Aneurin J Kennerley1, Benedikt A Poser2, Frida H Torkelsen1, Rainer Goebel2, Amanda Kaas2, and Laurentius Huber2
1Chemistry, University of York, York, United Kingdom, 2Maastricht Brain Imaging Centre, Maastricht University, Maastricht, Netherlands
Synopsis
With recent advances in ultra-high-field MRI hardware and sequence mechanisms, it has become possible to capture CBV-weighted fMRI signal across cortical layers. However, the exact contrast mechanisms of layer-dependent VASO has not been fully validated with gold-standard pre-clinical methods.
Introduction
Methodological advances in functional Magnetic Resonance Imaging (fMRI)
in recent years now allow researchers to approach the mesoscopic spatial regime
of cortical layers and cortical columns1. The cerebral blood volume (CBV)
sensitivity, and improved spatial specificity, offered by the non-invasive
vascular space occupancy (VASO) contrast mechanism, which can be easily
implemented on existing clinical MRI hardware, promises an unprecedented
non-invasive glimpse into the laminar circuits of the human brain. At clinical
field strengths (<3T) the VASO contrast relies the difference in blood and
tissue T1 times. The MR signal of blood compartment can be nulled (using an
inversion recovery approach) and functional changes in the blood volume can be
deduced from the complementary signal changes in the measured tissue
compartment. VASO is particularly attractive at high fields (7 T) due to
the increase in image SNR and the longer longitudinal relaxation time of blood,
which can amplify VASO's functional T1-contrast2. However, to
date it has not been conclusively established to what extent macrovascular contaminations
might contribute to layer-dependent CBV fMRI results and thus wider uptake of
the VASO fMRI method is compromised.
The goal of this current study was to utilise a multi-modal invasive
pre-clinical rodent model to investigate cortical surface macrovascular
contamination as a possible confound to the VASO contrast. We compared functional
changes (in response to somatosensory stimulation of the whisker pad) measured
with VASO and Blood Oxygenation Level Dependent (BOLD) fMRI, to high spatial
and temporal resolution concurrent 2D optical imaging spectroscopy (2D-OIS)
measurements of total and deoxygenated haemoglobin (HbT and Hbr respectively)
to validate the VASO CBV signal source. MION contrast agent based measurement of the CBV
pool, within the same animals and scanning sessions offered further validation
of the layer-dependent CBV profiles measured with VASO-fMRI. Ultimately, we sought
to compare layer-dependent fMRI profiles of CBV and BOLD across rodents and
humans in with the same non-invasive SS-SI-VASO2 sequence in similar areas of somatosensory cortex. Methods
Human MRI: Multiple human 12-min acquisitions were conducted in n=7
participants for passive stroking and finger tapping tasks. Human data
acquisition was approved by the Maastricht ethical review board:
ERCPN:180_03_06_2017 and the NIH Combined Neuroscience Institutional Review
Board-approved protocol (93-M-0170, ClinicalTrials.gov identifier:
NCT00001360). Functional data of GE-BOLD and cerebral blood volume (CBV) were
concomitantly acquired with SS-SI-VASO. fMRI readout parameters were: in-plane
resolution 0.7mm, slice-thickness: 1.2-1,8 mm perpendicular to the
cortex, TE=25ms, in-plane PF=6/8 with POCS8, FLASH-GRAPPA=1, TR=1.6+1.6s,
3D-EPI readout3, ‘classic’ 7T Magnetom (Siemens Healthineers), 32-ch
NOVA coil, SC72 body gradient.
Rodent MRI: All aspects of these methods and their
development were performed with UK Home Office approval under the Animals
(Scientific Procedures) Act 1986. Measurements were made on a 7T MRI system (Bruker
BioSpec, 310mm bore). Urethane anaesthetized animals (n=4) were artificially
ventilated and cannulated for monitoring arterial blood pressure and
intravenous infusion. A thinned skull cranial window allowed direct optical imaging
of the cortex (see below). fMRI measurements (TE = 13ms, 0.5x0.5x3mm) of BOLD
and CBV signal changes were obtained with concurrent optical measurements of
HbT and blood oxygen saturation changes4-6. For direct comparison to
VASO results, contrast agent measured CBV-MRI was performed (MION 8 mg/kg) with
the optical data used as a standard. Signal changes were corrected for BOLD
contamination.
Rodent 2D-OIS: Intrinsic optical imaging of the
underlying haemodynamics within the magnet bore utilised a non-magnetic
endoscope connected to a switching Galvanometer (Four λ’s = 495, 586, 559 and
575nm) and a CCD camera (32Hz frame rate)5. Spectral analysis was based Beer-Lambert
law and incorporated a MR based heterogeneous tissue model6; producing 2D
images over time, of oxy-, deoxy- and total haemoglobin changes (HbO2, Hbr and
HbT respectively).Results and Discussions
We find that in the rodent model both the BOLD fMRI signal
and 2D-OIS measures of blood oxygenation are sensitive to large pial veins. The
location of large pail vein signal matches with the location of the respective fMRI
contrasts (Fig 1.). However, we also see evidence of layer-unspecific CBV
signal changes at the location of large pial arteries. We find that the
layer-dependent layer-profiles are the same (within error) for VASO-fMRI and
MION-fMRI (Fig. 2). Note that MION and VASO are inherently measured in
different physical units. VASO is measured in [ΔCBV ml / 100 ml of tissue],
whereas MION is measured in [ΔCBV / CBVrest]. For a fair comparison, the local
distribution of CBVrest needs to be taken into account. CBV
sensitive layer fMRI responses in the primary somatosensory cortex are
comparable in shape across species (Fig. 3). We find that passive touch of
fingers in awake humans results in three times larger VASO signal change
compared to electrical whisker pad stimulation in anaesthetised rodents.Conclusion
We conclude that the layer-dependent CBV change measured with non-invasive VASO methods reveals highly localized activity changes (independent of large veins), as expected from established pre-clinical imaging modalities of OIS and MION-fMRI. The confirmation that the VASO contrast is indeed a reliable estimate of layer-specific CBV changes is very valuable in human neuro-imaging: This validation increases the applicability of human layer-dependent fMRI results for neuronal interpretation in neuroscience studies7-8.Acknowledgements
Laurentius Huber and Aneurin Kennerley received funding from the York-Maastricht Partnership for this project. Laurentius Huber is funded form the NWO VENI project 016.Veni.198.032. Benedikt Poser received funding from R01 MH111444/MH/NIMH NIH and 16.Vidi.178.052. Rainer Goebel received funding from the European FET Flagship project ‘Human Brain Project’ (FP7-ICT-2013-FET-F/604102 Grant Agreements, No. 7202070 (SGA1) and No. 785907 (SGA2)).References
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