Network Architecture of Verticality Processing in the Human Thalamus.

OBJECTIVE: Thalamic dysfunction in lesions or neurodegeneration may alter verticality perception and lead to postural imbalance and falls. The aim of the current study was to delineate the structural and functional connectivity network architecture of the vestibular representations in the thalamus by multimodal magnetic resonance imaging. METHODS: Seventy-four patients with acute unilateral isolated thalamic infarcts were studied prospectively with emphasis on the perception of verticality (tilts of the subjective visual vertical [SVV]). We used multivariate lesion-symptom mapping based on support-vector regression to determine the thalamic nuclei associated with ipsiversive and contraversive tilts of the SVV. The lesion maps were used to evaluate the white matter disconnection and whole brain functional connectivity in healthy subjects. RESULTS: Contraversive SVV tilts were associated with lesions of the ventral posterior lateral/medial, ventral lateral, medial pulvinar, and medial central/parafascicular nuclei. Clusters associated with ipsiversive tilts were located inferiorly (ventral posterior inferior nucleus) and laterally (ventral lateral, ventral posterior lateral, and reticular nucleus) to these areas. Distinct ascending vestibular brainstem pathways terminated in the subnuclei for ipsi- or contraversive verticality processing. The functional connectivity analysis showed specific patterns of cortical connections with the somatomotor network for lesions with contraversive tilts, and with the core multisensory vestibular representations (areas Ri, OP2-3, Ig, 3av, 2v) for lesions with ipsiversive tilts. INTERPRETATION: The functional specialization may allow both a stable representation of verticality for sensorimotor integration and flexible adaption to sudden changes in the environment. A targeted modulation of this circuitry could be a novel therapeutic strategy for higher level balance disorders of thalamocortical origin. ANN NEUROL 2023;94:133-145.

White matter volume loss drives cortical reshaping after thalamic infarcts.

OBJECTIVE: The integration of somatosensory, ocular motor and vestibular signals is necessary for self-location in space and goal-directed action. We aimed to detect remote changes in the cerebral cortex after thalamic infarcts to reveal the thalamo-cortical connections necessary for multisensory processing and ocular motor control. METHODS: Thirteen patients with unilateral ischemic thalamic infarcts presenting with vestibular, somatosensory, and ocular motor symptoms were examined longitudinally in the acute phase and after six months. Voxel- and surface-based morphometry were used to detect changes in vestibular and multisensory cortical areas and known hubs of central ocular motor processing. The results were compared with functional connectivity data in 50 healthy volunteers. RESULTS: Patients with paramedian infarcts showed impaired saccades and vestibular perception, i.e., tilts of the subjective visual vertical (SVV). The most common complaint in these patients was double vision or vertigo / dizziness. Posterolateral thalamic infarcts led to tilts of the SVV and somatosensory deficits without vertigo. Tilts of the SVV were higher in paramedian compared to posterolateral infarcts (median 11.2° vs 3.8°). Vestibular and ocular motor symptoms recovered within six months. Somatosensory deficits persisted. Structural longitudinal imaging showed significant volume reduction in subcortical structures connected to the infarcted thalamic nuclei (vestibular nuclei region, dentate nucleus region, trigeminal root entry zone, medial lemniscus, superior colliculi). Volume loss was evident in connections to the frontal, parietal and cingulate lobes. Changes were larger in the ipsilesional hemisphere but were also detected in homotopical regions contralesionally. The white matter volume reduction led to deformation of the cortical projection zones of the infarcted nuclei. CONCLUSIONS: White matter volume loss after thalamic infarcts reflects sensory input from the brainstem as well the cortical projections of the main affected nuclei for sensory and ocular motor processing. Changes in the cortical geometry seem not to reflect gray matter atrophy but rather reshaping of the cortical surface due to the underlying white matter atrophy.

Thalamocortical network: a core structure for integrative multimodal vestibular functions.

PURPOSE OF REVIEW: To apply the concept of nonreflexive sensorimotor and cognitive vestibular functions and disturbances to the current view of separate right and left thalamocortical systems. RECENT FINDINGS: The neuronal modules for sensorimotor and cognitive functions are organized in so-called provincial hubs with intracommunity connections that interact task-dependently via connector hubs. Thalamic subnuclei may serve not only as provincial hubs but also in higher order nuclei as connector hubs. Thus, in addition to its function as a cortical relay station of sensory input, the human thalamus can be seen as an integrative hub for brain networks of higher multisensory vestibular function. Imaging studies on the functional connectivity have revealed a dominance of the right side in right-handers at the upper brainstem and thalamus. A connectivity-based parcellation study has confirmed the asymmetrical organization (i.e., cortical dominance) of the parieto-insular vestibular cortex, an area surrounded by other vestibular cortical areas with symmetrical (nondominant) organization. Notably, imaging techniques have shown that there are no crossings of the vestibular pathways in between the thalamic nuclei complexes. Central vestibular syndromes caused by lesions within the thalamocortical network rarely manifest with rotational vertigo. This can be explained and mathematically simulated by the specific coding of unilateral vestibular dysfunction within different cell systems, the angular velocity cell system (rotational vertigo in lower brainstem lesions) in contrast to the head direction cell system (directional disorientation and swaying vertigo in thalamocortical lesions). SUMMARY: The structural and functional separation of the two thalamic nuclei complexes allowed a lateralization of the right and left hemispheric functions to develop. Furthermore, it made possible the simultaneous performance of sensorimotor and cognitive tasks, which require different spatial reference systems in opposite hemispheres, for example, egocentric manipulation of objects (handedness) and allocentric orientation of the self in the environment by the multisensory vestibular system.

Multisensory vestibular, vestibular-auditory, and auditory network effects revealed by parametric sound pressure stimulation.

Multisensory convergence and sensorimotor integration are important aspects for the mediation of higher vestibular cognitive functions at the cortical level. In contrast to the integration of vestibulo-visual or vestibulo-tactile perception, much less is known about the neural mechanism that mediates the integration of vestibular-otolith (linear acceleration/translation/gravity detection) and auditory processing. Vestibular-otolith and auditory afferents can be simultaneously activated using loud sound pressure stimulation, which is routinely used for testing cervical and ocular vestibular evoked myogenic potentials (VEMPs) in clinical neurotological testing. Due to the simultaneous activation of afferents there is always an auditory confound problem in fMRI studies of the neural topology of these systems. Here, we demonstrate that the auditory confounding problem can be overcome in a novel way that does not require the assumption of simple subtraction and additionally allows detection of non-linear changes in the response due to vestibular-otolith interference. We used a parametric sound pressure stimulation design that took each subject's vestibular stimulation threshold into account and analyzed for changes in BOLD-response below and above vestibular-otolith threshold. This approach helped to investigate the functional neuroanatomy of sound-induced auditory and vestibular integration using functional magnetic resonance imaging (fMRI). Results revealed that auditory and vestibular convergence are contained in overlapping regions of the caudal part of the superior temporal gyrus (STG) and the posterior insula. In addition, there are regions that were responsive only to suprathreshold stimulations, suggesting vestibular (otolith) signal processing in these areas. Based on these parametric analyses, we suggest that the caudal part of the STG and posterior insula could contain areas of vestibular contribution to auditory processing, i.e., higher vestibular cortices that provide multisensory integration that is important for tasks such as spatial localization of sound.

Simultaneous recording of cervical and ocular vestibular-evoked myogenic potentials.

OBJECTIVE: To increase clinical application of vestibular-evoked myogenic potentials (VEMPs) by reducing the testing time by evaluating whether a simultaneous recording of ocular and cervical VEMPs can be achieved without a loss in diagnostic sensitivity and specificity. METHODS: Simultaneous recording of ocular and cervical VEMPs on each side during monaural stimulation, bilateral simultaneous recording of ocular VEMPs and cervical VEMPs during binaural stimulation, and conventional sequential recording of ocular and cervical VEMPs on each side using air-conducted sound (500 Hz, 5-millisecond tone burst) were compared in 40 healthy participants (HPs) and 20 patients with acute vestibular neuritis. RESULTS: Either simultaneous recording during monaural and binaural stimulation effectively reduced the recording time by ≈55% of that for conventional sequential recordings in both the HP and patient groups. The simultaneous recording with monaural stimulation resulted in latencies and thresholds of both VEMPs and the amplitude of cervical VEMPs similar to those found during the conventional recordings but larger ocular VEMP amplitudes (156%) in both groups. In contrast, compared to the conventional recording, simultaneous recording of each VEMP during binaural stimulation showed reduced amplitudes (31%) and increased thresholds for cervical VEMPs in both groups. CONCLUSIONS: The results of simultaneous recording of cervical and ocular VEMPs during monaural stimulation were comparable to those obtained from the conventional recording while reducing the time to record both VEMPs on each side. CLINICALTRIALSGOV IDENTIFIER: NCT03049683.

Right-sided dominance of the bilateral vestibular system in the upper brainstem and thalamus.

MRI diffusion tensor imaging tractography was performed on the bilateral vestibular brainstem pathways, which run from the vestibular nuclei via the paramedian and posterolateral thalamic subnuclei to the parieto-insular vestibular cortex. Twenty-one right-handed healthy subjects participated. Quantitative analysis revealed a rope-ladder-like system of vestibular pathways in the brainstem with crossings at pontine and mesencephalic levels. Three structural types of right-left fiber distributions could be delineated: (1) evenly distributed pathways at the lower pontine level from the vestibular nuclei to the pontine crossing, (2) a moderate, pontomesencephalic right-sided lateralization between the pontine and mesencephalic crossings, and (3) a further increase of the right-sided lateralization above the mesencephalic crossing leading to the thalamic vestibular subnuclei. The increasing lateralization along the brainstem was the result of an asymmetric number of pontine and mesencephalic crossing fibers which was higher for left-to-right crossings. The dominance of the right vestibular meso-diencephalic circuitry in right-handers corresponds to the right-hemispheric dominance of the vestibular cortical network. The structural asymmetry apparent in the upper brainstem might be interpreted in relation to the different functions of the vestibular system depending on their anatomical level: a symmetrical sensorimotor reflex control of eye, head, and body mediated by the lower brainstem; a lateralized right-sided upper brainstem-thalamic function as part of the dominant right-sided cortical/subcortical vestibular system that enables a global percept of body motion and orientation in space.

Vestibular thalamus: Two distinct graviceptive pathways.

OBJECTIVE: To determine whether there are distinct thalamic regions statistically associated with either contraversive or ipsiversive disturbance of verticality perception measured by subjective visual vertical (SVV). METHODS: We used modern statistical lesion behavior mapping on a sample of 37 stroke patients with isolated thalamic lesions to clarify which thalamic regions are involved in graviceptive otolith processing and whether there are distinct regions associated with contraversive or ipsiversive SVV deviation. RESULTS: We found 2 distinct systems of graviceptive processing within the thalamus. Contraversive tilt of SVV was associated with lesions to the nuclei dorsomedialis, intralamellaris, centrales thalami, posterior thalami, ventrooralis internus, ventrointermedii, ventrocaudales and superior parts of the nuclei parafascicularis thalami. The regions associated with ipsiversive tilt of SVV were located in more inferior regions, involving structures such as the nuclei endymalis thalami, inferior parts of the nuclei parafascicularis thalami, and also small parts of the junction zone of the nuclei ruber tegmenti and brachium conjunctivum. CONCLUSIONS: Our data indicate that there are 2 anatomically distinct graviceptive signal processing mechanisms within the vestibular network in humans that lead, when damaged, to a vestibular tone imbalance either to the contraversive or to the ipsiversive side.

N-acetyl-L-leucine accelerates vestibular compensation after unilateral labyrinthectomy by action in the cerebellum and thalamus.

An acute unilateral vestibular lesion leads to a vestibular tone imbalance with nystagmus, head roll tilt and postural imbalance. These deficits gradually decrease over days to weeks due to central vestibular compensation (VC). This study investigated the effects of i.v. N-acetyl-DL-leucine, N-acetyl-L-leucine and N-acetyl-D-leucine on VC using behavioural testing and serial [18F]-Fluoro-desoxyglucose ([18F]-FDG)-µPET in a rat model of unilateral chemical labyrinthectomy (UL). Vestibular behavioural testing included measurements of nystagmus, head roll tilt and postural imbalance as well as sequential whole-brain [18F]-FDG-µPET was done before and on days 1,3,7 and 15 after UL. A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group). The course of postural compensation in the DL- and L-group was accelerated by about 6 days relative to controls. The effect of N-acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect. N-acetyl-L-leucine did not change the compensation of nystagmus or head roll tilt at any dose. Measurements of the regional cerebral glucose metabolism (rCGM) by means of µPET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7. A similar pattern was found when comparing the effect of N-acetyl-L-leucine on rCGM in an UL-group and a sham UL-group without vestibular damage. In conclusion, N-acetyl-L-leucine improves compensation of postural symptoms after UL in a dose-dependent and specific manner, most likely by activating the vestibulocerebellum and deactivating the posterolateral thalamus.

The bilateral central vestibular system: its pathways, functions, and disorders.

The bilateral anatomical organization of the vestibular system provides three functional advantages: optimal differentiation of head motion and orientation, sensory substitution of a unilateral peripheral failure, and central compensation of a peripheral or central vestibular tone imbalance. The structure is based on bilaterally ascending and descending pathways and at least four crossings: three in the brain stem and one in the cortex. The resulting sensorimotor functions can be subdivided into three major groups: (1) reflexive control of gaze, head, and body in three spatial planes (yaw, pitch, roll) at the brain stem/cerebellar level; (2) perception of self-motion and control of voluntary movement and balance at the cortical/subcortical level; and (3) higher vestibular cognitive functions (e.g., spatial memory and navigation). The bilateral representation of the vestibular system in multiple multisensory cortical areas and the vestibular dominance of the nondominant hemisphere raise the question of how one global percept of motion and orientation in space is formed.

The role of the thalamus in the human subcortical vestibular system.

Most of our knowledge concerning central vestibular pathways is derived from animal studies while evidence of the functional importance and localization of these pathways in humans is less well defined. The termination of these pathways at the thalamic level in humans is even less known. In this review we summarize the findings concerning the central subcortical vestibular pathways in humans and the role of these structures in the central vestibular system with regard to anatomical localization and function. Also, we review the role of the thalamus in the pathogenesis of higher order sensory deficits such as spatial neglect, pusher syndrome or thalamic astasia and the correlation of these phenomena with findings of a vestibular tone imbalance at the thalamic level. By highlighting thalamic structures involved in vestibular signal processing and relating the different nomenclatures we hope to provide a base for future studies on thalamic sensory signal processing.

Real versus imagined locomotion: a [18F]-FDG PET-fMRI comparison.

The cortical, cerebellar and brainstem BOLD-signal changes have been identified with fMRI in humans during mental imagery of walking. In this study the whole brain activation and deactivation pattern during real locomotion was investigated by [(18)F]-FDG-PET and compared to BOLD-signal changes during imagined locomotion in the same subjects using fMRI. Sixteen healthy subjects were scanned at locomotion and rest with [(18)F]-FDG-PET. In the locomotion paradigm subjects walked at constant velocity for 10 min. Then [(18)F]-FDG was injected intravenously while subjects continued walking for another 10 min. For comparison fMRI was performed in the same subjects during imagined walking. During real and imagined locomotion a basic locomotion network including activations in the frontal cortex, cerebellum, pontomesencephalic tegmentum, parahippocampal, fusiform and occipital gyri, and deactivations in the multisensory vestibular cortices (esp. superior temporal gyrus, inferior parietal lobule) was shown. As a difference, the primary motor and somatosensory cortices were activated during real locomotion as distinct to the supplementary motor cortex and basal ganglia during imagined locomotion. Activations of the brainstem locomotor centers were more prominent in imagined locomotion. In conclusion, basic activation and deactivation patterns of real locomotion correspond to that of imagined locomotion. The differences may be due to distinct patterns of locomotion tested. Contrary to constant velocity real locomotion (10 min) in [(18)F]-FDG-PET, mental imagery of locomotion over repeated 20-s periods includes gait initiation and velocity changes. Real steady-state locomotion seems to use a direct pathway via the primary motor cortex, whereas imagined modulatory locomotion an indirect pathway via a supplementary motor cortex and basal ganglia loop.