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

Laminar fMRI: applications for cognitive neuroscience

The cortex is a massively recurrent network, characterized by feedforward and feedback connections between brain areas as well as lateral connections within an area. Feedforward, horizontal and feedback responses largely activate separate layers of a cortical unit, meaning they can be dissociated by lamina-resolved neurophysiological techniques. Such techniques are invasive and are therefore rarely used in humans. However, recent developments in high spatial resolution fMRI allow for non-invasive, in vivo measurements of brain responses specific to separate cortical layers. This provides an important opportunity to dissociate between feedforward and feedback brain responses, and investigate communication between brain areas at a more fine- grained level than previously possible in the human species. In this review, we highlight recent studies that successfully used laminar fMRI to isolate layer-specific feedback responses in human sensory cortex. In addition, we review several areas of cognitive neuroscience that stand to benefit from this new technological development, highlighting contemporary hypotheses that yield testable predictions for laminar fMRI. We hope to encourage researchers with the opportunity to embrace this development in fMRI research, as we expect that many future advancements in our current understanding of human brain function will be gained from measuring lamina-specific brain responses

High-Field Functional MRI from the Perspective of Single Vessels in Rats and Humans

Functional MRI (fMRI) has been employed to map brain activity and connectivity based on the neurovascular coupled hemodynamic signal. However, in most cases of fMRI studies, the cerebral vascular hemodynamic signal has been imaged in a spatially smoothed manner due to the limit of spatial resolution. There is a need to improve the spatiotemporal resolution of fMRI to map dynamic signal from individual venule or individual arteriole directly. Here, the thesis aims to provide a vascular-specific view of hemodynamic response during active state or resting state. To better characterize the temporal features of task-related fMRI signal from different vascular compartments, we implemented a line-scanning method to acquire vessel-specific blood-oxygen-level-dependent (BOLD) / cerebral-blood-volume (CBV) fMRI signal at 100-ms temporal resolution with sensory or optogenetic stimulation. Furthermore, we extended the line-scanning method with multi-echo scheme to provide vessel-specific fMRI with the higher contrast-to-noise ratio (CNR), which allowed us to directly map the distinct evoked hemodynamic signal from arterioles and venules at different echo time (TE) from 3 ms to 30 ms. The line-scanning fMRI methods acquire single k-space line per TR under a reshuffled k space acquisition scheme which has the limitation of sampling the fMRI signal in real-time for resting-state fMRI studies. To overcome this, we implemented a balanced Steady-state free precession (SSFP) to map task-related and resting-state fMRI (rsfMRI) with high spatial resolution in anesthetized rats. We reveal venule-dominated functional connectivity for BOLD fMRI and arteriole-dominated functional connectivity for CBV fMRI. The BOLD signal from individual venules and CBV signal from individual arterioles show correlations at an ultra-slow frequency (< 0.1 Hz), which are correlated with the intracellular calcium signal measured in neighboring neurons. In complementary data from awake human subjects, the BOLD signal is spatially correlated among sulcus veins and specified intracortical veins of the visual cortex at similar ultra-slow rhythms. This work provides a high-resolution fMRI approach to resolve brain activation and functional connectivity at the level of single vessels, which opened a new avenue to investigate brian functional connectivity at the scale of vessels

Neural Representations of Visual Motion Processing in the Human Brain Using Laminar Imaging at 9.4 Tesla

During natural behavior, much of the motion signal falling into our eyes is due to our own movements. Therefore, in order to correctly perceive motion in our environment, it is important to parse visual motion signals into those caused by self-motion such as eye- or head-movements and those caused by external motion. Neural mechanisms underlying this task, which are also required to allow for a stable perception of the world during pursuit eye movements, are not fully understood. Both, perceptual stability as well as perception of real-world (i.e. objective) motion are the product of integration between motion signals on the retina and efference copies of eye movements. The central aim of this thesis is to examine whether different levels of cortical depth or distinct columnar structures of visual motion regions are differentially involved in disentangling signals related to self-motion, objective, or object motion. Based on previous studies reporting segregated populations of voxels in high level visual areas such as V3A, V6, and MST responding predominantly to either retinal or extra- retinal (‘real’) motion, we speculated such voxels to reside within laminar or columnar functional units. We used ultra-high field (9.4T) fMRI along with an experimental paradigm that independently manipulated retinal and extra-retinal motion signals (smooth pursuit) while controlling for effects of eye-movements, to investigate whether processing of real world motion in human V5/MT, putative MST (pMST), and V1 is associated to differential laminar signal intensities. We also examined motion integration across cortical depths in human motion areas V3A and V6 that have strong objective motion responses. We found a unique, condition specific laminar profile in human area V6, showing reduced mid-layer responses for retinal motion only, suggestive of an inhibitory retinal contribution to motion integration in mid layers or alternatively an excitatory contribution in deep and superficial layers. We also found evidence indicating that in V5/MT and pMST, processing related to retinal, objective, and pursuit motion are either integrated or colocalized at the scale of our resolution. In contrast, in V1, independent functional processes seem to be driving the response to retinal and objective motion on the one hand, and to pursuit signals on the other. The lack of differential signals across depth in these regions suggests either that a columnar rather than laminar segregation governs these functions in these areas, or that the methods used were unable to detect differential neural laminar processing. Furthermore, the thesis provides a thorough analysis of the relevant technical modalities used for data acquisition and data analysis at ultra-high field in the context of laminar fMRI. Relying on our technical implementations we were able to conduct two high-resolution fMRI experiments that helped us to further investigate the laminar organization of self-induced and externally induced motion cues in human high-level visual areas and to form speculations about the site and the mechanisms of their integration

Diving into the depth of primary motor cortex: a high-resolution investigation of the motor system using 7Tesla fMRI

Dissertação para a obtenção do Grau de Mestre em Engenharia BiomédicaHuman behaviour is grounded in our ability to perform complex tasks. While human motor function has been studied for over a century the cortical processes underlying motor behaviour are still under debate. Central to the execution of action is the primary motor cortex (M1), which has previously been considered to be responsible for the execution of movements planned in the premotor cortex, yet recent studies point to more complex roles for M1 in orchestrating motor-related information. The purpose of this project is to study the functional properties of primary motor cortex using ultra-high fMRI. The spatial resolution made possible by using a high field magnet allows us to investigate novel questions such as the existence of cortical columns, the functional organization pattern for single fingers and functional involvement of M1 in motor imagery and observation. Thirteen young healthy subjects participated in this study. Functional and anatomical high resolution images were acquired. Four functional scans were acquired for the different tasks: motor execution; motor imagery; movement observation and rest. The paradigm used was a randomized finger tapping. The images analysis was performed with the Brainvoyager QX program. Using the novel high resolution cortical grid sampling analysis tools, different cortical laminas of human M1 were examined. Our results reveal a distributed pattern (intermingled with somatotopic “hot spots”) for single fingers activity in M1. Furthermore we show novel evidence of columnar structures in M1 and show that non motor tasks such as motor imagery and action observation also activate this region. We conclude that the primary motor cortex has much more un-expected complex roles regarding the processing of movement related information, not only due to their involvement in tasks that do not imply muscle movement, but also due to their intriguing organization pattern

The Correlation between Astrocytic Calcium and fMRI Signals is Related to the Thalamic Regulation of Cortical States

BOLD fMRI has been wildly used for mapping brain activity, but the cellular contribution of BOLD signals is still controversial. In this study, we investigated the correlation between neuronal/astrocytic calcium and the BOLD signal using simultaneous GCaMP-mediated calcium and BOLD signal recording, in the event-related state and in resting state, in anesthetized and in free-moving rats. To our knowledge, the results provide the first demonstration that evoked and intrinsic astrocytic calcium signals could occur concurrently accompanied by opposite BOLD signals which are associated with vasodilation and vasoconstriction. We show that the intrinsic astrocytic calcium is involved in brain state changes and is related to the activation of central thalamus. First, by simultaneous LFP and fiber optic calcium recording, the results show that the coupling between LFP and calcium indicates that neuronal activity is the basis of the calcium signal in both neurons and astrocytes. Second, we found that evoked neuronal and astrocytic calcium signals are always positively correlated with BOLD responses. However, intrinsic astrocytic calcium signals are accompanied by the activation of the central thalamus followed by a striking negative BOLD signal in cortex, which suggests that central thalamus may be involved in the initiation of the intrinsic astrocytic calcium signal. Third, we confirmed that the intrinsic astrocytic calcium signal is preserved in free moving rats. Moreover, the occurrences of intrinsic astrocytic calcium spikes are coincident with the transition between different sleep stages, which suggests intrinsic astrocytic calcium spikes reflect brain state transitions. These results demonstrate that the correlation between astrocytic calcium and fMRI signals is related to the thalamic regulation of cortical states. On the other hand, by studying the relationship between vessel–specific BOLD signals and spontaneous calcium activity from adjacent neurons, we show that low frequency spontaneous neuronal activity is the cellular mechanism of the BOLD signal during resting state

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

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

Phase imaging for reducing macrovascular signal contributions in high-resolution fMRI

High resolution functional MRI allows for the investigation of neural activity within the cortical sheet. One consideration in high resolution fMRI is the choice of which sequence to use during imaging, as all methods come with sensitivity and specificity tradeoffs. The most used fMRI sequence is gradient-echo echo planar imaging (GE-EPI) which has the highest sensitivity but is not specific to microvasculature. GE-EPI results in a signal with pial vessel bias which increases complexity of performing studies targeted at structures within the cortex. This work seeks to explore the use of MRI phase signal as a macrovascular filter to correct this bias. First, an in-house phase combination method was designed and tested on the 7T MRI system. This method, the fitted SVD method, uses a low-resolution singular value decomposition and fitting to a polynomial basis to provide computationally efficient, phase sensitive, coil combination that is insensitive to motion. Second, a direct comparison of GE-EPI, GE-EPI with phase regression (GE-EPI-PR), and spin echo EPI (SE-EPI) was performed in humans completing a visual task. The GE-EPI-PR activation showed higher spatial similarity with SE-EPI than GE-EPI across the cortical surface. GE-EPI-PR produced a similar laminar profile to SE-EPI while maintaining a higher contrast-to-noise ratio across layers, making it a useful method in low SNR studies such as high-resolution fMRI. The final study extended this work to a resting state macaque experiment. Macaques are a common model for laminar fMRI as they allow for simultaneous imaging and electrophysiology. We hypothesized that phase regression could improve spatial specificity of the resting state data. Further analysis showed the phase data contained both system and respiratory artifacts which prevented the technique performing as expected under two physiological cleaning strategies. Future work will have to examine on-scanner physiology correction to obtain a phase timeseries without artifacts to allow for the phase regression technique to be used in macaques. This work demonstrates that phase regression reduces signal contributions from pial vessels and will improve specificity in human layer fMRI studies. This method can be completed easily with complex fMRI data which can be created using our fitted SVD method