Reliability of resting-state functional connectivity in the human spinal cord: Assessing the impact of distinct noise sources.

The investigation of spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord, where it has stimulated interest from a clinical perspective. A number of resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated robust functional connectivity between the time series of BOLD fluctuations in bilateral dorsal horns and between those in bilateral ventral horns, in line with the functional neuroanatomy of the spinal cord. A necessary step prior to extension to clinical studies is assessing the reliability of such resting-state signals, which we aimed to do here in a group of 45 healthy young adults at the clinically prevalent field strength of 3T. When investigating connectivity in the entire cervical spinal cord, we observed fair to good reliability for dorsal-dorsal and ventral-ventral connectivity, whereas reliability was poor for within- and between-hemicord dorsal-ventral connectivity. Considering how prone spinal cord fMRI is to noise, we extensively investigated the impact of distinct noise sources and made two crucial observations: removal of physiological noise led to a reduction in functional connectivity strength and reliability - due to the removal of stable and participant-specific noise patterns - whereas removal of thermal noise considerably increased the detectability of functional connectivity without a clear influence on reliability. Finally, we also assessed connectivity within spinal cord segments and observed that while the pattern of connectivity was similar to that of whole cervical cord, reliability at the level of single segments was consistently poor. Taken together, our results demonstrate the presence of reliable resting-state functional connectivity in the human spinal cord even after thoroughly accounting for physiological and thermal noise, but at the same time urge caution if focal changes in connectivity (e.g. due to segmental lesions) are to be studied, especially in a longitudinal manner.

Rapid volumetric brain changes after acute psychosocial stress.

Stress is an important trigger for brain plasticity: Acute stress can rapidly affect brain activity and functional connectivity, and chronic or pathological stress has been associated with structural brain changes. Measures of structural magnetic resonance imaging (MRI) can be modified by short-term motor learning or visual stimulation, suggesting that they also capture rapid brain changes. Here, we investigated volumetric brain changes (together with changes in T1 relaxation rate and cerebral blood flow) after acute stress in humans as well as their relation to psychophysiological stress measures. Sixty-seven healthy men (25.8±2.7 years) completed a standardized psychosocial laboratory stressor (Trier Social Stress Test) or a control version while blood, saliva, heart rate, and psychometrics were sampled. Structural MRI (T1 mapping / MP2RAGE sequence) at 3T was acquired 45 min before and 90 min after intervention onset. Grey matter volume (GMV) changes were analysed using voxel-based morphometry. Associations with endocrine, autonomic, and subjective stress measures were tested with linear models. We found significant group-by-time interactions in several brain clusters including anterior/mid-cingulate cortices and bilateral insula: GMV was increased in the stress group relative to the control group, in which several clusters showed a GMV decrease. We found a significant group-by-time interaction for cerebral blood flow, and a main effect of time for T1 values (longitudinal relaxation time). In addition, GMV changes were significantly associated with state anxiety and heart rate variability changes. Such rapid GMV changes assessed with VBM may be induced by local tissue adaptations to changes in energy demand following neural activity. Our findings suggest that endogenous brain changes are counteracted by acute psychosocial stress, which emphasizes the importance of considering homeodynamic processes and generally highlights the influence of stress on the brain.

High angular resolution susceptibility imaging and estimation of fiber orientation distribution functions in primate brain.

Uncovering brain-tissue microstructure including axonal characteristics is a major neuroimaging research focus. Within this scope, anisotropic properties of magnetic susceptibility in white matter have been successfully employed to estimate primary axonal trajectories using mono-tensorial models. However, anisotropic susceptibility has not yet been considered for modeling more complex fiber structures within a voxel, such as intersecting bundles, or an estimation of orientation distribution functions (ODFs). This information is routinely obtained by high angular resolution diffusion imaging (HARDI) techniques. In applications to fixed tissue, however, diffusion-weighted imaging suffers from an inherently low signal-to-noise ratio and limited spatial resolution, leading to high demands on the performance of the gradient system in order to mitigate these limitations. In the current work, high angular resolution susceptibility imaging (HARSI) is proposed as a novel, phase-based methodology to estimate ODFs. A multiple gradient-echo dataset was acquired in an entire fixed chimpanzee brain at 61 orientations by reorienting the specimen in the magnetic field. The constant solid angle method was adapted for estimating phase-based ODFs. HARDI data were also acquired for comparison. HARSI yielded information on whole-brain fiber architecture, including identification of peaks of multiple bundles that resembled features of the HARDI results. Distinct differences between both methods suggest that susceptibility properties may offer complementary microstructural information. These proof-of-concept results indicate a potential to study the axonal organization in post-mortem primate and human brain at high resolution.

Multi-echo investigations of positive and negative CBF and concomitant BOLD changes.

Unlike the positive blood oxygenation level-dependent (BOLD) response (PBR), commonly taken as an indication of an 'activated' brain region, the physiological origin of negative BOLD signal changes (i.e. a negative BOLD response, NBR), also referred to as 'deactivation' is still being debated. In this work, an attempt was made to gain a better understanding of the underlying mechanism by obtaining a comprehensive measure of the contributing cerebral blood flow (CBF) and its relationship to the NBR in the human visual cortex, in comparison to a simultaneously induced PBR in surrounding visual regions. To overcome the low signal-to-noise ratio (SNR) of CBF measurements, a newly developed multi-echo version of a center-out echo planar-imaging (EPI) readout was employed with pseudo-continuous arterial spin labeling (pCASL). It achieved very short echo and inter-echo times and facilitated a simultaneous detection of functional CBF and BOLD changes at 3 T with improved sensitivity. Evaluations of the absolute and relative changes of CBF and the effective transverse relaxation rate, R2*, the coupling ratios, and their dependence on CBF at rest, CBFrest, indicated differences between activated and deactivated regions. Analysis of the shape of the respective functional responses also revealed faster negative responses with more pronounced post-stimulus transients. Resulting differences in the flow-metabolism coupling ratios were further examined for potential distinctions in the underlying neuronal contributions.

Automated slice-specific z-shimming for functional magnetic resonance imaging of the human spinal cord.

Functional magnetic resonance imaging (fMRI) of the human spinal cord faces many challenges, such as signal loss due to local magnetic field inhomogeneities. This issue can be addressed with slice-specific z-shimming, which compensates for the dephasing effect of the inhomogeneities using a slice-specific gradient pulse. Here, we aim to address outstanding issues regarding this technique by evaluating its effects on several aspects that are directly relevant for spinal fMRI and by developing two automated procedures in order to improve upon the time-consuming and subjective nature of manual selection of z-shims: one procedure finds the z-shim that maximizes signal intensity in each slice of an EPI reference-scan and the other finds the through-slice field inhomogeneity for each EPI-slice in field map data and calculates the required compensation gradient moment. We demonstrate that the beneficial effects of z-shimming are apparent across different echo times, hold true for both the dorsal and ventral horn, and are also apparent in the temporal signal-to-noise ratio (tSNR) of EPI time-series data. Both of our automated approaches were faster than the manual approach, lead to significant improvements in gray matter tSNR compared to no z-shimming and resulted in beneficial effects that were stable across time. While the field-map-based approach performed slightly worse than the manual approach, the EPI-based approach performed as well as the manual one and was furthermore validated on an external corticospinal data-set (N > 100). Together, automated z-shimming may improve the data quality of future spinal fMRI studies and lead to increased reproducibility in longitudinal studies.

Deconvolution-based distortion correction of EPI using analytic single-voxel point-spread functions.

PURPOSE: To develop a postprocessing algorithm that corrects geometric distortions due to spatial variations of the static magnetic field amplitude, B0 , and effects from relaxation during signal acquisition in EPI. THEORY AND METHODS: An analytic, complex point-spread function is deduced for k-space trajectories of EPI variants and applied to corresponding acquisitions in a resolution phantom and in human volunteers at 3 T. With the analytic point-spread function and experimental maps of B0 (and, optionally, the effective transverse relaxation time, T2* ) as input, a point-spread function matrix operator is devised for distortion correction by a Thikonov-regularized deconvolution in image space. The point-spread function operator provides additional information for an appropriate correction of the signal intensity distribution. A previous image combination algorithm for acquisitions with opposite phase blip polarities is adapted to the proposed method to recover destructively interfering signal contributions. RESULTS: Applications of the proposed deconvolution-based distortion correction ("DecoDisCo") algorithm demonstrate excellent distortion corrections and superior performance regarding the recovery of an undistorted intensity distribution in comparison to a multifrequency reconstruction. Examples include full and partial Fourier standard EPI scans as well as double-shot center-out trajectories. Compared with other distortion-correction approaches, DecoDisCo permits additional deblurring to obtain sharper images in cases of significant T2* effects. CONCLUSION: Robust distortion corrections in EPI acquisitions are feasible with high quality by regularized deconvolution with an analytic point-spread function. The general algorithm, which is publicly released on GitHub, can be straightforwardly adapted for specific EPI variants or other acquisition schemes.

Increased sensitivity and signal-to-noise ratio in diffusion-weighted MRI using multi-echo acquisitions.

Post-mortem diffusion MRI (dMRI) enables acquisitions of structural imaging data with otherwise unreachable resolutions - at the expense of longer scanning times. These data are typically acquired using highly segmented image acquisition strategies, thereby resulting in an incomplete signal decay before the MRI encoding continues. Especially in dMRI, with low signal intensities and lengthy contrast encoding, such temporal inefficiency translates into reduced image quality and longer scanning times. This study introduces Multi Echo (ME) acquisitions to dMRI on a human MRI system - a time-efficient approach, which increases SNR (Signal-to-Noise Ratio) and reduces noise bias for dMRI images. The benefit of the introduced ME-dMRI method was validated using numerical Monte Carlo simulations and showcased on a post-mortem brain of a wild chimpanzee. The proposed Maximum Likelihood Estimation echo combination results in an optimal SNR without detectable signal bias. The combined strategy comes at a small price in scanning time (here 30% additional) and leads to a substantial SNR increase (here white matter: ~ 1.6x, equivalent to 2.6 averages, grey matter: ~ 1.9x, equivalent to 3.6 averages) and a general reduction of the noise bias.

A new approach to Z-spectrum acquisition: prospective baseline enhancement (PROBE) for CEST/Nuclear Overhauser Effect.

PURPOSE: To develop a prospective baseline enhancement that compensates for intermingled background effects in Z-spectra to achieve sensitivity enhancement of peaks related to CEST and nuclear Overhauser effect. METHODS: An MRI sequence-specific compensation of background effects is achieved through variation of the pulsed saturation power, ω1,max , with the chemical shift, δ . After a "scout acquisition" of a standard Z-spectrum, the background is modeled through an appropriate spin system. Subsequently, an optimization procedure yields ω1,max(δ) values that compensate for background contributions yielding a flat baseline. Contributions from metabolites not considered in the optimization procedure are enhanced as distinct perturbations to the baseline. For experimental verification, mapping of the lactate concentration in the presence of cross-linked bovine serum albumin was performed in phantoms at 7 T. As proof of concept, explorative experiments were performed in healthy human subjects at 3 T. RESULTS: Nuisance contributions from direct water saturation, macromolecular magnetization transfer, and exchanging background protons were successfully removed from the Z-spectrum in phantoms and in brain tissue. The lactate methyl, methine, and hydroxyl peaks were readily observable in vitro. The peak areas correlated linearly with known concentrations. Improvement of the detection limit was achieved by a sparse distribution of saturation frequencies, allowing for more efficient signal averaging. CONCLUSION: An optimization framework for high-resolution metabolite mapping by means of CEST/nuclear Overhauser effect was developed. It offers full flexibility to select spin-pool moieties, whose influence on the Z-spectrum will be compensated. Deviations from this background model will provide a contrast at the respective offset frequencies.

Characterization of pseudo-continuous arterial spin labeling: Simulations and experimental validation.

PURPOSE: To characterize pseudo-continuous arterial spin labeling (pCASL) through simulations of spin inversion and to discuss suitable parameter settings for measuring cerebral perfusion. METHODS: Simulations of arterial spin inversion in pCASL were performed based on the Bloch equation. Both the labeling and the control condition of pCASL were analyzed separately, and the labeling efficiency, α, was calculated depending on the averages of both, the radiofrequency (RF) field amplitude and labeling gradient strength. The influence of additional parameters characterizing the pCASL pulse sequence, such as the interpulse interval, the RF duty cycle, and the labeling gradient, also were studied. An echo-planar imaging protocol utilizing a short repetition time was developed for experimental validation by estimating α in the internal carotid artery. RESULTS: The effectiveness of the control condition of balanced pCASL crucially depends on both the labeling gradient amplitude and the RF duty cycle. The use of large values for both quantities improves the insensitivity to off-resonance gradients caused by magnetic field inhomogeneities. In addition, balanced and unbalanced pCASL become comparably effective. CONCLUSION: By use of appropriate parameter settings, labeling efficiencies of around 90% are feasible, independent of expected off-resonance gradients at 3T. Magn Reson Med 79:1638-1649, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Predictions interact with missing sensory evidence in semantic processing areas.

Human brain function draws on predictive mechanisms that exploit higher-level context during lower-level perception. These mechanisms are particularly relevant for situations in which sensory information is compromised or incomplete, as for example in natural speech where speech segments may be omitted due to sluggish articulation. Here, we investigate which brain areas support the processing of incomplete words that were predictable from semantic context, compared with incomplete words that were unpredictable. During functional magnetic resonance imaging (fMRI), participants heard sentences that orthogonally varied in predictability (semantically predictable vs. unpredictable) and completeness (complete vs. incomplete, i.e. missing their final consonant cluster). The effects of predictability and completeness interacted in heteromodal semantic processing areas, including left angular gyrus and left precuneus, where activity did not differ between complete and incomplete words when they were predictable. The same regions showed stronger activity for incomplete than for complete words when they were unpredictable. The interaction pattern suggests that for highly predictable words, the speech signal does not need to be complete for neural processing in semantic processing areas. Hum Brain Mapp 37:704-716, 2016. © 2015 Wiley Periodicals, Inc.

Three-dimensional echo-planar cine imaging of cerebral blood supply using arterial spin labeling.

OBJECTIVE: Echo-planar imaging (EPI) with CYlindrical Center-out spatiaL Encoding (EPICYCLE) is introduced as a novel hybrid three-dimensional (3D) EPI technique. Its suitability for the tracking of a short bolus created by pseudo-continuous arterial spin labeling (pCASL) through the cerebral vasculature is demonstrated. MATERIALS AND METHODS: EPICYCLE acquires two-dimensional planes of k-space along center-out trajectories. These "spokes" are rotated from shot to shot about a common axis to encode a k-space cylinder. To track a bolus of labeled blood, the same subset of evenly distributed spokes is acquired in a cine fashion after a short period of pCASL. This process is repeated for all subsets to fill the whole 3D k-space of each time frame. RESULTS: The passage of short pCASL boluses through the vasculature of a 3D imaging slab was successfully imaged using EPICYCLE. By choosing suitable sequence parameters, the impact of slab excitation on the bolus shape could be minimized. Parametric maps of signal amplitude, transit time, and bolus width reflected typical features of blood transport in large vessels. CONCLUSION: The EPICYCLE technique was successfully applied to track a short bolus of labeled arterial blood during its passage through the cerebral vasculature.

Investigating the dynamics of the brain response to music: A central role of the ventral striatum/nucleus accumbens.

Ventral striatal activity has been previously shown to correspond well to reward value mediated by music. Here, we investigate the dynamic brain response to music and manipulated counterparts using functional magnetic resonance imaging (fMRI). Counterparts of musical excerpts were produced by either manipulating the consonance/dissonance of the musical fragments or playing them backwards (or both). Results show a greater involvement of the ventral striatum/nucleus accumbens both when contrasting listening to music that is perceived as pleasant and listening to a manipulated version perceived as unpleasant (backward dissonant), as well as in a parametric analysis for increasing pleasantness. Notably, both analyses yielded a ventral striatal response that was strongest during an early phase of stimulus presentation. A hippocampal response to the musical stimuli was also observed, and was largely mediated by processing differences between listening to forward and backward music. This hippocampal involvement was again strongest during the early response to the music. Auditory cortex activity was more strongly evoked by the original (pleasant) music compared to its manipulated counterparts, but did not display a similar decline of activation over time as subcortical activity. These findings rather suggest that the ventral striatal/nucleus accumbens response during music listening is strongest in the first seconds and then declines.

Slab-selective, BOLD-corrected VASO at 7 Tesla provides measures of cerebral blood volume reactivity with high signal-to-noise ratio.

PURPOSE: MRI methods sensitive to functional changes in cerebral blood volume (CBV) may map neural activity with better spatial specificity than standard functional MRI (fMRI) methods based on blood oxygen level dependent (BOLD) effect. The purpose of this study was to develop and investigate a vascular space occupancy (VASO) method with high sensitivity to CBV changes for use in human brain at 7 Tesla (T). METHODS: To apply 7T VASO, several high-field-specific obstacles must be overcome, e.g., low contrast-to-noise ratio (CNR) due to convergence of blood and tissue T1 , increased functional BOLD signal change contamination, and radiofrequency field inhomogeneities. In the present method, CNR was increased by keeping stationary tissue magnetization in a steady-state different from flowing blood, using slice-selective saturation pulses. Interleaved acquisition of BOLD and VASO signals allowed correction for BOLD contamination. RESULTS: During visual stimulation, a relative CBV change of 28% ± 5% was measured, confined to gray matter in the occipital lobe with high sensitivity. CONCLUSION: By carefully considering all the challenges of high-field VASO and filling behavior of the relevant vasculature, the proposed method can detect and quantify CBV changes with high CNR in human brain at 7T.

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.

Reliability of task-based fMRI in the dorsal horn of the human spinal cord.

The application of functional magnetic resonance imaging (fMRI) to the human spinal cord is still a relatively small field of research and faces many challenges. Here we aimed to probe the limitations of task-based spinal fMRI at 3T by investigating the reliability of spinal cord blood oxygen level dependent (BOLD) responses to repeated nociceptive stimulation across two consecutive days in 40 healthy volunteers. We assessed the test-retest reliability of subjective ratings, autonomic responses, and spinal cord BOLD responses to short heat pain stimuli (1s duration) using the intraclass correlation coefficient (ICC). At the group level, we observed robust autonomic responses as well as spatially specific spinal cord BOLD responses at the expected location, but no spatial overlap in BOLD response patterns across days. While autonomic indicators of pain processing showed good-to-excellent reliability, both ß-estimates and z-scores of task-related BOLD responses showed poor reliability across days in the target region (gray matter of the ipsilateral dorsal horn). When taking into account the sensitivity of gradient-echo echo planar imaging (GE-EPI) to draining vein signals by including the venous plexus in the analysis, we observed BOLD responses with fair reliability across days. Taken together, these results demonstrate that heat pain stimuli as short as one second are able to evoke a robust and spatially specific BOLD response, which is however strongly variable within participants across time, resulting in low reliability in the dorsal horn gray matter. Further improvements in data acquisition and analysis techniques are thus necessary before event-related spinal cord fMRI as used here can be reliably employed in longitudinal designs or clinical settings.

Center-out echo-planar spectroscopic imaging with correction of gradient-echo phase and time shifts.

A procedure to prevent the formation of image and spectral Nyquist ghosts in echo-planar spectroscopic imaging is introduced. It is based on a novel Cartesian center-out echo-planar spectroscopic imaging trajectory, referred to as EPSICO, and combined with a correction of the gradient-echo phase and time shifts. Processing of homogenous sets of forward and reflected echoes is no longer necessary, resulting in an optimized spectral width. The proposed center-out trajectory passively prevents the formation of Nyquist ghosts by privileging the acquisition of the center k-space line with forward echoes at the beginning of an echo-planar spectroscopic imaging dwell time and by ensuring that all k-space lines and their respective complex conjugates are acquired at equal time intervals. With the proposed procedure, concentrations of N-acetyl aspartate, creatine, choline, glutamate, and myo-inositol were reliably determined in human white matter at 3 T.

Investigating brain response to music: a comparison of different fMRI acquisition schemes.

Functional magnetic resonance imaging (fMRI) in auditory experiments is a challenge, because the scanning procedure produces considerable noise that can interfere with the auditory paradigm. The noise might either mask the auditory material presented, or interfere with stimuli designed to evoke emotions because it sounds loud and rather unpleasant. Therefore, scanning paradigms that allow interleaved auditory stimulation and image acquisition appear to be advantageous. The sparse temporal sampling (STS) technique uses a very long repetition time in order to achieve a stimulus presentation in the absence of scanner noise. Although only relatively few volumes are acquired for the resulting data sets, there have been recent studies where this method has furthered remarkable results. A new development is the interleaved silent steady state (ISSS) technique. Compared with STS, this method is capable of acquiring several volumes in the time frame between the auditory trials (while the magnetization is kept in a steady state during stimulus presentation). In order to draw conclusions about the optimum fMRI procedure with auditory stimulation, different echo-planar imaging (EPI) acquisition schemes were compared: Continuous scanning, STS, and ISSS. The total acquisition time of each sequence was adjusted to about 12.5 min. The results indicate that the ISSS approach exhibits the highest sensitivity in detecting subtle activity in sub-cortical brain regions.

A modified EPI sequence for high-resolution imaging at ultra-short echo time.

A robust modification of echo-planar imaging dubbed double-shot echo-planar imaging with center-out trajectories and intrinsic navigation (DEPICTING) is proposed, which permits imaging at ultra-short echo time. The k-space data is sampled by two center-out trajectories with a minimal delay achieving a temporal efficiency similar to conventional single-shot echo-planar imaging. Intersegment phase and intensity imperfections are corrected by exploiting the intrinsic navigator information from both central lines, which are subsequently averaged for image reconstruction. Phase errors induced by inhomogeneities of the main magnetic field are corrected in k-space, recovering the superior point-spread function achieved with center-out trajectories. The minimal echo time (<2 msec) is nearly independent of the acquisition matrix permitting applications, which simultaneously require high spatial and temporal resolution. Examples of demonstrated applications include anatomical imaging, BOLD-based functional brain mapping, and quantitative perfusion imaging.

Dual echo EPI--the method of choice for fMRI in the presence of magnetic field inhomogeneities?

FMRI studies of the orbitofrontal cortex or the inferior temporal lobes are often compromised by susceptibility artefacts, which may result in signal reduction or loss in gradient echo (GE) EPI. Spin echo (SE) EPI is considerably more robust against susceptibility-related signal loss, but its intrinsic sensitivity to changes in the blood oxygenation level dependent (BOLD) contrast is generally lower. In this study, we performed a direct comparison of GE and SE fMRI using a single-shot dual echo EPI acquisition scheme. Transient hypercapnia, induced by breathing Carbogen (5% CO(2), 95% O(2)), was used as a global physiological stimulus to alter the BOLD contrast. In regions affected by magnetic field inhomogeneities, SE EPI provided significantly higher BOLD sensitivity than GE EPI. Such regions included the orbitofrontal cortex, temporal pole, anterior inferior temporal cortex, as well as parts of the lateral inferior temporal cortex and the lateral cerebellum. Dual echo fMRI benefits from the robustness of SE EPI in these critical regions while utilising the generally higher sensitivity of GE EPI in normal regions. It therefore provides an attractive solution for fMRI studies that require optimum sensitivity in both normal and critical brain regions. Furthermore, a general method is proposed to combine the GE and SE data into a single hybrid data set that provides optimum sensitivity in the whole brain. This method can be applied to any experimental design that can be expressed in terms of a generalised linear model. The feasibility of this approach is demonstrated both theoretically and experimentally.