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The functional MRI (fMRI) signal is an indirect measure of neuronal activity. In order to deconvolve the neuronal activity from the experimental fMRI data, biophysical generative models have been proposed describing the link between neuronal activity and the cerebral blood flow (the neurovascular coupling), and further the hemodynamic response and the BOLD signal equation. These generative models have been employed both for single brain area deconvolution and to infer effective connectivity in networks of multiple brain areas. In the current paper, we introduce a new fMRI model inspired by experimental observations about the physiological underpinnings of the BOLD signal and compare it with the generative models currently used in dynamic causal modeling (DCM), a widely used framework to study effective connectivity in the brain. We consider three fundamental aspects of such generative models for fMRI: (i) an adaptive two-state neuronal model that accounts for a wide repertoire of neuronal responses during and after stimulation; (ii) feedforward neurovascular coupling that links neuronal activity to blood flow; and (iii) a balloon model that can account for vascular uncoupling between the blood flow and the blood volume. Finally, we adjust the parameterization of the BOLD signal equation for different magnetic field strengths. This paper focuses on the form, motivation and phenomenology of DCMs for fMRI and the characteristics of the various models are demonstrated using simulations. These simulations emphasize a more accurate modeling of the transient BOLD responses — such as adaptive decreases to sustained inputs during stimulation and the post-stimulus undershoot. In addition, we demonstrate using experimental data that it is necessary to take into account both neuronal and vascular transients to accurately model the signal dynamics of fMRI data. By refining the models of the transient responses, we provide a more informed perspective on the underlying neuronal process and offer new ways of inferring changes in local neuronal activity and effective connectivity from fMRI. [Display omitted] •New physiological model for DCM of fMRI data supported by experimental observations•Excitatory–inhibitory neuronal model for a wide repertoire of neuronal responses•Feedforward neurovascular coupling that links neuronal activity to blood flow•Neuronal and vascular mechanisms to explain post-stimulus BOLD undershoot•Adjusted BOLD signal equation for different magnetic field strengths

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.

A body of animal and human evidence points to the norepinephrine (NE) locus coeruleus (LC) system in modulating memory for arousing experiences, but whether the LC would recast its role along memory stages remains unknown. Sedation precluded examination of LC dynamics during memory processing in animals. Here, we addressed the contribution of the LC during arousal-associated memory processing through a unique combination of dedicated ultra-high-field LC-imaging methods, a well-established emotional memory task, online physiological and saliva alpha-amylase measurements in young adults. Arousal-related LC activation followed amygdala engagement during encoding. During consolidation and recollection, activation transitioned to hippocampal involvement, reflecting learning and model updating. NE-LC activation is dynamic, plays an arousal-controlling role, and is not sufficient but requires interactions with the amygdala to form adaptive memories of emotional experiences. These findings have implications for understanding contributions of LC dysregulation to disruptions in emotional memory formation, observed in psychiatric and neurocognitive disorders.

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.

Multivariate pattern analysis (MVPA) in fMRI has been used to extract information from distributed cortical activation patterns, which may go undetected in conventional univariate analysis. However, little is known about the physical and physiological underpinnings of MVPA in fMRI as well as about the effect of spatial smoothing on its performance. Several studies have addressed these issues, but their investigation was limited to the visual cortex at 3T with conflicting results. Here, we used ultra-high field (7T) fMRI to investigate the effect of spatial resolution and smoothing on decoding of speech content (vowels) and speaker identity from auditory cortical responses. To that end, we acquired high-resolution (1.1mm isotropic) fMRI data and additionally reconstructed them at 2.2 and 3.3mm in-plane spatial resolutions from the original k-space data. Furthermore, the data at each resolution were spatially smoothed with different 3D Gaussian kernel sizes (i.e. no smoothing or 1.1, 2.2, 3.3, 4.4, or 8.8mm kernels). For all spatial resolutions and smoothing kernels, we demonstrate the feasibility of decoding speech content (vowel) and speaker identity at 7T using support vector machine (SVM) MVPA. In addition, we found that high spatial frequencies are informative for vowel decoding and that the relative contribution of high and low spatial frequencies is different across the two decoding tasks. Moderate smoothing (up to 2.2mm) improved the accuracies for both decoding of vowels and speakers, possibly due to reduction of noise (e.g. residual motion artifacts or instrument noise) while still preserving information at high spatial frequency. In summary, our results show that – even with the same stimuli and within the same brain areas – the optimal spatial resolution for MVPA in fMRI depends on the specific decoding task of interest.

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.

Physical activity may attenuate age-related cognitive decline by improving cerebrovascular function. The aim of this study was therefore to investigate effects of aerobic exercise training on cerebral blood flow (CBF), which is a sensitive physiological marker of cerebrovascular function, in sedentary older men. Seventeen apparently healthy men, aged 60-70 years and with a BMI between 25 and 35 kg/m , were included in a randomized, controlled cross-over trial. Study participants were randomly allocated to a fully-supervised, progressive, aerobic exercise training or no-exercise control period for 8 weeks, separated by a 12-week wash-out period. Measurements at the end of each period included aerobic fitness evaluated using peak oxygen consumption during incremental exercise (VO ), CBF measured with pseudo-continuous arterial spin labeling magnetic resonance imaging, and post-load glucose responses determined using an oral glucose tolerance test (OGTT). Furthermore, cognitive performance was assessed in the domains of executive function, memory, and psychomotor speed. VO significantly increased following aerobic exercise training compared to no-exercise control by 262 ± 236 mL ( < 0.001). CBF was increased by 27% bilaterally in the frontal lobe, particularly the subcallosal and anterior cingulate gyrus (cluster volume: 1008 mm ; < 0.05), while CBF was reduced by 19% in the right medial temporal lobe, mainly temporal fusiform gyrus (cluster volume: 408 mm ; < 0.05). Mean post-load glucose concentrations determined using an OGTT decreased by 0.33 ± 0.63 mmol/L ( = 0.049). Furthermore, executive function improved as the latency of response was reduced by 5% ( = 0.034), but no changes were observed in memory or psychomotor speed. Aerobic exercise training improves regional CBF in sedentary older men. These changes in CBF may underlie exercise-induced beneficial effects on executive function, which could be partly mediated by improvements in glucose metabolism. This clinical trial is registered on ClinicalTrials.gov as NCT03272061.

•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.

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 7T. 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. •We developed an MRI-method to estimate arterial/venous CBV and BOLD signal changes.•Hemodynamics of excitation and inhibition was investigated in human brain at 7T.•We found different timecourses, layer-dependence and arterio-venous interaction.•Our results suggest different neurovascular coupling for excitation and inhibition.