A perspective on cortical layering and layer-spanning neuronal elements

This review article addresses the function of the layers of the cerebral cortex. We develop the perspective that cortical layering needs to be understood in terms of its functional anatomy, i.e., the terminations of synaptic inputs on distinct cellular compartments and their effect on cortical activity. The cortex is a hierarchical structure in which feed forward and feedback pathways have a layer-specific termination pattern. We take the view that the influence of synaptic inputs arriving at different cortical layers can only be understood in terms of their complex interaction with cellular biophysics and the subsequent computation that occurs at the cellular level. We use high-resolution fMRI, which can resolve activity across layers, as a case study for implementing this approach by describing how cognitive events arising from the laminar distribution of inputs can be interpreted by taking into account the properties of neurons that span different layers. This perspective is based on recent advances in measuring subcellular activity in distinct feed-forward and feedback axons and in dendrites as they span across layers

First implementation of dynamic oxygen-17 (17O) magnetic resonance imaging at 7 Tesla during neuronal stimulation in the human brain.

OBJECTIVE First implementation of dynamic oxygen-17 (17O) MRI at 7 Tesla (T) during neuronal stimulation in the human brain. METHODS Five healthy volunteers underwent a three-phase 17O gas (17O2) inhalation experiment. Combined right-side visual stimulus and right-hand finger tapping were used to achieve neuronal stimulation in the left cerebral hemisphere. Data analysis included the evaluation of the relative partial volume (PV)-corrected time evolution of absolute 17O water (H217O) concentration and of the relative signal evolution without PV correction. Statistical analysis was performed using a one-tailed paired t test. Blood oxygen level-dependent (BOLD) experiments were performed to validate the stimulation paradigm. RESULTS The BOLD maps showed significant activity in the stimulated left visual and sensorimotor cortex compared to the non-stimulated right side. PV correction of 17O MR data resulted in high signal fluctuations with a noise level of 10% due to small regions of interest (ROI), impeding further quantitative analysis. Statistical evaluation of the relative H217O signal with PV correction (p = 0.168) and without (p = 0.382) did not show significant difference between the stimulated left and non-stimulated right sensorimotor ROI. DISCUSSION The change of cerebral oxygen metabolism induced by sensorimotor and visual stimulation is not large enough to be reliably detected with the current setup and methodology of dynamic 17O MRI at 7 T

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, urn:x-wiley:07403194:media:mrm28591:mrm28591-math-0004) 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 urn:x-wiley:07403194:media:mrm28591:mrm28591-math-0005 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

Depth-Dependent Physiological Modulators of the BOLD Response in the Human Motor Cortex

This dissertation proposes a set of methods for improving spatial localization of cerebral metabolic changes using functional magnetic resonance imaging (fMRI). Blood oxygen level dependent (BOLD) fMRI estabilished itself as the most frequently used technique for mapping brain activity in humans. It is non-invasive and allows to obtain information about brain oxygenation changes in a few minutes. It was discovered in 1990 and, since then, it contributed enormously to the developments in neuroscientific research. Nevertheless, the BOLD contrast suffers from inherent limitations. This comes from the fact that the observed response is the result of a complex interplay between cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen consumption (CMRO2) and has a strong dependency on baseline blood volume and oxygenation. Therefore, the observed response is mislocalized from the site where the metabolic activity takes place and it is subject to high variability across experiments due to normal brain physiology. Since the peak of BOLD changes can be as much as 4 mm apart from the site of metabolic changes, the problem of spatial mislocalization is particularly constraining at submillimeter resolution. Three methods are proposed in this work in order to overcome this limitation and make data more comparable. The first method involves a modification of an estabilished model for calibration of BOLD responses (the dilution model), in order to render it applicable at higher resolutions. The second method proposes a model-free scaling of the BOLD response, based on spatial normalization by a purely vascular response pattern. The third method takes into account the hypothesis that the cortical vasculature could act as a low-pass filter for BOLD fluctuations as the blood is carried downstream, and investigates differences in frequency composition of cortical laminae. All methods are described and tested on a depth-dependent scale in the human motor cortex

Lamina-dependent calibrated BOLD response in human primary motor cortex

Disentangling neural activity at different cortical depths during a functional task has recently generated growing interest, since this would allow to separate feedforward and feedback activity. The majority of layer-dependent studies have, so far, relied on gradient-recalled echo (GRE) blood-oxygenation-level dependent (BOLD) acquisitions, which are weighted towards the large draining veins at the cortical surface. The current study aims to obtain quantitative brain activity responses in the primary motor cortex on a laminar scale without the contamination due to accompanying secondary vascular effects. Evoked oxidative metabolism was evaluated using the Davis model, to investigate its applicability, advantages, and limits in lamina-dependent fMRI. Average values for the calibration parameter, M, and for changes in the cerebral metabolic rate of oxygen consumption (CMRO2) during a unilateral finger-tapping task were (11 ± 2)% and (30 ± 7)%, respectively, with distinct variation features across the cortical depth. The results presented here showed an uncoupling between BOLD-based functional magnetic resonance imaging (fMRI) and metabolic changes across cortical depth, while the tight coupling between CMRO2 and CBV was conserved across cortical layers. We conclude that the Davis model can help to obtain estimates of lamina-dependent metabolic changes without contamination from large draining veins, with high consistency and reproducibility across participants

Evidence for a Large-Scale Brain System Supporting Allostasis and Interoception in Humans

Large-scale intrinsic brain systems have been identified for exteroceptive senses (e.g., sight, hearing, touch). We introduce an analogous system for representing sensations from within the body, called interoception, and demonstrate its relation to regulating peripheral systems in the body, called allostasis. Employing the recently introduced Embodied Predictive Interoception Coding (EPIC) model, we used tract-tracing studies of macaque monkeys, followed by two intrinsic functional magnetic resonance imaging samples (N = 280 and N = 270) to evaluate the existence of an intrinsic allostatic/interoceptive system in the human brain. Another sample (N = 41) allowed us to evaluate the convergent validity of the hypothesized allostatic/interoceptive system by showing that individuals with stronger connectivity between system hubs performed better on an implicit index of interoceptive ability related to autonomic fluctuations. Implications include insights for the brain’s functional architecture, dissolving the artificial boundary between mind and body, and unifying mental and physical illness

Validating layer-specific VASO across species

Cerebral blood volume (CBV) has been shown to be a robust and important physiological parameter for quantitative interpretation of functional (f)MRI, capable of delivering highly localized mapping of neural activity. Indeed, with recent advances in ultra-high-field (≥7T) MRI hardware and associated sequence libraries, it has become possible to capture non-invasive CBV weighted fMRI signals across cortical layers. One of the most widely used approaches to achieve this (in humans) is through vascular-space-occupancy (VASO) fMRI. Unfortunately, the exact contrast mechanisms of layer-dependent VASO fMRI have not been validated for human fMRI and thus interpretation of such data is confounded. Here we validate the signal source of layer-dependent SS-SI VASO fMRI using multi-modal imaging in a rat model in response to neuronal activation (somatosensory cortex) and respiratory challenge (hypercapnia). In particular VASO derived CBV measures are directly compared to concurrent measures of total haemoglobin changes from high resolution intrinsic optical imaging spectroscopy (OIS). Quantified cortical layer profiling is demonstrated to be in agreement between VASO and contrast enhanced fMRI (using monocrystalline iron oxide nanoparticles, MION). Responses show high spatial localisation to layers of cortical processing independent of confounding large draining veins which can hamper BOLD fMRI studies, (depending on slice positioning). Thus, a cross species comparison is enabled using VASO as a common measure. We find increased VASO based CBV reactivity (3.1 ± 1.2 fold increase) in humans compared to rats. Together, our findings confirm that the VASO contrast is indeed a reliable estimate of layer-specific CBV changes. This validation study increases the neuronal interpretability of human layer-dependent VASO fMRI as an appropriate method in neuroscience application studies, in which the presence of large draining intracortical and pial veins limits neuroscientific inference with BOLD fMRI

Multimodal Investigation of Neuronal Responses

This thesis describes an investigation of neuronal responses with both magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). MEG and fMRI are widely used in neuroscience. However, aspects of the MEG and fMRI signal are still not well understood, particularly post-stimulus responses – responses which occur after a stimulus has ended. Post-stimulus responses have been shown to correlate with various illnesses and as a result, MEG and fMRI have yet to reach their full potential clinically. By developing carefully controlled experiments, MEG is used in this thesis to characterise post-stimulus responses to a grip-force task. The results showed that the beta-band post-stimulus response (post-movement beta rebound, PMBR) is modulated by task duration. Functional network analysis, using amplitude envelope correlation and a hidden Markov model, showed that the PMBR re-establishes networks after breaking down during a task, suggesting the PMBR is related to functional connectivity. The results of this thesis provide new information about the nature of the PMBR, demonstrating that it can be systematically controlled by task parameters and provides insight into its generation. It is hoped this research will contribute to a deeper understanding of the PMBR and provide a step forward for its use clinically. In fMRI, the origin of the post-stimulus response is also poorly understood. To investigate fMRI post-stimulus responses, an MR pulse sequence was developed and optimised to measure blood flow, volume and oxygenation changes simultaneously at 7 T. This was implemented with the grip-force task, allowing direct comparison between MEG and fMRI. This study provides new insights into the fMRI post-stimulus undershoot which warrant further investigation. Understanding the link between fMRI and MEG signals will help further understanding of both modalities and how they relate to neuronal activity. Finally, the applications of fMRI were explored by comparing fMRI responses in patients with focal hand dystonia (FHD) with healthy controls. 7 T fMRI was used to map cortical fingertip representations and measures were developed to compare overlap of digit representations between patients and healthy controls. This project provided an important opportunity to advance the understanding of FHD and was the first study to use fMRI to explore the effects of treatment on patients with FHD