Paving the way to better understand the effects of prolonged spaceflight on operational performance and its neural bases.

Space exploration objectives will soon move from low Earth orbit to distant destinations like Moon and Mars. The present work provides an up-to-date roadmap that identifies critical research gaps related to human behavior and performance in altered gravity and space. The roadmap summarizes (1) key neurobehavioral challenges associated with spaceflight, (2) the need to consider sex as a biological variable, (3) the use of integrative omics technologies to elucidate mechanisms underlying changes in the brain and behavior, and (4) the importance of understanding the neural representation of gravity throughout the brain and its multisensory processing. We then highlight the need for a variety of target-specific countermeasures, and a personalized administration schedule as two critical strategies for mitigating potentially adverse effects of spaceflight on the central nervous system and performance. We conclude with a summary of key priorities for the roadmaps of current and future space programs and stress the importance of new collaborative strategies across agencies and researchers for fostering an integrative cross- and transdisciplinary approach from cells, molecules to neural circuits and cognitive performance. Finally, we highlight that space research in neurocognitive science goes beyond monitoring and mitigating risks in astronauts but could also have significant benefits for the population on Earth.

The role of delta and theta oscillations during ego-motion in healthy adult volunteers.

The successful cortical processing of multisensory input typically requires the integration of data represented in different reference systems to perform many fundamental tasks, such as bipedal locomotion. Animal studies have provided insights into the integration processes performed by the neocortex and have identified region specific tuning curves for different reference frames during ego-motion. Yet, there remains almost no data on this topic in humans.In this study, an experiment originally performed in animal research with the aim to identify brain regions modulated by the position of the head and eyes relative to a translational ego-motion was adapted for humans. Subjects sitting on a motion platform were accelerated along a translational pathway with either eyes and head aligned or a 20° yaw-plane offset relative to the motion direction while EEG was recorded.Using a distributed source localization approach, it was found that activity in area PFm, a part of Brodmann area 40, was modulated by the congruency of translational motion direction, eye, and head position. In addition, an asymmetry between the hemispheres in the opercular-insular region was observed during the cortical processing of the vestibular input. A frequency specific analysis revealed that low-frequency oscillations in the delta- and theta-band are modulated by vestibular stimulation. Source-localization estimated that the observed low-frequency oscillations are generated by vestibular core-regions, such as the parieto-opercular region and frontal areas like the mid-orbital gyrus and the medial frontal gyrus.

The human corticocortical vestibular network.

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 cortical spatiotemporal correlate of otolith stimulation: Vestibular evoked potentials by body translations.

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.

Insula and sensory insular cortex and somatosensory control in patients with insular stroke.

BACKGROUND: In functional imaging studies, the insular cortex (IC) has been identified as an essential part of the processing of a whole spectrum of multimodal sensory input. However, there are no lesion studies including a sufficient number of patients, which would reinforce the functional imaging data obtained from healthy subjects. Such lesion studies should examine how damage to the IC affects sensory perception. We chose acute stroke patients with lesions affecting the IC in order to fill this gap. METHODS: A comprehensive sensory profiling by applying a quantitative sensory testing protocol was performed and a voxel-lesion behaviour mapping analysis in 24 patients with acute unilateral cortical damage was applied. RESULTS: Our data demonstrate that patients with lesions of the posterior IC have deficits in temperature perception, but did not show other sensory deficits such as hot or cold pain perception associated with specific lesion locations. CONCLUSION: Our data allow the conclusion that the posterior IC may represent the major region responsible for encoding warm and cold perception in the brain. To what extent focal IC lesions may also impair pain processing or induce post-stroke pain has to be addressed in future studies including more patients.

Interoceptive and multimodal functions of the operculo-insular cortex: tactile, nociceptive and vestibular representations.

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.

Meta-analytical definition and functional connectivity of the human vestibular cortex.

Contrary to most other sensory systems, no consensus has been reached within the scientific community about the exact locations and functions of human cortical areas processing vestibular information. Metaanalytical modelling using activation likelihood estimation (ALE) for the integration of neuroimaging results has already been successfully applied to several distinct tasks, thereby revealing the cortical localization of cognitive functions. We used the same algorithm and technique with all available and suitable PET and fMRI studies employing a vestibular stimulus. Most consistently across 28 experiments vestibular stimuli evoked activity in the right hemispheric parietal opercular area OP 2 implicating it as the core region for vestibular processing. Furthermore, we took our primary results as a seeding point and fed them into a functional connectivity analysis based on resting-state oscillations in 100 healthy subjects. This subsequent calculation confirmed direct connections of the area OP 2 with every other region found in the meta-analysis, in particular temporo-parietal regions, premotor cortex, and the midcingulate gyrus. Thus revealing a joint vestibular network in accordance with a concept from animal literature termed the inner vestibular circle. Moreover, there was also a significant vestibular connectivity overlap with frontal but not parietal cortical centres responsible for the generation of saccadic eye movements, likely to be involved in nystagmus fast phase generation. This was shown in an additional ocular motor meta-analysis. We conclude that the cytoarchitectonic area OP 2 in the parietal operculum, embedded in a joint vestibular network, should be the primary candidate for the human vestibular cortex. This area may represent the human homologue to the vestibular area PIVC as proposed by Guldin and Grüsser in non-human primates.

Lesions to the posterior insular cortex cause dysarthria.

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.