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Abstract Background Uni‐ or bilateral peripheral vestibular impairment causes objective spatial orientation deficits, which can be measured using pen‐and‐paper‐tests or sensorimotor tasks (navigation or pointing). For patients’ subjective orientation abilities, questionnaires are commonly used (e.g., Santa Barbara sense of direction scale [SBSODS]). However, the relationship between subjective assessment of spatial skills and objective vestibular function has only been scarcely investigated. Methods A total of 177 patients (mean age 57.86 ± 17.53 years, 90 females) who presented in our tertiary Center for Vertigo and Balance Disorders underwent neuro‐otological examinations, including bithermal water calorics, video head impulse test (vHIT), and testing of the subjective visual vertical (SVV), and filled out the SBSODS (German version). Correlation analyses and linear multiple regression model analyses were performed between vestibular test results and self‐assessment scores. Additionally, groupwise vestibular function for patients with low, average, and high self‐report scores was analyzed. Results Forty‐two patients fulfilled the diagnostic criteria for bilateral vestibulopathy, 93 for chronic unilateral vestibulopathy (68 unilateral caloric hypofunction and 25 isolated horizontal vestibulo‐ocular reflex deficits), and 42 patients had normal vestibular test results. SBSODS scores showed clear sex differences with higher subjective skill levels in males (mean score males: 4.94 ± 0.99, females 4.40 ± 0.94; Student's t‐test: t‐3.78, p

Abstract Background Deficits in spatial memory, orientation, and navigation are often neglected early signs of cognitive impairment or loss of vestibular function. Real-world navigation tests require complex setups. In contrast, simple pointing at targets in a three-dimensional environment is a basic sensorimotor ability which provides an alternative measure of spatial orientation and memory at bedside. The aim of this study was to test the reliability of a previously established 3D-Real-World Pointing Test (3D-RWPT) in patients with cognitive impairment due to different neurodegenerative disorders, bilateral vestibulopathy, or a combination of both compared to healthy participants. Methods The 3D-RWPT was performed using a static array of targets in front of the seated participant before and, as a transformation task, after a 90-degree body rotation around the yaw-axis. Three groups of patients were enrolled: (1) chronic bilateral vestibulopathy (BVP) with normal cognition (n = 32), (2) cognitive impairment with normal vestibular function (n = 28), and (3) combined BVP and cognitive impairment (n = 9). The control group consisted of age-matched participants (HP) without cognitive and vestibular deficits (n = 67). Analyses focused on paradigm-specific mean angular deviation of pointing in the azimuth (horizontal) and polar (vertical) spatial planes, of the preferred pointing strategy (egocentric or allocentric), and the resulting shape configuration of the pointing array relative to the stimulus array. Statistical analysis was performed using age-corrected ANCOVA-testing with Bonferroni correction and correlation analysis using Spearman’s rho. Results Patients with cognitive impairment employed more egocentric pointing strategies while patients with BVP but normal cognition and HP used more world-based solutions (pBonf 5.78 × 10-3**). Differences in pointing accuracy were only found in the azimuth plane, unveiling unique patterns where patients with cognitive impairment showed decreased accuracy in the transformation tasks of the 3D-RWPT (pBonf

Abstract Deficits in spatial memory are often early signs of neurological disorders. Here, we analyzed the geometrical shape configuration of 2D-projections of pointing performances to a memorized array of spatially distributed targets in order to assess the feasibility of this new holistic analysis method. The influence of gender differences and cognitive impairment was taken into account in this methodological study. 56 right-handed healthy participants (28 female, mean age 48.89 ± 19.35 years) and 22 right-handed patients with heterogeneous cognitive impairment (12 female, mean age 71.73 ± 7.41 years) underwent a previously validated 3D-real-world pointing test (3D-RWPT). Participants were shown a 9-dot target matrix and afterwards asked to point towards each target in randomized order with closed eyes in different body positions relative to the matrix. Two-dimensional projections of these pointing vectors (i.e., the shapes resulting from the individual dots) were then quantified using morphological analyses. Shape configurations in healthy volunteers largely reflected the real-world target pattern with gender-dependent differences (ANCOVA area males vs. females F(1,73) = 9.00, p 3.69 × 10−3, partial η2 = 0.10, post-hoc difference = 38,350.43, p bonf= 3.69 × 10−3**, Cohen’s d 0.76, t 3.00). Patients with cognitive impairment showed distorted rectangularity with more large-scale errors, resulting in decreased overall average diameters and solidity (ANCOVA diameter normal cognition/cognitive impairment F(1,71) = 9.30, p 3.22 × 10−3, partial η2 = 0.09, post-hoc difference = 31.22, p bonf= 3.19 × 10−3**, Cohen’s d 0.92, t 3.05; solidity normal cognition/cognitive impairment F(1,71) = 7.79, p 6.75 × 10−3, partial η2 = 0.08, post-hoc difference = 0.07, p bonf= 6.76 × 10−3** Cohen’s d 0.84, t 2.79). Shape configuration analysis of the 3D-RWPT target array appears to be a suitable holistic measure of spatial performance in a pointing task. The results of this methodological investigation support further testing in a clinical study for differential diagnosis of disorders with spatial memory deficits.

Importance: Triple-negative breast cancer is an aggressive subtype with a high incidence in young patients, a high incidence in non-Hispanic Black women, and a high risk of progression to metastatic cancer, a devastating sequela with a 12- to 18-month life expectancy. Until recently, one strategy for treating early-stage triple-negative breast cancer was chemotherapy after surgery. However, it was not known whether the addition of immune therapy to postsurgery chemotherapy would be beneficial., Objective: To evaluate the addition of immune therapy in the form of atezolizumab to postoperative chemotherapy in patients with the high-risk triple-negative breast cancer subtype., Design, Setting, and Participants: In this open-label international randomized phase 3 trial conducted in more than 330 centers in 31 countries, patients undergoing surgery as initial treatment for stage II or III triple-negative breast cancer were enrolled between August 2, 2018, and November 11, 2022. The last patient follow-up was on August 18, 2023., Interventions: Patients were randomized (1:1) to receive standard chemotherapy for 20 weeks with (n = 1101) or without (n = 1098) the immune therapy drug atezolizumab for up to 1 year., Main Outcomes and Measures: The primary end point was invasive disease-free survival (time between randomization and invasive breast cancer in the same or opposite breast, recurrence elsewhere in the body, or death from any cause)., Results: The median age of enrolled patients was 53 years and most self-reported as being of Asian or White race and neither Latino nor Hispanic ethnicity. The study independent data monitoring committee halted enrollment at 2199 of 2300 planned patients. All patients stopped atezolizumab following a planned early interim and futility analysis. The trial continued to a premature final analysis. With invasive disease-free survival events in 141 patients (12.8%) treated with atezolizumab-chemotherapy and 125 (11.4%) with chemotherapy alone (median follow-up, 32 months), the final stratified invasive disease-free survival hazard ratio was 1.11 (95% CI, 0.87-1.42; P = .38). Compared with chemotherapy alone, the regimen of atezolizumab plus chemotherapy was associated with more treatment-related grade 3 or 4 adverse events (54% vs 44%) but similar incidences of fatal adverse events (0.8% vs 0.6%) and adverse events leading to chemotherapy discontinuation. Chemotherapy exposure was similar in the 2 treatment groups., Conclusions and Relevance: The addition of the immune therapy drug atezolizumab to chemotherapy after surgery did not provide benefit among patients with triple-negative breast cancer who are at high risk of recurrent disease., Trial Registration: ClinicalTrials.gov Identifier: NCT03498716.

The intracellular tacrolimus concentration in CD3 + T lymphocytes is proposed to be a better representative of the active component of tacrolimus than the whole blood concentration. However, intracellular measurements are complicated. Therefore, the aim of this study was to describe the relationship between intracellular and whole blood tacrolimus concentrations in a population pharmacokinetic model. Twenty-eight de novo kidney transplant recipients, treated with a once-daily oral extended-release tacrolimus formulation, were followed during the first-month post-transplantation. Additional whole blood and intracellular tacrolimus concentrations were measured at day 6 ± 1 (pre-dose, 4 and 8 hours post-dose) and day 14 ± 3 (pre-dose) post-transplantation. Pharmacokinetic analysis was performed using nonlinear mixed effects modeling software (NONMEM). The ratio between intracellular (n = 109) and whole blood (n = 248) concentrations was best described by a two-compartment whole blood model with an additional intracellular compartment without mass transfer from the central compartment. The ratio remained stable over time. Prednisolone dose influenced the absorption rate of tacrolimus, while hemoglobin, CYP3A4*22 allele carrier, and CYP3A5 expresser status were associated with the oral clearance of tacrolimus (P-value < 0.001). Furthermore, the intracellular tacrolimus concentrations were correlated with the intracellular production of interleukin-2 (P-value 0.015). The intracellular tacrolimus concentration can be predicted from a measured whole blood concentration using this model, without the need for repeated intracellular measurements. This knowledge is particularly important when the intracellular concentration is ready to be implemented into clinical practice, to overcome the complexities of cell isolation and analytical methods., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: Spatial memory and orientation deficits often precede cognitive impairment in incipient dementia, e.g., Alzheimer's disease. Therefore, early diagnosis of spatial impairment may be crucial to the initiation of an adequate therapeutic intervention. Subjective tests, such as spatial anxiety and spatial discomfort questionnaires, and objective tests in the form of quantitative measures of orientation, are available. In these tests, vestibular hypofunction has often been neglected as a potential confounder. The major research question in this study was how self-assessed questionnaires correlate with the data from objective measures in participants with proven normal vestibular function., Methods: A heterogeneous group of 135 participants (72 females, 63 males, mean age 62.75 ± 14.46 years) from a tertiary center for vertigo and balance disorders consisting of two cohorts, with ( n  = 49) and without ( n  = 86) cognitive deficits in a screening test (MoCA), was examined (a) with a newly introduced inventory for subjective spatial discomfort (Extended Inventory for Spatial Orientation Discomfort, EISOD), (b) a well-established questionnaire for subjective spatial skills (Santa Barbara Sense of Direction Scale, SBSODS), and (c) the objective three-dimensional real-world pointing task (3D-RWPT) before and after horizontal body rotations. In all patients, acute central or peripheral vestibular deficits were ruled out by neuro-orthoptics, bithermal water calorics and video head impulse testing., Results: Self-assessed spatial orientation discomfort (EISOD) correlated with the amount of spatial impairment in the 3D-RWPT for both cohorts. The cognitively impaired patients showed significantly higher levels of spatial discomfort (i.e., lower scores; Welch's t -test t-2.58, p  < 0.01, Cohen's d - 0.46), and higher angular deviations in the (cognitively demanding) transformation paradigm of the 3D-RWPT (t 2.37, p 0.02, Cohen's d 0.44). They preferred retinotopic/egocentric spatial encoding strategies in the pointing task (Welch's t -test t-2.61, p  < 0.01, Cohen's d - 0.47). In contrast, the self-report of spatial abilities (SBSODS) yielded no significant group differences (t - 1.66, p 0.10) and was not reliably associated with objective accuracy in the pointing task., Conclusion: In patients without vestibular deficits, subjective spatial discomfort (EISOD) correlated with the accuracy in an objective 3D-pointing task for both cohorts, and higher discomfort was associated with more severe cognitive impairment. EISOD-scores showed higher correlation indices than a self-report of spatial skills using the SBSODS. When investigating spatial abilities in patients with suspected cognitive impairment, it appears reasonable that both subjective spatial discomfort, subjective spatial abilities, and objective spatial measures should be combined. Future research in patients with vestibular dysfunction is needed to understand the role of vestibular deficits for the development of spatial orientation discomfort., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gerb, Oertle, Becker-Bense, Brandt and Dieterich.)

Objective: The vestibular system is closely connected to emotion-processing neuronal circuits. Patients with bilateral vestibulopathy (BVP), a chronic loss of vestibular function, show remarkably lower rates of psychiatric comorbidities and vertigo-related anxiety (VRA) than those with episodic vertigo/dizziness (v/d). This study aimed to evaluate whether patients with BVP differ from those with episodic v/d in terms of VRA, general anxiety, and cognitions about body and health., Methods: This cross-sectional study involved a subsample of 202 patients with episodic v/d (i.e., vestibular migraine, vestibular paroxysmia, or Menière's disease) and 43 patients with BVP. All patients underwent standardised neurological/neurotological examinations, structured clinical interviews (SCID-I), and self-report questionnaires, such as the Vertigo Handicap Questionnaire (VHQ), Beck Anxiety Inventory (BAI), Trait Anxiety from the State-Trait-Anxiety Inventory (STAI-T), and Cognitions About Body and Health questionnaire (CABAH). Non-parametric tests were used for analysis. Due to multiple testing, the significance level was set at p ≤ .008., Results: Patients with episodic v/d exhibited higher VRA levels than those with BVP. However, this difference was not statistically significant (p = .04; r = 0.15, small effect). Additionally, patients with BVP reported more catastrophizing cognitions (p < .001; r = 0.25, small effect) and bodily weakness (p = .003; r = 0.22, small effect) compared to those with episodic v/d. There were no differences in general anxiety levels (BAI and STAI-T) between patients with v/d and those with BVP., Conclusion: Patients with episodic v/d and BVP differed in their appraisal (cognition). The difference in VRA (subjective feeling) was not statistically significant. These preliminary results are discussed using a component approach to emotions., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any personal, commercial, or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Vestibular migraine (VM), the most frequent episodic vertigo, is difficult to distinguish from Ménière's disease (MD) because reliable biomarkers are missing. The classical proof of MD was an endolymphatic hydrops (EH). However, a few intravenous gadolinium-enhanced MRI studies of the inner ear ( i MRI) also revealed an EH in VM. The major questions were the frequency and distribution characteristics of EH in VM for diagnostic use., Methods: In a prospective case-control study of 200 participants, 75 patients with VM (49 females; mean age 46 years) and 75 with MD (36 females; mean age 55 years), according to the Bárány and International Headache Society, and 50 age-matched participants with normal vestibulocochlear testing (HP), were enrolled. Analyses of i MRI of the endolymphatic space included volumetric quantification, stepwise regression, correlation with neurotological parameters and support vector machine classification., Results: EH was maximal in MD (80%), less in VM (32%) and minimal in HP (22%). EH was milder in VM (mean grade 0.3) compared with MD (mean grade 1.3). The intralabyrinthine distribution was preferably found in the vestibulum in VM, but mainly in the cochlea in MD. There was no interaural lateralisation of EH in VM but in the affected ear in MD. The grade of EH in the vestibulum was correlated in both conditions with the frequency and duration of the attacks., Conclusion: Three features of the i MRI evaluation were most supportive for the diagnosis of VM at group and individual levels: (1) the bilateral manifestation, (2) the low-grade EH and (3) the intraaural distribution., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The extent to which tissue-resident memory T (T RM ) cells in transplanted organs possess alloreactivity is uncertain. This study investigates the alloreactive potential of T RM cells in kidney explants from 4 patients who experienced severe acute rejection leading to graft loss. Alloreactive T cell receptor (TCR) clones were identified in pretransplant blood samples through mixed lymphocyte reactions, followed by single-cell RNA and TCR sequencing of the proliferated recipient T cells. Subsequently, these TCR clones were traced in the T RM cells of kidney explants, which were also subjected to single-cell RNA and TCR sequencing. The proportion of recipient-derived T RM cells expressing an alloreactive TCR in the 4 kidney explants varied from 0% to 9%. Notably, these alloreactive TCRs were predominantly found among CD4+ and CD8+ T RM cells with an effector phenotype. Intriguingly, these clones were present not only in recipient-derived T RM cells but also in donor-derived T RM cells, constituting up to 4% of the donor population, suggesting the presence of self-reactive T RM cells. Overall, our study demonstrates that T cells with alloreactive potential present in the peripheral blood prior to transplantation can infiltrate the kidney transplant and adopt a T RM phenotype., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This historical review on the semantic evolution of human senses and sensors revealed that Aristotle's list of the five senses sight, hearing, touch, taste, and smell is still in use among non-scientific lay persons. It is no surprise that his classification in the work "De Anima" (On the Soul) from 350 BC confuses the sensor "touch" with the now more comprehensively defined somatosensory system and that senses are missing such as the later discovered vestibular system and the musculotendinous proprioception of the position of parts of the body in space. However, it is surprising that in the three most influential ancient cultures, Egypt, Greece, and China-which shaped the history of civilization-the concept prevailed that the heart rather than the brain processes perception, cognition, and emotions. This "cardiocentric view" can be traced back to the "Doctrine of Aristotle," the "Book of the Dead" in ancient Egypt, and the traditional Chinese medicine of correspondence documented in the book "Huang di Neijing." In Greek antiquity the philosophers Empedocles, Democritus and Aristotle were proponents of the allocation of the spirit and the soul to the heart connected to the body via the blood vessels. Opponents were the pre-Socratic mathematician Pythagoras, the philosopher Plato, and especially the Greek physician Hippocrates who regarded the brain as the most powerful organ in humans in his work "De Morbo Sacro." The Greek physician Galen of Pergamon further elaborated on the concept of the brain ("cephalocentric hypothesis") connected to the body by a network of nerves. The fundamental concepts for understanding functions and disorders of the vestibular system, the perception of self-motion, verticality and balance control were laid by a remarkable group of 19th century scientists including Purkynӗ, Mach, Breuer, Helmholtz, and Crum-Brown. It was also in the 19th century that Bell described a new sense of a reciprocal sensorimotor loop between the brain and the muscles which he called "muscular sense," later termed "kinaesthesia" by Bastian and defined in 1906 as "proprioception" by Sherrington as "the perception of joint and body movements as well as position of the body or body segments, in space." Both, the vestibular system and proprioception could be acknowledged as senses six or seven. However, we hesitate to recommend "pain"-which is variously assigned to the somatosensory system or extero-, intero-, visceroception-as a separate sensory system. Pain sensors are often not specific but have multisensory functions. Because of this inconsistent, partly contradictory classification even by experts in the current literature on senses and sensors we consider it justified to recommend a comprehensive reorganization of classification features according to the present state of knowledge with an expansion of the number of senses. Such a project has also to include the frequent task-dependent multisensory interactions for perceptual and sensorimotor achievements, and higher functions or disorders of the visual and vestibular systems as soon as cognition or emotions come into play. This requires a cooperation of sensory physiologists, neuroscientists and experienced physicians involved in the management of patients with sensory and multisensory disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Brandt, Dieterich and Huppert.)

Background: Machine perfusion is the preferred preservation method for deceased donor kidneys. Perfusate fluid, which contains a complex mixture of components, offers potential insight into the organ's viability and function. This study explored immune cell release, particularly tissue-resident lymphocytes (TRLs), during donor kidney machine perfusion and its correlation with injury markers., Methods: Perfusate samples from hypothermic machine perfusion (HMP; n = 26) and normothermic machine perfusion (NMP; n = 16) of human donor kidneys were analyzed for TRLs using flow cytometry. Residency was defined by expressions of CD69, CD103, and CD49as. TRL release was quantified exclusively in NMP. Additionally, levels of cell-free DNA, neutrophil gelatinase-associated lipocalin, and soluble E-cadherin (sE-cadherin) were measured in NMP supernatants with quantitative polymerase chain reaction and enzyme-linked immunosorbent assay., Results: Both HMP and NMP samples contained a heterogeneous population of TRLs, including CD4 + tissue-resident memory T cells, CD8 + tissue-resident memory T cells, tissue-resident natural killer cells, tissue-resident natural killer T cells, and helper-like innate lymphoid cells. Median TRL proportions among total CD45 + lymphocytes were 0.89% (NMP) and 0.84% (HMP). TRL quantities in NMP did not correlate with donor characteristics, perfusion parameters, posttransplant outcomes, or cell-free DNA and neutrophil gelatinase-associated lipocalin concentrations. However, CD103 + TRL release positively correlated with the release of sE-cadherin, the ligand for the CD103 integrin., Conclusions: Human donor kidneys release TRLs during both HMP and NMP. The release of CD103 + TRLs was associated with the loss of their ligand sE-cadherin but not with general transplant injury biomarkers., Competing Interests: D.A.H. received lecture fees and consulting fees from Astellas Pharma, AstraZeneca, Chiesi Pharma, Medincell, Novartis Pharma, Sangamo Therapeutics, and Vifor Pharma. He received grant support from Astellas Pharma, Bristol-Myers Squibb, and Chiesi Pharma (paid to his institution). D.A.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The current diagnostic workup for chronic dizziness in elderly patients often neglects neuropsychological assessment, thus missing a relevant proportion of patients, who perceive dizziness as a subjective chief complaint of a concomitant cognitive impairment. This study aimed to establish risk prediction models for cognitive impairment in chronic dizzy patients based on data sources routinely collected in a dizziness center., Methods: One hundred patients (age: 74.7 ± 7.1 years, 41.0% women) with chronic dizziness were prospectively characterized by (1) neuro-otological testing, (2) quantitative gait assessment, (3) graduation of focal brain atrophy and white matter lesion load, and (4) cognitive screening (MoCA). A linear regression model was trained to predict patients' total MoCA score based on 16 clinical features derived from demographics, vestibular testing, gait analysis, and imaging scales. Additionally, we trained a binary logistic regression model on the same data sources to identify those patients with a cognitive impairment (i.e., MoCA < 25)., Results: The linear regression model explained almost half of the variance of patients' total MoCA score (R 2  = 0.49; mean absolute error: 1.7). The most important risk-predictors of cognitive impairment were age (β = - 0.75), pathological Romberg's sign (β = - 1.05), normal caloric test results (β = - 0.8), slower timed-up-and-go test (β = - 0.67), frontal (β = - 0.6) and temporal (β = - 0.54) brain atrophy. The binary classification yielded an area under the curve of 0.84 (95% CI 0.70-0.98) in distinguishing between cognitively normal and impaired patients., Conclusions: The need for cognitive testing in patients with chronic dizziness can be efficiently approximated by available data sources from routine diagnostic workup in a dizziness center., (© 2024. The Author(s).)

Healthy individuals with hybrid immunity, due to a SARS-CoV-2 infection prior to first vaccination, have stronger immune responses compared to those who were exclusively vaccinated. However, little is known about the characteristics of antibody, B- and T-cell responses in kidney disease patients with hybrid immunity. Here, we explored differences between kidney disease patients and controls with hybrid immunity after asymptomatic or mild coronavirus disease-2019 (COVID-19). We studied the kinetics, magnitude, breadth and phenotype of SARS-CoV-2-specific immune responses against primary mRNA-1273 vaccination in patients with chronic kidney disease or on dialysis, kidney transplant recipients, and controls with hybrid immunity. Although vaccination alone is less immunogenic in kidney disease patients, mRNA-1273 induced a robust immune response in patients with prior SARS-CoV-2 infection. In contrast, kidney disease patients with hybrid immunity develop SARS-CoV-2 antibody, B- and T-cell responses that are equally strong or stronger than controls. Phenotypic analysis showed that Spike (S)-specific B-cells varied between groups in lymph node-homing and memory phenotypes, yet S-specific T-cell responses were phenotypically consistent across groups. The heterogeneity amongst immune responses in hybrid immune kidney patients warrants further studies in larger cohorts to unravel markers of long-term protection that can be used for the design of targeted vaccine regimens., (© 2024. The Author(s).)

Purpose of Review: The aim of this study was to illuminate the extent of the bilateral central vestibular network from brainstem and cerebellum to subcortical and cortical areas and its interrelation to higher cortical functions such as spatial cognition and anxiety., Recent Findings: The conventional view that the main function of the vestibular system is the perception of self-motion and body orientation in space and the sensorimotor control of gaze and posture had to be developed further by a hierarchical organisation with bottom-up and top-down interconnections. Even the vestibulo-ocular and vestibulo-spinal reflexes are modified by perceptual cortical processes, assigned to higher vestibulo-cortical functions. A first comparative fMRI meta-analysis of vestibular stimulation and fear-conditioning studies in healthy participants disclosed widely distributed clusters of concordance, including the prefrontal cortex, anterior insula, temporal and inferior parietal lobe, thalamus, brainstem and cerebellum. In contrast, the cortical vestibular core region around the posterior insula was activated during vestibular stimulation but deactivated during fear conditioning. In recent years, there has been increasing evidence from studies in animals and humans that the central vestibular system has numerous connections related to spatial sensorimotor performance, memory, and emotion. The clinical implication of the complex interaction within various networks makes it difficult to assign some higher multisensory disorders to one particular modality, for example in spatial hemineglect or room-tilt illusion., Summary: Our understanding of higher cortical vestibular functions is still in its infancy. Different brain imaging techniques in animals and humans are one of the most promising methodological approaches for further structural and functional decoding of the vestibular and other intimately interconnected networks. The multisensory networking including cognition and emotion determines human behaviour in space., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role in transplanted organs under chronic immunosuppressed conditions. In this study, we aimed to characterize the TRL compartment in human kidney transplant nephrectomies and examine its potential role in antiviral immunity. The TRL compartment of kidney transplants contained diverse innate, innate-like, and adaptive TRL populations expressing the canonical residency markers CD69, CD103, and CD49a. Chimerism of donor and recipient cells was present in 43% of kidney transplants and occurred in all TRL subpopulations. Paired single-cell transcriptome and T cell receptor (TCR) sequencing showed that donor and recipient tissue-resident memory T (TRM) cells exhibit striking similarities in their transcriptomic profiles and share numerous TCR clonotypes predicted to target viral pathogens. Virus dextramer staining further confirmed that CD8 TRM cells of both donor and recipient origin express TCRs with specificities against common viruses, including CMV, EBV, BK polyomavirus, and influenza A. Overall, the study results demonstrate that a diverse population of TRLs resides in kidney transplants and offer compelling evidence that TRM cells of both donor and recipient origin reside within this TRL population and may contribute to local protection against viral pathogens.

Background: There is increasing evidence for close interrelations between vestibular and emotional brain networks. A study in patients with bilateral peripheral vestibulopathy (BVP) showed relatively low vertigo-related anxiety (VRA), despite high physical impairment. The current working hypothesis proposes the integrity of the peripheral vestibular system as a prerequisite for development of VRA. Here we contribute by evaluating VRA and vestibular-related handicap in central vestibular disorders., Methods: Of 6396 patients presenting in a tertiary vertigo centre, 306 were identified with four clear central vestibular disorders: pure cerebellar ocular motor disorder (COD; 61), cerebellar ataxia (CA; 63), atypical parkinsonian syndromes (APS; 28), vestibular migraine (VM; 154). Their results of the Vertigo Handicap Questionnaire (VHQ), with its subscales for anxiety and handicapped activity, were compared to those of 65 BVP patients. Postural instability was measured on a force-plate. Multivariate linear regression was used to adjust for patient demographics., Results: Patients with chronic central vestibular disorders (COD, CA, APS) had relatively low VRA levels comparable to those in BVP, independent of increased handicapped activity or postural instability. Only VM patients showed significantly higher VRA, although their activity impairment and postural instability were lowest. No significant differences within chronic central vestibular disorders were found for VRA and subjective activity impairment., Conclusions: Subjective and objective vestibular-related impairment are not necessarily correlated with vestibular-related anxiety in central vestibular disorders. Our findings rather support the hypothesis that, in addition to an intact peripheral, an intact central vestibular system could also serve as a prerequisite to develop specific VRA., (© 2023. The Author(s).)

Background: This study aims to investigate the presence of spatial cognitive impairments in patients with acute unilateral peripheral vestibulopathy (vestibular neuritis, AUPV) during both the acute phase and the recovery phase., Methods: A total of 72 AUPV patients (37 with right-sided AUPV and 35 with left-sided AUPV; aged 34-80 years, median 60.5; 39 males, 54.2%) and 35 healthy controls (HCs; aged 43-75 years, median 59; 20 males, 57.1%) participated in the study. Patients underwent comprehensive neurotological assessments, including video-oculography, video head impulse and caloric tests, ocular and cervical vestibular-evoked myogenic potentials, and pure-tone audiometry. Additionally, the Visual Object and Space Perception (VOSP) battery was used to evaluate visuospatial perception, while the Block design test and Corsi block-tapping test assessed visuospatial memory within the first 2 days (acute phase) and 4 weeks after symptom onset (recovery phase)., Results: Although AUPV patients were able to successfully perform visuospatial perception tasks within normal parameters, they demonstrated statistically worse performance on the visuospatial memory tests compared to HCs during the acute phase. When comparing right versus left AUPV groups, significant decreased scores in visuospatial perception and memory were observed in the right AUPV group relative to the left AUPV group. In the recovery phase, patients showed substantial improvements even in these previously diminished visuospatial cognitive performances., Conclusion: AUPV patients showed different spatial cognition responses, like spatial memory, depending on the affected ear, improving with vestibular compensation over time. We advocate both objective and subjective visuospatial assessments and the development of tests to detect potential cognitive deficits after unilateral vestibular impairments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oh, Nguyen, Kang, Kirsch, Boegle, Kim and Dieterich.)

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., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenskonflikt besteht.

Cytokines are regulators of the immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the contribution of cytokine-secreting CD4 + and CD8 + memory T cells to the SARS-CoV-2-specific humoral immune response in immunocompromised kidney patients is unknown. Here, we profiled 12 cytokines after stimulation of whole blood obtained 28 days post second 100 μg mRNA-1273 vaccination with peptides covering the SARS-CoV-2 spike (S)-protein from patients with chronic kidney disease (CKD) stage 4/5, on dialysis, kidney transplant recipients (KTR), and healthy controls. Unsupervised hierarchical clustering analysis revealed two distinct vaccine-induced cytokine profiles. The first profile was characterized by high levels of T-helper (Th) 1 (IL-2, TNF-α, and IFN-γ) and Th 2 (IL-4, IL-5, IL-13) cytokines, and low levels of Th 17 (IL-17A, IL-22) and Th 9 (IL-9) cytokines. This cluster was dominated by patients with CKD, on dialysis, and healthy controls. In contrast, the second cytokine profile contained predominantly KTRs producing mainly Th 1 cytokines upon re-stimulation, with lower levels or absence of Th 2 , Th 17 , and Th 9 cytokines. Multivariate analyses indicated that a balanced memory T cell response with the production of Th 1 and Th 2 cytokines was associated with high levels of S1-specific binding and neutralizing antibodies mainly at 6 months after second vaccination. In conclusion, seroconversion is associated with the balanced production of cytokines by memory T cells. This emphasizes the importance of measuring multiple T cell cytokines to understand their influence on seroconversion and potentially gain more information about the protection induced by vaccine-induced memory T cells., (© 2023. The Author(s).)

Background and Purpose: Acute ischemic stroke due to basilar artery occlusion (BAO) causes the most severe strokes and has a poor prognosis. Data regarding efficacy of endovascular thrombectomy in BAO are sparse. Therefore, in this study, we performed an analysis of the therapy of patients with BAO in routine clinical practice., Methods: Patients enrolled between June 2015 and December 2019 in the German Stroke Registry-Endovascular Treatment (GSR-ET) were analyzed. Primary outcomes were successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score of 2b-3), substantial neurological improvement (≥8-point National Institute of Health Stroke Scale [NIHSS] score reduction from admission to discharge or NIHSS score at discharge ≤1), and good functional outcome at 3 months (modified Rankin Scale [mRS] score of 0-2)., Results: Out of 6635 GSR-ET patients, 640 (9.6%) patients (age 72.2 ± 13.3, 43.3% female) experienced BAO (median [interquartile range] NIHSS score 17 [8, 27]). Successful reperfusion was achieved in 88.4%. Substantial neurological improvement at discharge was reached by 45.5%. At 3-month follow-up, good clinical outcome was observed in 31.1% of patients and the mortality rate was 39.2%. Analysis of mTICI3 versus mTICI2b groups showed considerable better outcome in those with mTICI3 (38.9% vs. 24.4%; p = 0.005). The strongest predictors of good functional outcome were intravenous thrombolysis (IVT) treatment (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.76-5.23) and successful reperfusion (OR 4.92, 95% CI 1.15-21.11), while the effect of time between symptom onset and reperfusion seemed to be small., Conclusions: Acute reperfusion strategies in BAO are common in daily practice and can achieve good rates of successful reperfusion, neurological improvement and good functional outcome. Our data suggest that, in addition to IVT treatment, successful and, in particular, complete reperfusion (mTICI3) strongly predicts good outcome, while time from symptom onset seemed to have a lower impact., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: A bidirectional functional link between vestibular and fear-related disorders has been previously suggested., Objective: To test a potential overlap of vestibular and fear systems with regard to their brain imaging representation maps., Methods: By use of voxel-based mapping permutation of subject images, we conducted a meta-analysis of earlier functional magnetic resonance imaging (fMRI) studies applying vestibular stimulation and fear conditioning in healthy volunteers., Results: Common clusters of concordance of vestibular stimulation and fear conditioning were found in the bilateral anterior insula cortex, ventrolateral prefrontal cortex and the right temporal pole, bilaterally in the adjacent ventrolateral prefrontal cortex, cingulate gyrus, secondary somatosensory cortex, superior temporal and intraparietal lobe, supplementary motor area and premotor cortex, as well as subcortical areas, such as the bilateral thalamus, mesencephalic brainstem including the collicular complex, pons, cerebellar vermis and bilateral cerebellar hemispheres. Peak areas of high concordance for activations during vestibular stimulation but deactivations during fear conditioning were centered on the posterior insula and S2., Conclusions: The structural overlap of both networks allows the following functional interpretations: first, the amygdala, superior colliculi, and antero-medial thalamus might represent a release of preprogramed sensorimotor patterns of approach or avoidance. Second, the activation (vestibular system) and deactivation (fear system) of the bilateral posterior insula is compatible with the view that downregulation of the fear network by acute vestibular disorders or unfamiliar vestibular stimulation makes unpleasant perceived body accelerations less distressing. This also fits the clinical observation that patients with bilateral vestibular loss suffer from less vertigo-related anxiety., (© 2023. The Author(s).)

Objective: Approximately 20% of strokes are embolic strokes of undetermined source (ESUS). Undetected atrial fibrillation (AF) remains an important cause. Yet, oral anticoagulation in unselected ESUS patients failed in secondary stroke prevention. Guidance on effective AF detection is lacking. Here, we introduce a novel, non-invasive AF risk assessment after ESUS., Methods: Catch-Up ESUS is an investigator-initiated, observational cohort study conducted between 2018 and 2019 at the Munich University Hospital. Besides clinical characteristics, patients received ≥72 h digital electrocardiogram recordings to generate the rhythm irregularity burden. Uni- and multivariable regression models predicted the primary endpoint of incident AF, ascertained by standardized follow-up including implantable cardiac monitors. Predictors included the novel rhythm irregularity burden constructed from digital electrocardiogram recordings. We independently validated our model in ESUS patients from the University Hospital Tübingen, Germany., Results: A total of 297 ESUS patients were followed for 15.6 ± 7.6 months. Incident AF (46 patients, 15.4%) occurred after a median of 105 days (25th to 75th percentile 31-33 days). Secondary outcomes were recurrent stroke in 7.7% and death in 6.1%. Multivariable-adjusted analyses identified the rhythm irregularity burden as the strongest AF-predictor (hazard ratio 3.12, 95% confidence interval 1.62-5.80, p < 0001) while accounting for the known risk factors age, CHA 2 DS 2 -VASc-Score, and NT-proBNP. Independent validation confirmed the rhythm irregularity burden as the most significant AF-predictor (hazard ratio 2.20, 95% confidence interval 1.45-3.33, p < 0001)., Interpretation: The novel, non-invasive, electrocardiogram-based rhythm irregularity burden may help adjudicating AF risk after ESUS, and subsequently guide AF-detection after ESUS. Clinical trials need to clarify if high-AF risk patients benefit from tailored secondary stroke prevention. ANN NEUROL 2023;93:479-488., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: . Transplant recipients may develop rejection despite having adequate tacrolimus whole blood predose concentrations (C 0 ). The intra-immune cellular concentration is potentially a better target than C 0 . However, little is known regarding intracellular tacrolimus concentration in T-lymphocytes and monocytes. We investigated the tacrolimus concentrations in both cell types and their relation with the expression and activity of FK-binding protein (FKBP)-12 and P-glycoprotein (P-gp)., Methods: . T-lymphocytes and monocytes were isolated from kidney transplant recipients followed by intracellular tacrolimus concentration measurement. FKBP-12 and P-gp were quantified with Western blot, flow cytometry, and the Rhodamine-123 assay. Interleukin-2 and interferon-γ in T-lymphocytes were measured to quantify the effect of tacrolimus., Results: . Tacrolimus concentration in T-lymphocytes was lower than in monocytes (15.3 [8.5-33.4] versus 131.0 [73.5-225.1] pg/million cells; P < 0.001). The activity of P-gp (measured by Rhodamine-123 assay) was higher in T-lymphocytes than in monocytes. Flow cytometry demonstrated a higher expression of P-gp (normalized mean fluorescence intensity 1.5 [1.2-1.7] versus 1.2 [1.1-1.4]; P = 0.012) and a lower expression of FKBP-12 (normalized mean fluorescence intensity 1.3 [1.2-1.7] versus 1.5 [1.4-2.0]; P = 0.011) in T-lymphocytes than monocytes. Western blot confirmed these observations. The addition of verapamil, a P-gp inhibitor, resulted in a 2-fold higher intra-T-cell tacrolimus concentration. This was accompanied by a significantly fewer cytokine-producing cells., Conclusions: . T-lymphocytes have a higher activity of P-gp and lower concentration of the FKBP-12 compared with monocytes. This explains the relatively lower tacrolimus concentration in T-lymphocytes. The addition of verapamil prevents loss of intracellular tacrolimus during the cell isolation process and is required to ensure adequate intracellular concentration measurement., Competing Interests: D.A.H. has received grant support (paid to the Erasmus MC) from Astellas Pharma and Chiesi Pharma and consulting fees from Astellas Pharma, Chiesi Pharma, MedinCell, Novartis Pharma and Sangamo Therapeutics. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This cohort study aims to evaluate the predictive validity of multimodal clinical assessment and quantitative measures of in- and off-laboratory mobility for fall-risk estimation in patients with cerebellar ataxia (CA).Occurrence, severity, and consequences of falling were prospectively assessed for 6 months in 93 patients with hereditary (N = 36) and sporadic or secondary (N = 57) forms of CA and 63 healthy controls. Participants completed a multimodal clinical and functional fall risk assessment, in-laboratory gait examination, and a 2-week inertial sensor-based daily mobility monitoring. Multivariate logistic regression analyses were performed to evaluate the predictive capacity of all clinical and in- and off-laboratory mobility measures with respect to fall (1) status (non-faller vs. faller), (2) frequency (occasional vs. frequent falls), and (3) severity (benign vs. injurious fall) of patients. 64% of patients experienced one or recurrent falls and 65% of these severe fall-related injuries during prospective assessment. Mobility impairments in patients corresponded to a mild-to-moderate ataxic gait disorder. Patients' fall status and frequency could be reliably predicted (78% and 81% accuracy, respectively), primarily based on their retrospective fall status. Clinical scoring of ataxic symptoms and in- and off-laboratory gait and mobility measures improved classification and provided unique information for the prediction of fall severity (84% accuracy).These results encourage a stepwise approach for fall risk assessment in patients with CA: fall history-taking readily and reliably informs the clinician about patients' general fall risk. Clinical scoring and instrument-based mobility measures provide further in-depth information on the risk of recurrent and injurious falling., (© 2022. The Author(s).)

Introduction: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD., Methods: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers., Results: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time., Discussion: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Although of high individual and socioeconomic relevance, a reliable prediction model for the prognosis of juvenile stroke (18-55 years) is missing. Therefore, the study presented in this protocol aims to prospectively validate the discriminatory power of a prediction score for the 3 months functional outcome after juvenile stroke or transient ischemic attack (TIA) that has been derived from an independent retrospective study using standard clinical workup data., Methods: PREDICT-Juvenile-Stroke is a multi-centre (n = 4) prospective observational cohort study collecting standard clinical workup data and data on treatment success at 3 months after acute ischemic stroke or TIA that aims to validate a new prediction score for juvenile stroke. The prediction score has been developed upon single center retrospective analysis of 340 juvenile stroke patients. The score determines the patient's individual probability for treatment success defined by a modified Rankin Scale (mRS) 0-2 or return to pre-stroke baseline mRS 3 months after stroke or TIA. This probability will be compared to the observed clinical outcome at 3 months using the area under the receiver operating characteristic curve. The primary endpoint is to validate the clinical potential of the new prediction score for a favourable outcome 3 months after juvenile stroke or TIA. Secondary outcomes are to determine to what extent predictive factors in juvenile stroke or TIA patients differ from those in older patients and to determine the predictive accuracy of the juvenile stroke prediction score on other clinical and paraclinical endpoints. A minimum of 430 juvenile patients (< 55 years) with acute ischemic stroke or TIA, and the same number of older patients will be enrolled for the prospective validation study., Discussion: The juvenile stroke prediction score has the potential to enable personalisation of counselling, provision of appropriate information regarding the prognosis and identification of patients who benefit from specific treatments., Trial Registration: The study has been registered at https://drks.de on March 31, 2022 ( DRKS00024407 )., (© 2023. The Author(s).)

Combining magnetic resonance imaging (MRI) sequences that permit the determination of vestibular nerve angulation (NA = change of nerve caliber or direction), structural nerve integrity via diffusion tensor imaging (DTI), and exclusion of endolymphatic hydrops (ELH) via delayed gadolinium-enhanced MRI of the inner ear (iMRI) could increase the diagnostic accuracy in patients with vestibular paroxysmia (VP). Thirty-six participants were examined, 18 with VP (52.6 ± 18.1 years) and 18 age-matched with normal vestibulocochlear testing (NP 50.3 ± 16.5 years). This study investigated whether (i) NA, (ii) DTI changes, or (iii) ELH occur in VP, and (iv) to what extent said parameters relate. Methods included vestibulocochlear testing and MRI data analyses for neurovascular compression (NVC) and NA verification, DTI and ELS quantification. As a result, (i) NA increased NVC specificity. (ii) DTI structural integrity was reduced on the side affected by VP (p < 0.05). (iii) 61.1% VP showed mild ELH and higher asymmetry indices than NP (p > 0.05). (iv) "Disease duration" and "total number of attacks" correlated with the decreased structural integrity of the affected nerve in DTI (p < 0.001). NVC distance within the nerve's root-entry zone correlated with nerve function (Roh = 0.72, p < 0.001), nerve integrity loss (Roh = - 0.638, p < 0.001), and ELS volume (Roh = - 0.604, p < 0.001) in VP. In conclusion, this study is the first to link eighth cranial nerve function, microstructure, and ELS changes in VP to clinical features and increased vulnerability of NVC in the root-entry zone. Combined MRI with NVC or NA verification, DTI and ELS quantification increased the diagnostic accuracy at group-level but did not suffice to diagnose VP on a single-subject level due to individual variability and lack of diagnostic specificity., (© 2022. The Author(s).)

Objective: The aim of the study was to deepen our insights into central compensatory processes of brain networks in patients with cerebellar ataxia (CA) before and with treatment with acetyl-DL-leucine (AL) by means of resting-state [ 18 F]-FDG-PET brain imaging., Methods: Retrospective analyses of [ 18 F]-FDG-PET data in 22 patients with CA (with vestibular and ocular motor disturbances) of different etiologies who were scanned before (PET A) and on AL treatment (PET B). Group subtraction analyses, e.g., for responders and non-responders, comparisons with healthy controls and correlation analyses of regional cerebral glucose metabolism (rCGM) with symptom duration, ataxia (SARA) and quality of life (QoL) scores were calculated., Results: Prior to treatment rCGM was consistently downregulated at the cerebellar level and increased in multisensory cortical areas, e.g., somatosensory, primary and secondary visual (including V5, precuneus), secondary vestibular (temporal gyrus, anterior insula), and premotor/supplementary motor areas. With AL (PET B vs. A) cerebellar hypometabolism was deepened and sensorimotor hypermetabolism increased only in responders with clinical benefit, but not for the non-responders and the whole CA group. A positive correlation of ataxia improvement with rCGM was found in visual and vestibular cortices, a negative correlation in cerebellar and brainstem areas. QoL showed a positive correlation with rCGM in the cerebellum and symptom duration in premotor and somatosensory areas., Conclusions: Central compensatory processes in CA mainly involve multisensory visual, vestibular, and somatosensory networks as well as premotor/primary motor areas at the cortical level. The enhanced divergence of cortical sensorimotor up- and cerebellar downregulation with AL in responders could reflect amplification of inhibitory cerebellar mechanisms., (© 2022. The Author(s).)

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.

Knowledge of the physiological endolymphatic space (ELS) is necessary to estimate endolymphatic hydrops (ELH) in patients with vestibulocochlear syndromes. Therefore, the current study investigated age-dependent changes in the ELS of participants with normal vestibulocochlear testing. Sixty-four ears of 32 participants with normal vestibulocochlear testing aged between 21 and 75 years (45.8 ± 17.2 years, 20 females, 30 right-handed, two left-handed) were examined by intravenous delayed gadolinium-enhanced magnetic resonance imaging of the inner ear (iMRI). Clinical diagnostics included neuro-otological assessment, video-oculography during caloric stimulation, and head-impulse test. iMRI data analysis provided semi-quantitative visual grading and automatic algorithmic quantitative segmentation of ELS volume (3D, mm 3 ) using a deep learning-based segmentation of the inner ear's total fluid space (TFS) and volumetric local thresholding, as described earlier. As a result, following a 4-point ordinal scale, a mild ELH (grade 1) was found in 21/64 (32.8%) ears uni- or bilaterally in either cochlear, vestibulum, or both. Age and ELS were found to be positively correlated for the inner ear (r(64) = 0.33, p < 0.01), and vestibulum (r(64) = 0.25, p < 0.05). For the cochlea, the values correlated positively without reaching significance (r(64) = 0.21). In conclusion, age-dependent increases of the ELS should be considered when evaluating potential ELH in single subjects and statistical group comparisons., (© 2022. The Author(s).)

Parkinson´s disease (PD) pathology progresses throughout the nervous system. Whereas motor symptoms are always present, there is a high variability in the prevalence of non-motor symptoms. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed-alpha-synuclein (ASYN) on the endogenous ASYN. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology in vivo and in vitro and compared the effect of endocytosed-ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type and ASYN-KO mice. Our results show that, in vivo, pathology progression did not occur in the absence of endogenous ASYN. Remarkably, the damage caused by endocytosed-ASYN, rotenone or paraquat was independent from endogenous ASYN and related to the alteration of the host´s mitochondrial membrane potential. Dopaminergic neurons were very sensitive to these noxae compared to other neuronal subtypes. These results suggest that ASYN-mitochondrial interactions play a major role in initiating the pathological process in the host neuron and endogenous ASYN is essential for the transsynaptical transmission of the pathology. Our results also suggest that protecting mitochondrial function is a valid primary therapeutic target., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

Visually-induced self-motion perception (vection) relies on interaction of the visual and vestibular systems. Neuroimaging studies have identified a lateralization of the thalamo-cortical multisensory vestibular network, with left-handers exhibiting a dominance of the left hemisphere and right-handers exhibiting a dominance of the right hemisphere. Using electroencephalography (EEG), we compare the early processing of a vection-consistent visual motion stimulus against a vection-inconsistent stimulus, to investigate the temporal activation of the vection network by visual motion stimulation and the lateralization of these processes in left- versus right-handers. In both groups, vection-consistent stimulation evoked attenuated central event-related potentials (ERPs) in an early (160-220 ms) and a late (260-300 ms) time window. Differences in estimated source activity were found across visual, sensorimotor, and multisensory vestibular cortex in the early window, and were observed primarily in the posterior cingulate, retrosplenial cortex, and precuneus in the late window. Group comparisons revealed a larger ERP condition difference (i.e. vection-consistent stimulation minus vection-inconsistent stimulation) in left-handers, which was accompanied by group differences in the cingulate sulcus visual (CSv) area. Together, these results suggest that handedness may influence ERP responses and activity in area CSv during vection-consistent and vection-inconsistent visual motion stimulation., (© 2022. The Author(s).)