Baseline GABA concentration and fMRI response

Resting-state brain activity has been widely investigated using blood oxygenation level dependent (BOLD) contrast techniques. However, BOLD signal changes reflect a combination of the effects of cerebral blood flow (CBF), cerebral blood volume (CBV), as well as the cerebral metabolic rate of oxygen (CMRO2). In this study, resting-state brain activation was detected and compared using the following techniques: (a) BOLD, using a gradient-echo echo planar imaging (GE-EPI) sequence; (b) CBV-weighted signal, acquired using gradient and spin echo (GRASE) based vascular space occupancy (VASO); and (c) CBF, using pseudo-continuous arterial spin labeling (pCASL). Reliable brain networks were detected using VASO and ASL, including sensorimotor, auditory, primary visual, higher visual, default mode, salience and left/right executive control networks. Differences between the resting-state activation detected with ASL, VASO and BOLD could potentially be due to the different temporal signal-to-noise ratio (tSNR) and the short post-labeling delay (PLD) in ASL, along with differences in the spin-echo readout of VASO. It is also possible that the dynamics of spontaneous fluctuations in BOLD, CBV and CBF could differ due to biological reasons, according to their location within the brain.

Methodological advancements of functional Magnetic Resonance Imaging (fMRI) in recent years allow researchers to approach the mesoscopic spatial regime of cortical layers and cortical columns. In principle, this could revolutionize the ability to tackle cortical information processing within micro-circuits and across brain systems. One of the major limitations of conventional gradient-echo BOLD fMRI, however, is that it probes neuronal activity changes only indirectly via evoked cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2) changes. Since, the resulting gradient-echo BOLD signal is mostly sensitive to ascending veins in the tissue and to pial veins, the achievable spatial specificity to neuronal activation is limited. Furthermore, the non-linear interaction of CBF, CBV and CMRO2 at high resolutions can hamper quantitative interpretations of the BOLD signal across cortical layer and columns with different baseline physiology. Measuring CBF, CBV or CMRO2 directly on a laminar and columnar level can overcome these limitations. This presentation will introduce laminar non-BOLD fMRI methods, summarize resent advancements, and provide an overview of how to use these methods to improve the neuroscientific interpretability in application studies. First, I will review the physiology of the cortical blood supply in the sub-millimeter regime and the corresponding practical challenges in high-resolution fMRI. Then, I will review the most-widely used non-BOLD fMRI methods to measure high-resolution CBF, CBV and CMRO2 responses and discuss them with respect to their sequence parameter space, sensitivity, specificity and applicability. Specific focus will be on the methods of arterial spin labeling (ASL), vascular space occupancy (VASO) and calibrated fMRI. Finally, I will conclude that non-BOLD methods at submillimeter resolution have an inherently low signal-to-noise ratio (SNR) are thus still challenging. However, their spatial specificity is improved, they are quantifiable, and, hence, the obtained results are physiologically interpretable. Therefore, they can potentially be superior alternatives to conventional GE-BOLD never the less. This conclusion will be discussed in the light of recent neuroscientific application studies that pinpoint laminar and columnar microcircuits in visual cortex, sensorimotor cortex, and prefrontal cortex. References 1. Polimeni, J.R., Fischl, B., Greve, D.N., and Wald, L.L. (2010). Laminar analysis of 7T BOLD using an imposed spatial activation pattern in human V1. Neuroimage 52, 1334–1346. 2. Kay, K., Jamison, K., Vizioli, L., Zhang, R., Margalit, E., and Ugurbil, K. (2018). A critical assessment of data quality and venous effects in ultra-high-resolution fMRI. BioRxiv 1–45. 3. Kim, S.-G., and Ogawa, S. (2012). Biophysical and physiological origins of blood oxygenation level-dependent fMRI signals. J. Cereb. Blood Flow Metab. 32, 1188–1206. 4. Goense, J.B.M., Whittingstall, K., and Logothetis, N.K. (2012). Neural and BOLD responses across the brain. Wiley Interdiscip. Rev. Cogn. Sci. 3, 75–86. 5. Huber, L., Uludaǧ, K., and Möller, H.E. (2017). Non-BOLD contrast for laminar fMRI in humans: CBF, CBV, and CMRO2. Neuroimage ahead of print. 6. Huber, Finn, Handwerker ... Bandettini (2018). Unique functional digit representation in human motor cortex across columns and layers. In 48th Society for Neuroscience, p. 675.03. 7. Finn, Huber, Jangraw, and Bandettini (2018). Layer-dependent activity in human prefrontal cortex during working memory. BioRxiv 425249. 8. Huber, Handwerker, Jangraw ... Bandettini (2017). High-resolution CBV-fMRI allows mapping of laminar activity and connectivity of cortical cortical input and output in human M1.

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

Functional magnetic resonance imaging (fMRI) is a unique window to the brain, enabling scientists to follow changes in brain activity in response to hormones, ageing, environment, drugs of abuse and other stimuli. There are two features that make fMRI unique when compared with other imaging modalities used in behavioural neuroscience. First, it can be entirely noninvasive: each animal can serve as its own control over the natural course of its life, vital for following neuroadaptation and other developmental processes critical to understanding behaviour. Second, fMRI has the spatial and temporal resolution to observe patterns of neuronal activity across the entire brain in less than a minute. Although fMRI does not have the cellular spatial resolution of immunostaining, nor the millisecond temporal resolution of electrophysiology, synchronised changes in neuronal activity across multiple brain areas seen with functional MRI can be viewed as functional neuroanatomical circuits coordinating the thoughts, memories and emotions for particular behaviours. Thus, fMRI affords a systems approach to the study of the brain, complementing and building from other neurobiological techniques to understand how behaviour is organised across multiple brain regions. In this review, we present a general background to fMRI and the different imaging modalities that can be used in fMRI studies. Included are examples of the application of fMRI in behavioural neuroscience research, along with discussion of the advantages and disadvantages of this technology.

The study of brain function using MRI relies on acquisition techniques that are sensitive to different aspects of the hemodynamic response contiguous to areas of neuronal activity. For this purpose different contrasts such as arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional MRI techniques have been developed to investigate cerebral blood flow (CBF) and blood oxygenation, respectively. Analysis of such data typically proceeds by separate, linear modeling of the appropriate CBF or BOLD time courses. In this work an approach is developed that provides simultaneous inference on hemodynamic changes via a nonlinear physiological model of ASL data acquired at multiple echo times. Importantly, this includes a significant contribution by changes in the static magnetization, M, to the ASL signal. Inference is carried out in a Bayesian framework. This is able to extract, from dual-echo ASL data, probabilistic estimates of percentage changes of CBF, R(2) (*), and the static magnetization, M. This approach provides increased sensitivity in inferring CBF changes and reduced contamination in inferring BOLD changes when compared with general linear model approaches on single-echo ASL data. We also consider how the static magnetization, M, might be related to changes in CBV by assuming the same mechanism for water exchange as in vascular space occupancy.

Detecting resting-state brain activity by spontaneous cerebral blood volume fluctuations using whole brain vascular space occupancy imaging

Improved cortical-layer specificity of vascular space occupancy fMRI with slab inversion relative to spin-echo BOLD at 9.4 T

Sub-millimeter resolution functional magnetic resonance imaging (fMRI) at ultra-high field (≥ 7T) has offered an unprecedented opportunity to probe mesoscopic computations at a columnar or laminar level. However, its application has been primarily restricted to the neocortex. Inferior brain regions, particularly the hippocampus (HC), are challenging targets for laminar fMRI. Recent developments in acquisition methods have shown the feasibility of laminar recordings in the HC using gradient-echo blood oxygenation level-dependent (BOLD) contrast. Nonetheless, the spatial specificity of the BOLD signal is compromised by the draining veins’ bias. Cerebral blood volume (CBV)-sensitive sequences including vascular space occupancy (VASO) have emerged as a promising approach to capture the laminar activity with mitigated venous bias. Yet, its feasibility in the HC is unclear and challenged by methodological constraints. Here, we optimized VASO to mitigate the macrovasculature contribution in HC. By evaluating a series of advanced acquisition strategies tailored to HC, we obtained improved VASO signal quality with minimal artifacts. The optimized protocol was further validated with an autobiographical memory task. Our findings show that combining the high detection power of gradient-echo BOLD with the vein-bias-mitigated VASO contrast allows for differentiation between neural activity-related BOLD signals and those biased by draining veins. These results demonstrate the feasibility of submillimeter VASO acquired with conventional 7T scanners in the HC to map the circuit-level mechanisms of memory retrieval across HC subfields, laying a foundation to investigate the microcircuitry of HC-driven complex cognitive functions and their alterations in neurodegeneration and epilepsy.

Integrated VASO and perfusion contrast: A new tool for laminar functional MRI

Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI) method that provides a highly repeatable quantitative measure of cerebral blood flow (CBF). As compared to the more commonly used blood oxygenation level dependent (BOLD) contrast-based methods, ASL techniques measure a more biologically specific correlate of neural activity, with the potential for more accurate estimation of the location and magnitude of neural function. Recent advances in acquisition and analysis methods have improved the somewhat limited sensitivity of ASL to perfusion changes associated with neural activity. In addition, ASL perfusion measures are insensitive to the low-frequency fluctuations commonly observed in BOLD experiments and can make use of imaging sequences that are less sensitive than BOLD contrast to signal loss caused by magnetic susceptibility effects. ASL measures of perfusion can aid in the interpretation of the BOLD signal change and, when combined with BOLD, can measure the change in oxygen utilization accompanying changes in behavioral state. Whether used alone to probe neural activity or in combination with BOLD techniques, ASL methods are contributing to the field's understanding of healthy and disordered brain function.

Cerebrovascular reactivity measured with arterial spin labeling and blood oxygen level dependent techniques

Technical aspects and utility of fMRI using BOLD and ASL

Frequency-dependent neural activity, CBF, and BOLD fMRI to somatosensory stimuli in isoflurane-anesthetized rats

Reproducibility of BOLD, perfusion, and CMRO2 measurements with calibrated-BOLD fMRI

Functional neuroimaging is most commonly performed using the blood-oxygenation-level-dependent (BOLD) approach, which is sensitive to changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and the cerebral metabolic rate of oxygen (CMRO(2)). However, the precise mechanism by which neuronal activity elicits a hemodynamic response remains controversial. Here, visual stimulation (14 secs flashing checkerboard) and breath-hold (4 secs exhale+14 secs breath hold) experiments were performed in alternating sequence on healthy volunteers using BOLD, CBV-weighted, and CBF-weighted fMRI. After visual stimulation, the BOLD signal persisted for 33+/-5 secs (n=9) and was biphasic with a negative component (undershoot), whereas CBV and CBF returned to baseline without an undershoot at 20+/-5 and 20+/-3 secs, respectively. After breath hold, the BOLD signal returned to baseline (23+/-7 secs) at the same time (P>0.05) as CBV (21+/-6 secs) and CBF (18+/-3 secs), without a poststimulus undershoot. These data suggest that the BOLD undershoot after visual activation reflects a persistent increase in CMRO(2). These observations support the view that CBV and CBF responses elicited by neuronal activation are not necessarily coupled to local tissue metabolism.