Downbeat Nystagmus Is Abolished by Alcohol in Nonalcoholic Wernicke Encephalopathy.

Background and Objectives: Lesions of the cerebellar flocculus cause enduring downbeat nystagmus (DBN) with unrelenting oscillopsia. Unlike most patients with DBN, the flocculus is structurally spared in nonalcoholic Wernicke encephalopathy (nWE) with chronic DBN. The objective was to study the effects of alcohol in nWE. Methods: We recorded eye movements of a unique patient with nWE under controlled alcohol consumption who said his oscillopsia disappeared with a few drinks of alcohol. Results: His DBN was markedly diminished by alcohol (by 77.4%), although he remained alert with normal saccades. Discussion: This striking observation may be caused by the differential effect of alcohol on the perihypoglossal complex and the paramedian tract neurons, which control the level of activity in the flocculus, with opposite (inhibition and excitation, respectively) effects. The finding suggests new ideas about the treatment and pathophysiology of DBN with a structurally intact cerebellum.

Unbalancing the Attentional Priority Map via Gaze-Contingent Displays Induces Neglect-Like Visual Exploration.

Selective spatial attention is a crucial cognitive process that guides us to the behaviorally relevant objects in a complex visual world by using exploratory eye movements. The spatial location of objects, their (bottom-up) saliency and (top-down) relevance is assumed to be encoded in one "attentional priority map" in the brain, using different egocentric (eye-, head- and trunk-centered) spatial reference frames. In patients with hemispatial neglect, this map is supposed to be imbalanced, leading to a spatially biased exploration of the visual environment. As a proof of concept, we altered the visual saliency (and thereby attentional priority) of objects in a naturalistic scene along a left-right spatial gradient and investigated whether this can induce a bias in the exploratory eye movements of healthy humans (n = 28; all right-handed; mean age: 23 years, range 19-48). We developed a computerized mask, using high-end "gaze-contingent display (GCD)" technology, that immediately and continuously reduced the saliency of objects on the left-"left" with respect to the head (body-centered) and the current position on the retina (eye-centered). In both experimental conditions, task-free viewing and goal-driven visual search, this modification induced a mild but significant bias in visual exploration similar to hemispatial neglect. Accordingly, global eye movement parameters changed (reduced number and increased duration of fixations) and the spatial distribution of fixations indicated an attentional bias towards the right (rightward shift of first orienting, fixations favoring the scene's outmost right over left). Our results support the concept of an attentional priority map in the brain as an interface between perception and behavior and as one pathophysiological ground of hemispatial neglect.

Behavioral deficits in left hemispatial neglect are related to a reduction of spontaneous neuronal activity in the right superior parietal lobule.

Focal brain lesions may induce dysfunctions in distant brain regions leading to behavioral impairments. Based on this concept of 'diaschisis', spatial neglect following stroke has been related to structural damage of the right-lateralized ventral attention network (VAN) and disrupted inter-hemispheric functional connectivity (FC) in the bilateral dorsal attention network (DAN). We questioned whether neglect-related behavioral deficits may be determined by local dysfunction of a specific region within these brain networks. We investigated acute right-hemisphere stroke patients with left hemispatial neglect using resting-state functional MRI, neuropsychological tests of spatial attention and clinical assessment of neglect-related functional disability. In addition to conventional FC analyses between different cortical regions of interest (ROIs) in the DAN/VAN, we extracted the fractional amplitude of low frequency fluctuations (fALFF) from each ROI as a marker of regional spontaneous neuronal activity. Although DAN regions (as opposed to the VAN regions) were largely spared from structural brain damage, they exhibited a significant reduction of inter-hemispheric FC. However, significant fMRI-behavior correlations were revealed specifically for the fALFF of one DAN-ROI in the right superior parietal lobule (SPL): the smaller the fALFF in the right posterior intraparietal sulcus, the more severe the patient's pathological attention bias and neglect-related functional impairment. In line with 'diaschisis', our findings confirm a crucial role of the non-lesioned but dysfunctional right SPL for the emergence of spatial neglect and its behavioral consequences. They further support targeting the SPL dysfunction by non-invasive brain stimulation in neglect rehabilitation.

Brain Activations During Optokinetic Stimulation in Acute Right-Hemisphere Stroke Patients and Hemispatial Neglect: An fMRI Study.

Objective. Leftward optokinetic stimulation (OKS) is a promising therapeutic approach for right-hemisphere stroke patients with left hemispatial neglect. We questioned whether the putative neural basis is an activation of frontoparietal brain regions involved in the control of eye movements and spatial attention. Methods. We used functional magnetic resonance imaging to investigate brain activations during OKS in acute right-hemisphere stroke patients (RHS, n = 19) compared with healthy control subjects (HC, n = 9). Based on neuropsychological testing we determined the ipsilesional attention bias in all RHS patients, 11 showed manifest hemispatial neglect. Results. In HC subjects, OKS in either direction led to bilateral activation of the visual cortex (V1-V4), frontal (FEF) and supplementary (SEF) eye fields, intraparietal sulcus (IPS), basal ganglia, and thalamus. RHS patients' activations were generally reduced compared with HC. Nevertheless, leftward OKS bilaterally activated the visual cortex (V1-V4), FEF, SEF, IPS, and thalamus. The neural response to OKS was negatively correlated with patients' behavioral impairment: The greater the individual attention bias/neglect the weaker the brain activations. Conclusion. In RHS patients, leftward OKS activates frontoparietal regions (FEF, IPS) that are spared from structural brain damage and functionally involved in both oculomotor control and spatial attention. This may provide a neural basis for the known therapeutic effects of OKS on hemispatial neglect. In acute stroke stages, reduced activation levels correlating with neglect severity indicate functional downregulation of the underlying dorsal attention network. Therefore, chronic RHS patients with less severe neglect after recovery of network disturbances may be more suitable candidates for OKS rehabilitation.

"The ipsilesional attention bias in right-hemisphere stroke patients as revealed by a realistic visual search task: Neuroanatomical correlates and functional relevance": Correction to Machner et al. (2018).

Reports an error in "The ipsilesional attention bias in right-hemisphere stroke patients as revealed by a realistic visual search task: Neuroanatomical correlates and functional relevance" by Björn Machner, Inga Könemund, Janina von der Gablentz, Paul M. Bays and Andreas Sprenger (Neuropsychology, 2018[Oct], Vol 32[7], 850-865). In the article, The copyright attribution was incorrectly listed and the Creative Commons CC-BY license disclaimer was incorrectly omitted from the author note. The correct copyright is "© 2018 The Author(s)" and the omitted disclaimer is below. The online version of this article has been corrected. "This article has been published under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s). Author(s) grant(s) the American Psychological Association the exclusive right to publish the article and identify itself as the original publisher." (The following abstract of the original article appeared in record 2018-51197-002.) Objective: Right-hemisphere stroke may cause an ipsilesional attention bias and left hemispatial neglect. Computerized time-limited tasks are more sensitive than conventional paper-pencil tests in detecting these spatial attention deficits. However, their frequency in the acute stage of stroke, the neuroanatomical basis and functional relevance for patients' everyday life are unclear. METHOD: A realistic visual search task is introduced, in which eye movements are recorded while the patient searches for paperclips among different everyday objects on a computer display. The "desk task" performance of 34 acute right-hemisphere stroke patients was compared to established paper-pencil tests for neglect and the Posner reaction time task, and finally correlated to structural brain lesions. RESULTS: Most of the patients, even those without clinical neglect signs and with normal paper-pencil test performance, exhibited a clear ipsilesional attention bias in the desk task. This bias was highly correlated to the left-right asymmetry in the Posner task and to neglect-related functional impairment scores. Lesion-symptom mapping revealed task-specific differences: deficits in the desk task were associated with lesions of the superior temporal gyrus, contralesional unawareness in the Posner task with ventral frontal cortex lesions and paper-pencil cancellation bias with damage to the inferior parietal lobe. Neglect behavior was further associated with distinct frontoparietal white matter tract disconnections (inferior longitudinal fasciculus, superior longitudinal fasciculus, arcuate). CONCLUSIONS: Results from the novel desk task indicate a functional relevance of spatial attention deficits in right-hemisphere stroke patients, even if they are "subclinical." This should be considered especially in patients without obvious clinical neglect signs. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The ipsilesional attention bias in right-hemisphere stroke patients as revealed by a realistic visual search task: Neuroanatomical correlates and functional relevance.

OBJECTIVE: Right-hemisphere stroke may cause an ipsilesional attention bias and left hemispatial neglect. Computerized time-limited tasks are more sensitive than conventional paper-pencil tests in detecting these spatial attention deficits. However, their frequency in the acute stage of stroke, the neuroanatomical basis and functional relevance for patients' everyday life are unclear. METHOD: A realistic visual search task is introduced, in which eye movements are recorded while the patient searches for paperclips among different everyday objects on a computer display. The "desk task" performance of 34 acute right-hemisphere stroke patients was compared to established paper-pencil tests for neglect and the Posner reaction time task, and finally correlated to structural brain lesions. RESULTS: Most of the patients, even those without clinical neglect signs and with normal paper-pencil test performance, exhibited a clear ipsilesional attention bias in the desk task. This bias was highly correlated to the left-right asymmetry in the Posner task and to neglect-related functional impairment scores. Lesion-symptom mapping revealed task-specific differences: deficits in the desk task were associated with lesions of the superior temporal gyrus, contralesional unawareness in the Posner task with ventral frontal cortex lesions and paper-pencil cancellation bias with damage to the inferior parietal lobe. Neglect behavior was further associated with distinct frontoparietal white matter tract disconnections (inferior longitudinal fasciculus, superior longitudinal fasciculus, arcuate). CONCLUSIONS: Results from the novel desk task indicate a functional relevance of spatial attention deficits in right-hemisphere stroke patients, even if they are "subclinical." This should be considered especially in patients without obvious clinical neglect signs. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Patients with primary biliary cholangitis and fatigue present with depressive symptoms and selected cognitive deficits, but with normal attention performance and brain structure.

BACKGROUND: In primary biliary cholangitis (PBC) fatigue is a major clinical challenge of unknown etiology. By demonstrating that fatigue in PBC is associated with an impaired cognitive performance, previous studies have pointed out the possibility of brain abnormalities underlying fatigue in PBC. Whether structural brain changes are present in PBC patients with fatigue, however, is unclear. To evaluate the role of structural brain abnormalities in PBC patients severely affected from fatigue we, therefore, performed a case-control cerebral magnetic resonance imaging (cMRI) study and correlated changes of white and grey brain matter with the cognitive and attention performance. METHODS: 20 female patients with PBC and 20 female age-matched controls were examined in this study. The assessment of fatigue, psychological symptoms, cognitive and attention performance included clinical questionnaires, established cognition tests and a computerized test battery of attention performance. T1-weighted cMRI and diffusion tensor imaging (DTI) scans were acquired with a 3 Tesla scanner. Structural brain alterations were investigated with voxel-based morphometry (VBM) and DTI analyses. Results were correlated to the cognitive and attention performance. RESULTS: Compared to healthy controls, PBC patients had significantly higher levels of fatigue and associated psychological symptoms. Except for an impairment of verbal fluency, no cognitive or attention deficits were found in the PBC cohort. The VBM and DTI analyses revealed neither major structural brain abnormalities in the PBC cohort nor correlations with the cognitive and attention performance. CONCLUSIONS: Despite the high burden of fatigue and selected cognitive deficits, the attention performance of PBC patients appears to be comparable to healthy people. As structural brain alterations do not seem to be present in PBC patients with fatigue, fatigue in PBC must be regarded as purely functional. Future studies should evaluate, whether functional brain changes underlie fatigue in PBC.

ISLES 2015 - A public evaluation benchmark for ischemic stroke lesion segmentation from multispectral MRI.

Ischemic stroke is the most common cerebrovascular disease, and its diagnosis, treatment, and study relies on non-invasive imaging. Algorithms for stroke lesion segmentation from magnetic resonance imaging (MRI) volumes are intensely researched, but the reported results are largely incomparable due to different datasets and evaluation schemes. We approached this urgent problem of comparability with the Ischemic Stroke Lesion Segmentation (ISLES) challenge organized in conjunction with the MICCAI 2015 conference. In this paper we propose a common evaluation framework, describe the publicly available datasets, and present the results of the two sub-challenges: Sub-Acute Stroke Lesion Segmentation (SISS) and Stroke Perfusion Estimation (SPES). A total of 16 research groups participated with a wide range of state-of-the-art automatic segmentation algorithms. A thorough analysis of the obtained data enables a critical evaluation of the current state-of-the-art, recommendations for further developments, and the identification of remaining challenges. The segmentation of acute perfusion lesions addressed in SPES was found to be feasible. However, algorithms applied to sub-acute lesion segmentation in SISS still lack accuracy. Overall, no algorithmic characteristic of any method was found to perform superior to the others. Instead, the characteristics of stroke lesion appearances, their evolution, and the observed challenges should be studied in detail. The annotated ISLES image datasets continue to be publicly available through an online evaluation system to serve as an ongoing benchmarking resource (www.isles-challenge.org).

Extra tree forests for sub-acute ischemic stroke lesion segmentation in MR sequences.

BACKGROUND: To analyse the relationship between structure and (dys-)function of the brain after stroke, accurate and repeatable segmentation of the lesion area in magnetic resonance (MR) images is required. Manual delineation, the current gold standard, is time consuming and suffers from high intra- and inter-observer differences. NEW METHOD: A new approach is presented for the automatic and reproducible segmentation of sub-acute ischemic stroke lesions in MR images in the presence of other pathologies. The proposition is based on an Extra Tree forest framework for voxel-wise classification and mainly intensity derived image features are employed. RESULTS: A thorough investigation of multi-spectral variants, which combine the information from multiple MR sequences, finds the fluid attenuated inversion recovery sequence to be both required and sufficient for a good segmentation result. The accuracy can be further improved by adding features extracted from the T1-weighted and the diffusion weighted sequences. The use of other sequences is discouraged, as they impact negatively on the results. COMPARISON WITH EXISTING METHODS: Quantitative evaluation was carried out on 37 clinical cases. With a Dice coefficient of 0.65, the method outperforms earlier published methods. CONCLUSIONS: The approach proves especially suitable to differentiate between new stroke and other white matter lesions based on the FLAIR sequence alone. This, and the high overlap, renders it suitable for automatic screening of large databases of MR scans, e.g. for a subsequent neuropsychological investigation. Finally, each feature's importance is assessed in detail and the approach's statistical dependency on clinical and image characteristics is investigated.

Randomized controlled trial on hemifield eye patching and optokinetic stimulation in acute spatial neglect.

BACKGROUND AND PURPOSE: Right hemisphere stroke patients frequently experience spatial neglect, a severe lack of awareness for contralesional hemispace. Although neglect counts among the strongest predictors for poor functional outcome after stroke, there is no established therapy, particularly not for the acute stage. METHODS: In a randomized controlled trial, we compared the combined treatment of hemifield eye patching and repetitive optokinetic stimulation in acute stroke patients with neglect to the spontaneous course. Outcome measures were a neuropsychological test battery for neglect as well as scales of functional independence and clinical impairment. Outcomes were assessed at baseline (day 1), post treatment (day 8), and at 1-month follow-up (day 30). RESULTS: Final analysis included 21 acute right hemisphere stroke patients with neglect (23 enrolled, 2 lost to follow-up) allocated either to the treatment (1 week hemifield eye patching and daily sessions of optokinetic stimulation, n=11) or the control group (no neglect-specific treatment, n=10). At baseline, both groups did not differ in neuropsychological test performance, clinical impairment, or functional disability. At the post treatment session, both groups had improved in all these measures, and results were stable or further improved at follow-up. However, there was no significant difference in this change between the treatment and the control group. CONCLUSIONS: An early intervention of combined hemifield eye patching and optokinetic stimulation in acute stroke patients with spatial neglect has no additive effect to the spontaneous remitting course of the disorder. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01617343.

Altered resting-state functional connectivity in patients with chronic bilateral vestibular failure.

Patients with bilateral vestibular failure (BVF) suffer from gait unsteadiness, oscillopsia and impaired spatial orientation. Brain imaging studies applying caloric irrigation to patients with BVF have shown altered neural activity of cortical visual-vestibular interaction: decreased bilateral neural activity in the posterior insula and parietal operculum and decreased deactivations in the visual cortex. It is unknown how this affects functional connectivity in the resting brain and how changes in connectivity are related to vestibular impairment. We applied a novel data driven approach based on graph theory to investigate altered whole-brain resting-state functional connectivity in BVF patients (n= 22) compared to age- and gender-matched healthy controls (n= 25) using resting-state fMRI. Changes in functional connectivity were related to subjective (vestibular scores) and objective functional parameters of vestibular impairment, specifically, the adaptive changes during active (self-guided) and passive (investigator driven) head impulse test (HIT) which reflects the integrity of the vestibulo-ocular reflex (VOR). BVF patients showed lower bilateral connectivity in the posterior insula and parietal operculum but higher connectivity in the posterior cerebellum compared to controls. Seed-based analysis revealed stronger connectivity from the right posterior insula to the precuneus, anterior insula, anterior cingulate cortex and the middle frontal gyrus. Excitingly, functional connectivity in the supramarginal gyrus (SMG) of the inferior parietal lobe and posterior cerebellum correlated with the increase of VOR gain during active as compared to passive HIT, i.e., the larger the adaptive VOR changes the larger was the increase in regional functional connectivity. Using whole brain resting-state connectivity analysis in BVF patients we show that enduring bilateral deficient or missing vestibular input leads to changes in resting-state connectivity of the brain. These changes in the resting brain are robust and task-independent as they were found in the absence of sensory stimulation and without a region-related a priori hypothesis. Therefore they may indicate a fundamental disease-related change in the resting brain. They may account for the patients' persistent deficits in visuo-spatial attention, spatial orientation and unsteadiness. The relation of increasing connectivity in the inferior parietal lobe, specifically SMG, to improvement of VOR during active head movements reflects cortical plasticity in BVF and may play a clinical role in vestibular rehabilitation.

Impact of dynamic bottom-up features and top-down control on the visual exploration of moving real-world scenes in hemispatial neglect.

Patients with hemispatial neglect are severely impaired in orienting their attention to contralesional hemispace. Although motion is one of the strongest attentional cues in humans, it is still unknown how neglect patients visually explore their moving real-world environment. We therefore recorded eye movements at bedside in 19 patients with hemispatial neglect following acute right hemisphere stroke, 14 right-brain damaged patients without neglect and 21 healthy control subjects. Videos of naturalistic real-world scenes were presented first in a free viewing condition together with static images, and subsequently in a visual search condition. We analyzed number and amplitude of saccades, fixation durations and horizontal fixation distributions. Novel computational tools allowed us to assess the impact of different scene features (static and dynamic contrast, colour, brightness) on patients' gaze. Independent of the different stimulus conditions, neglect patients showed decreased numbers of fixations in contralesional hemispace (ipsilesional fixation bias) and increased fixation durations in ipsilesional hemispace (disengagement deficit). However, in videos left-hemifield fixations of neglect patients landed on regions with particularly high dynamic contrast. Furthermore, dynamic scenes with few salient objects led to a significant reduction of the pathological ipsilesional fixation bias. In visual search, moving targets in the neglected hemifield were more frequently detected than stationary ones. The top-down influence (search instruction) could neither reduce the ipsilesional fixation bias nor the impact of bottom-up features. Our results provide evidence for a strong impact of dynamic bottom-up features on neglect patients' scanning behaviour. They support the neglect model of an attentional priority map in the brain being imbalanced towards ipsilesional hemispace, which can be counterbalanced by strong contralateral motion cues. Taking into account the lack of top-down control in neglect patients, bottom-up stimulation with moving real-world stimuli may be a promising candidate for future neglect rehabilitation schemes.