Layer-dependent fMRI allows measurements of information flow in cortical circuits, as afferent and efferent connections terminate in different cortical layers. However, it is unknown to what level human fMRI is specific and sensitive enough to reveal directional functional activity across layers. To answer this question, we developed acquisition and analysis methods for blood-oxygen-level-dependent (BOLD) and cerebral-blood-volume (CBV)-based laminar fMRI and used these to discriminate four different tasks in the human motor cortex (M1). In agreement with anatomical data from animal studies, we found evidence for somatosensory and premotor input in superficial layers of M1 and for cortico-spinal motor output in deep layers. Laminar resting-state fMRI showed directional functional connectivity of M1 with somatosensory and premotor areas. Our findings demonstrate that CBV-fMRI can be used to investigate cortical activity in humans with unprecedented detail, allowing investigations of information flow between brain regions and outperforming conventional BOLD results that are often buried under vascular biases.

Highlights: 21• A CBV-sensitive fMRI method is developed for high resolution fMRI in humans. 22• Lamina-dependent CBV fMRI responses are shown in humans. 23• VASO cortical profiles are validated with Fe-contrast agent fMRI in animals. 24• Sensitivity to large veins can be minimized using VASO-CBV instead of BOLD fMRI. 25• Ipsilateral fMRI responses to finger-tapping are positive in M1 and negative in S1. 26 27 Abstract 28Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging 29 (fMRI) in human or animal brain can be used to address questions regarding the functioning of 30 cortical circuits, such as the effect of different afferent and efferent connectivity on activity in 31 specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level dependent 32 (BOLD) responses to large draining veins reduces its local specificity and can render the 33 interpretation of the underlying laminar neural activity impossible. Application of the more spatially 34 specific cerebral blood volume (CBV) based fMRI in humans has been hindered by the low sensitivity 35 of the non-invasive modalities available. Here, a Vascular Space Occupancy (VASO) variant, adapted 36 for use at high field, is further optimized to capture layer-dependent activity changes in human 37 motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that 38 the VASO signal peaks in grey matter at 0.8 -1.6 mm depth, and deeper compared to the superficial 39 and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-40 established iron-oxide contrast agent based fMRI methods in animals showed the same cortical 41 profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate 42 its potential of revealing small lamina-dependent signal differences due to modulations of the input-43 output characteristics, layer-dependent VASO responses were investigated in the ipsilateral 44 hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex 45 *7. Manuscript Click here to view linked References 2 and negative activation in ipsilateral primary sensory cortex were observed. This feature is only 1 visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently 2 because of a lack of partial volume effects. Based on the results presented here we conclude that 3 VASO offers good reproducibility, high sensitivity, and lower sensitivity than GE-BOLD to changes in 4 larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans. 5Abbreviations: BOLD = blood oxygenation level dependent; CBV = cerebral blood volume; CNR = 6 contrast-to-noise ratio; CSF = cerebrospinal fluid; ΔCBV = change in CBV; EPI = echo planar imaging; 7 Fe = iron; fMRI = functional magnetic resonance imaging; GE = gradient echo; GM = grey matter; ROI 8 = region of interest; SNR = signal-to-noise ratio; SS-SI-VASO = slice-selective slab-inversion VASO...

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.

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Poser, B. A. (2018). Techniques for blood volume fMRI with VASO: From low-resolution mapping towards sub-millimeter layerdependent applications. Neuroimage, 164,[131][132][133][134][135][136][137][138][139][140][141][142][143] Document license: CC BY-NC-ND Please check the document version of this publication:• A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website.• The final author version and the galley proof are versions of the publication after peer review.• The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal.If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the "Taverne" license above, please follow below link for the End User Agreement:www.umlib.nl/taverne-license Take down policyIf you believe that this document breaches copyright please contact us at:repository@maastrichtuniversity.nl providing details and we will investigate your claim. applications at ultra-high magnetic fields (7 T and higher). Non-invasive CBV fMRI using

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