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. 2019 Dec 1;40(17):5083-5093.
doi: 10.1002/hbm.24759. Epub 2019 Aug 12.

Cerebral lesion correlates of sympathetic cardiovascular activation in multiple sclerosis

Klemens Winder  1 , Ralf A Linker  2 , Frank Seifert  1 , Ruihao Wang  1 , De-Hyung Lee  2 , Tobias Engelhorn  3 , Arnd Dörfler  3 , Kilian Fröhlich  1 , Max Hilz  1   4
Affiliations

Cerebral lesion correlates of sympathetic cardiovascular activation in multiple sclerosis

Klemens Winder et al. Hum Brain Mapp. .

Abstract

Cardiovascular autonomic dysfunction is common in multiple sclerosis (MS) and contributes significantly to disability. We hypothesized that cerebral MS-lesions in specific areas of the central autonomic network might account for imbalance of the sympathetic and parasympathetic cardiovascular modulation. Therefore, we used voxel-based lesion symptom mapping (VLSM) to determine associations between cardiovascular autonomic dysfunction and cerebral MS-related lesion sites. In 74 MS-patients (mean age 37.0 ± 10.5 years), we recorded electrocardiographic RR-intervals and systolic and diastolic blood pressure. Using trigonometric regressive spectral analysis, we assessed low (0.04-0.15 Hz) and high (0.15-0.5 Hz) frequency RR-interval-and blood pressure-oscillations and determined parasympathetically mediated RR-interval-high-frequency modulation, mainly sympathetically mediated RR-interval-low-frequency modulation, sympathetically mediated blood pressure-low-frequency modulation, and the ratios of sympathetic and parasympathetic RR-interval-modulation as an index of sympathetic-parasympathetic balance. Cerebral MS-lesions were analyzed on imaging scans. We performed a VLSM-analysis correlating parameters of autonomic dysfunction with cerebral MS-lesion sites. The VLSM-analysis showed associations between increased RR-interval low-frequency/high-frequency ratios and lesions most prominently in the left insular, hippocampal, and right frontal inferior opercular region, and a smaller lesion cluster in the right middle cerebellar peduncle. Increased blood pressure-low-frequency powers were associated with lesions primarily in the right posterior parietal white matter and again left insular region. Our data indicate associations between a shift of cardiovascular sympathetic-parasympathetic balance toward increased sympathetic modulation and left insular and hippocampal lesions, areas of the central autonomic network. The VLSM-analysis further distinguished between right inferior fronto-opercular lesions disinhibiting cardiac sympathetic activation and right posterior parietal lesions increasing sympathetic blood pressure modulation.

Keywords: autonomic dysfunction; insular lesion; multiple sclerosis; visceral arousal; voxel-based lesion symptom mapping.

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Conflict of interest statement

F.S. received travel or speaker honoraria from Merz Pharmaceuticals GmbH, funding for travel to conference from Novartis Pharma GmbH, speaker honoraria from Desitin Arzneimittel GmbH. M.J.H. received personal compensation for activities from Sanofi‐Genzyme, Germany and Novartis Pharma GmbH, Germany. D.H.L. and RAL received travel grants or speaker honoraria from Bayer Health Care Pharmaceuticals (NJ), Biogen Idec (Cambridge, MA), Merck Serono (Germany), Novartis Pharma GmbH, and TEVA Pharmaceutical Industries (Germany).

Figures

Figure 1
Figure 1
Process of lesion delineation and spatial normalization. (a) T2‐weighted MR images in original space. (b) The T2‐weighted axial image was used to define the area of T2‐hyperintense MS‐lesions shown as a red contour and below the red lesion shape. (c) The lesion shape, the T2‐weighted as well as the T1‐weighted MRI scans were then transformed into stereotaxic space which generated the normalized map. The normalized lesion map was also applied to the normalized T1‐weighted brain to qualitatively demonstrate the accuracy of image normalization [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 2
Figure 2
Overlap and distribution of T2‐hyperintense multiple sclerosis lesions of all patients. The number of overlapping lesions is illustrated by different colors coding increasing frequencies from dark red to yellow. Regions with higher lesion overlap counts are found symmetrically in periventricular regions, most prominently in the parietal periventricular white matter, as well as in the subinsular regions, and periaqueductal midbrain gray. Montreal Neurological Institute (MNI) z‐coordinates of each transverse section are given. L, left hemisphere; N, number of individuals with a lesion in a given voxel; R, right hemisphere [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 3
Figure 3
Results of the voxel‐wise t‐test statistics comparing parameters of autonomic arousal between patients with and without lesions in a given voxel. Lesioned voxels in the left insular juxtacortical white matter, hippocampus (axial slices), and right inferior opercular juxtacortical region (coronal slice) were most prominently associated with a shift of cardiac sympatho‐vagal balance toward increased sympathetic modulation, as evidenced by increased LF/HF‐ratios of RR‐intervals. A false discovery rate (FDR) correction of q < 0.01 was applied (z‐score = 3.5). A smaller lesion cluster correlated also in the right middle cerebellar peduncle (a). Lesioned voxels most prominently in the right posterior parietal‐juxtacortical region, as well as in the left insular regions were associated with increased sympathetic blood pressure modulation, as shown by an increase of BPsys‐LF‐powers (z‐score = 3.6). Only voxels that were damaged in at least four individuals were included in the analysis. L, left hemisphere; R, right hemisphere; z = z‐score [Color figure can be viewed at http://wileyonlinelibrary.com]
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