High-Field fMRI for Human Applications: An Overview of Spatial Resolution and Signal Specificity

In the last decade, dozens of 7 Tesla scanners have been purchased or installed around the world, while 3 Tesla systems have become a standard. This increased interest in higher field strengths is driven by a demonstrated advantage of high fields for available signal-to-noise ratio (SNR) in the magnetic resonance signal. Functional imaging studies have additional advantages of increases in both the contrast and the spatial specificity of the susceptibility based BOLD signal. One use of this resultant increase in the contrast to noise ratio (CNR) for functional MRI studies at high field is increased image resolution. However, there are many factors to consider in predicting exactly what kind of resolution gains might be made at high fields, and what the opportunity costs might be. The first part of this article discusses both hardware and image quality considerations for higher resolution functional imaging. The second part draws distinctions between image resolution, spatial specificity, and functional specificity of the fMRI signals that can be acquired at high fields, suggesting practical limitations for attainable resolutions of fMRI experiments at a given field, given the current state of the art in imaging techniques. Finally, practical resolution limitations and pulse sequence options for studies in human subjects are considered

Temporal Multivariate Pattern Analysis (tMVPA): a single trial approach exploring the temporal dynamics of the BOLD signal

fMRI provides spatial resolution that is unmatched by non-invasive neuroimaging techniques. Its temporal dynamics however are typically neglected due to the sluggishness of the hemodynamic signal. We present temporal multivariate pattern analysis (tMVPA), a method for investigating the temporal evolution of neural representations in fMRI data, computed on single-trial BOLD time-courses, leveraging both spatial and temporal components of the fMRI signal. We implemented an expanding sliding window approach that allows identifying the time-window of an effect. We demonstrate that tMVPA can successfully detect condition-specific multivariate modulations over time, in the absence of mean BOLD amplitude differences. Using Monte-Carlo simulations and synthetic data, we quantified family-wise error rate (FWER) and statistical power. Both at the group and single-subject levels, FWER was either at or significantly below 5%. We reached the desired power with 18 subjects and 12 trials for the group level, and with 14 trials in the single-subject scenario. We compare the tMVPA statistical evaluation to that of a linear support vector machine (SVM). SVM outperformed tMVPA with large N and trial numbers. Conversely, tMVPA, leveraging on single trials analyses, outperformed SVM in low N and trials and in a single-subject scenario. Recent evidence suggesting that the BOLD signal carries finer-grained temporal information than previously thought, advocates the need for analytical tools, such as tMVPA, tailored to investigate BOLD temporal dynamics. The comparable performance between tMVPA and SVM, a powerful and reliable tool for fMRI, supports the validity of our technique

Recent Advances in High-Resolution MR Application and Its Implications for Neurovascular Coupling Research

The current understanding of fMRI, regarding its vascular origins, is based on numerous assumptions and theoretical modeling, but little experimental validation exists to support or challenge these models. The known functional properties of cerebral vasculature are limited mainly to the large pial surface and the small capillary level vessels. However, a significant lack of knowledge exists regarding the cluster of intermediate-sized vessels, mainly the intracortical, connecting these two groups of vessels and where, arguably, key blood flow regulation takes place. In recent years, advances in MR technology and methodology have enabled the probing of the brain, both structurally and functionally, at resolutions and coverage not previously attainable. Functional MRI has been utilized to map functional units down to the levels of cortical columns and lamina. These capabilities open new possibilities for investigating neurovascular coupling and testing hypotheses regarding fundamental cerebral organization. Here, we summarize recent cutting-edge MR applications for studying neurovascular and functional imaging, both in humans as well as in animal models. In light of the described imaging capabilities, we put forward a theory in which a cortical column, an ensemble of neurons involved in a particular neuronal computation is spatially correlated with a specific vascular unit, i.e., a cluster of an emerging principle vein surrounded by a set of diving arteries. If indeed such a correlation between functional (neuronal) and structural (vascular) units exist as a fundamental intrinsic cortical feature, one could conceivably delineate functional domains in cortical areas that are not known or have not been identified

The nonhuman primate neuroimaging and neuroanatomy project

Multi-modal neuroimaging projects such as the Human Connectome Project (HCP) and UK Biobank are advancing our understanding of human brain architecture, function, connectivity, and their variability across individuals using high-quality non-invasive data from many subjects. Such efforts depend upon the accuracy of non-invasive brain imaging measures. However, ‘ground truth’ validation of connectivity using invasive tracers is not feasible in humans. Studies using nonhuman primates (NHPs) enable comparisons between invasive and non-invasive measures, including exploration of how “functional connectivity” from fMRI and “tractographic connectivity” from diffusion MRI compare with long-distance connections measured using tract tracing. Our NonHuman Primate Neuroimaging & Neuroanatomy Project (NHP_NNP) is an international effort (6 laboratories in 5 countries) to: (i) acquire and analyze high-quality multi-modal brain imaging data of macaque and marmoset monkeys using protocols and methods adapted from the HCP; (ii) acquire quantitative invasive tract-tracing data for cortical and subcortical projections to cortical areas; and (iii) map the distributions of different brain cell types with immunocytochemical stains to better define brain areal boundaries. We are acquiring high-resolution structural, functional, and diffusion MRI data together with behavioral measures from over 100 individual macaques and marmosets in order to generate non-invasive measures of brain architecture such as myelin and cortical thickness maps, as well as functional and diffusion tractography-based connectomes. We are using classical and next-generation anatomical tracers to generate quantitative connectivity maps based on brain-wide counting of labeled cortical and subcortical neurons, providing ground truth measures of connectivity. Advanced statistical modeling techniques address the consistency of both kinds of data across individuals, allowing comparison of tracer-based and non-invasive MRI-based connectivity measures. We aim to develop improved cortical and subcortical areal atlases by combining histological and imaging methods. Finally, we are collecting genetic and sociality-associated behavioral data in all animals in an effort to understand how genetic variation shapes the connectome and behavior

Denoising Diffusion MRI: Considerations and implications for analysis

Development of diffusion MRI (dMRI) denoising approaches has experienced considerable growth over the last years. As noise can inherently reduce accuracy and precision in measurements, its effects have been well characterised both in terms of uncertainty increase in dMRI-derived features and in terms of biases caused by the noise floor, the smallest measurable signal given the noise level. However, gaps in our knowledge still exist in objectively characterising dMRI denoising approaches in terms of both of these effects and assessing their efficacy. In this work, we reconsider what a denoising method should and should not do and we accordingly define criteria to characterise the performance. We propose a comprehensive set of evaluations, including i) benefits in improving signal quality and reducing noise variance, ii) gains in reducing biases and the noise floor and improving, iii) preservation of spatial resolution, iv) agreement of denoised data against a gold standard, v) gains in downstream parameter estimation (precision and accuracy), vi) efficacy in enabling noise-prone applications, such as ultra-high-resolution imaging. We further provide newly acquired complex datasets (magnitude and phase) with multiple repeats that sample different SNR regimes to highlight performance differences under different scenarios. Without loss of generality, we subsequently apply a number of exemplar patch-based denoising algorithms to these datasets, including Non-Local Means, Marchenko-Pastur PCA (MPPCA) in the magnitude and complex domain and NORDIC, and compare them with respect to the above criteria and against a gold standard complex average of multiple repeats. We demonstrate that all tested denoising approaches reduce noise-related variance, but not always biases from the elevated noise floor. They all induce a spatial resolution penalty, but its extent can vary depending on the method and the implementation. Some denoising approaches agree with the gold standard more than others and we demonstrate challenges in even defining such a standard. Overall, we show that dMRI denoising performed in the complex domain is advantageous to magnitude domain denoising with respect to all the above criteria

Cortical depth dependent functional responses in humans at 7T: improved specificity with 3D GRASE

Ultra high fields (7T and above) allow functional imaging with high contrast-to-noise ratios and improved spatial resolution. This, along with improved hardware and imaging techniques, allow investigating columnar and laminar functional responses. Using gradient-echo (GE) (T2* weighted) based sequences, layer specific responses have been recorded from human (and animal) primary visual areas. However, their increased sensitivity to large surface veins potentially clouds detecting and interpreting layer specific responses. Conversely, spin-echo (SE) (T2 weighted) sequences are less sensitive to large veins and have been used to map cortical columns in humans. T2 weighted 3D GRASE with inner volume selection provides high isotropic resolution over extended volumes, overcoming some of the many technical limitations of conventional 2D SE-EPI, whereby making layer specific investigations feasible. Further, the demonstration of columnar level specificity with 3D GRASE, despite contributions from both stimulated echoes and conventional T2 contrast, has made it an attractive alternative over 2D SE-EPI. Here, we assess the spatial specificity of cortical depth dependent 3D GRASE functional responses in human V1 and hMT by comparing it to GE responses. In doing so we demonstrate that 3D GRASE is less sensitive to contributions from large veins in superficial layers, while showing increased specificity (functional tuning) throughout the cortex compared to GE