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In recent years the field of fMRI research has enjoyed expanded technical abilities related to resolution, as well as use across many fields of brain research. At the same time, the field has also dealt with uncertainty related to many known and unknown effects of artifact in fMRI data. In this review we discuss an emerging fMRI technology, called multi-echo (ME)-fMRI, which focuses on improving the fidelity and interpretability of fMRI. Where the essential problem of standard single-echo fMRI is the indeterminacy of sources of signals, whether BOLD or artifact, this is not the case for ME-fMRI. By acquiring multiple echo images per slice, the ME approach allows T2* decay to be modeled at every voxel at every time point. Since BOLD signals arise by changes in T2* over time, an fMRI experiment sampling the T2* signal decay can be analyzed to distinguish BOLD from artifact signal constituents. While the ME approach has a long history of use in theoretical and validation studies, modern MRI systems enable whole-brain multi-echo fMRI at high resolution. This review covers recent multi-echo fMRI acquisition methods, and the analysis steps for this data to make fMRI at once more principled, straightforward, and powerful. After a brief overview of history and theory, T2* modeling and applications will be discussed. These applications include T2* mapping and combining echoes from ME data to increase BOLD contrast and mitigate dropout artifacts. Next, the modeling of fMRI signal changes to detect signal origins in BOLD-related T2* versus artifact-related S0 changes will be reviewed. A focus is on the use of ME-fMRI data to extract and classify components from spatial ICA, called multi-echo ICA (ME-ICA). After describing how ME-fMRI and ME-ICA lead to a general model for analysis of fMRI signals, applications in animal and human imaging will be discussed. Applications include removing motion artifacts in resting state data at subject and group level. New imaging methods such as multi-band multi-echo fMRI and imaging at 7T are demonstrated throughout the review, and a practical analysis pipeline is described. The review culminates with evidence from recent studies of major boosts in statistical power from using multi-echo fMRI for detecting activation and connectivity in healthy individuals and patients with neuropsychiatric disease. In conclusion, the review shows evidence that the multi-echo approach expands the range of experiments that is practicable using fMRI. These findings suggest a compelling future role of the multi-echo approach in subject-level and clinical fMRI. •An emerging fMRI technology, multi-echo (ME)-fMRI, makes fMRI more interpretable by enabling the detection of BOLD or artifact origins of acquired signals.•This review covers recent multi-echo fMRI acquisition methods, and the analysis steps for this data that make fMRI at once more principled, straightforward, and powerful.•After an overview of history and theory of ME-fMRI, T2* modeling and applications is discussed.•A focus is on the use of ME-fMRI data to extract and classify components from spatial ICA, called multi-echo ICA (ME-ICA).•New imaging methods such as multi-band multi-echo fMRI and imaging at 7T are demonstrated throughout the review, and a practical analysis pipeline is described.

•A new software toolbox is introduced for layer-specific functional MRI: LayNii.•LayNii is a suite of command-line executable C++ programs for Linux, Windows, and macOS.•LayNii is designed for layer-fMRI data that suffer from SNR and coverage constraints.•LayNii performs layerification in the native voxel space of functional data.•LayNii performs layer-smoothing, GE-BOLD deveining, QA, and VASO analysis. High-resolution fMRI in the sub-millimeter regime allows researchers to resolve brain activity across cortical layers and columns non-invasively. While these high-resolution data make it possible to address novel questions of directional information flow within and across brain circuits, the corresponding data analyses are challenged by MRI artifacts, including image blurring, image distortions, low SNR, and restricted coverage. These challenges often result in insufficient spatial accuracy of conventional analysis pipelines. Here we introduce a new software suite that is specifically designed for layer-specific functional MRI: LayNii. This toolbox is a collection of command-line executable programs written in C/C++ and is distributed opensource and as pre-compiled binaries for Linux, Windows, and macOS. LayNii is designed for layer-fMRI data that suffer from SNR and coverage constraints and thus cannot be straightforwardly analyzed in alternative software packages. Some of the most popular programs of LayNii contain ‘layerification’ and columnarization in the native voxel space of functional data as well as many other layer-fMRI specific analysis tasks: layer-specific smoothing, model-based vein mitigation of GE-BOLD data, quality assessment of artifact dominated sub-millimeter fMRI, as well as analyses of VASO data. [Display omitted]

Locus Coeruleus (LC) is a neuromelanin-rich brainstem structure that is the source of noradrenaline in the cortex and is thought to modulate attention and memory. LC imaging in vivo is commonly performed with a 2D T1-weighted Turbo Spin Echo (TSE) MRI sequence, an approach that suffers from several drawbacks at 3T, including long acquisition times and highly anisotropic spatial resolution. In this study, we developed a high-resolution Magnetization Transfer (MT) sequence for LC imaging at both 7T and 3T and compared its performance to a TSE sequence. Results indicate that LC imaging can be achieved with an MT sequence at both 7 and 3T at higher spatial resolution than the 3T TSE. Furthermore, we investigated whether the currently disputed source of contrast in the LC region with a TSE sequence relates to MT effects or shortened T1 and T2* due to increased iron concentration. Our results suggest that the contrast in the LC area relates to MT effects. To conclude, in this study we managed to image the LC, for the first time, at 7T and at an increased resolution compared to the current state-of-the-art. Imaging the LC is highly relevant for clinical diagnostics as structural tissue properties of the LC may hold promise as a biomarker in neurodegenerative diseases. •Locus coeruleus MRI contrast is predominantly due to Magnetization Transfer effects.•Locus coeruleus imaging was achieved at 7T with a Magnetization Transfer approach.•Locus coeruleus MRI contrast was not feasible with T1 or T2* weighted images.•At 7T and 3T, the proposed approach outperformed the standard one in resolution.

The human brain coordinates a wide variety of motor activities. On a large scale, the cortical motor system is topographically organized such that neighboring body parts are represented by neighboring brain areas. This homunculus-like somatotopic organization along the central sulcus has been observed using neuroimaging for large body parts such as the face, hands and feet. However, on a finer scale, invasive electrical stimulation studies show deviations from this somatotopic organization that suggest an organizing principle based on motor actions rather than body part moved. It has not been clear how the action-map organization principle of the motor cortex in the mesoscopic (sub-millimeter) regime integrates into a body map organization principle on a macroscopic scale (cm). Here we developed and applied advanced mesoscopic (sub-millimeter) fMRI and analysis methodology to non-invasively investigate the functional organization topography across columnar and laminar structures in humans. Compared to previous methods, in this study, we could capture locally specific blood volume changes across entire brain regions along the cortical curvature. We find that individual fingers have multiple mirrored representations in the primary motor cortex depending on the movements they are involved in. We find that individual digits have cortical representations up to 3 ​mm apart from each other arranged in a column-like fashion. These representations are differentially engaged depending on whether the digits’ muscles are used for different motor actions such as flexion movements, like grasping a ball or retraction movements like releasing a ball. This research provides a starting point for non-invasive investigation of mesoscale topography across layers and columns of the human cortex and bridges the gap between invasive electrophysiological investigations and large coverage non-invasive neuroimaging. [Display omitted] •A sub-millimeter fMRI method is developed to image neural microcircuitry in humans.•The method can capture large FOVs with thin slices for ‛columnar’ and ‛laminar’ mapping.•An analysis pipeline is developed to investigate topographical representations that have only been visible in animals so far.•Novel findings include a mirrored finger representation in the human motor cortex.

Quantitative susceptibility mapping (QSM) allows new insights into tissue composition and organization by assessing its magnetic property. Previous QSM studies have already demonstrated that magnetic susceptibility is highly sensitive to myelin density and fiber orientation as well as to para- and diamagnetic trace elements. Image resolution in QSM with current approaches is limited by the long acquisition time of 3D scans and the need for high signal to noise ratio (SNR) to solve the dipole inversion problem. We here propose a new total-generalized-variation (TGV) based method for QSM reconstruction, which incorporates individual steps of phase unwrapping, background field removal and dipole inversion in a single iteration, thus yielding a robust solution to the reconstruction problem. This approach has beneficial characteristics for low SNR data, allowing for phase data to be rapidly acquired with a 3D echo planar imaging (EPI) sequence. The proposed method was evaluated with a numerical phantom and in vivo at 3 and 7T. Compared to total variation (TV), TGV–QSM enforced higher order smoothness which yielded solutions closer to the ground truth and prevented stair-casing artifacts. The acquisition time for images with 1mm isotropic resolution and whole brain coverage was 10s on a clinical 3Tesla scanner. In conclusion, 3D EPI acquisition combined with single-step TGV reconstruction yields reliable QSM images of the entire brain with 1mm isotropic resolution in seconds. The short acquisition time combined with the robust reconstruction may enable new QSM applications in less compliant populations, clinical susceptibility tensor imaging, and functional resting state examinations. •QSM of the entire brain with 1mm resolution can be acquired in 10s at 3T.•Background field removal and dipole inversion are a single reconstruction step.•TGV instead of TV penalty avoids stair-casing artifacts in the QSM reconstruction.

Laminar fMRI at ultra-high magnetic field strength is typically carried out using the Blood Oxygenation Level-Dependent (BOLD) contrast. Despite its unrivalled sensitivity to detecting activation, the BOLD contrast is limited in its spatial specificity due to signals stemming from intra-cortical ascending and pial veins. Alternatively, regional changes in perfusion (i.e., cerebral blood flow through tissue) are colocalised to neuronal activation, which can be non-invasively measured using Arterial Spin Labelling (ASL) MRI. In addition, ASL provides a quantitative marker of neuronal activation in terms of perfusion signal, which is simultaneously acquired along with the BOLD signal. However, ASL for laminar imaging is challenging due to the lower SNR of the perfusion signal and higher RF power deposition i.e., specific absorption rate (SAR) of ASL sequences. In the present study, we present for the first time in humans, isotropic sub-millimetre spatial resolution functional perfusion images using Flow-sensitive Alternating Inversion Recovery (FAIR) ASL with a 3D-EPI readout at 7 T. We show that robust statistical activation maps can be obtained with perfusion-weighting in a single session. We observed the characteristic BOLD amplitude increase towards the superficial laminae, and, in apparent discrepancy, the relative perfusion profile shows a decrease of the amplitude and the absolute perfusion profile a much smaller increase towards the cortical surface. Considering the draining vein effect on the BOLD signal using model-based spatial “convolution”, we show that the empirically measured perfusion and BOLD profiles are, in fact, consistent with each other. This study demonstrates that laminar perfusion fMRI in humans is feasible at 7 T and that caution must be exercised when interpreting BOLD signal laminar profiles as direct representation of the cortical distribution of neuronal activity.

Earlier research in cats has shown that both cerebral blood volume (CBV) and cerebral blood flow (CBF) can be used to identify layer-dependent fMRI activation with spatial specificity superior to gradient-echo blood-oxygen-level-dependent (BOLD) contrast (Jin and Kim, 2008a). CBF contrast of perfusion fMRI at ultra-high field has not been widely applied in humans to measure laminar activity due to its low sensitivity, while CBV contrast for fMRI using vascular space occupancy (VASO) has been successfully used. However, VASO can be compromised by interference of blood in-flow effects and a temporally limited acquisition window around the blood-nulling time point. Here, we proposed to use DANTE (Delay Alternating with Nutation for Tailored Excitation) pulse trains combined with 3D-EPI to acquire an integrated VASO and perfusion (VAPER) contrast. The signal origin of the VAPER contrast was theoretically evaluated with respect to its CBV and CBF contributions using a four-compartment simulation model. The feasibility of VAPER to measure layer-dependent activity was empirically investigated in human primary motor cortex at 7 ​T. We demonstrated this new tool, with its highly specified functional layer profile, robust reproducibility, and improved sensitivity, to allow investigation of layer-specific cortical functions.

•We collected 0.35 mm isotropic quantitative T2* brain images using MRI at 7 Tesla in living humans.•We show that this dataset can be used to visualize fine details of cortical substructures including clear demarcations of layers and vessels.•We provide quantitative measurements of depth-dependent (also referred as layer-dependent) T2* (and R2*)values in primary visual and auditory cortices. Mesoscopic (0.1-0.5 mm) interrogation of the living human brain is critical for advancing neuroscience and bridging the resolution gap with animal models. Despite the variety of MRI contrasts measured in recent years at the mesoscopic scale, in vivo quantitative imaging of T2* has not been performed. Here we provide a dataset containing empirical T2* measurements acquired at 0.35 × 0.35 × 0.35 mm3 voxel resolution using 7 Tesla MRI. To demonstrate unique features and high quality of this dataset, we generate flat map visualizations that reveal fine-scale cortical substructures such as layers and vessels, and we report quantitative depth-dependent T2* (as well as R2*) values in primary visual cortex and auditory cortex that are highly consistent across subjects. This dataset is freely available at https://doi.org/10.17605/OSF.IO/N5BJ7, and may prove useful for anatomical investigations of the human brain, as well as for improving our understanding of the basis of the T2*-weighted (f)MRI signal.

•Dual-echo out-in simultaneous multi-slice spiral readout was successfully implemented in an ASL sequence for concurrent measurements of CBF and BOLD contrasts at 7T.•In-vivo measurements resulted in robust detection of perfusion and BOLD activation, with no loss of sensitivity compared to Cartesian acquisitions.•For 7T fMRI applications at moderate spatial resolution (2 mm isotropic), dual-echo spiral acquisitions show promise for simultaneous acquisitions of non-BOLD and BOLD contrasts with no loss in temporal resolution. Measurement of cerebral blood flow (CBF) using the Arterial Spin Labeling (ASL) technique is a desirable fMRI approach due to the higher specificity of CBF to the site of neural activation. However, ASL has inherent limitations, such as a low signal-to-noise ratio (SNR) and low coverage/resolution due to the limited readout window following the labeling. Recently, ASL has been implemented at ultra-high field (UHF) strengths in an attempt to mitigate the SNR challenges. Even though ASL intrinsically allows concurrent acquisition of CBF and BOLD contrasts, a compromise in the echo time (TE) for either of the contrasts is inevitable with single-echo acquisitions. Long durations of the Cartesian EPI readout do not allow for multi-echo acquisitions for resolutions ≤2 mm where both contrasts can be acquired at their optimal TE at UHF. With its higher acquisition efficiency, single-shot spiral imaging provides a promising alternative to EPI, and with a dual-echo, out-in trajectory allows both CBF and BOLD contrasts to be acquired at their respective optimal TE. In this work, we implemented a dual-echo spiral out-in ASL sequence with simultaneous multi-slice (SMS) readout for increased coverage, and validated its application to fMRI with a visuomotor paradigm. Conventional Cartesian EPI acquisitions with matched parameters served as a reference. The dual-echo spiral ASL acquisitions resulted in robust CBF and BOLD activations maps. The absolute and relative CBF changes measured with the dual-echo spiral readout were in agreement with previous reports in the literature as well as the reference Cartesian acquisitions. The BOLD response amplitude was higher compared to the Cartesian acquisitions, attributable to a more optimal TE of the second echo. In conclusion, dual-echo spiral out-in SMS acquisition shows promise for concurrent acquisitions of BOLD and non-BOLD contrasts that require a short TE, with no loss in temporal resolution.

•ME-ICA and ICA-AROMA provide effective denoising for multi-echo 7T fMRI data.•High tSNR can be achieved in the brainstem with a multi-echo acquisition at 7T.•After ME-ICA, the data is best post-processed to correct for spatially diffuse noise.•ICA-AROMA-aggr might be too aggressive in denoising the multi-echo 7T fMRI data. In functional magnetic resonance imaging (fMRI) of the brain the measured signal is corrupted by several (e.g. physiological, motion, and thermal) noise sources and depends on the image acquisition. Imaging at ultrahigh field strength is becoming increasingly popular as it offers increased spatial accuracy. The latter is of particular benefit in brainstem neuroimaging given the small cross-sectional area of most nuclei. However, physiological noise scales with field strength in fMRI acquisitions. Although this problem is in part solved by decreasing voxel size, it is clear that adequate physiological denoising is of utmost importance in brainstem-focused fMRI experiments. Multi-echo sequences have been reported to facilitate highly effective denoising through TE-dependence of Blood Oxygen Level Dependent (BOLD) signals, in a denoising method referred to as multi-echo independent component analysis (ME-ICA). It has not been explored previously how ME-ICA compares to other data-driven denoising approaches at ultrahigh field strength. In the current study, we compared the efficacy of several denoising methods, including anatomical component based correction (aCompCor), Automatic Removal of Motion Artifacts (ICA-AROMA) aggressive and non-aggressive options, ME-ICA, and a combination of ME-ICA and aCompCor. We assessed several data quality metrics, including temporal signal-to-noise ratio (tSNR), delta variation signal (DVARS), spectral density of the global signal, functional connectivity and Shannon spectral entropy. Moreover, we looked at the ability of each method to uncouple the global signal and respiration. In line with previous reports at lower field strengths, we demonstrate that after applying ME-ICA, the data is best post-processed in order to remove spatially diffuse noise with a method such as aCompCor. Our findings indicate that ME-ICA combined with aCompCor and the aggressive option of ICA-AROMA are highly effective denoising approaches for multi-echo data acquired at 7T. ME-ICA combined with aCompCor potentially preserves more signal-of-interest as compared to the aggressive option of ICA-AROMA.