions and a 1 cm border zone of normal appearing pericontusion, and within a rim of perilesional reduced ADC consistent with cytotoxic edema and metabolic compromise. Seven healthy volunteers underwent imaging at 21%, 60%, and 100% oxygen. In volunteers there was no ADC change with hyperoxia, and contusion and pericontusion ADC values were higher than volunteers (P < 0.01). There was no ADC change after hyperoxia within contusion, but an increase within pericontusion (P < 0.05). We identified a rim of perilesional cytotoxic edema in 13 patients, and hyperoxia resulted in an ADC increase towards normal (P=0.02). We demonstrate that hyperoxia may result in benefit within the perilesional rim of cytotoxic edema. Future studies should address whether a longer period of hyperoxia has a favorable impact on the evolution of tissue injury.

Background & objective Percent whole brain volume change (PBVC) measured from serial MRI scans is widely accepted as a sensitive marker of disease progression in Alzheimer's disease (AD). However, the utility of PBVC in the differential diagnosis of dementia remains to be established. We compared PBVC in AD and dementia with Lewy bodies (DLB), and investigated associations with clinical measures. Methods 72 participants (14 DLBs, 25 ADs, and 33 healthy controls (HCs)) underwent clinical assessment and 3 Tesla T1-weighted MRI at baseline and repeated at 12 months. We used FSL-SIENA to estimate PBVC for each subject. Voxelwise analyses and ANCOVA compared PBVC between DLB and AD, while correlational tests examined associations of PBVC with clinical measures. Results AD had significantly greater atrophy over 1 year (1.8%) compared to DLB (1.0%; p = 0.01) and HC (0.9%; p, Highlights • AD showed faster global and regional brain atrophy in comparison to DLB. • Similar rates of global and regional atrophy were found in DLB and HC. • Longitudinal imaging could improve clinical differentiation of DLB from AD. • Atrophy rates might not be a useful marker to track disease progression in DLB.

The aim of these studies was to provide reference data on intersubject variability and reproducibility of metabolite ratios for Choline/Creatine (Cho/Cr), N-acetyl aspartate/Choline (NAA/Cho) and N-acetyl aspartate/Creatine (NAA/Cr), and individual signal-intensity normalised metabolite concentrations of NAA, Cho and Cr. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical Metabolic Imaging and Data Acquisition Software (MIDAS) sequences were obtained along with standard structural imaging. Metabolite maps were created and regions of interest applied in normalised space. The baseline data from all 32 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were variable across the different brain regions. The within and between session reproducibility measurements were similar for Cho/Cr, NAA/Choline, Cho and Cr (11.8%, 11.4%, 14.3 and 10.6% vs. 11.9%, 11.4%, 13.5% and 10.5% respectively), but for NAA/Creatine and NAA between session reproducibility was lower (9.3% and 9.1% vs. 10.1% and 9.9%; p

We studied neuroinflammation in individuals with late-life, depression, as a risk factor for dementia, using [11C]PK11195 positron emission tomography (PET). Five older participants with major depression and 13 controls underwent PET and multimodal 3T magnetic resonance imaging (MRI), with blood taken to measure C-reactive protein (CRP). We found significantly higher CRP levels in those with late-life depression and raised [11C]PK11195 binding compared with controls in brain regions associated with depression, including subgenual anterior cingulate cortex, and significant hippocampal subfield atrophy in cornu ammonis 1 and subiculum. Our findings suggest neuroinflammation requires further investigation in late-life depression, both as a possible aetiological factor and a potential therapeutic target.

The aim of these studies was to provide reference data on intersubject variability and reproducibility of diffusion tensor imaging. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical diffusion tensor sequences were obtained along with standard structural imaging. Fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity maps were created and regions of interest applied in normalised space. The baseline data from all 26 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were different across the brain. The regional mean (range) coefficient of variation figures for within session reproducibility were 2.1 (0.9–5.5%), 1.2 (0.4–3.9%), 1.2 (0.4–3.8%) and 1.8 (0.4–4.3%) for fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity, and were lower than between session reproducibility measurements (2.4 (1.1–5.9%), 1.9 (0.7–5.7%), 1.7 (0.7–4.7%) and 2.4 (0.9–5.8%); p

BackgroundIncreasing life expectancy necessitates the better understanding of the neurophysiological underpinnings of age-related cognitive changes. The majority of research examining structural-cognitive relationships in aging focuses on the role of age-related changes to grey matter integrity. In the current study, we examined the relationship between age-related changes in white matter and language production. More specifically, we concentrated on word-finding failures, which increase with age.Methodology/principal findingsWe used Diffusion tensor MRI (a technique used to image, in vivo, the diffusion of water molecules in brain tissue) to relate white matter integrity to measures of successful and unsuccessful picture naming. Diffusion tensor images were used to calculate Fractional Anisotropy (FA) images. FA is considered to be a measure of white matter organization/integrity. FA images were related to measures of successful picture naming and to word finding failures using voxel-based linear regression analyses. Successful naming rates correlated positively with white matter integrity across a broad range of regions implicated in language production. However, word finding failure rates correlated negatively with a more restricted region in the posterior aspect of superior longitudinal fasciculus.Conclusions/significanceThe use of DTI-MRI provides evidence for the relationship between age-related white matter changes in specific language regions and word finding failures in old age.

Background Traumatic brain injury is a major cause of morbidity and mortality worldwide. Ameliorating the neurocognitive and physical deficits that accompany traumatic brain injury would be of substantial benefit, but the mechanisms that underlie them are poorly characterized. This study aimed to use diffusion tensor imaging to relate clinical outcome to the burden of white matter injury. Methodology/Principal Findings Sixty-eight patients, categorized by the Glasgow Outcome Score, underwent magnetic resonance imaging at a median of 11.8 months (range 6.6 months to 3.7 years) years post injury. Control data were obtained from 36 age-matched healthy volunteers. Mean fractional anisotropy, apparent diffusion coefficient (ADC), and eigenvalues were obtained for regions of interest commonly affected in traumatic brain injury. In a subset of patients where conventional magnetic resonance imaging was completely normal, diffusion tensor imaging was able to detect clear abnormalities. Significant trends of increasing ADC with worse outcome were noted in all regions of interest. In the white matter regions of interest worse clinical outcome corresponded with significant trends of decreasing fractional anisotropy. Conclusions/Significance This study found that clinical outcome was related to the burden of white matter injury, quantified by diffusivity parameters late after traumatic brain injury. These differences were seen even in patients with the best outcomes and patients in whom conventional magnetic resonance imaging was normal, suggesting that diffusion tensor imaging can detect subtle injury missed by other techniques. An improved in vivo understanding of the pathology of traumatic brain injury, including its distribution and extent, may enhance outcome evaluation and help to provide a mechanistic basis for deficits that remain unexplained by other approaches.