Effects of spaceflight on the brain.

The number of long duration human spaceflights has increased substantially over the past 15 years, leading to the discovery of numerous effects on the CNS. Microgravity results in headward fluid shifts, ventricular expansion, an upward shift of the brain within the skull, and remodelling of grey and white matter. The fluid changes are correlated with changes to perivascular space and spaceflight associated neuro-ocular syndrome. Microgravity alters the vestibular processing of head tilt and results in reduced tactile and proprioceptive inputs during spaceflight. Sensory adaptation is reflected in postflight effects, evident as transient sensorimotor impairment. Another major concern is that galactic cosmic radiation, which spacefarers will be exposed to when going beyond the magnetosphere around Earth, might have a negative effect on CNS function. Research with rodents points to the potential disruptive effects of space radiation on blood-brain barrier integrity and brain structures. More work is needed to understand and mitigate these effects on the CNS before humans travel to Mars, as the flight durations will be longer than anyone has previously experienced.

Assessing Stress Induced by Fluid Shifts and Reduced Cerebral Clearance during Robotic-Assisted Laparoscopic Radical Prostatectomy under Trendelenburg Positioning (UroTreND Study).

In addition to general anesthesia and mechanical ventilation, robotic-assisted laparoscopic radical prostatectomy (RALP) necessitates maintaining a capnoperitoneum and placing the patient in a pronounced downward tilt (Trendelenburg position). While the effects of the resulting fluid shift on the cardiovascular system seem to be modest and well tolerated, the effects on the brain and the blood-brain barrier have not been thoroughly investigated. Previous studies indicated that select patients showed an increase in the optic nerve sheath diameter (ONSD), detected by ultrasound during RALP, which suggests an elevation in intracranial pressure. We hypothesize that the intraoperative fluid shift results in endothelial dysfunction and reduced cerebral clearance, potentially leading to transient neuronal damage. This prospective, monocentric, non-randomized, controlled clinical trial will compare RALP to conventional open radical prostatectomy (control group) in a total of 50 subjects. The primary endpoint will be the perioperative concentration of neurofilament light chain (NfL) in blood using single-molecule array (SiMoA) as a measure for neuronal damage. As secondary endpoints, various other markers for endothelial function, inflammation, and neuronal damage as well as the ONSD will be assessed. Perioperative stress will be evaluated by questionnaires and stress hormone levels in saliva samples. Furthermore, the subjects will participate in functional tests to evaluate neurocognitive function. Each subject will be followed up until discharge. Conclusion: This trial aims to expand current knowledge as well as to develop strategies for improved monitoring and higher safety of patients undergoing RALP. The trial was registered with the German Clinical Trials Register DRKS00031041 on 11 January 2023.

Is vestibular function related to human hippocampal volume?

BACKGROUND: Recent studies implicate the effect of vestibular loss on cognitive decline, including hippocampal volume loss. As hippocampal atrophy is an important biomarker of Alzheimer's disease, exploring vestibular dysfunction as a risk factor for dementia and its role in hippocampal atrophy is of interest. OBJECTIVE: To replicate previous literature on whole-brain and hippocampal volume in semicircular canal dysfunction (bilateral vestibulopathy; BV) and explore the association between otolith function and hippocampal volume. METHODS: Hippocampal and whole-brain MRI volumes were compared in adults aged between 55 and 83 years. Participants with BV (n = 16) were compared to controls individually matched on age, sex, and hearing status (n = 16). Otolith influence on hippocampal volume in preserved semicircular canal function was evaluated (n = 34). RESULTS: Whole-brain and targeted hippocampal approaches using volumetric and surface-based measures yielded no significant differences when comparing BV to controls. Binary support vector machines were unable to classify inner ear health status above chance level. Otolith parameters were not associated with hippocampal volume in preserved semicircular canal function. CONCLUSIONS: No significant differences in whole-brain or hippocampal volume were found when comparing BV participants with healthy controls. Saccular parameters in subjects with preserved semicircular canal function were not associated with hippocampal volume changes.

Eye-brain axis in microgravity and its implications for Spaceflight Associated Neuro-ocular Syndrome.

Long-duration human spaceflight can lead to changes in both the eye and the brain, which have been referred to as Spaceflight Associated Neuro-ocular Syndrome (SANS). These changes may manifest as a constellation of symptoms, which can include optic disc edema, optic nerve sheath distension, choroidal folds, globe flattening, hyperopic shift, and cotton wool spots. Although the underpinning mechanisms for SANS are not yet known, contributors may include intracranial interstitial fluid accumulation following microgravity induced headward fluid shift. Development and validation of SANS countermeasures contribute to our understanding of etiology and accelerate new technology including exercise modalities, Lower Body Negative Pressure suits, venous thigh cuffs, and Impedance Threshold Devices. However, significant knowledge gaps remain including biomarkers, a full set of countermeasures and/or treatment regimes, and finally reliable ground based analogs to accelerate the research. This review from the European Space Agency SANS expert group summarizes past research and current knowledge on SANS, potential countermeasures, and key knowledge gaps, to further our understanding, prevention, and treatment of SANS both during human spaceflight and future extraterrestrial surface exploration.

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.

Vestibular mapping of the naturalistic head-centered motion spectrum.

BACKGROUND: Naturalistic head accelerations can be used to elicit vestibular evoked potentials (VestEPs). These potentials allow for analysis of cortical vestibular processing and its multi-sensory integration with a high temporal resolution. METHODS: We report the results of two experiments in which we compared the differential VestEPs elicited by randomized translations, rotations, and tilts in healthy subjects on a motion platform. RESULTS: An event-related potential (ERP) analysis revealed that established VestEPs were verifiable in all three acceleration domains (translations, rotations, tilts). A further analysis of the VestEPs showed a significant correlation between rotation axes (yaw, pitch, roll) and the amplitude of the evoked potentials. We found increased amplitudes for rotations in the roll compared to the pitch and yaw plane. A distributed source localization analysis showed that the activity in the cingulate sulcus visual (CSv) area best explained direction-dependent amplitude modulations of the VestEPs, but that the same cortical network (posterior insular cortex, CSv) is involved in processing vestibular information, regardless of the motion direction. CONCLUSION: The results provide evidence for an anisotropic, direction-dependent processing of vestibular input by cortical structures. The data also suggest that area CSv plays an integral role in ego-motion perception and interpretation of spatial features such as acceleration direction and intensity.

In Vivo Localization of the Human Velocity Storage Mechanism and Its Core Cerebellar Networks by Means of Galvanic-Vestibular Afternystagmus and fMRI.

Humans are able to estimate head movements accurately despite the short half-life of information coming from our inner ear motion sensors. The observation that the central angular velocity estimate outlives the decaying signal of the semicircular canal afferents led to the concept of a velocity storage mechanism (VSM). The VSM can be activated via visual and vestibular modalities and becomes manifest in ocular motor responses after sustained stimulation like whole-body rotations, optokinetic or galvanic vestibular stimulation (GVS). The VSM has been the focus of many computational modelling approaches; little attention though has been paid to discover its actual structural correlates. Animal studies localized the VSM in the medial and superior vestibular nuclei. A significant modulation by cerebellar circuitries including the uvula and nodulus has been proposed. Nevertheless, the corresponding neuroanatomical structures in humans have not been identified so far. The aim of the present study was to delineate the neural substrates of the VSM using high-resolution infratentorial fMRI with a fast T2* sequence optimized for infratentorial neuroimaging and via video-oculography (VOG). The neuroimaging experiment (n=20) gave first in vivo evidence for an involvement of the vestibular nuclei in the VSM and substantiate a crucial role for cerebellar circuitries. Our results emphasize the importance of cerebellar feedback loops in VSM most likely represented by signal increases in vestibulo-cerebellar hubs like the uvula and nodulus and lobule VIIIA. The delineated activation maps give new insights regarding the function and embedment of Crus I, Crus II, and lobule VII and VIII in the human vestibular system.

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.

Future research directions to identify risks and mitigation strategies for neurostructural, ocular, and behavioral changes induced by human spaceflight: A NASA-ESA expert group consensus report.

A team of experts on the effects of the spaceflight environment on the brain and eye (SANS: Spaceflight-Associated Neuro-ocular Syndrome) was convened by NASA and ESA to (1) review spaceflight-associated structural and functional changes of the human brain and eye, and any interactions between the two; and (2) identify critical future research directions in this area to help characterize the risk and identify possible countermeasures and strategies to mitigate the spaceflight-induced brain and eye alterations. The experts identified 14 critical future research directions that would substantially advance our knowledge of the effects of spending prolonged periods of time in the spaceflight environment on SANS, as well as brain structure and function. They used a paired comparison approach to rank the relative importance of these 14 recommendations, which are discussed in detail in the main report and are summarized briefly below.

The effect of prolonged spaceflight on cerebrospinal fluid and perivascular spaces of astronauts and cosmonauts.

Long-duration spaceflight induces changes to the brain and cerebrospinal fluid compartments and visual acuity problems known as spaceflight-associated neuro-ocular syndrome (SANS). The clinical relevance of these changes and whether they equally affect crews of different space agencies remain unknown. We used MRI to analyze the alterations occurring in the perivascular spaces (PVS) in NASA and European Space Agency astronauts and Roscosmos cosmonauts after a 6-mo spaceflight on the International Space Station (ISS). We found increased volume of basal ganglia PVS and white matter PVS (WM-PVS) after spaceflight, which was more prominent in the NASA crew than the Roscosmos crew. Moreover, both crews demonstrated a similar degree of lateral ventricle enlargement and decreased subarachnoid space at the vertex, which was correlated with WM-PVS enlargement. As all crews experienced the same environment aboard the ISS, the differences in WM-PVS enlargement may have been due to, among other factors, differences in the use of countermeasures and high-resistive exercise regimes, which can influence brain fluid redistribution. Moreover, NASA astronauts who developed SANS had greater pre- and postflight WM-PVS volumes than those unaffected. These results provide evidence for a potential link between WM-PVS fluid and SANS.

Brain Connectometry Changes in Space Travelers After Long-Duration Spaceflight.

Humans undergo extreme physiological changes when subjected to long periods of weightlessness, and as we continue to become a space-faring species, it is imperative that we fully understand the physiological changes that occur in the human body, including the brain. In this study, we present findings of brain structural changes associated with long-duration spaceflight based on diffusion magnetic resonance imaging (dMRI) data. Twelve cosmonauts who spent an average of six months aboard the International Space Station (ISS) were scanned in an MRI scanner pre-flight, ten days after flight, and at a follow-up time point seven months after flight. We performed differential tractography, a technique that confines white matter fiber tracking to voxels showing microstructural changes. We found significant microstructural changes in several large white matter tracts, such as the corpus callosum, arcuate fasciculus, corticospinal, corticostriatal, and cerebellar tracts. This is the first paper to use fiber tractography to investigate which specific tracts exhibit structural changes after long-duration spaceflight and may direct future research to investigate brain functional and behavioral changes associated with these white matter pathways.

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.

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.

Delineating neural responses and functional connectivity changes during vestibular and nociceptive stimulation reveal the uniqueness of cortical vestibular processing.

Vestibular information is ubiquitous and often processed jointly with visual, somatosensory and proprioceptive information. Among the cortical brain regions associated with human vestibular processing, area OP2 in the parietal operculum has been proposed as vestibular core region. However, delineating responses uniquely to vestibular stimulation in this region using neuroimaging is challenging for several reasons: First, the parietal operculum is a cytoarchitectonically heterogeneous region responding to multisensory stimulation. Second, artificial vestibular stimulation evokes confounding somatosensory and nociceptive responses blurring responses contributing to vestibular perception. Furthermore, immediate effects of vestibular stimulation on the organization of functional networks have not been investigated in detail yet. Using high resolution neuroimaging in a task-based and functional connectivity approach, we compared two equally salient stimuli-unilateral galvanic vestibular (GVS) and galvanic nociceptive stimulation (GNS)-to disentangle the processing of both modalities in the parietal operculum and characterize their effects on functional network architecture. GNS and GVS gave joint responses in area OP1, 3, 4, and the anterior and middle insula, but not in area OP2. GVS gave stronger responses in the parietal operculum just adjacent to OP3 and OP4, whereas GNS evoked stronger responses in area OP1, 3 and 4. Our results underline the importance of considering this common pathway when interpreting vestibular neuroimaging experiments and underpin the role of area OP2 in central vestibular processing. Global network changes were found during GNS, but not during GVS. This lack of network reconfiguration despite the saliency of GVS may reflect the continuous processing of vestibular information in the awake human.

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.

IE-Map: a novel in-vivo atlas and template of the human inner ear.

Brain atlases and templates are core tools in scientific research with increasing importance also in clinical applications. Advances in neuroimaging now allowed us to expand the atlas domain to the vestibular and auditory organ, the inner ear. In this study, we present IE-Map, an in-vivo template and atlas of the human labyrinth derived from multi-modal high-resolution magnetic resonance imaging (MRI) data, in a fully non-invasive manner without any contrast agent or radiation. We reconstructed a common template from 126 inner ears (63 normal subjects) and annotated it with 94 established landmarks and semi-automatic segmentations of all relevant macroscopic vestibular and auditory substructures. We validated the atlas by comparing MRI templates to a novel CT/micro-CT atlas, which we reconstructed from 21 publicly available post-mortem images of the bony labyrinth. Templates in MRI and micro-CT have a high overlap, and several key anatomical measures of the bony labyrinth in IE-Map are in line with micro-CT literature of the inner ear. A quantitative substructural analysis based on the new template, revealed a correlation of labyrinth parameters with total intracranial volume. No effects of gender or laterality were found. We provide the validated templates, atlas segmentations, surface meshes and landmark annotations as open-access material, to provide neuroscience researchers and clinicians in neurology, neurosurgery, and otorhinolaryngology with a widely applicable tool for computational neuro-otology.

Macro- and microstructural changes in cosmonauts' brains after long-duration spaceflight.

Long-duration spaceflight causes widespread physiological changes, although its effect on brain structure remains poorly understood. In this work, we acquired diffusion magnetic resonance imaging to investigate alterations of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) compositions in each voxel, before, shortly after, and 7 months after long-duration spaceflight. We found increased WM in the cerebellum after spaceflight, providing the first clear evidence of sensorimotor neuroplasticity. At the region of interest level, this increase persisted 7 months after return to Earth. We also observe a widespread redistribution of CSF, with concomitant changes in the voxel fractions of adjacent GM. We show that these GM changes are the result of morphological changes rather than net tissue loss, which remained unclear from previous studies. Our study provides evidence of spaceflight-induced neuroplasticity to adapt motor strategies in space and evidence of fluid shift-induced mechanical changes in the brain.