Measuring the iron content of dopaminergic neurons in substantia nigra with MRI relaxometry.

In Parkinson's disease, the depletion of iron-rich dopaminergic neurons in nigrosome 1 of the substantia nigra precedes motor symptoms by two decades. Methods capable of monitoring this neuronal depletion, at an early disease stage, are needed for early diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is particularly suitable for this task due to its sensitivity to tissue microstructure and in particular, to iron. However, the exact mechanisms of MRI contrast in the substantia nigra are not well understood, hindering the development of powerful biomarkers. In the present report, we illuminate the contrast mechanisms in gradient and spin echo MR images in human nigrosome 1 by combining quantitative 3D iron histology and biophysical modeling with quantitative MRI on post mortem human brain tissue. We show that the dominant contribution to the effective transverse relaxation rate (R2*) in nigrosome 1 originates from iron accumulated in the neuromelanin of dopaminergic neurons. This contribution is appropriately described by a static dephasing approximation of the MRI signal. We demonstrate that the R2* contribution from dopaminergic neurons reflects the product of cell density and cellular iron concentration. These results demonstrate that the in vivo monitoring of neuronal density and iron in nigrosome 1 may be feasible with MRI and provide directions for the development of biomarkers for an early detection of dopaminergic neuron depletion in Parkinson's disease.

Mapping Short Association Fibers in the Early Cortical Visual Processing Stream Using In Vivo Diffusion Tractography.

Short association fibers (U-fibers) connect proximal cortical areas and constitute the majority of white matter connections in the human brain. U-fibers play an important role in brain development, function, and pathology but are underrepresented in current descriptions of the human brain connectome, primarily due to methodological challenges in diffusion magnetic resonance imaging (dMRI) of these fibers. High spatial resolution and dedicated fiber and tractography models are required to reliably map the U-fibers. Moreover, limited quantitative knowledge of their geometry and distribution makes validation of U-fiber tractography challenging. Submillimeter resolution diffusion MRI-facilitated by a cutting-edge MRI scanner with 300 mT/m maximum gradient amplitude-was used to map U-fiber connectivity between primary and secondary visual cortical areas (V1 and V2, respectively) in vivo. V1 and V2 retinotopic maps were obtained using functional MRI at 7T. The mapped V1-V2 connectivity was retinotopically organized, demonstrating higher connectivity for retinotopically corresponding areas in V1 and V2 as expected. The results were highly reproducible, as demonstrated by repeated measurements in the same participants and by an independent replication group study. This study demonstrates a robust U-fiber connectivity mapping in vivo and is an important step toward construction of a more complete human brain connectome.

fMRI protocol optimization for simultaneously studying small subcortical and cortical areas at 7 ​T.

Most fundamental cognitive processes rely on brain networks that include both cortical and subcortical structures. Studying such networks using functional magnetic resonance imaging (fMRI) requires a data acquisition protocol that provides blood-oxygenation-level dependent (BOLD) sensitivity across the entire brain. However, when using standard single echo, echo planar imaging protocols, researchers face a tradeoff between BOLD-sensitivity in cortex and in subcortical areas. Multi echo protocols avoid this tradeoff and can be used to optimize BOLD-sensitivity across the entire brain, at the cost of an increased repetition time. Here, we empirically compare the BOLD-sensitivity of a single echo protocol to a multi echo protocol. Both protocols were designed to meet the specific requirements for studying small, iron rich subcortical structures (including a relatively high spatial resolution and short echo times), while retaining coverage and BOLD-sensitivity in cortical areas. The results indicate that both sequences lead to similar BOLD-sensitivity across the brain at 7 â€‹T.

In-vivo magnetic resonance imaging (MRI) of laminae in the human cortex.

The human neocortex is organized radially into six layers which differ in their myelination and the density and arrangement of neuronal cells. This cortical cyto- and myeloarchitecture plays a central role in the anatomical and functional neuroanatomy but is primarily accessible through invasive histology only. To overcome this limitation, several non-invasive MRI approaches have been, and are being, developed to resolve the anatomical cortical layers. As a result, recent studies on large populations and structure-function relationships at the laminar level became possible. Early proof-of-concept studies targeted conspicuous laminar structures such as the stria of Gennari in the primary visual cortex. Recent work characterized the laminar structure outside the visual cortex, investigated the relationship between laminar structure and function, and demonstrated layer-specific maturation effects. This paper reviews the methods and in-vivo MRI studies on the anatomical layers in the human cortex based on conventional and quantitative MRI (excluding diffusion imaging). A focus is on the related challenges, promises and potential future developments. The rapid development of MRI scanners, motion correction techniques, analysis methods and biophysical modeling promise to overcome the challenges of spatial resolution, precision and specificity of systematic imaging of cortical laminae.

Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults - A randomized controlled trial.

INTRODUCTION: The polyphenol resveratrol has been suggested to exert beneficial effects on memory and the aging hippocampus due to calorie-restriction mimicking effects. However, the evidence based on human interventional studies is scarce. We therefore aimed to determine the effects of resveratrol on memory performance, and to identify potential underlying mechanisms using a broad array of blood-based biomarkers as well as hippocampus connectivity and microstructure assessed with ultra-high field magnetic resonance imaging (UHF-MRI). METHODS: In this double-blind, randomized controlled trial, 60 elderly participants (60-79 years) with a wide body-mass index (BMI) range of 21-37 kg/m2 were randomized to receive either resveratrol (200 mg/day) or placebo for 26 weeks (registered at ClinicalTrials.gov: NCT02621554). Baseline and follow-up assessments included the California Verbal Learning Task (CVLT, main outcome), the ModBent task, anthropometry, markers of glucose and lipid metabolism, inflammation and neurotrophins derived from fasting blood, multimodal neuroimaging at 3 and 7 T, and questionnaires to assess confounding factors. RESULTS: Multivariate repeated-measures ANOVA did not detect significant time by group effects for CVLT performance. There was a trend for preserved pattern recognition memory after resveratrol, while performance decreased in the placebo group (n.s., p = 0.07). Further exploratory analyses showed increases in both groups over time in body fat, cholesterol, fasting glucose, interleukin 6, high sensitive C-reactive protein, tumor necrosis factor alpha and in mean diffusivity of the subiculum and presubiculum, as well as decreases in physical activity, brain-derived neurotrophic factor and insulin-like growth factor 1 at follow-up, which were partly more pronounced after resveratrol. DISCUSSION: This interventional study failed to show significant improvements in verbal memory after 6 months of resveratrol in healthy elderly with a wide BMI range. A non-significant trend emerged for positive effects on pattern recognition memory, while possible confounding effects of unfavorable changes in lifestyle behavior, neurotrophins and inflammatory markers occurred. Our findings also indicate the feasibility to detect (un)healthy aging-related changes in measures of hippocampus microstructure after 6 months using 7T diffusion MRI. More studies incorporating a longer duration and larger sample size are needed to determine if resveratrol enhances memory performance in healthy older adults.

Developing 3D microscopy with CLARITY on human brain tissue: Towards a tool for informing and validating MRI-based histology.

Recent breakthroughs in magnetic resonance imaging (MRI) enabled quantitative relaxometry and diffusion-weighted imaging with sub-millimeter resolution. Combined with biophysical models of MR contrast the emerging methods promise in vivo mapping of cyto- and myelo-architectonics, i.e., in vivo histology using MRI (hMRI) in humans. The hMRI methods require histological reference data for model building and validation. This is currently provided by MRI on post mortem human brain tissue in combination with classical histology on sections. However, this well established approach is limited to qualitative 2D information, while a systematic validation of hMRI requires quantitative 3D information on macroscopic voxels. We present a promising histological method based on optical 3D imaging combined with a tissue clearing method, Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging compatible Tissue hYdrogel (CLARITY), adapted for hMRI validation. Adapting CLARITY to the needs of hMRI is challenging due to poor antibody penetration into large sample volumes and high opacity of aged post mortem human brain tissue. In a pilot experiment we achieved transparency of up to 8 mm-thick and immunohistochemical staining of up to 5 mm-thick post mortem brain tissue by a combination of active and passive clearing, prolonged clearing and staining times. We combined 3D optical imaging of the cleared samples with tailored image processing methods. We demonstrated the feasibility for quantification of neuron density, fiber orientation distribution and cell type classification within a volume with size similar to a typical MRI voxel. The presented combination of MRI, 3D optical microscopy and image processing is a promising tool for validation of MRI-based microstructure estimates.

Uncertainty and expectancy deviations require cortico-subcortical cooperation.

In a dynamic and uncertain environment it is beneficial to learn the causal structure of the environment in order to minimize uncertainty. This requires determining estimates of probable outcomes, which will guide expectations about incoming information. One key factor in this learning process is to detect whether an unexpected event constitutes a low probability, but valid outcome, or an outright error. The present 7T-fMRI study investigated the role of subcortical structures in regulating this probabilistic inferential learning process. A new task was designed, in which participants learned to calculate the value, and therefore to anticipate the outcome of different visual sequences. Three types of sequences provided unambiguous, ambiguous, and incongruent contextual evidence and each sequence had two outcomes, which differed in their probability of occurrence. We hypothesized that subcortical regions are necessary when expectations are violated, and that their involvement will depend on the nature of the unexpected event. The results show increased dorsomedial striatal and thalamic activation for less probable sequences; in addition, ambiguous sequences also display larger activation in the red nuclei. Incongruent sequences displayed a pattern of subcortical activation restricted to the dorsolateral and the posterior dorsomedial striatum. These results confirm that different subcortical structures regulate uncertainty and expectancy deviations; this is crucial not only for learning to predict events in the environment, but also for flexible cognitive control in general.

Comparing functional MRI protocols for small, iron-rich basal ganglia nuclei such as the subthalamic nucleus at 7 T and 3 T.

The basal ganglia (BG) form a network of subcortical nuclei. Functional magnetic resonance imaging (fMRI) in the BG could provide insight in its functioning and the underlying mechanisms of Deep Brain Stimulation (DBS). However, fMRI of the BG with high specificity is challenging, because the nuclei are small and variable in their anatomical location. High resolution fMRI at field strengths of 7 Tesla (T) could help resolve these challenges to some extent. A set of MR protocols was developed for functional imaging of the BG nuclei at 3 T and 7 T. The protocols were validated using a stop-signal reaction task (Logan et al. []: J Exp Psychol: Human Percept Perform 10:276-291). Compared with sub-millimeter 7 T fMRI protocols aimed at cortex, a reduction of echo time and spatial resolution was strictly necessary to obtain robust Blood Oxygen Level Dependent (BOLD) sensitivity in the BG. An fMRI protocol at 3 T with identical resolution to the 7 T showed no robust BOLD sensitivity in any of the BG nuclei. The results suggest that the subthalamic nucleus, as well as the substantia nigra, red nucleus, and the internal and external parts of the globus pallidus show increased activation in failed stop trials compared with successful stop and go trials. Hum Brain Mapp 38:3226-3248, 2017. © 2017 Wiley Periodicals, Inc.

Habenula volume increases with disease severity in unmedicated major depressive disorder as revealed by 7T MRI.

The habenula is a paired epithalamic structure involved in the pathogenesis of major depressive disorder (MDD). Evidence comes from its impact on the regulation of serotonergic and dopaminergic neurons, the role in emotional processing and studies on animal models of depression. The present study investigated habenula volumes in 20 unmedicated and 20 medicated MDD patients and 20 healthy controls for the first time by applying a triplanar segmentation algorithm on 7 Tesla magnetic resonance (MR) whole-brain T1 maps. The hypothesis of a right-side decrease of habenula volumes in the MDD patients was tested, and the relationship between volumetric abnormalities and disease severity was exploratively investigated. Absolute and relative total and hemispheric habenula volumes did not differ significantly between the three groups. In the patients with short duration of disease for which medication effects could be ruled out, significant correlations were found between bilateral habenula volumes and HAMD-17- and BDI-II-related severities. In the medicated patients, this positive relationship disappeared. Our findings suggest an involvement of habenula pathology in the beginning of MDD, while general effects independent of severity or stage of disease did not occur. Our findings warrant future combined tractographic and functional investigation using ultra-high-resolution in vivo MR imaging.

Open Science CBS Neuroimaging Repository: Sharing ultra-high-field MR images of the brain.

Magnetic resonance imaging at ultra high field opens the door to quantitative brain imaging at sub-millimeter isotropic resolutions. However, novel image processing tools to analyze these new rich datasets are lacking. In this article, we introduce the Open Science CBS Neuroimaging Repository: a unique repository of high-resolution and quantitative images acquired at 7 T. The motivation for this project is to increase interest for high-resolution and quantitative imaging and stimulate the development of image processing tools developed specifically for high-field data. Our growing repository currently includes datasets from MP2RAGE and multi-echo FLASH sequences from 28 and 20 healthy subjects respectively. These datasets represent the current state-of-the-art in in-vivo relaxometry at 7 T, and are now fully available to the entire neuroimaging community.

Recent applications of UHF-MRI in the study of human brain function and structure: a review.

The increased availability of ultra-high-field (UHF) MRI has led to its application in a wide range of neuroimaging studies, which are showing promise in transforming fundamental approaches to human neuroscience. This review presents recent work on structural and functional brain imaging, at 7 T and higher field strengths. After a short outline of the effects of high field strength on MR images, the rapidly expanding literature on UHF applications of blood-oxygenation-level-dependent-based functional MRI is reviewed. Structural imaging is then discussed, divided into sections on imaging weighted by relaxation time, including quantitative relaxation time mapping, phase imaging and quantitative susceptibility mapping, angiography, diffusion-weighted imaging, and finally magnetization-transfer imaging. The final section discusses studies using the high spatial resolution available at UHF to identify explicit links between structure and function. Copyright © 2015 John Wiley & Sons, Ltd.

The traveling heads: multicenter brain imaging at 7 Tesla.

OBJECTIVE: This study evaluates the inter-site and intra-site reproducibility of 7 Tesla brain imaging and compares it to literature values for other field strengths. MATERIALS AND METHODS: The same two subjects were imaged at eight different 7 T sites. MP2RAGE, TSE, TOF, SWI, EPI as well as B1 and B0 field maps were analyzed quantitatively to assess inter-site reproducibility. Intra-site reproducibility was measured with rescans at three sites. RESULTS: Quantitative measures of MP2RAGE scans showed high agreement. Inter-site and intra-site reproducibility errors were comparable to 1.5 and 3 T. Other sequences also showed high reproducibility between the sites, but differences were also revealed. The different RF coils used were the main source for systematic differences between the sites. CONCLUSION: Our results show for the first time that multi-center brain imaging studies of the supratentorial brain can be performed at 7 T with high reproducibility and similar reliability as at 3T. This study develops the basis for future large-scale 7 T multi-site studies.

High-resolution 7T fMRI of Human Hippocampal Subfields during Associative Learning.

Examining the function of individual human hippocampal subfields remains challenging because of their small sizes and convoluted structures. Previous human fMRI studies at 3 T have successfully detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, CA3, and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study, we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution fMRI scanning at 7 T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases.

Cortical lamina-dependent blood volume changes in human brain at 7 T.

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8-1.6mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans.

A computational framework for ultra-high resolution cortical segmentation at 7Tesla.

This paper presents a computational framework for whole brain segmentation of 7Tesla magnetic resonance images able to handle ultra-high resolution data. The approach combines multi-object topology-preserving deformable models with shape and intensity atlases to encode prior anatomical knowledge in a computationally efficient algorithm. Experimental validation on simulated and real brain images shows accuracy and robustness of the method and demonstrates the benefits of an increased processing resolution.

Dorsomedial striatum involvement in regulating conflict between current and presumed outcomes.

The balance between automatic and controlled processing is essential to human flexible but optimal behavior. On the one hand, the automation of habitual behavior and processing is indispensable, and, on the other hand, strategic processing is needed in light of unexpected, conflicting, or new situations. Using ultra-high-field high-resolution functional magnetic resonance imaging (7T-fMRI), the present study examined the role of subcortical structures in mediating this balance. Participants were asked to judge the congruency of sentences containing a semantically ambiguous or unambiguous word. Ambiguous sentences had three possible resolutions: dominant meaning, subordinate meaning, and incongruent. The dominant interpretation represents the most habitual response, whereas both the subordinate and incongruent options clash with this automatic response, and, hence, require cognitive control. Moreover, the subordinate resolution entails a less expected but correct outcome, while the incongruent condition is simply wrong. The current results reveal the involvement of the anterior dorsomedial striatum in modulating and resolving conflict between actual and expected outcomes, and highlight the importance of cortical and subcortical cooperation in this process.

Investigation of the neurovascular coupling in positive and negative BOLD responses in human brain at 7 T.

Decreases in stimulus-dependent blood oxygenation level dependent (BOLD) signal and their underlying neurovascular origins have recently gained considerable interest. In this study a multi-echo, BOLD-corrected vascular space occupancy (VASO) functional magnetic resonance imaging (fMRI) technique was used to investigate neurovascular responses during stimuli that elicit positive and negative BOLD responses in human brain at 7 T. Stimulus-induced BOLD, cerebral blood volume (CBV), and cerebral blood flow (CBF) changes were measured and analyzed in 'arterial' and 'venous' blood compartments in macro- and microvasculature. We found that the overall interplay of mean CBV, CBF and BOLD responses is similar for tasks inducing positive and negative BOLD responses. Some aspects of the neurovascular coupling however, such as the temporal response, cortical depth dependence, and the weighting between 'arterial' and 'venous' contributions, are significantly different for the different task conditions. Namely, while for excitatory tasks the BOLD response peaks at the cortical surface, and the CBV change is similar in cortex and pial vasculature, inhibitory tasks are associated with a maximum negative BOLD response in deeper layers, with CBV showing strong constriction of surface arteries and a faster return to baseline. The different interplays of CBV, CBF and BOLD during excitatory and inhibitory responses suggests different underlying hemodynamic mechanisms.

Anatomical brain imaging at 7T using two-dimensional GRASE.

PURPOSE: Specific absorption rate is a serious problem at high field strengths, especially for sequences involving many high power radiofrequency pulses, such as turbo spin echo (TSE). GRASE (gradient and spin echo) may overcome this problem by omitting a certain number of refocusing pulses of a TSE sequence, and replacing them with segmented echo-planar imaging readouts. METHODS: GRASE and TSE were compared using similar sequence parameters at a field strength of 7T. The signal-to-noise ratio (SNR) per unit time, contrast, and point spread function (PSF) were determined. High-resolution human brain images were acquired and the implementation of an inversion recovery preparation for T(1) weighting was evaluated. RESULTS: TSE and GRASE images at 7T showed very similar SNR and contrast. The slightly worse PSF for GRASE is balanced by a significant reduction in scan time or increase in spatial coverage compared with TSE. Furthermore, implementing an additional inversion recovery preparation enables the acquisition of T(1)-weighted images with high SNR per unit time. CONCLUSION: GRASE is highly suitable for structural scanning at ultra-high field strengths and is a valid alternative to the commonly used TSE sequence.

Fast accurate MR thermometry using phase referenced asymmetric spin-echo EPI at high field.

PURPOSE: A novel highly accurate method for MR thermometry, effective at high field, is introduced and validated, which corrects for slow and fast field fluctuations by means of reference images. METHODS: An asymmetric spin-echo echo planar imaging sequence was made frequency-selective to water or a reference substance by controlling the slice-select gradient polarity and the duration of the excitation and refocusing radiofrequency pulses. Images were acquired pairwise, and the temperature-sensitive water images were corrected for field fluctuations using the reference images. In a phantom radiofrequency heating experiment, dissolved dimethyl sulfoxide was used as a reference substance. Temperature stability was tested in vivo on the human brain, referenced using subcutaneous scalp fat. Water and fat phase images were acquired only 50 ms apart. Bloch simulations validated the frequency selection accuracy. RESULTS: Asymmetric spin-echo imaging using a simple frequency selection method provides highly accurate referenced MR thermometry in phantoms and in vivo at 7 T. Effects of field fluctuations caused by field drift, breathing, and heart beat were corrected. The technique is highly robust against B1 inhomogeneities. CONCLUSION: Frequency selection using gradient-reversal can enable fast accurate referenced in vivo MR thermometry, assisting thermal characterization of radiofrequency coils and possibly in vivo SAR monitoring.

Mapping of arterial transit time by intravascular signal selection.

The arterial transit time (δa ) is a potentially important physiological parameter which may provide valuable information for the characterization of cerebrovascular diseases. The present study shows that δa can be measured by arterial spin labeling (ASL) applied quasi-continuously in an amplitude-modulated fashion at the human neck. Imaging was performed using short repetition times and excitation flip angles of 90°, which resulted in the selection of an ASL signal of mostly intravascular origin. Model-independent estimates of δa were obtained directly from the temporal shift of the ASL time series. An extended two-compartment perfusion model was developed in order to simulate the basic features of the proposed method and to validate the evaluation procedure. Vascular structures found in human δa maps, such as the circle of Willis or cerebral border zones, hint at the sensitivity of the method to most sizes of arterial vessels. Group-averaged values of δa measured from the carotid bifurcation to the tissue of interest in selected regions of the human brain ranged from 925 ms in the insular cortex to 2000 ms in the thalamic region.