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Microstructural and structural connectivity alterations in dexmedetomidine-induced loss of consciousness
Timo Roine1,2, Oskari Kantonen3, Jaakko Langsjö3,4, Kimmo Kaskinoro5, Roosa Kallionpää2,5,6, Annalotta Scheinin3,5, Katja Valli2,5,6,7, Timo Laitio5, Antti Revonsuo2,6,7, and Harry Scheinin3,5,8
1Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Espoo, Finland, 2Turku Brain and Mind Center, University of Turku, Turku, Finland, 3Turku PET Centre, University of Turku and the Hospital District of Southwest Finland, Turku, Finland, 4Department of Intensive Care, Tampere University Hospital, Tampere, Finland, 5Division of Perioperative Services, Intensive Care and Pain Medicine, Turku University Hospital, University of Turku, Turku, Finland, 6Department of Psychology and Speech-Language Pathology, University of Turku, Turku, Finland, 7Department of Cognitive Neuroscience and Philosophy, School of Bioscience, University of Skövde, Skövde, Sweden, 8Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland

Synopsis

We used diffusion MRI to investigate brain microstructure and structural connectivity in 10 healthy subjects before and during dexmedetomidine-induced loss of consciousness. We found rapid local changes both in the microstructural properties and in the structural brain connectivity networks, most prominently in the left angular gyrus and its connections indicating possible involvement of the area in consciousness. Moreover, our results indicate that conventional high b-value diffusion MRI acquisitions, in addition to sequences specifically designed to capture functional changes, are sensitive to at least major brain state changes.

Introduction

Diffusion MRI can be used to investigate brain microstructure and structural connectivity1. Modern acquisitions for the estimation of connectivity typically involve high diffusion-weighting (b>2500 s/mm2), while sequences designed to be sensitive to brain function, such as intra-voxel incoherent motion (IVIM), typically involve low diffusion-weighting (in IVIM, typically b=50-250 s/mm2). In this study, we used high diffusion-weighting to investigate whether rapid intra-subject microstructural and connectivity alterations could be observed during dexmedetomidine-induced loss of consciousness (LOC).

Methods

We acquired diffusion-weighted (DW) and T1-weighted MRI data from 10 healthy subjects before and during dexmedetomidine-induced LOC. Dexmedetomidine was administered intravenously using target-controlled infusion until loss of responsiveness to verbal commands. Then, the drug concentration was increased by 50% to induce presumable LOC. Diffusion MRI data were acquired in 64 gradient orientations using a diffusion-weighting of b=3000 s/mm2 and three b=0 s/mm2 images. In addition, three b=0 s/mm2 images were acquired with reverse phase-encoding. The voxel size was 2 mm × 2 mm × 2 mm.

The DW data were corrected for bias field2, subject motion3, eddy current induced4, and echo-planar imaging distortions5, and the structural data were aligned to the DW images with rigid body registration6. Cortical parcellation of the T1-weighted images was performed in FreeSurfer7 by using the Destrieux atlas8 combined with the subcortical gray matter structures segmented with FSL's9 FIRST10, resulting in 164 gray matter regions.

Then, global microstructural brain properties were calculated by performing constrained spherical deconvolution (CSD)-based11-12 whole-brain tractography13. We investigated traditional diffusion tensor-based microstructural metrics14, such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and coefficient of planarity (CP)15. Local microstructural alterations along the white matter tract skeleton were investigated with tract-based spatial statistics (TBSS)16 and controlled for the family-wise error (FWE) rate using a significance threshold of α=0.05 with threshold-free cluster enhancement17.

Structural brain connectivity networks18 were reconstructed by combining the parcellation8,10 with the streamlines reconstructed with CSD-based tractography12-13, resulting in a connectivity matrix of 164 × 164. Anatomically constrained tractography19 and spherical deconvolution informed filtering of tractograms (SIFT)20 were used to improve the anatomical correspondence of the reconstructed streamlines, resulting in 10 million streamlines. The number of streamlines connecting a pair of regions was used as the connection weight18. Global (betweenness centrality21, normalized global efficiency22, normalized characteristic path length23, normalized clustering coefficient24-25, small-worldness23, and strength) and local (betweenness centrality21 and local efficiency22) graph theoretical properties were investigated26-27. Normalization was performed by comparing the networks to 100 randomized networks with equal weight, degree, and strength distributions28. Statistical analyses were performed with a paired t-test and a corrected for FWE using a significance threshold of α=0.05.

Results

We found no global microstructural changes, as shown in Figure 1. However, significant local microstructural changes were observed with TBSS. MD was decreased in LOC on the left hemisphere, most prominently in the inferior fronto-occipital and inferior longitudinal fasciculi close to the left inferior parietal lobe (P<0.05). AD was decreased more widely, for example in the corpus callosum and more significantly on the right side (P<0.05). The local microstructural differences in MD and AD are shown in Figure 2. In addition, we observed a decrease in FA in the left anterior thalamic radiation and the fornix and an increase in RD in the sagittal stratum.

In the structural brain connectivity networks, we found no global changes in the graph theoretical properties, as shown in Table 1. However, local betweenness centrality was significantly decreased (P=0.00027) in the left angular gyrus of the inferior parietal lobe (Figure 3). There were no other significant node-level findings after FWE-correction.

Discussion

We found no global microstructural or connectivity changes related to LOC. However, we observed significant local microstructural changes in MD and AD most prominently in the inferior parietal lobe, and significantly decreased node-level centrality in the left angular gyrus of the inferior parietal lobe in the structural brain networks.

The overlap of the findings indicates that the inferior parietal lobe, more specifically the angular gyrus, may be associated with consciousness. Although the connectivity alteration was only observed unilaterally, the microstructural alterations were bilateral, and more pronounced for AD in the right hemisphere. The right angular gyrus has previously been reported in positron emission tomography studies of consciousness29-30. In addition, our results indicate that conventional diffusion MRI acquisitions are sensitive to major brain state changes, which may cause local alterations both in the observed brain microstructure and connectivity.

In the future, we plan to analyze more specific metrics such as fiber density and cross section31 and investigate their relationship to both structural and functional brain connectivity.

Conclusion

We found rapid local abnormalities related to dexmedetomidine-induced LOC in structural brain connectivity of the left angular gyrus in the inferior parietal lobe, and in the local brain microstructure of the corpus callosum and near the inferior parietal lobe.

Acknowledgements

This work was supported by the Emil Aaltonen Foundation, the Finnish Cultural Foundation, the Academy of Finland (grants #266467 and #266434), and the Jane and Aatos Erkko Foundation.

References

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Figures

Figure 1. Global microstructural properties within the whole-brain tractogram reconstructed with constrained spherical deconvolution. No significant differences were found in the loss of consciousness (LOC) state compared to awake state (Base). FA: fractional anisotropy, AD: axial diffusivity, MD: mean diffusivity, RD: radial diffusivity, CP: coefficient of planarity

Figure 2. Local microstructural differences in mean diffusivity (A, B, E) and axial diffusivity (C, D). In Fig. 2E the location of the left angular gyrus is highlighted. The color scale from red to yellow describes the statistical significance of the decrease in the microstructural metric in the loss of consciousness (LOC) state compared to awake state. The white matter skeleton is visualized in green. The images are presented in radiological convention (left hemisphere on the right and vice versa).

Figure 3. Local alterations in betweenness centrality of the structural brain connectivity networks. Statistical significance is illustrated by the color of the node from white (not significant) via yellow and red to black (most significant) as shown by the color bar. The size of the node reflects the volume of the gray matter area. The color of the edges corresponds to the direction – red: left (L)-right (R), blue: inferior (I)-superior (S), green: anterior (A)-posterior (P) The betweenness centrality of the left angular gyrus was significantly decreased (P=0.00027).

Table 1. Global network properties (mean ± standard deviation) in the structural brain networks in loss of consciousness (LOC) state compared to awake state (Base). BC: betweenness centrality, nEff: normalized global efficiency, nλ: normalized characteristic path length, nCC: normalized clustering coefficient, SW: small-worldness

Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)
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