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Background Little is known about the cortical organization of human vestibular information processing. Instead of a dedicated primary vestibular cortex, a distributed network of regions across the cortex respond to vestibular input. The aim of this study is to characterize the human corticocortical vestibular network and compare it to established results in non-human primates. Methods We collected high-resolution multi-shell diffusion-weighted (DWI) and state-of-the-art resting-state functional MR images of 29 right-handed normal subjects. Ten cortical vestibular regions per hemisphere were predefined from previous vestibular stimulation studies and applied as regions of interest. Four different structural corticocortical vestibular networks accounting for relevant constraints were investigated. The analyses included the investigation of common network measures and hemispheric differences for functional and structural connectivity patterns alike. In addition, the results of the structural vestibular network were compared to findings previously reported in non-human primates with respect to tracer injections (Guldin and Grusser, 1998). Results All structural networks independent of the applied constraints showed a recurring subdivision into identical three submodules. The structural human network was characterized by a predominantly intrahemispheric connectivity, whereas the functional pattern highlighted a strong connectivity for all homotopic nodes. A significant laterality preference towards the right hemisphere can be observed throughout the analyses: (1) with larger nodes, (2) stronger connectivity values structurally and functionally, and (3) a higher functional relevance. Similar connectivity patterns to non-human primate data were found in sensory and higher association cortices rather than premotor and motor areas. Conclusion Our analysis delineated a remarkably stable organization of cortical vestibular connectivity. Differences found between primate species may be attributed to phylogeny as well as methodological differences. With our work we solidified evidence for lateralization within the corticocortical vestibular network. Our results might explain why cortical lesions in humans do not lead to persistent vestibular symptoms. Redundant structural routing throughout the network and a high-degree functional connectivity may buffer the network and reestablish network integrity quickly in case of injury.

The vestibular organ senses linear and rotational acceleration of the head during active and passive motion. These signals are necessary for bipedal locomotion, navigation, the coordination of eye and head movements in 3D space. The temporal dynamics of vestibular processing in cortical structures have hardly been studied in humans, let alone with natural stimulation. The aim was to investigate the cortical vestibular network related to natural otolith stimulation using a hexapod motion platform. We conducted two experiments, 1. to estimate the sources of the vestibular evoked potentials (VestEPs) by means of distributed source localization (n=49), and 2. to reveal modulations of the VestEPs through the underlying acceleration intensity (n=24). For both experiments subjects were accelerated along the main axis (left/right, up/down, fore/aft) while the EEG was recorded. We were able to identify five VestEPs (P1, N1, P2, N2, P3) with latencies between 38 and 461 ms as well as an evoked beta-band response peaking with a latency of 68 ms in all subjects and for all acceleration directions. Source localization gave the cingulate sulcus visual (CSv) area and the opercular-insular region as the main origin of the evoked potentials. No lateralization effects due to handedness could be observed. In the second experiment, area CSv was shown to be integral in the processing of acceleration intensities as sensed by the otolith organs, hinting at its potential role in ego-motion detection. These robust VestEPs could be used to investigate the mechanisms of inter-regional interaction in the natural context of vestibular processing and multisensory integration.

Aim Galvanic vestibular stimulation (GVS) allows for robust vestibular responses and is therefore the gold standard in neuroimaging studies focusing on the central vestibular system. Nevertheless, there are several confounding side-effects which hinder the delineation of pure vestibular responses. Besides stimulating vestibular hair cells and afferent fibers [1] , mastoidal GVS also evokes somatosensory, vagal and nociceptive responses. Furthermore, GVS induces reflectory head movements leading to motion artefacts. Aim of our fMRI study was to assess and control for the impact of these confounders by means of local anaesthesia, optimized head fixation, and a sham-GVS stimulation with different current intensities. Methods We examined 44 right-handed healthy subjects (21 F; mean age 28 years) in three sessions (interval length between session > 24 h) with different conditions: GVS with 3.5 mA with/without local anaesthesia, sham-GVS with 3.5 mA/1 mA, and GVS with/without head fixation (headfixation system: Pearltec, Switzerland). Structural and functional images were obtained in a clinical 3T scanner (Siemens Magnetom Verio) with a 32-channel head coil. The protocol included a GVS stimulation session consisting of a T2*-weighted EPI sequence (TR 2s, 31 ascending slices, 3 mm in-plane resolution, slice thickness 3.5 mm), a MPRAGE sequence, and a resting-state session. Data analysis was performed using SPM 12 (Version 6407 Wellcome Department of Imaging Neuroscience, UK) and the motion fingerprint toolbox (Wilke, Neuroimage 2012) after standard preprocessing using DARTEL-based normalization. Results were considered significant at FDR p 0.05 (corrected at cluster level). Results Pain perception during GVS decreased significantly after local anesthesia (NRS-11 reduction from 4.5 to 1.7, Wilcoxon signed-rank test, Z = −3.79, p = 0.00). GVS with lidocaine evoked responses in the vestibular network, predominantly in right OP2 and the medial cingulate cortex bilaterally, which were absent during sham stimulation. Without anesthesia, confluent activation cluster were found in anterior and posterior insula-opercular regions. Activation of the insula was also shown bilaterally during sham-GVS, with a predominant effect in area OP1 and area PF with a current intensity of 3.5 mA. Sham-GVS with 1 mA led to bilateral responses in area Fp1, the precentral gyrus and the left posterior cingulum. Motion finger print analysis in GVS with and without head fixation revealed head motion predominantly in the roll plane, leading to inter-slice motion artefacts in temporo-parietal-opercular regions. These artefacts were eliminated using a new head fixation system. Conclusion In this fMRI study, we evaluated and minimized the effects of several confounders in GVS. Head motion artefacts as well as nociceptive and somatosensory responses may hinder the localization of actual vestibular response patterns, particularly in the insula and parietal operculum. Our results highlight the importance of controlling for these side-effects and lead the way towards a precise definition of the human vestibular cortical network.

Aim Some videooculography (VOG) studies have reported a spontaneous upbeat nystagmus (UBN) in the absence of fixation in a number of healthy subjects ( Bisdorff et al., 2000 ). These oscillations of the vertical gaze system are thought to be under the influence of the gravitational force vector, termed vestibular nystagmus. The neural basis of this UBN and whether structural differences can be attributed to it, however, remain unclear. Aim of our combined voxel-based morphometry (VBM) and VOG approach within the context of a larger vestibular stimulation study was to investigate the anatomical substrate of this UBN in healthy subjects. Methods 44 right-handed healthy subjects (21 F; mean age 28 years) were examined in supine position by means of VOG (EyeSeeCam©) without fixation before and after bimastoidal galvanic vestibular stimulation (GVS). Then structural and functional images were obtained in a clinical 3T scanner (Siemens Magnetom Verio, Erlangen, Germany) with a 32-channel head coil. The protocol included an isotropic (1 × 1 × 1 m) MPRAGE sequence and a resting-state session with 165 volumes, each consisting of 36 slices of a T2 ∗ -weighted ascending EPI sequence (TR 2.31s). Data analysis was performed using the VBM12 toolbox within SPM 12 (Version 6407 Wellcome Department of Imaging Neuroscience, London, UK) in Matlab 2015b (The MathWorks, Natick, Massachusetts, USA) after standard preprocessing. T-contrasts were calculated with respect to the rest condition and were considered significant at p Results In the VOG experiment, a spontaneous UBN occurred in 20 of 44 subjects (9 F) with a mean slow phase velocity (SPV) of 2,3°/s (SD = 1.1). After GVS, SPV decreased significantly by 52% (mean reduction of SPV = 1.06 °/s, SD = 1.0; paired t(19) = 0.03, p Conclusion Individual structural differences in the uvula could account for the physiological UBN in the absence of fixation in supine position. The uvula contributes to the processing of otolith information and responds both to translation and changes in orientation relative to gravity ( Angelaki et al., 2004 ). The tonsil on the other hand seems to be crucial for gaze-holding. Our results point to the importance of a balanced interplay of uvula and tonsil in vertical gaze control. The combination of a minimized influence of gravity on vertical eye movements in supine position and the absence of visual information might demask central oscillatory signals within the vertical gaze system. High frequency dampening via GVS might in return result in an artificial external stabilization of this system, reflected in a decrease of UBN. Supported by the German Foundation for Neurology (DSN) and the German Research Foundation.

Item does not contain fulltext Key nodes of neural networks for ocular motor control and visual motion processing have been localized using saccades, smooth pursuit, and optokinetic nystagmus (OKN). Within the context of an independent fMRI study using OKN, 9 bilateral network nodes were localized comprising cortical eye fields in frontal (FEF), supplementary motor (SEF), cingulate (CEF) and parietal cortex (PEF), visual motion centers MT+ and V6, the superior colliculus (SC), the lateral geniculate nucleus (LGN) and the globus pallidus (GP). Here, we examined the network's functional hierarchy as present in the structural co-variation (SCoV) and resting-state (RS) fMRI, and the effect of RS condition (eyes open/closed) on its' functional connectivity (FC). Two publicly available samples were analyzed consisting of the enhanced NKI sample with RS (TR 1.4s) and structural MR data (n = 124; age 46.7 ± 17.6; 40 male) and the "Beijing: eyes open eyes closed sample" measuring RS (TR 2s; n = 48; age 22.5 ± 2.2; 24 male). For the FC analysis, ICA-based denoising (FSL) was applied before spatial preprocessing (SPM) and band-pass filtering. Each bilateral ROI was represented by the first eigenvariate of the respective voxels' time-series and partial correlation were computed using FSLNets. One group t-tests were computed over Fisher's z transformed correlation coefficients. Each ROIs volume was approximated with voxel-based morphometry (VBM8) using non-linearly modulated gray matter density and partial correlations were computed for SCoV. Hierarchical cluster analysis was applied to determine sub-clustering within the OKN network. Edge-wise comparisons between RS conditions were performed using permutation testing and Bonferroni correction. Both FC and SCoV revealed two major subcluster. MT+ and V6 were similar to LGN and SC. The cortical eye fields clustered together with the GP. As effect of RS condition, with eyes closed the CEF switched to the visual subcluster. The edge-wise comparison revealed generally higher FC with eyes open and in particular a decrease of FC between MT+ and PEF, FEF and SEF as well as between V6 and SEF. Hierarchical clustering based on RS and structural data revealed a task-independent sub-division of the network for ocular-motor control and visual motion processing into two streams either involved in top-down (efferent voluntary) ocular-motor control (FEF, PEF, SEF, GP) and in more bottom-up visual target tracking (MT+, V6, LGN, SC) streams. This general network hierarchy was equally present in the RS with eyes open and eyes closed, with the CEF fulfilling a condition specific role in the network. The edge-wise comparison between RS conditions strengthens the evidence for a specific influence of MT+ on the ocular-motor control subcluster. These findings indicate a systematic influence of the resting condition not only on FC of the visual system, but on the state of the whole OKN network, while a general system hierarchy is omnipresent independent of RS condition. 2 p.

Background: Up to now, there are few systematic studies in a sufficient number of patients with lesions involving the insular cortex (IC) examining whether damage of the IC is directly related to dysarthria. Thus, this is the first study applying modern voxel-lesion behaviour mapping (VLBM) aimed to examine whether the IC is involved in dysarthria – and if so – which part of the IC is involved. Methods: Twenty-five patients with acute stroke lesions affecting the IC and peri-insular region were investigated employing VLBM analysis. Results: Present data indicated that dysarthria is associated with stroke lesions affecting the right- and left-sided posterior IC. Conclusions: Owing to the known extensive spectrum of cortical and subcortical somatosensory and motor connections, it seems that the IC might be one region involved in the generation of speech motor execution.

Several works have revealed a robust visual–vestibular interaction at the cortical level in humans. The same has been shown at an infratentorial level in other primates. Most stimuli applied in the context of ocular motor neuroimaging research are fixed and therefore highly artificial in nature for methodological reasons. Advances in imaging techniques now allow for robust brainstem fMRI, thus opening up a whole new terrain for investigation. The aim of this study was to investigate the neural correlate for ocular motor adaption control (AC) with changing stimulus parameters (speed/direction) and the functional connectivity (FC) of the localised governing hubs at the level of the brainstem and the cerebellum. The effects of constant and linear accelerating small-field optokinetic (OKN) stimuli in the horizontal and vertical direction were studied in 20 volunteers lying supine with their ears plugged in a clinical 3T scanner (Siemens Magnetom Trio, Erlangen, Germany). The protocol included two sessions, each consisting of a T2*-weighted EPI sequence (2mm isotropic resolution, TA 2.93s) in alternating blocks of visual fixation and during OKN stimulation (left/right, up/down). Horizontal (vertical) OKN speeds were either fixed at 30°/s (20°/s) or accelerated during stimulus blocks from 15° to 45°/s (10°/s–30°/s). Resting-state data was acquired prior to task fMRI for 5min (3mm isotropic resolution, 37 slices, TA 2.67s, whole-brain coverage). Data was analysed with SPM8 and DPARSFA after standard preprocessing. T-contrasts were calculated with respect to the rest condition and were considered significant at p . The task revealed a cerebellar network including the dorsal ocular motor vermis (OMV), the fastigial ocular motor region, the posterior inferior vermis, the flocculus and paraflocculus, the culmen (lobule VI) and the declive. In the brainstem, we were able to significantly activate the ocular motor and abducens nuclei, the paramedian pontine reticular formation (PPRF), the dorsolateral pontine nucleus (DLPN), the nucleus reticularis tegmenti pontis (NRTP), the prepositus nucleus (NPH), riMLF and the interstitial nucleus of Cajal (INC). AC was localised to the OMV and pontine structures (NTRB and PPRF). Activation clusters throughout all OKN tasks were significantly larger with higher peak maxima in the left cerebellar hemisphere. We found a significant deactivation of the ventral uvula and the cerebellar tonsils (lobule VIII) during constant more so than during accelerating OKN stimulation. FC maps with the dorsal ocular motor vermis as a seed region gave a significant connectivity with all other regions found in the task-based part of our experiment as well as the dorsal visual stream and all cortical eyefields. Our study gives in vivo evidence for the basic visual–vestibular interactions at the level of the infratentorial networks. Ocular motor areas of the human brainstem could be mapped at an unprecedented detail. AC for the OKN task itself independent of direction was found to be localised mainly in the OMV. Velocity-fixed more so than accelerating OKN stimuli lead to a significant deactivation of a cerebellar core vestibular area known to govern the velocity storage mechanism, the ventral uvula. Extending the cortical concept of a right-hemispheric predominance for visual-spatial processing we found a complementary left-sided dominance for OKN responses in the cerebellum (Dieterich et al., 2003). Taken together, these findings should open up another chapter in our understanding of visual–vestibular interactions in the human brain.

Introduction Visual motion processing on one hand and ocular motor functions on the other are rarely studied together in vivo in humans. The interrelation of these functional networks is rather unclear, even though their functional dependence seems obvious. In several fMRI studies the essential nodes of both networks could be localized using voluntary optokinetic ('look') nystagmus (OKN) in the horizontal plane incorporating visual motion tracking (Dieterich et al., 2009). Here, functional connectivity (FC) between these nodes representing both networks was studies using resting-state FC. Methods Resting-state fMRI data of 200 healthy adults (age 44.1±17.9; 79 male) were included in the cross correlation analysis of 9 bilateral nodes including frontal (FEF), supplementary (SEF), cingulate (CEF) and parietal eye fields (PEF), V5 and V6, as well as the superior colliculus (SupCol), the lateral geniculate body (CGL) and the globus pallidus (GlobPal). The necessary ROIs were obtained in a separate OKN fmri experiment with 21 healthy subjects. After spatial preprocessing and confound removal using 24 motion regression and mean signal within white matter and cerebral spinal fluid and band-pass filtering (0.01–0.08Hz), each ROI was represented by the first eigenvariate of the respective voxels' time-series. For each node pair partial correlations were computed within subjects and Fisher Z transformed for one group t -tests corrected for the influence of age and gender resulting in an 18×18 cross correlation matrix. Subsequently, hierarchical cluster analysis was applied to analyze sub-clustering within the overall network. Results The analysis showed consistent FC between each regions respective homotopical partner. Hierarchical clustering revealed an overall split between one cluster comprising SEF, FEF, CEF and GlobPal and a second including CGL, SubCol, V6 as well as PEF and V5. Conclusion This new approach revealed an observer- and task-indepedent separation of the cortical eye fields into two main groups either responsible for voluntary ocular motor control (SEF, FEF, CEF, and GlobPal) or involved in visual motion target tracking streams (CGL, SupCol, PEF, V5, and V6). The further subgrouping of PEF and V5 together with area V6 representing an isolated cluster within the second group seem to reflect their order and importance along the dorsal visual stream known from lesion studies (Pierrot-Deseilligny et al., 2004). The other subgroup of CGL and SupCol may represent the early nodes of the network involved in voluntary and reflexive ocular motor control. In sum, these neuroscientifically sound network findings for visual motion and ocular motor control derived from task-free data give a promising outlook for the novel concept of hierarchical clustering (Figs. 1 and 2).

The operculo-insular cortex has been termed the 'homeostatic control center' or 'general magnitude estimator' of the human mind. In this study, somatosensory, nociceptive and caloric vestibular stimuli were applied to reveal, whether there are mainly common, or possibly specific regions activated by one modality alone and whether lateralization effects, time pattern differences or influences of the aversive nature of the stimuli could be observed. Activation of the dorsal posterior insula was caused by all stimuli alike thus terming this area multimodal. Early phases of the noxious heat and caloric vestibular stimulation led to responses in the anterior insula. Using conjunction analyses we found that left- and right-sided tactile stimulation, but not nociceptive stimulation, caused a joint activation of the cytoarchitectonic area OP1 and nociceptive but not tactile stimulation of the anterior insula bilaterally. Tactile activation in the parietal operculum (SII, OP1) was distinct from nociceptive activation (OP3 and frontal operculum). The joint activation by all three stimuli located in the dorsal posterior insula argues for the presence of multisensory structures. The distinct activation of the anterior insula by aversive stimuli and the posterior insula by multisensory signals supports the concept of a partitioned insular cortex recently introduced based on connectivity studies and meta-analyses.

Repetitive transcranial magnetic stimulation (rTMS) has been applied to sensory research and for the treatment of disorders in psychiatry and neurology since 1993 ( Wassermann and Zimmermann, 2012 ). The widespread cortical vestibular system, however, has to date not been targeted. Aim of our study was to manipulate vestibular regions in the human cortex by temporary virtual lesioning through rTMS and analyse the changes in the perception of a galvanic vestibular stimulation (GVS) as well as the differing activation patterns in functional neuroimaging. The effects of rectangular and sinusoidal bimastoidal GVS were studied in 16 healthy volunteers (8 F; mean age 23 years) in a 3T scanner. Data was analysed with SPM12. Results of the baseline fMRI session were used as functional localizers for three rTMS target regions: (1) cingulate sulcus visual (CSv) bilaterally, (2) the right inferior parietal lobule (BA40), and (3) the right polysensory superior temporal sulcus area (STP) ( Smith, 2012 ). The vestibular fMRI sessions with GVS were repeated within minutes after virtual lesioning of the target regions with low-frequency rTMS (1 Hz, 1800 pulses, 90% active motor threshold) followed by a psychophysical debriefing and a clinical neurootological examination. Generally speaking virtual lesioning of vestibular cortex areas by means of rTMS resulted in a reduced, never in a more pronounced, activation pattern of the cortical vestibular regions. (1) RTMS of area CSv bilaterally led to a reduction in vestibular activation of area 6, area MST, and the inferior parietal lobule in both hemispheres. For unilateral galvanic stimuli this effect was constricted to the cerebral hemisphere ipsilateral to the side of excitation. More subjects perceived their head to be rotating in space during sinusoidal GVS instead of the sensation of the whole body twirling compared to all other sessions (72% vs 30%). (2) Virtual lesioning of the right inferior parietal lobule lead to reduced activation of the target region itself and area 6 in the same hemisphere during GVS. Here, subjects showed the largest reduction in grading the perceived amount of rotation induced by rectangular GVS (mean reduction of 45 ± 7° compared to the baseline session). The effect of a significantly reduced sensation of head rotation during GVS was seen in all target areas. (3) RTMS of area STP lead to a significant isolated deactivation of the left midbrain during GVS. There were no pathological findings in our healthy subjects after the virtual lesioning in the ensuing clinical neurootological examinations. The realignment parameters of the vestibular stimulations as a correlate for a potential vestibular motor response also gave no significant differences between the four sessions. This is the first demonstration by means of psychophysics, fMRI and rTMS that points at the potential for a manipulation of vestibular cortex regions. Global cerebral network effects within the vestibular system were only seen after rTMS lesioning of the vestibular midline structure CSv bilaterally. The resulting shift from body to isolated head rotation in space in the perception after GVS for the lesioned area CSv could reflect its role in egomotion processing. The quantitative perceptual findings for the right inferior parietal lobule as an rTMS lesion site on the other hand might suggest a leading role for this region in egocentric referencing within the confines of a three-dimensional environment.

Background and aims: The pedunculopontine nucleus (PPN) is a new deep brain stimulation (DBS) target, thought to be particularly for useful in ameliorating gait disturbance in Parkinson’s disease. Recent evidence shows a prominent theta (4–7 Hz) rhythm in the PPN (Tsang et al., Neurology, 2010; Simon et al., J. Neurophysiol., 2010; Shimamoto et al., JNNP, 2010). Given that theta activity is modulated by vestibular signals elsewhere in the brain, e.g. hippocampus, (Shin, Synapse, 2010; Chen et al., Neuroimage, 2010), we assessed whether vestibular signals modulate PPN theta activity. Methods: We recorded local field potentials (LFPs) in three patients with implanted bilateral subthalamic nucleus (STN) and PPN DBS electrodes at 2000 Hz and filtered at 0.5–500 Hz at rest and during passive, yaw-plane whole body rotations (i.e., vestibular stimulation) at 0.2 and 0.4 Hz with eyes closed and then open with manifest vestibular ocular reflex activation (i.e., nystagmus) and then with VOR suppression (VORS). Frequency power spectra and the average power across a 1–1000 Hz frequency range were obtained. Results: PPN LFPs showed significant modulation during vestibular activation (rotations) compared to rest with power changes ca. four times larger than those found in the STN. The PPN LFP was dominated by theta (4–7 Hz) activity which was enhanced during all tasks compared to rest (including eyes open vs. closed at rest) except for VORS where there was a clear reduction in theta activity and this was more prominent for ‘fast’ (i.e., 0.4 Hz rotations) rotations. The pattern of theta activity was the same for right and left PPN including task-dependent modulation. To rule out the possibility that this theta activity was purely driven by nystagmus, we recorded LFPs during optokinetic nystagmus (OKN). OKN was associated with a decrease of theta power compared to rest. Conclusions: This is the first demonstration of vestibular modulation of PPN activity (in either animals or humans). Human PPN activity is increased during vestibular activation with a relative suppression of theta during VORS. This pattern of a reduction of activity during VORS compared to VOR is seen in the vestibular nuclei. Thus, the PPN may represent an important component of vestibular processing within the brainstem. We speculate that given the role of the vestibular system in balance and posture, PPN DBS may be work to improve gait and balance control via vestibular circuits.