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BackgroundSpatial 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.MethodsA 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.ResultsSelf-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

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.

Abstract In a retrospective study, the data of direction-dependent deviations in dynamic subjective visual vertical (SVV) testing were analysed in 1811 dizzy patients (174 benign paroxysmal positional vertigo, 99 unilateral vestibulopathy, 67 bilateral vestibulopathy, 151 Menière’s disease, 375 vestibular migraine, 82 cerebellar disorder, 522 functional dizziness, 341 unclear diagnosis) and in 59 healthy controls. Major findings were (i) a significant gender difference with higher directional deviations in females over the entire range of age, (ii) a significant increase of directional deviations with increasing age for both genders and in all disease subgroups as well as in healthy controls, and (iii) a lack of significant difference of directional deviations between all tested diseases. Thus, the data allow no recommendation for performing additional angular deviation analysis in dynamic SVV testing as part of routine clinical management of dizzy patients. However, as shown in earlier longitudinal studies, it still appears reasonable that dynamic SVV in acute rather than chronic vestibular disorders may provide a useful instrument for the monitoring of acute unilateral vestibular tonus imbalances in the course of the disease.

Abstract 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 (

Abstract 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.

Abstract 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.

BackgroundThis 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.MethodsA 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).ResultsAlthough 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.ConclusionAUPV 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.

Abstract Neuronal lesions trigger mechanisms of structural and functional neuroplasticity, which can support recovery. However, the temporal and spatial appearance of structure–function changes and their interrelation remain unclear. The current study aimed to directly compare serial whole-brain in vivo measurements of functional plasticity (by [18F]FDG-PET) and structural synaptic plasticity (by [18F]UCB-H-PET) before and after bilateral labyrinthectomy in rats and investigate the effect of locomotor training. Complex structure–function changes were found after bilateral labyrinthectomy: in brainstem-cerebellar circuits, regional cerebral glucose metabolism (rCGM) decreased early, followed by reduced synaptic density. In the thalamus, increased [18F]UCB-H binding preceded a higher rCGM uptake. In frontal-basal ganglia loops, an increase in synaptic density was paralleled by a decrease in rCGM. In the group with locomotor training, thalamic rCGM and [18F]UCB-H binding increased following bilateral labyrinthectomy compared to the no training group. Rats with training had considerably fewer body rotations. In conclusion, combined [18F]FDG/[18F]UCB-H dual tracer imaging reveals that adaptive neuroplasticity after bilateral vestibular loss is not a uniform process but is composed of complex spatial and temporal patterns of structure–function coupling in networks for vestibular, multisensory, and motor control, which can be modulated by early physical training.

BackgroundStroke accounts for 5–10% of all presentations with acute vertigo and dizziness. The objective of the current study was to examine determinants of long-term functioning and health-related quality of life (HRQoL) in a patient cohort with vestibular stroke.MethodsThirty-six patients (mean age: 66.1 years, 39% female) with an MRI-proven vestibular stroke were followed prospectively (mean time: 30.2 months) in the context of the EMVERT (EMergency VERTigo) cohort study at the Ludwig-Maximilians Universität, Munich. The following scores were obtained once in the acute stage (1 year after stroke): European Quality of Life Scale-five dimensions-five levels questionnaire (EQ-5D-5L) and Visual Analog Scale (EQ-VAS) for HRQoL, Dizziness Handicap Inventory (DHI) for symptom severity, and modified Rankin Scale (mRS) for general functioning and disability. Anxiety state and trait were evaluated by STAI-S/STAI-T, and depression was evaluated by the Patient Health Questionnaire-9 (PHQ-9). Voxel-based lesion mapping was applied in normalized MRIs to analyze stroke volume and localization. Multiple linear regression models were calculated to determine predictors of functional outcome (DHI, EQ-VAS at follow-up).ResultsMean DHI scores improved significantly from 45.0 in the acute stage to 18.1 at follow-up (p < 0.001), and mean mRS improved from 2.1 to 1.1 (p < 0.001). Mean HRQoL (EQ-5D-5L index/EQ-VAS) changed from 0.69/58.8 to 0.83/65.2 (p = 0.01/p = 0.11). Multiple linear regression models identified higher scores of STAI-T and DHI at the time of acute vestibular stroke and larger stroke volume as significant predictors for higher DHI at follow-up assessment. The effect of STAI-T was additionally enhanced in women. There was a significant effect of patient age on EQ-VAS, but not DHI during follow-up.ConclusionThe average functional outcome of strokes with the chief complaint of vertigo and dizziness is favorable. The most relevant predictors for individual outcomes are the personal anxiety trait (especially in combination with the female sex), the initial symptom intensity, and lesion volume. These factors should be considered for therapeutic decisions both in the acute stage of stroke and during subsequent rehabilitation.

ObjectiveThis study aims to investigate the efficacy of botulinum toxin type A (BTX-A) in the prophylactic management of vestibular migraine (VM) and to determine whether this treatment modulates intrinsic functional brain network.MethodsVestibular migraine patients (n = 20, mean age 45.4 years) who were resistant to conventional prophylactic therapies had BTX-A injection and rs-fMRI before and 2 months after the injection. We also measured the changes in the frequency of vertigo and migraine attacks, symptomatic functional disability scores, and neuropsychiatric inventories.ResultsAfter BTX-A injection, the mean monthly frequencies of migraine and vertigo episodes decreased significantly compared with the baseline (p < 0.01, paired t-test). The Headache Impact Test-6 score and the Migraine Disability Assessment, and the vertigo parameters, measured by the Dizziness Handicap Inventory and the Vertigo Symptom Scale, showed an improvement, as did the anxiety and depression scores 2 months after BTX-A treatment. The low-frequency fluctuation analysis of the rs-fMRI data found significant changes in the functional connectivity of the right superior temporal gyrus. Adoption of this cluster as the seed region increased the functional connectivity with the left post-central gyrus, right supramarginal gyrus, and right middle temporal gyrus after BTX-A treatment.ConclusionThis prospective study suggests that BTX-A treatment is effective at ameliorating migraine and vertigo symptoms in VM patients who were resistant to conventional therapies. Along with symptomatic improvements, changes in the functional connectivity within the multisensory vestibular and pain networks suggest a dysmodulation of multimodal sensory integration and abnormal cortical processing of the vestibular and pain signals in VM patients.

Abstract The differential impact of complete and incomplete bilateral vestibulopathy (BVP) on spatial orientation, visual exploration, and navigation-induced brain network activations is still under debate. In this study, 14 BVP patients (6 complete, 8 incomplete) and 14 age-matched healthy controls performed a navigation task requiring them to retrace familiar routes and recombine novel routes to find five items in real space. [18F]-fluorodeoxyglucose-PET was used to determine navigation-induced brain activations. Participants wore a gaze-controlled, head-fixed camera that recorded their visual exploration behaviour. Patients performed worse, when recombining novel routes (p

BackgroundIn-vivo MR-based high-resolution volumetric quantification methods of the endolymphatic hydrops (ELH) are highly dependent on a reliable segmentation of the inner ear's total fluid space (TFS). This study aimed to develop a novel open-source inner ear TFS segmentation approach using a dedicated deep learning (DL) model.MethodsThe model was based on a V-Net architecture (IE-Vnet) and a multivariate (MR scans: T1, T2, FLAIR, SPACE) training dataset (D1, 179 consecutive patients with peripheral vestibulocochlear syndromes). Ground-truth TFS masks were generated in a semi-manual, atlas-assisted approach. IE-Vnet model segmentation performance, generalizability, and robustness to domain shift were evaluated on four heterogenous test datasets (D2-D5, n = 4 × 20 ears).ResultsThe IE-Vnet model predicted TFS masks with consistently high congruence to the ground-truth in all test datasets (Dice overlap coefficient: 0.9 ± 0.02, Hausdorff maximum surface distance: 0.93 ± 0.71 mm, mean surface distance: 0.022 ± 0.005 mm) without significant difference concerning side (two-sided Wilcoxon signed-rank test, p>0.05), or dataset (Kruskal-Wallis test, p>0.05; post-hoc Mann-Whitney U, FDR-corrected, all p>0.2). Prediction took 0.2 s, and was 2,000 times faster than a state-of-the-art atlas-based segmentation method.ConclusionIE-Vnet TFS segmentation demonstrated high accuracy, robustness toward domain shift, and rapid prediction times. Its output works seamlessly with a previously published open-source pipeline for automatic ELS segmentation. IE-Vnet could serve as a core tool for high-volume trans-institutional studies of the inner ear. Code and pre-trained models are available free and open-source under https://github.com/pydsgz/IEVNet.

Background: Recent evidence suggests that the dorsal medial frontal cortex (dMFC) may make an important contribution to perceptual decision-making, and not only to motor control. Objective/hypothesis: By fitting psychometric functions to behavioural data after TMS we tested whether the dMFC is critical specifically for the precision and/or bias of perceptual judgements. Additionally we aimed to disentangle potential roles of the dMFC in dealing with perceptual versus response switching. Methods: A subjective visual vertical task (SVV) was used in which participants weight visual (and other, e.g., vestibular) information to establish whether a line is oriented vertically. To ensure a high perceptual demand (putatively necessary to demonstrate a dMFC involvement) SVV lines were presented inside pop-out targets within a visual search array. Distinct features of perceptual performance were analysed before as compared to following theta-burst TMS stimulation of the dMFC, a control site, or no stimulation, in three groups, each of 20 healthy participants. Results: dMFC stimulation improved the precision of verticality judgments. Moreover, dMFC stimulation improved accuracy, selectively when response switches occurred with perceptual repeats. Conclusion: These findings point to a causal role of the dMFC in establishing the precision of perceptual decision making, demonstrably dissociable from an additional role in motor control in attentionally demanding contexts.

Abstract Objective Patients with acute central vestibular syndrome suffer from vertigo, spontaneous nystagmus, postural instability with lateral falls, and tilts of visual vertical. Usually, these symptoms compensate within months. The mechanisms of compensation in vestibular infarcts are yet unclear. This study focused on structural changes in gray and white matter volume that accompany clinical compensation. Methods We studied patients with acute unilateral brain stem infarcts prospectively over 6 months. Structural changes were compared between the acute phase and follow‐up with a group of healthy controls using voxel‐based morphometry. Results Restitution of vestibular function following brain stem infarcts was accompanied by downstream structural changes in multisensory cortical areas. The changes depended on the location of the infarct along the vestibular pathways in patients with pathological tilts of the SVV and on the quality of the vestibular percept (rotatory vs graviceptive) in patients with pontomedullary infarcts. Patients with pontomedullary infarcts with vertigo or spontaneous nystagmus showed volumetric increases in vestibular parietal opercular multisensory and (retro‐) insular areas with right‐sided preference. Compensation of graviceptive deficits was accompanied by adaptive changes in multiple multisensory vestibular areas in both hemispheres in lower brain stem infarcts and by additional changes in the motor system in upper brain stem infarcts. Interpretation This study demonstrates multisensory neuroplasticity in both hemispheres along with the clinical compensation of vestibular deficits following unilateral brain stem infarcts. The data further solidify the concept of a right‐hemispheric specialization for core vestibular processing. The identification of cortical structures involved in central compensation could serve as a platform to launch novel rehabilitative treatments such as transcranial stimulations.

Abstract Stroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, reopen occluded arteries but do not protect against ischemia‐induced damage that occurs before reperfusion or neuronal damage induced by ischemia/reperfusion. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis in Caenorhabditis elegans dauer larva and that GA itself can rescue this phenotype. During the process of desiccation/rehydration, a metabolic stop/start similar to the one observed during ischemia/reperfusion occurs. In this study, the protective effect of GA is tested in different ischemia models, i.e., in commonly used stroke models in mice and swine. The results show that GA, given during reperfusion, strongly protects against ischemic damage and improves functional outcome. Evidence that GA exerts its effect by counteracting the glutamate‐dependent increase in intracellular calcium during excitotoxicity is provided. These results suggest that GA treatment has the potential to reduce mortality and disability in stroke patients.

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.

This study aimed to investigate the disparity in locomotor and spatial memory deficits caused by left- or right-sided unilateral vestibular deafferentation (UVD) using a mouse model of unilateral labyrinthectomy (UL) and to examine the effects of galvanic vestibular stimulation (GVS) on the deficits over 14 days. Five experimental groups were established: the left-sided and right-sided UL (Lt.-UL and Rt.-UL) groups, left-sided and right-sided UL with bipolar GVS with the cathode on the lesion side (Lt.-GVS and Rt.-GVS) groups, and a control group with sham surgery. We assessed the locomotor and cognitive-behavioral functions using the open field (OF), Y maze, and Morris water maze (MWM) tests before (baseline) and 3, 7, and 14 days after surgical UL in each group. On postoperative day (POD) 3, locomotion and spatial working memory were more impaired in the Lt.-UL group compared with the Rt.-UL group (p < 0.01, Tamhane test). On POD 7, there was a substantial difference between the groups; the locomotion and spatial navigation of the Lt.-UL group recovered significantly more slowly compared with those of the Rt.-UL group. Although the differences in the short-term spatial cognition and motor coordination were resolved by POD 14, the long-term spatial navigation deficits assessed by the MWM were significantly worse in the Lt.-UL group compared with the Rt.-UL group. GVS intervention accelerated the vestibular compensation in both the Lt.-GVS and Rt.-GVS groups in terms of improvement of locomotion and spatial cognition. The current data imply that right- and left-sided UVD impair spatial cognition and locomotion differently and result in different compensatory patterns. Sequential bipolar GVS when the cathode (stimulating) was assigned to the lesion side accelerated recovery for UVD-induced spatial cognition, which may have implications for managing the patients with spatial cognitive impairment, especially that induced by unilateral peripheral vestibular damage on the dominant side.

Metabolic connectivity patterns on the basis of [18F]-FDG positron emission tomography (PET) are used to depict complex cerebral network alterations in different neurological disorders and therefore may have the potential to support diagnostic decisions. In this study, we established a novel statistical classification method taking advantage of differential time-dependent states of whole-brain metabolic connectivity following unilateral labyrinthectomy (UL) in the rat and explored its classification accuracy.The dataset consisted of repeated [18F]-FDG PET measurements at baseline and 1, 3, 7, and 15 days (= maximum of 5 classes) after UL with 17 rats per measurement day. Classification in different stages after UL was performed by determining connectivity patterns for the different classes by Pearson's correlation between uptake values in atlas-based segmented brain regions. Connections were fitted with a linear function, with which different thresholds on the correlation coefficient (r = [0.5, 0.85]) were investigated. Rats were classified by determining the congruence of their PET uptake pattern with the fitted connectivity patterns in the classes.Overall, the classification accuracy with this method was 84.3% for 3 classes, 75.0% for 4 classes, and 54.1% for 5 classes and outperformed random classification as well as machine learning classification on the same dataset. The optimal classification thresholds of the correlation coefficient and distance-to-fit were found to be |r| > 0.65 and d = 4 when using Siegel's slope estimator for fitting.This connectivity-based classification method can compete with machine learning classification and may have methodological advantages when applied to support PET-based diagnostic decisions in neurological network disorders (such as neurodegenerative syndromes).

Objectives: To investigate the deficits of spatial memory and navigation from unilateral vestibular deafferentation (UVD) and to determine the efficacy of galvanic vestibular stimulation (GVS) for recovery from these deficits using a mouse model of unilateral labyrinthectomy (UL).Methods: Thirty-six male C57BL/6 mice were allocated into three groups that comprise a control group and two experimental groups, UVD with (GVS group) and without GVS intervention (non-GVS group). In the experimental groups, we assessed the locomotor and cognitive behavioral function before (baseline) and 3, 7, and 14 days after surgical UL, using the open field (OF), Y maze, and Morris water maze (MWM) tests. In the GVS group, the stimulations were applied for 30 min daily from postoperative day (POD) 0–4 via the electrodes inserted subcutaneously close to both bony labyrinths.Results: Locomotion and spatial cognition were significantly impaired in the mice with UVD non-GVS group compared to the control group. GVS significantly accelerated recovery of locomotion compared to the control and non-GVS groups on PODs 3 (p < 0.001) and 7 (p < 0.05, Kruskal–Wallis and Mann–Whitney U tests) in the OF and Y maze tests. The mice in the GVS group were better in spatial working memory assessed with spontaneous alternation performance and spatial reference memory assessed with place recognition during the Y maze test than those in the non-GVS group on POD 3 (p < 0.001). In addition, the recovery of long-term spatial navigation deficits during the MWM, as indicated by the escape latency and the probe trial, was significantly better in the GVS group than in the non-GVS group 2 weeks after UVD (p < 0.01).Conclusions: UVD impairs spatial memory, navigation, and motor coordination. GVS accelerated recoveries in short- and long-term spatial memory and navigation, as well as locomotor function in mice with UVD, and may be applied to the patients with acute unilateral vestibular failure.

In-vivo non-invasive verification of endolymphatic hydrops (ELH) by means of intravenous delayed gadolinium (Gd) enhanced magnetic resonance imaging of the inner ear (iMRI) is rapidly developing into a standard clinical tool to investigate peripheral vestibulo-cochlear syndromes. In this context, methodological comparative studies providing standardization and comparability between labs seem even more important, but so far very few are available. One hundred eight participants [75 patients with Meniere's disease (MD; 55.2 ± 14.9 years) and 33 vestibular healthy controls (HC; 46.4 ± 15.6 years)] were examined. The aim was to understand (i) how variations in acquisition protocols influence endolymphatic space (ELS) MR-signals; (ii) how ELS quantification methods correlate to each other or clinical data; and finally, (iii) how ELS extent influences MR-signals. Diagnostics included neuro-otological assessment, video-oculography during caloric stimulation, head-impulse test, audiometry, and iMRI. Data analysis provided semi-quantitative (SQ) visual grading and automatic algorithmic quantitative segmentation of ELS area [2D, mm2] and volume [3D, mm3] using deep learning-based segmentation and volumetric local thresholding. Within the range of 0.1–0.2 mmol/kg Gd dosage and a 4 h ± 30 min time delay, SQ grading and 2D- or 3D-quantifications were independent of signal intensity (SI) and signal-to-noise ratio (SNR; FWE corrected, p < 0.05). The ELS quantification methods used were highly reproducible across raters or thresholds and correlated strongly (0.3–0.8). However, 3D-quantifications showed the least variability. Asymmetry indices and normalized ELH proved the most useful for predicting quantitative clinical data. ELH size influenced SI (cochlear basal turn p < 0.001), but not SNR. SI could not predict the presence of ELH. In conclusion, (1) Gd dosage of 0.1–0.2 mmol/kg after 4 h ± 30 min time delay suffices for ELS quantification. (2) A consensus is needed on a clinical SQ grading classification including a standardized level of evaluation reconstructed to anatomical fixpoints. (3) 3D-quantification methods of the ELS are best suited for correlations with clinical variables and should include both ears and ELS values reported relative or normalized to size. (4) The presence of ELH increases signal intensity in the basal cochlear turn weakly, but cannot predict the presence of ELH.

Objective: Intravenous contrast agent enhanced, high-resolution magnetic resonance imaging of the inner ear (iMRI) confirmed that patients with Menière's disease (MD) and vestibular migraine (VM) could present with endolymphatic hydrops (EH). The present study aimed to investigate EH characteristics and their interrelation to neurotologic testing in patients with VM, MD, or VM with concurrent MD (VM-MD).Methods: Sixty–two patients (45 females, aged 23–81 years) with definite or probable VM (n = 25, 19 definite), MD (n = 29, 17 definite), or showing characteristics of both diseases (n = 8) were included in this study. Diagnostic workup included neurotologic assessments including video-oculography (VOG) during caloric stimulation and head-impulse test (HIT), ocular and cervical vestibular evoked myogenic potentials (o/cVEMP), pure tone audiometry (PTA), as well as iMRI. EH's degree was assessed visually and via volumetric quantification using a probabilistic atlas-based segmentation of the bony labyrinth and volumetric local thresholding (VOLT).Results: Although a relevant number of VM patients reported varying auditory symptoms (13 of 25, 52.0%), EH in VM was only observed twice. In contrast, EH in VM-MD was prevalent (2/8, 25%) and in MD frequent [23/29, 79.3%; χ2(2) = 29.1, p < 0.001, φ = 0.7]. Location and laterality of EH and neurophysiological testing classifications were highly associated (Fisher exact test, p < 0.005). In MD, visual semi-quantitative grading and volumetric quantification correlated highly to each other (rS = 0.8, p < 0.005, two-sided) and to side differences in VOG during caloric irrigation (vestibular EH ipsilateral: rS = 0.6, p < 0.05, two-sided). In VM, correlations were less pronounced. VM-MD assumed an intermediate position between VM and MD.Conclusion: Cochlear and vestibular hydrops can occur in MD and VM patients with auditory symptoms; this suggests inner ear damage irrespective of the diagnosis of MD or VM. The EH grades often correlated with auditory symptoms such as hearing impairment and tinnitus. Further research is required to uncover whether migraine is one causative factor of EH or whether EH in VM patients with auditory symptoms suggests an additional pathology due to MD.

Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.

Unilateral damage to the inner ear results in an acute vestibular syndrome, which is compensated within days to weeks due to adaptive cerebral plasticity. This process, called central vestibular compensation (VC), involves a wide range of functional and structural mechanisms at the cellular and network level. The short-term dynamics of whole-brain functional network recruitment and recalibration during VC has not been depicted in vivo. The purpose of this study was to investigate the interplay of separate and distinct brain regions and in vivo networks in the course of VC by sequential [18F]-FDG-PET-based statistical and graph theoretical analysis with the aim of revealing the metabolic connectome before and 1, 3, 7, and 15 days post unilateral labyrinthectomy (UL) in the rat. Temporal changes in metabolic brain connectivity were determined by Pearson's correlation (|r| > 0.5, p < 0.001) of regional cerebral glucose metabolism (rCGM) in 57 segmented brain regions. Metabolic connectivity analysis was compared to univariate voxel-wise statistical analysis of rCGM over time and to behavioral scores of static and dynamic sensorimotor recovery. Univariate statistical analysis revealed an ipsilesional relative rCGM decrease (compared to baseline) and a contralesional rCGM increase in vestibular and limbic networks and an increase in bilateral cerebellar and sensorimotor networks. Quantitative analysis of the metabolic connections showed a maximal increase from baseline to day 3 post UL (interhemispheric: 2-fold, ipsilesional: 3-fold, contralesional: 12-fold) and a gradual decline until day 15 post UL, which paralleled the dynamics of vestibular symptoms. In graph theoretical analysis, an increase in connectivity occurred especially within brain regions associated with brainstem-cerebellar and thalamocortical vestibular networks and cortical sensorimotor networks. At the symptom peak (day 3 post UL), brain networks were found to be organized in large ensembles of distinct and highly connected hubs of brain regions, which separated again with progressing VC. Thus, we found rapid changes in network organization at the subcortical and cortical level and in both hemispheres, which may indicate an initial functional substitution of vestibular loss and subsequent recalibration and reorganization of sensorimotor networks during VC.

Objective: Structural reorganization following cerebellar infarcts is not yet known. This study aimed to demonstrate structural volumetric changes over time in the cortical vestibular and multisensory areas (i.e., brain plasticity) after acute cerebellar infarcts with vestibular and ocular motor symptoms. Additionally, we evaluated whether structural reorganization in the patients topographically correlates with cerebello-cortical connectivity that can be observed in healthy participants. Methods: We obtained high-resolution structural imaging in seven patients with midline cerebellar infarcts at two time points. These data were compared to structural imaging of a group of healthy age-matched controls using voxel-based morphometry (2×2 ANOVA approach). The maximum overlap of the infarcts was used as a seed region for a separate resting-state functional connectivity analysis in healthy volunteers. Results: Volumetric changes were detected in the multisensory cortical vestibular areas around the parieto-opercular and (retro-) insular cortex. Furthermore, structural reorganization was evident in parts of the frontal, temporal, parietal, limbic, and occipital lobes and reflected functional connections between the main infarct regions in the cerebellum and the cerebral cortex in healthy individuals. Conclusions: This study demonstrates structural reorganization in the parieto-opercular insular vestibular cortex after acute vestibulo-cerebellar infarcts. Additionally, the widely distributed structural reorganization after midline cerebellar infarcts provides additional in vivo evidence for the multifaceted contribution of cerebellar processing to cortical functions that extend beyond vestibular or ocular motor function.

Background: Diagnosing stroke as a cause of acute vertigo, dizziness, or double vision remains a challenge, because symptom characteristics can be variable. The purpose of this study was to prospectively investigate lesion-symptom relationships in patients with acute vestibular or ocular motor stroke.Methods: Three hundred and fifty one patients with acute and isolated vestibular or ocular motor symptoms of unclear etiology were enrolled in the EMVERT lesion trial. Symptom quality was assessed by the chief complaint (vertigo, dizziness, double vision), symptom intensity by the visual analog scale, functional impairment by EQ-5D-5L, and symptom duration by daily rating. Acute vestibular and ocular motor signs were registered by videooculography. A standardized MRI (DWI-/FLAIR-/T2-/T2*-/3D-T1-weighted sequences) was recorded within 7 days of symptom onset. MRIs with DWI lesions were further processed for voxel-based lesion-symptom mapping (VLSM).Results: In 47 patients, MRI depicted an acute unilateral stroke (13.4%). The chief complaints were dizziness (42.5%), vertigo (40.4%) and double vision (17.0%). Lesions in patients with vertigo or dizziness showed a large overlap in the cerebellar hemisphere. VLSM indicated that strokes in the medial cerebellar layers 7b, 8, 9 were associated with vertigo, strokes in the lateral cerebellar layer 8, crus 1, 2 with dizziness, and pontomesencephalic strokes with double vision. Symptom intensity and duration varied largely between patients. Higher symptom intensity and longer duration were associated with medial cerebellar lesions. Hemispheric lesions of the cortex were rare and presented with milder symptoms of shorter duration.Conclusions: Prospective evaluation of patients with acute vestibular or ocular motor stroke revealed that symptom quality, intensity and duration were not suited to differentiating peripheral from central etiologies. Lesions in the lateral cerebellum, thalamus, or cortex presented with unspecific, mild and transient symptoms prone to being misdiagnosed.

Background: Mal de debarquement syndrome (MdDS) is characterized by a subjective perception of self-motion after exposure to passive motion, mostly after sea travel. A transient form of MdDS (t-MdDS) is common in healthy individuals without pathophysiological certainty. In the present cross-sectional study, the possible neuropsychiatric and functional neuroimaging changes in local fishermen with t-MdDS were evaluated.Methods: The present study included 28 fishermen from Buan County in South Korea; 15 (15/28, 53.6%) participants experienced t-MdDS for 1–6 h, and 13 were asymptomatic (13/28, 46.4%). Vestibular function tests were performed using video-oculography, the video head impulse test, and ocular and cervical vestibular-evoked myogenic potentials. Visuospatial function was also assessed by the Corsi block test. Brain imaging comprised structural MRI, resting-state functional MRI, and [18F]FDG PET scans.Results: The results of vestibular function tests did not differ between the fishermen with and those without t-MdDS. However, participants with t-MdDS showed better performance in visuospatial memory function than those without t-MdDS (6.40 vs. 5.31, p-value = 0.016) as determined by the Corsi block test. Structural brain MRIs were normal in both groups. [18F]FDG PET showed a relative hypermetabolism in the bilateral occipital and prefrontal cortices and hypometabolism in the vestibulocerebellum (nodulus and uvula) in participants with t-MdDS compared to those without t-MdDS. Resting-state functional connectivities were significantly decreased between the vestibular regions of the flocculus, superior temporal gyrus, and parietal operculum and the visual association areas of the middle occipital gyrus, fusiform gyrus, and cuneus in participants with t-MdDS. Analysis of functional connectivity of the significant regions in the PET scans revealed decreased connectivity between the prefrontal cortex and visual processing areas in the t-MdDS group.Conclusion: Increased visuospatial memory, altered metabolism in the prefrontal cortex, visual cognition cortices, and the vestibulocerebellum, and decreased functional connectivity between these two functional areas might indicate reductions in the integration of vestibular input and enhancement of visuospatial attention in subjects with t-MdDS. Current functional neuroimaging similarities from transient MdDS via chronic MdDS to functional dizziness and anxiety disorders suggest a shared mechanism of enhanced self-awareness as a kind of continuum or as overlap disorders.

Abstract Introduction Functional dizziness comprises a class of dizziness disorders, including phobic postural vertigo (PPV), that cause vestibular symptoms in the absence of a structural organic origin. For this reason, functional brain mechanisms have been implicated in these disorders. Methods Here, functional network organization was investigated in 17 PPV patients and 18 healthy controls (HCs) during functional magnetic resonance imaging with a visual motion stimulus, data initially collected and described by Popp et al. (2018). Graph theoretical measures (degree centrality [DC], clustering coefficient [CC], and eccentricity) of 160 nodes within six functional networks were compared between HC and PPV patients during visual motion and static visual patterns. Results Graph theoretical measures analyzed during the static condition revealed significantly different DC in the default‐mode, sensorimotor, and cerebellar networks. Furthermore, significantly different group differences in network organization changes between static visual and visual motion stimulation were observed. In PPV, DC and CC showed a significantly stronger increase in the sensorimotor network during visual stimulation, whereas cerebellar network showed a significantly stronger decrease in DC. Conclusion These results suggest that the altered visual motion processing seen in PPV patients may arise from a modified state of sensory and cerebellar network connectivity.

The present study in rats was conducted to identify brain regions affected by the interruption of vestibular transmission and to explore selected aspects of their functional connections. We analyzed, by positron emission tomography (PET), the regional cerebral glucose metabolism (rCGM) of cortical, and subcortical cerebral regions processing vestibular signals after an experimental lesion of the left laterodorsal thalamic nucleus, a relay station for vestibular input en route to the cortical circuitry. PET scans upon galvanic vestibular stimulation (GVS) were conducted in each animal prior to lesion and at post-lesion days (PLD) 1, 3, 7, and 20, and voxel-wise statistical analysis of rCGM at each PLD compared to pre-lesion status were performed. After lesion, augmented metabolic activation by GVS was detected in cerebellum, mainly contralateral, and in contralateral subcortical structures such as superior colliculus, while diminished activation was observed in ipsilateral visual, entorhinal, and somatosensory cortices, indicating compensatory processes in the non-affected sensory systems of the unlesioned side. The changes in rCGM observed after lesion resembled alterations observed in patients suffering from unilateral thalamic infarction and may be interpreted as brain plasticity mechanisms associated with vestibular compensation and substitution. The second set of experiments aimed at the connections between cortical and subcortical vestibular regions and their neurotransmitter systems. Neuronal tracers were injected in regions processing vestibular and somatosensory information. Injections into the anterior cingulate cortex (ACC) or the primary somatosensory cortex (S1) retrogradely labeled neuronal somata in ventral posteromedial (VPM), posterolateral (VPL), ventrolateral (VL), posterior (Po), and laterodorsal nucleus, dorsomedial part (LDDM), locus coeruleus, and contralateral S1 area. Injections into the parafascicular nucleus (PaF), VPM/VPL, or LDDM anterogradely labeled terminal fields in S1, ACC, insular cortex, hippocampal CA1 region, and amygdala. Immunohistochemistry showed tracer-labeled terminal fields contacting cortical neurons expressing the μ-opioid receptor. Antibodies to tyrosine hydroxylase, serotonin, substance P, or neuronal nitric oxide-synthase did not label any of the traced structures. These findings provide evidence for opioidergic transmission in thalamo-cortical transduction.

Rationale: Treatment of aphasia is still challenging for clinicians and patients. So far, there is proven evidence for “face-to-face” speech therapy. However, the digital age potentially offers new and complementary strategies that may add to treatment outcome in a cost-effective way. Neolexon® is a commercial tablet-based software for treatment of aphasia, which can be applied with the help of a therapist or as self-training by the patient.Aims and hypothesis: In the Lexi study, we aim to determine whether treatment with Neolexon® is superior to standard therapy in acute post-stroke aphasia.Sample size estimates: A sample size of 180 patients, 90 for each group, will be included with an assumed dropout rate of ~20%.Methods and design: Prospective, randomized, parallel group, open-label, blinded-endpoint clinical, and experimental controlled non-invasive trial (PROBE). Adult German native speakers with acute aphasia after stroke are included. Computer-generated, blocked, and stratified randomization by aphasia severity will assign patients to one of two groups: 4 weeks of either standard logopedic speech therapy or logopedic speech therapy with the app version of Neolexon®. Both groups will be instructed in self-training: the frequency and duration of self-training will be documented. Screening for aphasia will be performed using the Language Screening Test (LAST). The severity of aphasia in general and in subitems will be assessed using the Bielefelder Aphasie Screening (BIAS) and the Aphasia Check List (ACL). Follow-up will be assessed after 3 months.Study outcomes: Based on the consensus in our study team, we considered a 10% mean difference in the change of percentile rank (PR) of BIAS to be a minimal and clinically important difference. The primary endpoint is defined as a significant difference in BIAS comparing the two groups. Differences in quality of life, Beck Depression Inventory (BDI), and modified Ranking Scale (mRS) will be evaluated as secondary outcome parameters.Discussion: This trial will determine whether speech therapy with the use of Neolexon® is superior to standard logopedic therapy. Subgroups with the greatest response to Neolexon® will be described. The trial was prospectively registered on the “EU Clinical Trials Register” (NCT04080817)1.

Previous unimodal PET and fMRI studies in humans revealed a reproducible vestibular brain activation pattern, but with variations in its weighting and expansiveness. Hybrid studies minimizing methodological variations at baseline conditions are rare and still lacking for task-based designs. Thus, we applied for the first time hybrid 3T PET-MRI scanning (Siemens mMR) in healthy volunteers using galvanic vestibular stimulation (GVS) in healthy volunteers in order to directly compare H215O-PET and BOLD MRI responses. List mode PET acquisition started with the injection of 750 MBq H215O simultaneously to MRI EPI sequences. Group-level statistical parametric maps were generated for GVS vs. rest contrasts of PET, MR-onset (event-related), and MR-block. All contrasts showed a similar bilateral vestibular activation pattern with remarkable proximity of activation foci. Both BOLD contrasts gave more bilateral wide-spread activation clusters than PET; no area showed contradictory signal responses. PET still confirmed the right-hemispheric lateralization of the vestibular system, whereas BOLD-onset revealed only a tendency. The reciprocal inhibitory visual-vestibular interaction concept was confirmed by PET signal decreases in primary and secondary visual cortices, and BOLD-block decreases in secondary visual areas. In conclusion, MRI activation maps contained a mixture of CBF measured using H215O-PET and additional non-CBF effects, and the activation-deactivation pattern of the BOLD-block appears to be more similar to the H215O-PET than the BOLD-onset.

Objectives: In this study, based on the known vestibulo-hippocampal connections, we asked whether mild chronic vestibulopathy leads only to vestibular-related deficits or whether there are effects on hippocampal function, structure, and cognition in general. In more detail, we assessed whether chronic vestibulopathy leads to (a) deficits in vestibular tasks without cognitive demand (balancing), (b) deficits in spatial cognitive tasks that require vestibular input (path integration, rotational memory), (c) deficits in spatial cognitive tasks that do not rely on vestibular input, (d) deficits in general cognitive function, and (e) atrophy in the brain. Methods: A total of 15 patients with chronic uni- or bilateral vestibulopathy (56.8 ± 10.1 years; 4 females) were included in this study and were age- and gender-matched by the control participants (57.6 ± 10.5) in a pairwise manner. Given their clinical symptoms and their deficits of the vestibulo-ocular reflex (VOR) the patients could be classified as being mildly affected. All participants of the underwent the following tests: clinical balance (CBT), triangle completion (TCT) for path integration, rotational memory (RM), the visuo-spatial subset of the Berlin intelligence structure test (BIS-4) and d2-R for attention and concentration, and a structural MRI for gray matter analysis using voxel-based morphometry (VBM). Results: Compared to the healthy controls, the vestibulopathy patients performed significantly worse in terms of CBT, TCT, and RM but showed no differences in terms of the BIS-4 and d2-R. There were also no significant volumetric gray matter differences between the two groups. Conclusions: This study provides evidence that both non-cognitive and cognitive functions that rely on vestibular input (balancing, path integration, rotational memory) are impaired, even in mild chronic vestibulopathy, while other cognitive functions, which rely on visual input (visuo-spatial memory, attention), are unimpaired in this condition, together with an overall intact brain structure. These findings may reflect a segregation between vestibular- and visual-dependent processes in the medial temporal lobe on the one hand and a structure–function dissociation on the other.

Neurodegenerative parkinsonian syndromes comprise a number of disorders that are characterized by similar clinical features but are separated on the basis of different pathologies, i.e., aggregates of α-synuclein or tau protein. Due to the overlap of signs and symptoms a precise differentiation is often difficult, especially early in the disease course. Enormous efforts have been taken to develop tau-selective PET imaging agents, but strong off-target binding to monoamine oxidase B (MAO-B) has been observed across first generation ligands. Nonetheless, astrogliosis-related MAO-B elevation is a common histopathological known feature of all parkinsonian syndromes and might be itself an interesting imaging target. Therefore, this study aimed to investigate the performance of [18F]-THK5351, a combined MAO-B and tau tracer for differential diagnosis of parkinsonian syndromes. [18F]-THK5351 PET was performed in 34 patients: six with Parkinson’s disease (PD), nine with multiple system atrophy with predominant parkinsonism (MSA-P), six with MSA with predominant cerebellar ataxia (MSA-C), and 13 with progressive supranuclear palsy (PSP) Richardson’s syndrome. Volume-of-interest-based quantification of standardized-uptake-values was conducted in different parkinsonian syndrome-related target regions. PET results were subjected to multinomial logistic regression to create a prediction model discriminating among groups. Furthermore, we correlated tracer uptake with clinical findings. Elevated [18F]-THK5351 uptake in midbrain and diencephalon differentiated PSP patients from PD and MSA-C. MSA-C patients were distinguishable by high tracer uptake in the pons and cerebellar deep white matter when compared to PSP and PD patients, whereas MSA-P patients tended to show higher tracer uptake in the lentiform nucleus. A multinomial logistic regression classified 33/34 patients into the correct clinical diagnosis group. Tracer uptake in the pons, cerebellar deep white matter, and striatum was closely associated with the presence of cerebellar and parkinsonian symptoms of MSA patients. The current study demonstrates that combined MAO-B and tau binding of THK5351 facilitates differential diagnosis of parkinsonian syndromes. Furthermore, our data indicate a correlation of MSA phenotype with [18F]-THK5351 uptake in certain brain regions, illustrating their relevance for the emergence of clinical symptoms and underlining the potential of THK5351 PET as a biomarker that correlates with pathological changes as well as with disease stage.

Objectives: To reveal the neural basis of Wernicke's encephalopathy (WE) with impaired vestibulo-ocular reflex (VOR), we evaluated resting-state functional connectivity (rs-fc) in the vestibular processing brain regions.Methods: Rs-fc between the vestibular regions and the rest of the brain were compared with neurotological features including the head-impulse tests (vHIT) and caloric responses in patients with WE (n = 5, mean age 53.4 ± 10 years) and healthy controls (n = 20, mean age 55.0 ± 9.2 years). Rs-fc analyses employed a region of interest (ROI)-based approach using regions selected a priori that participate in vestibular processing including the cerebellar vermis, insula, parietal operculum, and calcarine cortex.Results: The main neurologic findings for patients with WE were mental changes; gait ataxia; spontaneous and gaze-evoked nystagmus (GEN); and bilaterally positive HIT for the horizontal canals. Video HIT documented bilateral horizontal canal dysfunction with decreased gain and corrective saccades. Caloric irrigation and rotation chair testing revealed prominent bilateral horizontal canal paresis. Patients with WE also had decreased spatial memory, which substantially recovered after treatments. Functional connections at the predefined seed regions, including the insular cortex and parietal operculum, were attenuated in the WE group compared to healthy controls.Conclusions: WE is related to impaired VOR and visuospatial dysfunction, and fMRI documented changes in the rs-fc of multisensory vestibular processing regions including the insula, parietal operculum, and superior temporal gyrus, which participate in integration of vestibular perception.

Objective: To review current knowledge of the perception of verticality, its normal function and disorders. This is based on an integrative graviceptive input from the vertical semicircular canals and the otolith organs.Methods: The special focus is on human psychophysics, neurophysiological and imaging data on the adjustments of subjective visual vertical (SVV) and the subjective postural vertical. Furthermore, examples of mathematical modeling of specific vestibular cell functions for orientation in space in rodents and in patients are briefly presented.Results: Pathological tilts of the SVV in the roll plane are most sensitive and frequent clinical vestibular signs of unilateral lesions extending from the labyrinths via the brainstem and thalamus to the parieto-insular vestibular cortex. Due to crossings of ascending graviceptive fibers, peripheral vestibular and pontomedullary lesions cause ipsilateral tilts of the SVV; ponto-mesencephalic lesions cause contralateral tilts. In contrast, SVV tilts, which are measured in unilateral vestibular lesions at thalamic and cortical levels, have two different characteristic features: (i) they may be ipsi- or contralateral, and (ii) they are smaller than those found in lower brainstem or peripheral lesions. Motor signs such as head tilt and body lateropulsion, components of ocular tilt reaction, are typical for vestibular lesions of the peripheral vestibular organ and the pontomedullary brainstem (vestibular nucleus). They are less frequent in midbrain lesions (interstitial nucleus of Cajal) and rare in cortical lesions. Isolated body lateropulsion is chiefly found in caudal lateral medullary brainstem lesions. Vestibular function in the roll plane and its disorders can be mathematically modeled by an attractor model of angular head velocity cell and head direction cell function. Disorders manifesting with misperception of the body vertical are the pusher syndrome, the progressive supranuclear palsy, or the normal pressure hydrocephalus; they may affect roll and/or pitch plane.Conclusion: Clinical determinations of the SVV are easy and reliable. They indicate acute unilateral vestibular dysfunctions, the causative lesion of which extends from labyrinth to cortex. They allow precise topographical diagnosis of side and level in unilateral brainstem or peripheral vestibular disorders. SVV tilts may coincide with or differ from the perception of body vertical, e.g., in isolated body lateropulsion.

Unilateral inner ear damage is followed by behavioral recovery due to central vestibular compensation. The dose-dependent therapeutic effect of Ginkgo biloba extract EGb 761 on vestibular compensation was investigated by behavioral testing and serial cerebral [18F]-Fluoro-desoxyglucose ([18F]-FDG)-μPET in a rat model of unilateral labyrinthectomy (UL). Five groups of 8 animals each were treated with EGb 761-supplemented food at doses of 75, 37.5 or 18.75 mg/kg body weight 6 weeks prior and 15 days post UL (groups A,B,C), control food prior and EGb 761-supplemented food (75 mg/kg) for 15 days post UL (group D), or control food throughout (group E). Plasma levels of EGb 761 components bilobalide, ginkgolide A and B were analyzed prior and 15 days post UL. Behavioral testing included clinical scoring of nystagmus, postural asymmetry, head roll tilt, body rotation during sensory perturbation and instrumental registration of mobility in an open field before and 1, 2, 3, 5, 7, 15 days after UL. Whole-brain [18F]-FDG-μPET was recorded before and 1, 3, 7, 15 days after UL. The EGb 761 group A (75 mg/kg prior/post UL) showed a significant reduction of nystagmus scores (day 3 post UL), of postural asymmetry (1, 3, 7 days post UL), and an increased mobility in the open field (day 7 post UL) as compared to controls (group E). Application of EGb 761 at doses of 37.5 and 18.75 mg/kg prior/post UL (groups B,C) resulted in faster recovery of postural asymmetry, but did not influence mobility relative to controls. Locomotor velocity increased with higher plasma levels of ginkgolide A and B. [18F]-FDG-μPET revealed a significant decrease of the regional cerebral glucose metabolism (rCGM) in the vestibular nuclei and cerebellum and an increase in the hippocampal formation with higher plasma levels of ginkgolides and bilobalide 1 and 3 days post UL. Decrease of rCGM in the vestibular nucleus area and increase in the hippocampal formation with higher plasma levels persisted until day 15 post UL. In conclusion, Ginkgo biloba extract EGb 761 improves vestibulo-ocular motor, vestibulo-spinal compensation, and mobility after UL. This rat study supports the translational approach to investigate EGb 761 at higher dosages for acceleration of vestibular compensation in acute vestibular loss.

BACKGROUND:The value of conventional magnetic resonance imaging (MRI) for amyotrophic lateral sclerosis (ALS) is low. Functional and quantitative MRI could be more accurate. We aimed to examine the value of diffusion tensor imaging (DTI) with fractional anisotropy (FA) measurements of the cervical and upper thoracic spinal cord in patients with ALS. PATIENTS AND METHODS:Fourteen patients with ALS and 15 sex- and age-matched controls were examined with DTI at a 3T MRI scanner. Region-of-interest (ROI) based fractional anisotropy measurements were performed at the levels C2-C4, C5-C7 and Th1-Th3. ROIs were placed at different anatomical locations of the axial cross sections of the spinal cord. RESULTS:FA was significantly reduced in ALS patients in anterolateral ROIs and the whole cross section at the C2-C4 level and the cross section of the Th1-Th3 level. There was a trend towards a statistically significant FA reduction in the anterolateral ROIs at the C5-C7 level in ALS patients. No significant differences between patients and controls were found in posterior ROIs. CONCLUSION:FA was reduced in ROIs representing the motor tracts in ALS patients. DTI with FA measurements is a promising method in this circumstance. However, for DTI to become a valuable and established method in the diagnostic workup of ALS, larger studies and further standardisation are warranted.

Background: Mental health comorbidities are frequent in patients with vertigo and dizziness. The current study was conducted in a specialized interdisciplinary university center for vertigo and dizziness. Clinical routines consist of a structured work-up in which neuro-otological and neurological tests are performed to first detect possible organic vestibular deficits. In addition, psychiatric disorders and comorbidities are considered. The study aimed to evaluate neurologists' awareness of psychiatric next to somatic disorders within patients' first examination in terms of diagnostic congruence between neurologists' diagnoses and structured clinical assessment of mental disorders.Methods: The study involved 392 patients. Diagnostic evaluation included (a) structured history-taking (including psychosocial anamnesis), neurological, and neuro-otological diagnostics conducted by neurologists and (b) a structured clinical interview for mental disorders (SCID-I) conducted by psychologists and final-year medical or psychology students. Cohen's Kappa was calculated to determine agreement rates regarding depression and anxiety disorders; additionally, sensitivity and specificity were evaluated.Results: Neurologists' assessments led to at least one psychiatric diagnosis among the main diagnoses in 40 (10.2 %) patients, whereas the structured clinical interview led to at least one DSM-IV psychiatric diagnosis in 174 (44.4%) of the patients. Agreement was low (κ < 0.2); sensitivity was low (15%) but specificity was high (98%).Conclusions: Agreement between the diagnosis of neurologists and structured clinical interviews for psychiatric disorders is low. Since psychiatric disorders are frequent in vertigo and dizziness and tend to take a chronic course, improving early recognition and implementing appropriate care concepts is vital.

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear-induced striatal asymmetries identified here intersect with non-ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left-right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.

ObjectiveVestibular signals are involved in higher cortical functions like spatial orientation and its disorders. Vestibular dysfunction contributes, for example, to spatial neglect which can be transiently improved by caloric stimulation. The exact roles and mechanisms of the vestibular and visual systems for the recovery of neglect are not yet known.MethodsResting-state functional connectivity (fc) magnetic resonance imaging was recorded in a patient with hemispatial neglect during the acute phase and after recovery 6 months later following a right middle cerebral artery infarction before and after caloric vestibular stimulation. Seeds in the vestibular [parietal operculum (OP2)], the parietal [posterior parietal cortex (PPC); 7A, hIP3], and the visual cortex (VC) were used for the analysis.ResultsDuring the acute stage after caloric stimulation the fc of the right OP2 to the left OP2, the anterior cingulum, and the para/hippocampus was increased bilaterally (i.e., the vestibular network), while the interhemispheric fc was reduced between homologous regions in the VC. After 6 months, similar fc increases in the vestibular network were found without stimulation. In addition, fc increases of the OP2 to the PPC and the VC were seen; interhemispherically this was true for both PPCs and for the right PPC to both VCs.ConclusionImprovement of neglect after caloric stimulation in the acute phase was associated with increased fc of vestibular cortex areas in both hemispheres to the para-hippocampus and the dorsal anterior cingulum, but simultaneously with reduced interhemispheric VC connectivity. This disclosed a, to some extent, similar but also distinct short-term mechanism (vestibular stimulation) of an improvement of spatial orientation compared to the long-term recovery of neglect.

Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers.Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls.Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status.Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82.Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD.

The functional relevance of reactive gliosis for recovery from acute unilateral vestibulopathy is unknown. In the present study, glial activation was visualized in vivo by [18F]GE180-PET in a rat model of unilateral labyrinthectomy (UL) and compared to behavioral vestibular compensation (VC) overtime. 14 Sprague-Dawley rats underwent a UL by transtympanic injection of bupivacaine/arsenilate, 14 rats a SHAM UL (injection of normal saline). Glial activation was depicted with [18F]GE180-PET and ex vivo autoradiography at baseline and 7, 15, 30 days after UL/SHAM UL. Postural asymmetry and nystagmus were registered at 1, 2, 3, 7, 15, 30 days after UL/SHAM UL. Signs of vestibular imbalance were found only after UL, which significantly decreased until days 15 and 30. In parallel, [18F]GE180-PET and ex vivo autoradiography depicted glial activation in the ipsilesional vestibular nerve and nucleus on days 7 and 15 after UL. Correlation analysis revealed a strong negative association of [18F]GE180 uptake in the ipsilesional vestibular nucleus on day 7 with the rate of postural recovery (R = −0.90, p

The aim of the study was to uncover mechanisms of central compensation of vestibular function at brainstem, cerebellar, and cortical levels in patients with acute unilateral midbrain infarctions presenting with an acute vestibular tone imbalance. Eight out of 17 patients with unilateral midbrain infarctions were selected on the basis of signs of a vestibular tone imbalance, e.g., graviceptive (tilts of perceived verticality) and oculomotor dysfunction (skew deviation, ocular torsion) in F18-fluordeoxyglucose (FDG)-PET at two time points: A) in the acute stage, and B) after recovery 6 months later. Lesion-behavior mapping analyses with MRI verified the exact structural lesion sites. Group subtraction analyses and comparisons with healthy controls were performed with Statistic Parametric Mapping for the PET data. A comparison of PET A of acute-stage patients with that of healthy controls showed increases in glucose metabolism in the cerebellum, motion-sensitive visual cortex areas, and inferior temporal lobe, but none in vestibular cortex areas. At the supratentorial level bilateral signal decreases dominated in the thalamus, frontal eye fields, and anterior cingulum. These decreases persisted after clinical recovery in contrast to the increases. The transient activations can be attributed to ocular motor and postural recovery (cerebellum) and sensory substitution of vestibular function for motion perception (visual cortex). The persisting deactivation in the thalamic nuclei and frontal eye fields allows alternative functional interpretations of the thalamic nuclei: either a disconnection of ascending sensory input occurs or there is a functional mismatch between expected and actual vestibular activity. Our data support the view that both thalami operate separately for each hemisphere but receive vestibular input from ipsilateral and contralateral midbrain integration centers. Normally they have gatekeeper functions for multisensory input to the cortex and automatic motor output to subserve balance and locomotion, as well as sensorimotor integration.

Patients with somatoform vertigo and dizziness (SVD) disorders often report instability of stance or gait and fear of falling. Posturographic measurements indeed indicated a pathological postural strategy. Our goal was to evaluate the effectiveness of a psychotherapeutic and psychoeducational short-term intervention (PTI) using static posturography and psychometric examination. Seventeen SVD patients took part in the study. The effects of PTI on SVD were evaluated with quantitative static posturography. As primary endpoint a quotient characterizing the relation between horizontal and vertical sway was calculated (QH/V), reflecting the individual postural strategy. Results of static posturography were compared to those of age- and gender-matched healthy volunteers (n=28); baseline measurements were compared to results after PTI. The secondary endpoint was the participation-limiting consequences of SVD as measured by the Vertigo Handicap Questionnaire (VHQ). Compared to the healthy volunteers, the patients with SVD showed a postural strategy characterized by stiffening-up that resulted in a significantly reduced body sway quotient before PTI (patients: QH/V=0.31 versus controls: QH/V=0.38; p=0.022). After PTI the postural behavior normalized, and psychological distress was reduced. PTI therefore appears to modify pathological balance behaviour. The postural strategy of patients with SVD possibly results from anxious anticipatory cocontraction of the antigravity muscles.

Visuo-spatial neglect and vestibular disorders have common clinical findings and involve the same cortical areas. We questioned (1) whether visuo-spatial hemineglect is not only a disorder of spatial attention but may also reflect a disorder of higher cortical vestibular function and (2) whether a vestibular tone imbalance due to an acute peripheral dysfunction can also cause symptoms of neglect or extinction. Therefore, patients with an acute unilateral peripheral vestibular failure (VF) were tested for symptoms of hemineglect.Twenty-eight patients with acute VF were assessed for signs of vestibular deficits and spatial neglect using clinical measures and various common standardized paper-pencil tests. Neglect severity was evaluated further with the Center of Cancellation method. Pathological neglect test scores were correlated with the degree of vestibular dysfunction determined by the subjective visual vertical and caloric testing.Three patients showed isolated pathological scores in one or the other neglect test, either ipsilesionally or contralesionally to the VF. None of the patients fulfilled the diagnostic criteria of spatial hemineglect or extinction.A vestibular tone imbalance due to unilateral failure of the vestibular endorgan does not cause spatial hemineglect, but evidence indicates it causes mild attentional deficits in both visual hemifields.

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

Animal experiments report contradictory findings on the presence of a behavioural and neuronal anisotropy exhibited in vertical and horizontal capabilities of spatial orientation and navigation. We performed a pointing experiment in humans on the imagined 3-D direction of the location of various invisible goals that were distributed horizontally and vertically in a familiar multilevel hospital building. The 21 participants were employees who had worked for years in this building. The hypothesis was that comparison of the experimentally determined directions and the true directions would reveal systematic inaccuracy or dimensional anisotropy of the localizations. The study provides first evidence that the internal representation of a familiar multilevel building was distorted compared to the dimensions of the true building: vertically 215% taller and horizontally 51% shorter. This was not only demonstrated in the mathematical reconstruction of the mental model based on the analysis of the pointing experiments but also by the participants' drawings of the front view and the ground plan of the building. Thus, in the mental model both planes were altered in different directions: compressed for the horizontal floor plane and stretched for the vertical column plane. This could be related to human anisotropic behavioural performance of horizontal and vertical navigation in such buildings.