Dear Sirs,

A few video-oculography (VOG) studies have reported a constant spontaneous upbeat nystagmus (UBN) in the absence of fixation in a number of healthy subjects [2, 6]. These oscillations of the vertical gaze system are thought to be under the influence of the gravitational force vector and have been shown to be modulated by otolith input [4]. The phenomenon is therefore termed a vestibular nystagmus. The neural basis of UBN and whether structural differences can be attributed to it have not been investigated to date. In a combined voxel-based morphometry (VBM) imaging and VOG approach within the context of a vestibular stimulation study, we aimed to investigate the neuroanatomical substrate of this UBN.

We examined 44 right-handed healthy subjects (21 F; mean age 28 years) in supine position by means of VOG (EyeSeeCam©) without fixation before and after a bimastoidal galvanic vestibular stimulation (GVS). Structural and functional MR-images were obtained in a clinical 3T scanner (Siemens Magnetom Verio) with a 32-channel head coil. The protocol consisted of an isotropic (1 × 1 × 1 mm) MPRAGE sequence of the whole brain (TE 4.76 ms, flip angle 15°, FOV 100 mm, bandwidth 140 Hz/Px). Data analysis and quality assurance were performed using the VBM12 toolbox (Release 754, Christian Gaser, Jena) within the SPM12 framework (Version 6407, Wellcome Department of Imaging Neuroscience, London, UK) and Matlab 2015b (The MathWorks, Natick, Massachusetts, USA) after standard preprocessing including an 8 mm Gaussian smoothing kernel. T-contrasts were calculated on the modulated normalized images and considered significant at p < 0.001, using permutation testing based on the threshold-free cluster enhancement (TFCE) statistic image [9].

VOG recording revealed a spontaneous UBN in supine position in 20 of 44 subjects (9F) with a mean slow phase velocity (SPV) of 2.3°/s (SD = 1.1). After GVS, the SPV decreased significantly by 52% over all subjects [mean reduction of SPV = 1.06°/s, SD = 1.0; paired t(19) = 0.03, p < 0.05). VBM analysis revealed a significant cluster (p < 0.001, TFCE) of increased gray-matter volume in the left tonsil in subjects with UBN, whereas subjects without UBN showed a significant increase in gray-matter volume in the right cerebellar lobule VIIIB and tonsil (Fig. 1). A separate analysis for subjects with UBN gave a significant positive correlation between the gray-matter volume of the left crus 1 and the degree of UBN reduction after GVS (Fig. 2). In addition, the right cerebellar tonsil showed a positive correlation with the mean SPV of UBN within those subjects.

Fig. 1
figure 1

Gray-matter differences in subjects with and without physiological upbeat nystagmus. Voxel-based morphometry analysis reveals structural differences in subjects with (upper image) and without (lower image) physiological upbeat nystagmus (UBN). Subjects with UBN show increased gray-matter volume in the left cerebellar tonsil (yellow, TFCE, p < 0.001). Conversely, subjects without UBN show increased gray-matter volume in the right tonsil/lobule VIII (blue, TFCE, p < 0.001). Gray-matter images are overlaid on the SUIT template [3]. Color scales indicate z scores

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Fig. 2
figure 2

Correlation analysis of gray-matter changes with reduction in physiological upbeat nystagmus. The slow phase velocity (SPV) of the spontaneous upbeat nystagmus (UBN) decreased significantly (mean reduction of SPV = 1.06°/s) after galvanic vestibular stimulation (GVS). Box plots on the left show the distribution of slow phase velocity before GVS (left box plot, dark yellow) and after GVS (right box plot, light yellow). On the right, a positive correlation of the degree of UBN reduction after GVS with the gray-matter volume in left crus 1 (yellow, TFCE, p < 0.001) is shown. Results are overlaid on the SUIT template [3]. Color scale indicate z scores

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In conclusion, our data indicate that individual structural differences in the cerebellar tonsils could account for the presence and strength of the UBN in the absence of fixation. Increased gray-matter volume was found in the left cerebellar tonsil in subjects with UBN, and in the right cerebellar tonsil in subjects without UBN. The cerebellar tonsil is known to be a crucial element for gaze-holding and supposed to be part of the central vestibular and neural integrator network [1, 5]. UBN could be partially caused by a leakiness within this integrator network, revealed by means of an orbital centering mechanism in darkness [4]. On the other hand, the UBN might also reflect a neural compensatory mechanism correcting for an ocular drift as a passive effect of gravity. An underlying controlling network of anti-gravitational pathways has been proposed comprising otolith afferences, the flocculus, the superior vestibular nuclei, and the crossing ventral tegmental tract [7, 8].Our data hint at the cerebellar tonsil as an additional hub within this anti-gravitational vestibular network. GVS and predominantly its otolith arousal might lead to an artificial external stabilization of this system, reflected by a decrease in slow phase velocity of the physiological UBN after GVS.