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Impaired cerebral waste clearance (i.e., glymphatics) is evident in aging and neurodegenerative disorders, such as Alzheimer's disease, where an impaired waste clearance system could be related to the accumulation of pathological proteins (e.g., tau). One marker of impaired cerebral clearance is the abundance of enlarged perivascular spaces (PVS). Preclinical studies propose a similar clearance system in the eye, driven by intraocular pressure (IOP). This cross-sectional pilot study explores the link between ocular and cerebral waste clearance by examining the association between MRI-visible PVS, tear fluid total-tau, and IOP. Thirty cognitively healthy participants, all aged over 55 years, underwent 7 Tesla MRI, with PVS visually rated in the centrum semiovale (CSO) and basal ganglia. Tear fluid was collected using paper Schirmer's strips and analyzed for total-tau using enzyme-linked immunosorbent assay. IOP was measured using non-contact tonometry. Partial Spearman's correlation coefficients of eye and brain markers were calculated, adjusted for age, sex, tear fluid-wetting length, and hemispheric region of interest volume. Higher CSO PVS scores in the left and right hemisphere were associated with higher levels of tear fluid total-tau. Higher CSO PVS scores in both hemispheres were related to lower ipsilateral IOP. The exploratory results suggest that higher tear fluid total-tau and a reduced driving force of ocular waste clearance are connected to impaired cerebral waste clearance in cognitive healthy individuals. This study connects the potential ocular glymphatic system to the cerebral waste clearance system. Clarifying waste clearance biology and validating eye biomarkers for cerebral waste clearance could provide treatment targets and diagnostic opportunities for neurological diseases., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pain is a complex experience that involves sensory, emotional, and motivational components. It has been suggested that pain arising from the head and orofacial regions evokes stronger emotional responses than pain from the body. Indeed, recent work in rodents reports different patterns of activation in ascending pain pathways during noxious stimulation of the skin of the face when compared to noxious stimulation of the body. Such differences may dictate different activation patterns in higher brain regions, specifically in those areas processing the affective component of pain. We aimed to use ultra-high field functional magnetic resonance imaging (fMRI at 7-Tesla) to determine whether noxious thermal stimuli applied to the surface of the face and body evoke differential activation patterns within the ascending pain pathway in awake humans (n=16). Compared to the body, noxious heat stimulation to the face evoked more widespread signal changes in prefrontal cortical regions and numerous brainstem and subcortical limbic areas. Moreover, facial pain evoked significantly different signal changes in the lateral parabrachial nucleus, substantia nigra, paraventricular hypothalamus, and paraventricular thalamus, to those evoked by body pain. These results are consistent with recent preclinical findings of differential activation in the brainstem and subcortical limbic nuclei and associated cortices during cutaneous pain of the face when compared with the body. The findings suggest one potential mechanism by which facial pain could evoke a greater emotional impact than that evoked by body pain., Competing Interests: Declaration of competing interest The authors declare there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Response inhibition and interference resolution are often considered subcomponents of an overarching inhibition system that utilizes the so-called cortico-basal-ganglia loop. Up until now, most previous functional magnetic resonance imaging (fMRI) literature has compared the two using between-subject designs, pooling data in the form of a meta-analysis or comparing different groups. Here, we investigate the overlap of activation patterns underlying response inhibition and interference resolution on a within-subject level, using ultra-high field MRI. In this model-based study, we furthered the functional analysis with cognitive modelling techniques to provide a more in-depth understanding of behaviour. We applied the stop-signal task and multi-source interference task to measure response inhibition and interference resolution, respectively. Our results lead us to conclude that these constructs are rooted in anatomically distinct brain areas and provide little evidence for spatial overlap. Across the two tasks, common BOLD responses were observed in the inferior frontal gyrus and anterior insula. Interference resolution relied more heavily on subcortical components, specifically nodes of the commonly referred to indirect and hyperdirect pathways, as well as the anterior cingulate cortex, and pre-supplementary motor area. Our data indicated that orbitofrontal cortex activation is specific to response inhibition. Our model-based approach provided evidence for the dissimilarity in behavioural dynamics between the two tasks. The current work exemplifies the importance of reducing inter-individual variance when comparing network patterns and the value of UHF-MRI for high resolution functional mapping., Competing Interests: Declaration of Competing Interest We have no competing interest to declare regarding this work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Over the past two decades, magnetic resonance imaging (MRI) studies have explored brain activation patterns during acute noxious stimuli. Whilst these human investigations have detailed changes in primarily cortical regions, they have generally not explored discrete changes within small brain areas that are critical in driving behavioural, autonomic, and endocrine responses to pain, such as within subregions of the hypothalamus, amygdala, and midbrain periaqueductal gray matter (PAG). Ultra-high field (7-Tesla) MRI provides enough signal-to-noise at high spatial resolutions to investigate activation patterns within these small brain regions during acute noxious stimulation in awake humans. In this study we used 7T functional MRI to concentrate on hypothalamic, amygdala, and PAG signal changes during acute noxious orofacial stimuli. Noxious heat stimuli were applied in three separate fMRI scans to three adjacent sites on the face in 16 healthy control participants (7 females). Images were processed using SPM12 and custom software, and blood oxygen level dependent signal changes within the hypothalamus, amygdala, and PAG assessed. We identified altered activity within eight unique subregions of the hypothalamus, four unique subregions of the amygdala, and a single region in the lateral PAG. Specifically, within the hypothalamus and amygdala, signal intensity largely decreased during noxious stimulation, and increased in the lateral PAG. Furthermore, we found sex-related differences in discrete regions of the hypothalamus and amygdala. This study reveals that the activity of discrete nuclei during acute noxious thermal stimulation in awake humans., Competing Interests: Declaration of Competing Interest No conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

In this article, we provide an overview of current neuroimaging methods for studying perivascular spaces (PVS) in humans using brain MRI. In recent years, an increasing number of studies highlighted the role of PVS in cerebrospinal/interstial fluid circulation and clearance of cerebral waste products and their association with neurological diseases. Novel strategies and techniques have been introduced to improve the quantification of PVS and to investigate their function and morphological features in physiological and pathological conditions. After a brief introduction on the anatomy and physiology of PVS, we examine the latest technological developments to quantitatively analyze the structure and function of PVS in humans with MRI. We describe the applications, advantages, and limitations of these methods, providing guidance and suggestions on the acquisition protocols and analysis techniques that can be applied to study PVS in vivo. Finally, we review the human neuroimaging studies on PVS across the normative lifespan and in the context of neurological disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Magnetic Resonance Spectroscopy (MRS) allows for the non-invasive quantification of neurochemicals and has the potential to differentiate between the pathologically distinct diseases, multiple sclerosis (MS) and AQP4Ab-positive neuromyelitis optica spectrum disorder (AQP4Ab-NMOSD). In this study we characterised the metabolite profiles of brain lesions in 11 MS and 4 AQP4Ab-NMOSD patients using an optimised MRS methodology at ultra-high field strength (7T) incorporating correction for T2 water relaxation differences between lesioned and normal tissue. MS metabolite results were in keeping with the existing literature: total N-acetylaspartate (NAA) was lower in lesions compared to normal appearing brain white matter (NAWM) with reciprocal findings for myo-Inositol. An unexpected subtlety revealed by our technique was that total NAA differences were likely driven by NAA-glutamate (NAAG), a ubiquitous CNS molecule with functions quite distinct from NAA though commonly quantified together with NAA in MRS studies as total NAA. Surprisingly, AQP4Ab-NMOSD showed no significant differences for total NAA, NAA, NAAG or myo-Inositol between lesion and NAWM sites, nor were there any differences between MS and AQP4Ab-NMOSD for a priori hypotheses. Post-hoc testing revealed a significant correlation between NAWM Ins:NAA and disability (as measured by EDSS) for disease groups combined, driven by the AP4Ab-NMOSD group. Utilising an optimised MRS methodology, our study highlights some under-explored subtleties in MRS profiles, such as the absence of myo-Inositol concentration differences in AQP4Ab-NMOSD brain lesions versus NAWM and the potential influence of NAAG differences between lesions and normal appearing white matter in MS., Competing Interests: Declaration of Competing Interest GT reported no declarations of interest.; YK reported no declarations of interest.; RM reported no declarations of interest.; SM reported receiving travel grants from Biogen, Novartis, Bayer, Merck & Co, Roche, and Almirall and honorarium from Biogen for advisory work.; AW reported no declarations of interest.; AC reported no declarations of interest.; RE reported no declarations of interest.; GDL is supported by the NIHR Biomedical Research Centre (BRC), Oxford and has research funding from the Oxford BRC, MRC(UK), UK MS Society, and National Health and Medical Research (Australia). GD has received travel expenses from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, American Academy of Neurology, and MS Academy, and honoraria as an invited speaker for Novartis, American Academy of Neurology, and MS Academy.; AW reported no declarations of interest.; MC reported no declarations of interest.; IT reported no declarations of interest.; JP reported no declarations of interest.; CS reported no declarations of interest.; UE reported no declarations of interest., (Copyright © 2021. Published by Elsevier Inc.)

Diffusion MRI (dMRI) in ex vivo human brain specimens is an important research tool for neuroanatomical investigations and the validation of dMRI techniques. Many ex vivo dMRI applications have benefited from very high dMRI resolutions achievable on small-bore preclinical or animal MRI scanners for small tissue samples. However, the investigation of entire human brains post mortem provides the important context of entire white matter (WM) network systems and entire gray matter (GM) areas connected through these systems. The investigation of intact ex vivo human brains in large bore systems creates challenges due to the limited gradient performance and transmit radio-frequency (B 1 +) inhomogeneities, specially at ultra-high field (UHF, 7T and higher). To overcome these issues, it is necessary to tailor ex vivo diffusion-weighted sequences specifically for high resolution and high diffusion-weighting. Here, we present k T -dSTEAM, which achieves B 1 + homogenization across whole human brain specimens using parallel transmit (pTx) on a 9.4T MR system. We use k T -dSTEAM to obtain multi-shell high b-value and high resolution diffusion-weighted data in ex vivo whole human brains. Isotropic whole brain data can be acquired at high b-value (6000-8000 s/mm 2 ) at high resolution (1000 μm) and at moderate b-value (3000 s/mm 2 ) at ultra-high isotropic resolution (400 μm). As an illustration of the advantages of the ultra-high resolution, tractography across the WM/GM border shows less of the unwanted gyral crown bias, and more high-curvature paths connecting the sulcal wall than at lower resolution. The k T -dSTEAM also allows for acquisition of T 1 and T 2 weighted images suitable for estimating quantitative T 1 and T 2 maps. Finally, multi-shell analysis of k T -dSTEAM data at variable mixing time (TM) is shown as an approach for ex vivo data analysis which is adapted to the strengths of STEAM diffusion-weighting. Here, we use this gain for multi-orientation modelling and crossing-fiber tractography. We show that multi-shell data allows superior multiple orientation tractography of known crossing fiber structures in the brain stem., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Quantitative Susceptibility Mapping (QSM) provides a way of measuring iron concentration and myelination non-invasively and has the potential of becoming a tool of paramount importance in the study of a host of different pathologies. However, several experimental factors and the physical properties of magnetic susceptibility (χ) can impair the reliability of QSM, and it is therefore essential to assess QSM reproducibility for repeated acquisitions and different field strength. In particular, it has recently been demonstrated that QSM measurements strongly depend on echo time (TE): the same tissue, measured on the same scanner, exhibits different apparent frequency shifts depending on the TE used. This study aims to assess the influence of TE on intra-scanner and inter-scanner reproducibility of QSM, by using MRI systems operating at 3T and 7T. To maximize intra-scanner reproducibility it is necessary to match the TEs of the acquisition protocol, but the application of this rule leads to inconsistent QSM values across scanners operating at different static magnetic field. This study however demonstrates that, provided a careful choice of acquisition parameters, and in particular by using TEs at 3T that are approximately 2.6 times longer than those at 7T, highly reproducible whole-brain χ maps can be achieved also across different scanners, which renders QSM a suitable technique for longitudinal follow-up in clinical settings and in multi-center studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Deep brain stimulation of the subthalamic nucleus (STN) is a widely performed surgical treatment for patients with Parkinson's disease. The goal of the surgery is to place an electrode centered in the motor region of the STN while lowering the effects of electrical stimulation on the non-motor regions. However, distinguishing the motor region from the neighboring associative and limbic areas in individual patients using imaging modalities was until recently difficult to obtain in vivo. Here, using ultra-high field MR imaging, we have performed a dissection of the subdivisions of the STN of individual Parkinson's disease patients. We have acquired 7T diffusion-weighted images of seventeen patients with Parkinson's disease scheduled for deep brain stimulation surgery. Using a structural connectivity-based parcellation protocol, the STN's connections to the motor, limbic, and associative cortical areas were used to map the individual subdivisions of the nucleus. A reproducible patient-specific parcellation of the STN into a posterolateral motor and gradually overlapping central associative area was found in all STNs, taking up on average 55.3% and 55.6% of the total nucleus volume. The limbic area was found in the anteromedial part of the nucleus. Our results suggest that 7T MR imaging may facilitate individualized and highly specific planning of deep brain stimulation surgery of the STN., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The hippocampus, like the neocortex, has a morphological structure that is complex and variable in its folding pattern, especially in the hippocampal head. The current study presents a computational method to unfold hippocampal grey matter, with a particular focus on the hippocampal head where complexity is highest due to medial curving of the structure and the variable presence of digitations. This unfolding was performed on segmentations from high-resolution, T2-weighted 7T MRI data from 12 healthy participants and one surgical patient with epilepsy whose resected hippocampal tissue was used for histological validation. We traced a critical image feature composed of the hippocampal sulcus and stratum radiatum lacunosum-moleculare, (SRLM) in these images, then employed user-guided semi-automated techniques to detect and subsequently unfold the surrounding hippocampal grey matter. This unfolding was performed by solving Laplace's equation in three dimensions of interest (long-axis, proximal-distal, and laminar). The resulting 'unfolded coordinate space' provides an intuitive way of mapping the hippocampal subfields in 2D space (long-axis and proximal-distal), such that similar borders can be applied in the head, body, and tail of the hippocampus independently of variability in folding. This unfolded coordinate space was employed to map intracortical myelin and thickness in relation to subfield borders, which revealed intracortical myelin differences that closely follow the subfield borders used here. Examination of a histological resected tissue sample from a patient with epilepsy reveals that our unfolded coordinate system has biological validity, and that subfield segmentations applied in this space are able to capture features not seen in manual tracing protocols., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The capacity of functional MRI (fMRI) to resolve cortical columns depends on several factors. These include the spatial scale of the columnar pattern, the point-spread of the fMRI response, the voxel size, and the signal-to-noise ratio (SNR) considering thermal and physiological noise. However, it remains unknown how these factors combine, and what is the voxel size that optimizes fMRI of cortical columns. Here we combine current knowledge into a quantitative model of fMRI of realistic patterns of cortical columns with different spatial scales and degrees of irregularity. We compare different approaches for identifying patterns of cortical columns, including univariate and multivariate based detection, multi-voxel pattern analysis (MVPA) based decoding, and high-resolution imaging and reconstruction of the pattern of cortical columns. We present the dependence of the performance of each approach on the parameters of the imaged pattern as well as those of the data acquisition. In addition, we predict voxel sizes that optimize fMRI of cortical columns under various scenarios. We found that all measures associated with multivariate detection and decoding could be approximately calculated from a measure we termed "multivariate contrast-to-noise ratio" (mv-CNR), which is a function of the contrast-to-noise ratio (CNR) and number of voxels. Furthermore, mv-CNR implied that the optimal voxel width for detection and decoding is independent of changes in response amplitude, SNR and imaged volume that are not caused by changes in voxel size. For regular patterns, optimal voxel widths for detection, decoding and imaging/reconstructing the pattern of cortical columns were approximately half the main cycle length of the organization. Optimal voxel widths for irregular patterns were less dependent on the main cycle length, and differed between univariate detection, multivariate detection and decoding, and reconstruction. We compared the effects of different factors of Gradient Echo fMRI at 3 Tesla (T), Gradient Echo fMRI at 7T, and Spin-Echo fMRI at 7T on the detection, decoding, and reconstruction measures considered and found that in all cases the width of the fMRI point-spread had the most significant effect. In contrast, different response amplitudes and noise characteristics played a relatively minor role. We recommend specific voxel widths for optimal univariate detection, for multivariate detection and decoding, and for high-resolution imaging of cortical columns under these three data-acquisition scenarios. Our study supports the planning, optimization, and interpretation of high-resolution fMRI of cortical columns and the decoding of information conveyed by these columns., (Copyright © 2017 Elsevier Inc. All rights reserved.)

There is a long-standing debate about the neurocognitive implementation of mental imagery. One form of mental imagery is the imagery of visual motion, which is of interest due to its naturalistic and dynamic character. However, so far only the mere occurrence rather than the specific content of motion imagery was shown to be detectable. In the current study, the application of multi-voxel pattern analysis to high-resolution functional data of 12 subjects acquired with ultra-high field 7T functional magnetic resonance imaging allowed us to show that imagery of visual motion can indeed activate the earliest levels of the visual hierarchy, but the extent thereof varies highly between subjects. Our approach enabled classification not only of complex imagery, but also of its actual contents, in that the direction of imagined motion out of four options was successfully identified in two thirds of the subjects and with accuracies of up to 91.3% in individual subjects. A searchlight analysis confirmed the local origin of decodable information in striate and extra-striate cortex. These high-accuracy findings not only shed new light on a central question in vision science on the constituents of mental imagery, but also show for the first time that the specific sub-categorical content of visual motion imagery is reliably decodable from brain imaging data on a single-subject level., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Fluid-attenuated inversion recovery (FLAIR) imaging is an important clinical 'work horse' for brain MRI and has proven to facilitate imaging of both intracortical lesions as well as cortical layers at 7T MRI. A prominent observation on 7T FLAIR images is a hyperintense rim at the cortical surface and around the ventricles. We aimed to clarify the anatomical correlates and underlying contrast mechanisms of this hyperintense rim., Materials and Methods: Two experiments with post-mortem human brain tissue were performed. FLAIR and T2-weighted images were obtained at typical in vivo (0.8mm isotropic) and high resolution (0.25mm isotropic). At one location the cortical surface was partly removed, and scanned again. Imaging was followed by histological and immunohistochemical analysis. Additionally, several simulations were performed to evaluate the potential contribution from an artifact due to water diffusion., Results: The hyperintense rim corresponded to the outer - glia rich - layer of the cortex and disappeared upon removal of that layer. At the ventricles, the rim corresponded to the ependymal layer, and was not present at white matter/fluid borders at an artificial cut. The simulations supported the hypothesis that the hyperintense rim reflects the tissue properties in the outer cortical layers (or ependymal layer for the ventricles), and is not merely an artifact, although not all observations were explained by the simulated model of the contrast mechanism., Conclusions: 7T FLAIR seems to amplify the signal from layers I-III of the cortex and the ependyma around the ventricles. Although diffusion of water from layer I into CSF does contribute to this effect, a long T2 relaxation time constant in layer I, and probably also layer II-III, is most likely the major contributor, since the rim disappears upon removal of that layer. This knowledge can help the interpretation of imaging results in cortical development and in patients with cortical pathology., (Copyright © 2014 Elsevier Inc. All rights reserved.)

One of the main goals of ultra-high field MRI is to increase the spatial resolution reached in structural and functional images. Here, the possibility to obtain in vivo images of the human brain with voxel volumes below 0.02mm(3) is shown at 9.4T. To optimize SNR and suppress ringing artifacts, an acquisition-weighted 3D gradient-echo sequence is used, which acquires more averages in the center than in the outer regions of k-space. The weighting function is adjusted to avoid losses in spatial resolution and scan duration compared to a conventional experiment with an equal number of scans and otherwise identical parameters. Spatial resolution and SNR of the weighted sequence are compared to conventionally acquired images by means of phantom and in vivo measurements, and show improved image quality with unchanged spatial resolution and an SNR increase of up to 36% in phantoms and 20%±5% in vivo. Ultra-high resolution images with a voxel volume of 0.014mm(3) (0.13×0.13×0.8mm(3)) from the human brain have sufficient SNR and show fine intracortical detail, demonstrating the potential of the technique. The combination of acquisition-weighted imaging and highly sensitive array coils at ultra-high fields thus makes it possible to obtain images with ultra-high spatial resolutions within acceptable scan times., (© 2013.)