Central vestibular networking for sensorimotor control, cognition, and emotion.

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.

Network Architecture of Verticality Processing in the Human Thalamus.

OBJECTIVE: Thalamic dysfunction in lesions or neurodegeneration may alter verticality perception and lead to postural imbalance and falls. The aim of the current study was to delineate the structural and functional connectivity network architecture of the vestibular representations in the thalamus by multimodal magnetic resonance imaging. METHODS: Seventy-four patients with acute unilateral isolated thalamic infarcts were studied prospectively with emphasis on the perception of verticality (tilts of the subjective visual vertical [SVV]). We used multivariate lesion-symptom mapping based on support-vector regression to determine the thalamic nuclei associated with ipsiversive and contraversive tilts of the SVV. The lesion maps were used to evaluate the white matter disconnection and whole brain functional connectivity in healthy subjects. RESULTS: Contraversive SVV tilts were associated with lesions of the ventral posterior lateral/medial, ventral lateral, medial pulvinar, and medial central/parafascicular nuclei. Clusters associated with ipsiversive tilts were located inferiorly (ventral posterior inferior nucleus) and laterally (ventral lateral, ventral posterior lateral, and reticular nucleus) to these areas. Distinct ascending vestibular brainstem pathways terminated in the subnuclei for ipsi- or contraversive verticality processing. The functional connectivity analysis showed specific patterns of cortical connections with the somatomotor network for lesions with contraversive tilts, and with the core multisensory vestibular representations (areas Ri, OP2-3, Ig, 3av, 2v) for lesions with ipsiversive tilts. INTERPRETATION: The functional specialization may allow both a stable representation of verticality for sensorimotor integration and flexible adaption to sudden changes in the environment. A targeted modulation of this circuitry could be a novel therapeutic strategy for higher level balance disorders of thalamocortical origin. ANN NEUROL 2023;94:133-145.

Atrial Fibrillation Risk Assessment after Embolic Stroke of Undetermined Source.

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, CHA2 DS2 -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.

Multimodal Mobility Assessment Predicts Fall Frequency and Severity in Cerebellar Ataxia.

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.

Endovascular thrombectomy for basilar artery occlusion stroke: Analysis of the German Stroke Registry-Endovascular Treatment.

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.

PREDICT-juvenile-stroke: PRospective evaluation of a prediction score determining individual clinical outcome three months after ischemic stroke in young adults - a study protocol.

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 ).

In vivo neuroplasticity in vestibular animal models.

An acute unilateral vestibulopathy leads to symptoms of vestibular tone imbalance, which gradually decrease over days to weeks due to central vestibular compensation. Animal models of acute peripheral vestibular lesions are optimally suited to investigate the mechanisms underlying this lesion-induced adaptive neuroplasticity. Previous studies applied ex vivo histochemical techniques or local in vivo electrophysiological recordings mostly in the vestibular nucleus complex to delineate the mechanisms involved. Recently, the use of imaging methods, such as positron emission tomography (PET) or magnetic resonance imaging (MRI), in vestibular animal models have opened a complementary perspective by depicting whole-brain structure and network changes of neuronal activity over time and in correlation to behaviour. Here, we review recent multimodal imaging studies in vestibular animal models with a focus on PET-based measurements of glucose metabolism, glial activation and synaptic plasticity. [18F]-FDG-PET studies indicate dynamic alterations of regional glucose metabolism in brainstem-cerebellar, thalamic, cortical sensory and motor, as well as limbic areas starting early after unilateral labyrinthectomy (UL) in the rat. Sequential whole-brain analysis of the metabolic connectome during vestibular compensation shows a significant increase of connections mostly in the contralesional hemisphere after UL, which reaches a maximum at day 3 and thereby parallels the course of vestibular recovery. Glial activation in the ipsilesional vestibular nerve and nucleus peak between days 7 and 15 after UL. Synaptic density in brainstem-cerebellar circuits decreases until 8 weeks after UL, while it increases in frontal, motor and sensory cortical areas. We finally report how pharmacological compounds modulate the functional and structural plasticity mechanisms during vestibular compensation.

Pattern and implications of neurological examination findings in autosomal dominant Alzheimer disease.

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.

Chronic vestibular syndromes in the elderly: Presbyvestibulopathy-an isolated clinical entity?

BACKGROUND AND PURPOSE: Recently, the Classification Committee of the Bárány Society defined the new syndrome of "presbyvestibulopathy" for elderly patients with chronic vestibular symptoms due to a mild bilateral peripheral vestibular hypofunction. However, control of stance and gait requires multiple functioning systems, for example, the somatosensory, visual, auditory, musculoskeletal, and cardio- and cerebrovascular systems. The aim of this cross-sectional database-driven study was to evaluate the frequency and characteristics of presbyvestibulopathy and additional gait-relevant comorbidities. METHODS: In total, 707 patients aged ≥60 years with chronic vertigo/dizziness were admitted to our tertiary hospital and received detailed neurological, neuro-orthoptic, and laboratory audiovestibular examination. Medical history, comorbidities, functional impairment, and quality of life (Dizziness Handicap Inventory [DHI], European Quality of Life Scale, Vestibular Activities and Participation) were compared between presbyvestibulopathy and bilateral vestibulopathy in a matched-paired study. RESULTS: In 95.5% of patients, complaints were better accounted for by another vestibular, neurological, cardiac, or psychiatric disease, and 32 patients (4.5%) met the diagnostic criteria for presbyvestibulopathy. Of these 32 patients, the majority showed further relevant comorbidities in other sensorimotor systems. Only one patient of 707 had "isolated" presbyvestibulopathy (0.14%). The mean total DHI scores indicated lower moderate impairment in presbyvestibulopathy than in bilateral vestibulopathy (40.6 vs. 49.0), which was confirmed by significant differences in the matched-paired analysis (p < 0.001). CONCLUSIONS: Isolated presbyvestibulopathy is a very rare entity. It is regularly accompanied by other multisensory dysfunctions. These results indicate a potential role of mild vestibular hypofunction as a cofactor in multifactorial impairment. Thus, patients should be treated in an interdisciplinary setting with an awareness of diverse comorbidities.

Vestibular compensation of otolith graviceptive dysfunction in stroke patients.

BACKGROUND AND PURPOSE: A sensitive and frequent clinical sign of a vestibular tone imbalance is the tilt of the perceived subjective visual vertical (SVV). There are no data yet focusing on lesion location at the cortical level as a factor for predicting compensation from the tilt of the SVV. METHODS: With modern voxelwise lesion behavior mapping analysis, the present study determines whether lesion location in 23 right-hemispheric cortical stroke patients with an otolith dysfunction could predict the compensation of a vestibular tone imbalance in the chronic stage. RESULTS: Our statistical anatomical lesion analysis revealed that lesions of the posterior insular cortex are involved in vestibular otolith compensation. CONCLUSION: The insular cortex appears to be a critical anatomical region for predicting a tilt of the SVV as a chronic disorder in stroke patients.

Minor stroke in large vessel occlusion: A matched analysis of patients from the German Stroke Registry-Endovascular Treatment (GSR-ET) and patients from the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR).

BACKGROUND AND PURPOSE: Reperfusion treatment in patients presenting with large vessel occlusion (LVO) and minor neurological deficits is still a matter of debate. We aimed to compare minor stroke patients treated with endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) or IVT alone. METHODS: Patients enrolled in the German Stroke Registry-Endovascular Treatment (GSR-ET) and the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) between June 2015 and December 2019 were analyzed. Minor stroke was defined as National Institutes of Health Stroke Scale (NIHSS) score ≤5, and LVO as occlusion of the internal carotid, carotid-T, middle cerebral, basilar, vertebral or posterior cerebral arteries. GSR-ET and SITS-ISTR IVT-treated patients were matched in a 1:1 ratio using propensity-score (PS) matching. The primary outcome was good functional outcome at 3 months (modified Rankin Scale score 0-2). RESULTS: A total of 272 GSR-ET patients treated with EVT and IVT (age 68.6 ± 14.0 years, 43.4% female, NIHSS score 4 [interquartile range 2-5]) were compared to 272 IVT-treated SITS-ISTR patients (age 69.4 ± 13.7, 43.4% female, NIHSS score 4 [2-5]). Good functional outcome was seen in 77.0% versus 82.9% (p = 0.119), mortality in 5.9% versus 7.9% (p = 0.413), and intracranial hemorrhage in 8.8% versus 12.5% (p = 0.308) of patients in the GSR-ET versus the SITS-ISTR IVT group, respectively. In a second PS-matched analysis, 624 GSR-ET patients (IVT rate 56.7%) and 624 SITS-ISTR patients (IVT rate 100%), good outcome was more often observed in the SITS-ISTR patients (68.2% vs. 80.9%; p < 0.001), and IVT independently predicted good outcome (odds ratio 2.16, 95% confidence interval 1.43-3.28). CONCLUSIONS: Our study suggests similar effectiveness of IVT alone compared to EVT with or without IVT in minor stroke patients. There is an urgent need for randomized controlled trials on this topic.

Seizure prevalence in neurodegenerative diseases-a study of autopsy proven cases.

BACKGROUND AND PURPOSE: Knowledge about the seizure prevalence in the whole symptomatic course, from disease onset to death, in neurodegenerative diseases (ND) is lacking. Therefore, the aim was to investigate seizure prevalence and associated clinical implications in neuropathologically diagnosed ND. METHODS: Clinical records of cases from the Neurobiobank Munich, Germany, were analyzed. Neuropathological diagnoses of the assessed cases included Alzheimer disease (AD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Seizure prevalence during the whole symptomatic disease phase was assessed and compared amongst ND. Associations between first clinical symptom and seizure prevalence and between seizures and disease duration were examined. RESULTS: In all, 454 patients with neuropathologically diagnosed ND and with available and meaningful clinical records were investigated (AD, n = 144; LBD, n = 103; PSP, n = 93; FTLD, n = 53; MSA, n = 36; CBD, n = 25). Seizure prevalence was 31.3% for AD, 20.0% for CBD, 12.6% for LBD, 11.3% for FTLD, 8.3% for MSA and 7.5% for PSP. Seizure prevalence was significantly higher in AD compared to FTLD (p = 0.005), LBD (p = 0.001), MSA (p = 0.005) and PSP (p < 0.001). No other significant differences regarding seizure prevalence were found between the studied ND. Cognitive first symptoms in ND were associated with an increased seizure prevalence (21.1% vs. 11.0% in patients without cognitive first symptoms) and motor first symptoms with a decreased seizure prevalence (10.3% vs. 20.5% in patients without motor first symptoms). Seizures were associated with a longer disease duration in MSA (12.3 vs. 7.0 years in patients without seizures; p = 0.017). CONCLUSIONS: Seizures are a clinically relevant comorbidity in ND, particularly in AD. Knowledge of the first clinical symptom in ND may allow for estimation of seizure risk.

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

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

Tandem Lesions in Anterior Circulation Stroke: Analysis of the German Stroke Registry-Endovascular Treatment.

[Figure: see text].

Dynamic whole-brain metabolic connectivity during vestibular compensation in the rat.

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.

Metabolic connectivity-based single subject classification by multi-regional linear approximation in the rat.

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).

Early uneven ear input induces long-lasting differences in left-right motor function.

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.

The importance of the insular cortex for vestibular and spatial syndromes.

BACKGROUND AND PURPOSE: The aim of the study was to identify the neuroanatomical correlates and associations of neuropsychological syndromes after acute unilateral right-hemisphere brain lesions. The neuropsychological syndromes considered were orientation in three-dimensional space such as tilts of the subjective visual vertical or of the subjective haptic vertical, pusher syndrome, visual neglect and unawareness of paresis (anosognosia for hemiparesis). These neuropsychological phenomena have been found to occur separately or in different combinations after lesions to the right insular cortex. METHOD: Magnetic resonance imaging scans were obtained from 82 patients with acute right-hemispheric stroke. A lesion-behavior mapping analysis was conducted to specify the neuroanatomical correlates of the above-mentioned neuropsychological syndromes. RESULTS: In all analyses of the individual neuropsychological syndromes the insular cortex was affected. CONCLUSIONS: Thus, the insular cortex is involved in (self-)perception and orientation within a three-dimensional space. Since isolated lesions of the insular cortex did not induce the above neuropsychological phenomena, there have to be other regions involved.

Safety and efficacy of mechanical thrombectomy in infective endocarditis: A matched case-control analysis from the German Stroke Registry-Endovascular Treatment.

BACKGROUND AND PURPOSE: Up to 30% of infective endocarditis (IE) patients have ischemic stroke as a complication. Standard treatment with mechanical thrombectomy (MT) with or without intravenous thrombolysis for large vessel occlusion (LVO) has not been evaluated formally in these patients. METHODS: Patients enrolled in the German Stroke Registry-Endovascular Treatment (GSR-ET) between June 2015 and December 2019 were analyzed. Patients with stroke due to IE and patients with cardioembolic stroke and atrial fibrillation (AF) were compared using propensity score matching. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction score = 2b-3. Modified Rankin Scale (mRS) = 0-2 at 3 months indicated good outcome. RESULTS: Of 6635 patients, 55 patients (age = 69.0 ± 13.3 years, 43.6% female, median premorbid mRS (pmRS) = 1, interquartile range [IQR] = 0-1, National Institutes of Health Stroke Scale [NIHSS] = 15, IQR = 10-21) presented with septic embolic stroke due to IE and were compared to 104 patients (age = 66.5 ± 13.4 years, 39.4% female, pmRS = 0, IQR = 0-2, NIHSS = 16, IQR = 10-20) with cardioembolic stroke due to AF. Successful recanalization was achieved in 74.5% of endocarditis patients compared to 87.5% of controls (p = 0.039). Intracranial hemorrhage rates were comparable (30.9% vs. 21.6%, p = 0.175). Good functional outcome was 20.0% in patients with IE compared to 43.3% in matched patients (p = 0.006), with a significantly higher mortality (60.0% vs. 28.8%, p < 0.001). IE was strongly associated with poor outcome (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.11-0.87, p = 0.03 for good outcome) and mortality (OR = 4.49, 95% CI = 1.80-10.68, p = 0.001). CONCLUSIONS: Although MT results in high successful recanalization rates with acceptable safety profile, patients with LVO stroke due to IE have poor outcome.

First symptom guides diagnosis and prognosis in neurodegenerative diseases-a retrospective study of autopsy proven cases.

BACKGROUND AND PURPOSE: Clinical diagnostic criteria for neurodegenerative diseases have been framed based on clinical phenomenology. However, systematic knowledge about the first reported clinical symptoms in neurodegenerative diseases is lacking. Therefore, the aim was to determine the prevalence and clinical implications of the first clinical symptom (FS) as assessed by medical history in neuropathologically proven neurodegenerative diseases. METHODS: Neuropathological diagnoses from the Neurobiobank Munich, Germany, were matched with clinical records for analyses of the diagnostic and prognostic values of FSs. RESULTS: In all, 301 patients with the neuropathological diagnoses Alzheimer disease (AD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD) including the neuropathologically indistinguishable clinical phenotypes Parkinson disease and dementia with Lewy bodies, multiple system atrophy (MSA) and corticobasal degeneration (CBD) were studied. Memory disturbance was the most common FS in AD (34%), FTLD (19%) and LBD (26%), gait disturbance in PSP (35%) and MSA (27%) and aphasia and personality changes in CBD (20%, respectively). In a model adjusting for prevalence in the general population, AD was predicted by memory disturbance in 79.0%, aphasia in 97.2%, personality changes in 96.0% and by cognitive disturbance in 99.0%. Gait disturbance and tremor predicted LBD in 54.6% and 97.3%, coordination disturbance MSA in 59.4% and dysarthria FTLD in 73.0%. Cognitive FSs were associated with longer survival in AD (12.0 vs. 5.3 years; p < 0.001) and FTLD (8.2 vs. 4.1 years; p = 0.005) and motor FSs with shorter survival in PSP (7.2 vs. 9.7; p = 0.048). CONCLUSIONS: Assessing FSs in neurodegenerative diseases may be beneficial for accuracy of diagnosis and prognosis and thereby may improve clinical care and precision of study recruitment.