Disability in cerebellar ataxia syndromes is linked to cortical degeneration.

OBJECTIVE: We aimed to relate clinical measures of disability in chronic cerebellar degeneration to structural whole-brain changes using voxel-based and surface-based morphometry (vbm and sbm). We were particularly interested in remote effects of cerebellar degeneration in the cerebral cortex. METHODS: We recruited 30 patients with cerebellar degeneration of different aetiologies (downbeat nystagmus syndrome, DBN n = 14, spinocerebellar ataxia, SCA n = 9, sporadic adult late-onset ataxia, SAOA n = 7). All patients were thoroughly characterised in the motor, cognitive, vestibular and ocular-motor domains. Vbm and sbm were used to evaluate structural differences between cerebellar degeneration patients and a group of healthy age- and gender-matched volunteers. Linear regression models were used to correlate functional measures of disease progression and postural stability with whole brain volumetry. RESULTS: Patients with SCA and SAOA showed widespread volume loss in the cerebellar hemispheres and less prominently in the vermis. Patients with DBN showed a distinct pattern of grey matter volume (GMV) loss that was restricted to the vestibular and ocular-motor representations in lobules IX, X and V-VII. Falls were associated with brainstem white matter volume. VBM and SBM linear regression models revealed associations between severity of ataxic symptoms, cognitive performance and preferred gait velocity. This included extra-cerebellar (sub-)cortical hubs of the motor and locomotion network (putamen, caudate, thalamus, primary motor cortex, prefrontal cortex) and multisensory areas involved in spatial navigation and cognition. CONCLUSION: Functional disability in multiple domains was associated with structural changes in the cerebral cortex.

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.

The human egomotion network.

All volitional movement in a three-dimensional space requires multisensory integration, in particular of visual and vestibular signals. Where and how the human brain processes and integrates self-motion signals remains enigmatic. Here, we applied visual and vestibular self-motion stimulation using fast and precise whole-brain neuroimaging to delineate and characterize the entire cortical and subcortical egomotion network in a substantial cohort (n=131). Our results identify a core egomotion network consisting of areas in the cingulate sulcus (CSv, PcM/pCi), the cerebellum (uvula), and the temporo-parietal cortex including area VPS and an unnamed region in the supramarginal gyrus. Based on its cerebral connectivity pattern and anatomical localization, we propose that this region represents the human homologue of macaque area 7a. Whole-brain connectivity and gradient analyses imply an essential role of the connections between the cingulate sulcus and the cerebellar uvula in egomotion perception. This could be via feedback loops involved updating visuo-spatial and vestibular information. The unique functional connectivity patterns of PcM/pCi hint at central role in multisensory integration essential for the perception of self-referential spatial awareness. All cortical egomotion hubs showed modular functional connectivity with other visual, vestibular, somatosensory and higher order motor areas, underlining their mutual function in general sensorimotor integration.

Evaluating the rare cases of cortical vertigo using disconnectome mapping.

In rare cases, cortical infarcts lead to vertigo. We evaluated structural and functional disconnection in patients with acute vertigo due to unilateral ischemic cortical infarcts compared to infarcts without vertigo in a similar location with a focus on the connectivity of the vestibular cortex, i.e., the parieto-opercular (retro-)insular cortex (PIVC). Using lesion maps from the ten published case reports, we computed lesion-functional connectivity networks in a set of healthy individuals from the human connectome project. The probability of lesion disconnection was evaluated by white matter disconnectome mapping. In all ten cases with rotational vertigo, disconnections of interhemispheric connections via the corpus callosum were present but were spared in lesions of the PIVC without vertigo. Further, the arcuate fascicle was affected in 90% of the lesions that led to vertigo and spared in lesions that did not lead to vertigo. The lesion-functional connectivity network included vestibulo-cerebellar hubs, the vestibular nuclei, the PIVC, the retro-insular and posterior insular cortex, the multisensory vestibular ventral intraparietal area, motion-sensitive areas (temporal area MT+ and cingulate visual sulcus) as well as hubs for ocular motor control (lateral intraparietal area, cingulate and frontal eye fields). However, this was not sufficient to differentiate between lesions with and without vertigo. Disruption of interhemispheric connections of both PIVC via the corpus callosum and intra-hemispheric disconnection via the arcuate fascicle might be the distinguishing factor between vestibular cortical network lesions that manifest with vertigo compared to those without vertigo.

Reorganization of sensory networks after subcortical vestibular infarcts: A longitudinal symptom-related voxel-based morphometry study.

BACKGROUND AND PURPOSE: We aimed to delineate common principles of reorganization after infarcts of the subcortical vestibular circuitry related to the clinical symptomatology. Our hypothesis was that the recovery of specific symptoms is associated with changes in distinct regions within the core vestibular, somatosensory, and visual cortical and subcortical networks. METHODS: We used voxel- and surface-based morphometry to investigate structural reorganization of subcortical and cortical brain areas in 42 patients with a unilateral, subcortical infarct with vestibular and ocular motor deficits in the acute phase. The patients received structural neuroimaging and clinical monitoring twice (acute phase and after 6 months) to detect within-subject changes over time. RESULTS: In patients with vestibular signs such as tilts of the subjective visual vertical (SVV) and ocular torsion in the acute phase, significant volumetric increases in the superficial white matter around the parieto-opercular (retro-)insular vestibular cortex (PIVC) were found at follow-up. In patients with SVV tilts, spontaneous nystagmus, and rotatory vertigo in the acute phase, gray matter volume decreases were located in the cerebellum and the visual cortex bilaterally at follow-up. Patients with saccade pathology demonstrated volumetric decreases in cerebellar, thalamic, and cortical centers for ocular motor control. CONCLUSIONS: The findings support the role of the PIVC as the key hub for vestibular processing and reorganization. The volumetric decreases represent the reciprocal interaction of the vestibular, visual, and ocular motor systems during self-location and egomotion detection. A modulation in vestibular and ocular motor as well as visual networks was induced independently of the vestibular lesion site.

The cingulate oculomotor cortex.

Knowledge about the relevance and extent of human eye movement control in the cingulate cortex to date is very limited. Experiments in non-human primates brought about evidence for a potentially central role of the dorsal bank of the cingulate sulcus in saccadic eye movements. In humans, a putative cingulate eye field (CEF) in the same region has been proposed; however, its function and location still remain controversial. Another area in the posterior cingulate cortex, the cingulate sulcus visual area (CSv), has been shown to respond to visual motion cues and also ocular motor tasks. In this study we used multi-band neuroimaging (n = 46) to comprehensively characterize oculomotor responses along the entire cingulate cortex during the most common types of eye movements. We were able to robustly localize the CEF to the anterior portion of the midcingulate gyrus. The region gave responses during all oculomotor tasks and is embedded within the ventral attention network. Area CSv, which is located in the anterior portion of the posterior cingulate gyrus, on the other hand responded to smooth pursuit and optokinetic nystagmus only. It likewise represents a node within the ventral attention network but at the same time seems to be a distinctive part of the somatomotor network. Our findings support an executive role of the CEF, suggesting a cognitive control function in maintaining and adapting different kinds of eye movements. CSv on the other hand might be an interface for relaying oculomotor, visual motion and broad sensory signals related to self-motion.

Functional hierarchy of oculomotor and visual motion subnetworks within the human cortical optokinetic system.

Optokinetic look nystagmus (look OKN) is known to engage cortical visual motion and oculomotor hubs. Their functional network hierarchy, however, and the role of the cingulate eye field (CEF) and the dorsolateral prefrontal cortex (DLPFC) in particular have not been investigated. We used look OKN in fMRI to identify all cortical visual motion and oculomotor hubs involved. Using these activations as seed regions, we employed hierarchical clustering in two differing resting state conditions from a separate public data set. Robust activations in the CEF highlight its functional role in OKN and involvement in higher order oculomotor control. Deactivation patterns indicate a decreased modulatory involvement of the DLPFC. The hierarchical clustering revealed a changeable organization of the eye fields, hMT, V3A, and V6 depending on the resting state condition, segregating executive from higher order visual subnetworks. Overall, hierarchical clustering seems to allow for a robust delineation of physiological cortical networks.

Ageing-related changes in the cortical processing of otolith information in humans.

Acoustic short tone bursts (STB) trigger ocular and cervical vestibular-evoked myogenic potentials (oVEMPs/cVEMPs) by activating irregular otolith afferents. Simultaneously, STBs introduce an artificial net acceleration signal of otolith origin into the vestibular network. VEMP parameters as diagnostic otolith processing markers have been shown to decline after the age of thirty. To delineate the differential effects of healthy ageing on the cortical vestibular subnetwork processing otolith information, we measured cVEMPs and the differential effects of unilateral STB in three age groups (20-40, 40-60 and 60+; n = 42) using functional neuroimaging. STB evoked responses in the main vestibular hubs in the parieto-opercular cortex. Whereas cVEMP amplitudes declined linearly with age, analysis of the BOLD response size depicted a u-shaped curve. Vestibular perception of the otolith stimulus on the other hand remained unchanged with age. Therefore, we propose that the comparably larger BOLD responses past the age of sixty could reflect a mechanism of central sensitisation for otolith perception to counterbalance the concurrent peripheral vestibular and somatosensory function decline.

Delineating function and connectivity of optokinetic hubs in the cerebellum and the brainstem.

Optokinetic eye movements are crucial for keeping a stable image on the retina during movements of the head. These eye movements can be differentiated into a cortically generated response (optokinetic look nystagmus) and the highly reflexive optokinetic stare nystagmus, which is controlled by circuits in the brainstem and cerebellum. The contributions of these infratentorial networks and their functional connectivity with the cortical eye fields are still poorly understood in humans. To map ocular motor centres in the cerebellum and brainstem, we studied stare nystagmus using small-field optokinetic stimuli in the horizontal and vertical directions in 22 healthy subjects. We were able to differentiate ocular motor areas of the pontine brainstem and midbrain in vivo for the first time. Direction and velocity-dependent activations were found in the pontine brainstem (nucleus reticularis, tegmenti pontis, and paramedian pontine reticular formation), the uvula, flocculus, and cerebellar tonsils. The ocular motor vermis, on the other hand, responded to constant and accelerating velocity stimulation. Moreover, deactivation patterns depict a governing role for the cerebellar tonsils in ocular motor control. Functional connectivity results of these hubs reveal the close integration of cortico-cerebellar ocular motor and vestibular networks in humans. Adding to the cortical concept of a right-hemispheric predominance for visual-spatial processing, we found a complementary left-sided cerebellar dominance for our ocular motor task. A deeper understanding of the role of the cerebellum and especially the cerebellar tonsils for eye movement control in a clinical context seems vitally important and is now feasible with functional neuroimaging.