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Zusammenfassung. Die Vorhersage des Schlaganfall-Outcome bleibt aufgrund einer hohen interindividuellen Variabilität eine Herausforderung. Die steigende Lebenserwartung und die Zunahme der Anzahl von chronisch kranken Patienten werden die Variabilität im Schlaganfall-Outcome weiter erhöhen. Die Bedeutung von durch den Schlaganfall hervorgerufenen kognitiven Defiziten sollte in dieser Hinsicht nicht unterschätzt werden. Sie sind relevant für die spätere Alltagsselbstständigkeit aber auch unmittelbar für die somatische Rehabilitation. Die kognitive Störung nach Schlaganfall kann i) in einer oder mehreren kognitiven Domänen auftreten und damit unterschiedlichste Profile zeigen; ii) in der Ausprägung stark variieren – von leichter kognitiver Störung bis hin zu klinisch manifester Demenz; iii) sich sofort nach dem Ereignis oder um einige Monate verzögert manifestieren. Viele demographische, klinische Faktoren oder Schlaganfallfaktoren sind als Prädiktoren für relevante kognitive Verschlechterung nach Schlaganfall bekannt. Bisher wurden diese Risikofaktoren aber unabhängig voneinander untersucht. Ein umfassendes Modell, welches einheitlich alle diese Faktoren zusammen berücksichtigte, fehlte bis jetzt. Wir schlagen vor, dass die Konzepte für Hirnreserve und kognitive Reserve, die bereits für die Erfassung der inter-individuellen Variabilität bei neurodegenerativen Erkrankungen etabliert sind, auch für eine Vorhersage von kognitiven Defiziten nach Schlaganfall hilfreich sein können. Dabei lässt sich der Schweregrad der kognitiven Störung als Interaktion zwischen Hirnreserve (z. B. Hirnvolumen), kognitiver Reserve (z. B. Ausbildungsniveau) und Schlaganfallfaktoren (z. B. Läsionsgrösse, Anatomie) verstehen. Die ersten Studien konnten diese Hypothese bestätigen. Zukünftig dürfte die Berücksichtigung dieser Faktoren eine wesentlich präzisere Vorhersage der kognitiven Störung nach Schlaganfall erlauben. Für die Klinik bietet dies dann die Möglichkeit, im Rahmen einer individualisierten Rehabilitation gefährdete Patienten frühzeitig zu erkennen und diesen ggf. zusätzliche Interventionen zur Prävention einer Demenz nach Schlaganfall zukommen zu lassen.

We aimed to assess the association of diabetes mellitus (DM) and admission hyperglycaemia (AH), respectively, and outcome in patients with acute ischaemic stroke with large vessel occlusion in the anterior circulation treated with endovascular therapy (EVT) in daily clinical practice.Consecutive EVT patients admitted to our stroke centre between February 2015 and April 2020 were included in this observational cohort study. Patients with versus without DM and with versus without AH (glucose ≥ 7.8 mmol/L) were compared.We included 1020 patients (48.9% women, median age = 73.1 years); 282 (27.6%) had DM, and 226 (22.2%) had AH. Patients with versus without DM less often showed successful reperfusion (odds ratio [OR]subadjusted/sub = 0.61, p = 0.023) and worse 3-month functional outcome (modified Rankin Scale [mRS] = 0-2: 31.3% vs. 48%, ORsubadjusted/sub = 0.59, p = 0.004; death: 38.9% vs. 24.1%, ORsubadjusted/sub = 1.75, p = 0.002; mRS shift: psubadjusted/sub lt; 0.0001; if moderate/good collaterals and mismatch, mRS = 0-2: ORsubadjusted/sub = 0.52, p = 0.005; death: ORsubadjusted/sub = 1.95, p = 0.005). If analysis was additionally adjusted for AH, only mRS shift was still significantly worse in patients with DM (psubadjusted/sub = 0.012). Patients with versus without AH showed similar successful reperfusion rates and worse 3-month functional outcome (mRS = 0-2: 28.3% vs. 50.4%, ORsubadjusted/sub = 0.52, p lt; 0.0001; death: 40.4% vs. 22.4%, ORsubadjusted/sub = 1.80, p = 0.001; mRS shift: psubadjusted/sub lt; 0.0001; if moderate/good collaterals and mismatch, mRS = 0-2: ORsubadjusted/sub = 0.38, p lt; 0.0001; death: ORsubadjusted/sub = 2.39, p lt; 0.0001). If analysis was additionally adjusted for DM, 3-month functional outcome remained significantly worse in patients with AH (mRS = 0-2: ORsubadjusted/sub = 0.58, p = 0.004; death: ORsubadjusted/sub = 1.57, p = 0.014; mRS shift: psubadjusted/sub = 0.004). DM independently predicted recurrent/progressive in-hospital ischaemic stroke (OR = 1.71, p = 0.043) together with admission National Institutes of Health Stroke Scale score (OR = 0.95, p = 0.005), and AH independently predicted in-hospital symptomatic intracranial haemorrhage (OR = 2.21, p = 0.001). The association of admission continuous glucose levels and most outcome variables was (inversely) J-shaped.Hyperglycaemia more than DM was associated with worse 3-month outcome in the patients studied, more likely so in the case of moderate/good collaterals and mismatch in admission imaging.

Post-stroke cognitive deficits and dementia

The concepts of brain reserve and cognitive reserve were recently suggested as valuable predictors of stroke outcome. To test this hypothesis, we used age, years of education and lesion size as clinically feasible coarse proxies of brain reserve, cognitive reserve, and the extent of stroke pathology correspondingly. Linear and logistic regression models were used to predict cognitive outcome (Montreal Cognitive Assessment) and stroke-induced impairment and disability (NIH Stroke Scale; modified Rankin Score) in a sample of 104 chronic stroke patients carefully controlled for potential confounds. Results revealed 46% of explained variance for cognitive outcome (p

Behavioural deficits in stroke reflect both structural damage at the site of injury, and widespread network dysfunction caused by structural, functional, and metabolic disconnection. Two recent methods allow for the estimation of structural and functional disconnection from clinical structural imaging. This is achieved by embedding a patient’s lesion into an atlas of functional and structural connections in healthy subjects, and deriving the ensemble of structural and functional connections that pass through the lesion, thus indirectly estimating its impact on the whole brain connectome. This indirect assessment of network dysfunction is more readily available than direct measures of functional and structural connectivity obtained with functional and diffusion MRI, respectively, and it is in theory applicable to a wide variety of disorders. To validate the clinical relevance of these methods, we quantified the prediction of behavioural deficits in a prospective cohort of 132 first-time stroke patients studied at 2 weeks post-injury (mean age 52.8 years, range 22–77; 63 females; 64 right hemispheres). Specifically, we used multivariate ridge regression to relate deficits in multiple functional domains (left and right visual, left and right motor, language, spatial attention, spatial and verbal memory) with the pattern of lesion and indirect structural or functional disconnection. In a subgroup of patients, we also measured direct alterations of functional connectivity with resting-state functional MRI. Both lesion and indirect structural disconnection maps were predictive of behavioural impairment in all domains (0.16

Reference data for sleep are needed for the interpretation of clinical sleep parameters. This analysis aimed to provide polysomnography-measured, spectral analytic and subjective reference data based on a sample of healthy adults. In addition, effects of age and sex were investigated.The sample was selected from the archival database of the Sleep Center at the University Medical Center Freiburg and consisted of 206 healthy adults aged 19 to 73 years. For an adaptation and a second examination night, polysomnography parameters, spectral analytic data, and subjective sleep estimations are presented.With increasing age, sleep became shorter (less total sleep time, more wake time after sleep onset) and lighter (eg, more percentage of stage N1 sleep, increase in fast activity in the beta range). Sleep in females was deeper than sleep in males (eg, higher percentage of stage N3 sleep). Females had higher overall power density than males. Altogether, it is apparent that sleep parameters exhibit high standard deviations, suggesting a high variability within healthy adults and complicating the specification of reference values.Our data suggest that the informative value of sleep reference data in healthy individuals is limited because of high interindividual and intraindividual variation within sleep variables. More research, preferably in the form of meta-analyses and/or large international databases, is needed to further investigate the relevance of such reference data for mental and physical health. In the absence of such knowledge, giving patients feedback about deviations from the norm in their sleep profile may give rise to ill-founded concerns and worry.

Advanced lesion mapping and connectivity analyses are currently the main tools used to understand the mechanisms underlying post-stroke cognitive deficits. However, the factors contributing to pre-stroke architecture of cognitive networks are often ignored, even though they reportedly play a decisive role in the manifestation of cognitive impairment in neurodegeneration. The present review on post-stroke cognitive deficits therefore adopts the concept of brain and cognitive reserve, which was originally developed to account for the individual differences in the course of aging and neurodegenerative diseases. By focusing on spatial neglect, a typical network disorder, it is discussed how individual susceptibility to stroke lesion might explain the reported discrepancies in lesion anatomy, non-spatial deficits and recovery courses. A detailed analysis of the literature reveals that premorbid brain (age, brain atrophy, previous strokes, leukoaraiosis, genetic factors, etc.) and cognitive reserve (IQ, life experience, education, occupation, premorbid cognitive impairment, etc.) greatly impact the brain's capacity for compensation. Furthermore, the interaction between pre-stroke brain/cognitive reserve and the degree of stroke-induced system impairment (e.g., hypoperfusion, lesion load) determines both the extent of neglect symptoms variability and the course of recovery. Premorbid brain/cognitive reserves should thus be considered to: (i) understand the mechanisms of post-stroke cognitive disorders and sufficiently explain their inter-individual variability; (ii) provide a prognosis for cognitive recovery and hence post-stroke dependency; (iii) identify individual targets for cognitive rehabilitation: in the case of reduced brain/cognitive reserve, neglect might occur even with a confined lesion, and non-spatial training of general attentional capacity should represent the main therapeutic target also for treatment of neglect; this might be true also for non-cognitive domains, e.g., motor deficit. This alternative view of how neglect and other cognitive deficits occur and recover promotes discussion about plasticity and recovery to a general rather than a single stroke-based domain, providing more efficiency in recovery research.

Objective:To distinguish white matter remodeling directly induced by stroke lesion from that evoked by remote network dysfunction, using spatial neglect as a model.Methods:We examined 24 visual neglect/extinction patients and 17 control patients combining comprehensive analyses of diffusion tensor metrics and global fiber tracking with neuropsychological testing in the acute (6.3 ± 0.5 days poststroke) and chronic (134 ± 7 days poststroke) stroke phases.Results:Compared to stroke controls, patients with spatial neglect/extinction displayed longitudinal white matter alterations with 2 defining signatures: (1) perilesional degenerative changes characterized by congruently reduced fractional anisotropy and increased radial diffusivity (RD), axial diffusivity, and mean diffusivity, all suggestive of direct axonal damage by lesion and therefore nonspecific for impaired attention network and (2) transneuronal changes characterized by an increased RD in contralesional frontoparietal and bilateral occipital connections, suggestive of primary periaxonal involvement; these changes were distinctly related to the degree of unrecovered neglect symptoms in chronic stroke, hence emerging as network-specific alterations.Conclusions:The present data show how stroke entails global alterations of lesion-spared network architecture over time. Sufficiently large lesions of widely interconnected association cortex induce distinct, large-scale structural reorganization in domain-specific network connections. Besides their relevance to unrecovered domain-specific symptoms, these effects might also explain mechanisms of domain-general deficits in stroke patients, pointing to potential targets for therapeutic intervention.

Visual neglect and extinction are two distinct visuospatial attention deficits that frequently occur after right hemisphere cerebral stroke. However, their different lesion profiles remain a matter of debate. In the left hemisphere, a domain-general dual-loop model with distinct computational abilities onto which several cognitive functions may project, has been proposed: a dorsal stream for sensori-motor mapping in time and space and a ventral stream for comprehension and representation of concepts. We wondered whether such a distinction may apply to visual extinction and neglect in left hemisphere lesions. Of 165 prospectively studied patients with acute left hemispheric ischemic stroke with a single lesion on MRI, 122 had no visuospatial attention deficit, 10 had extinction, 31 neglect and 2 had both, visual extinction and neglect. Voxel-based-lesion-symptom mapping (VLSM, FDR

Questionnaire studies suggest that stroke patients experience sustained problems with sleep and daytime sleepiness, but physiological sleep studies focussing specifically on the chronic phase of stroke are lacking. Here we report for the first time physiological data of sleep and daytime sleepiness obtained through the two gold-standard methods, nocturnal polysomnography and the Multiple Sleep Latency Test. Data from community-dwelling patients with chronic right-hemispheric stroke (12 months) were compared to sex- and age-matched controls. Behavioural and physiological measures suggested that stroke patients had poorer sleep with longer sleep latencies and lower sleep efficiency. Patients further spent more time awake during the night, and showed greater high-frequency power during nonREM sleep than controls. At the same time the Multiple Sleep Latency Test revealed greater wake efficiency in patients than controls. Importantly these findings were not due to group differences in sleep disordered breathing or periodic limb movements. Post-stroke insomnia is presently not adequately addressed within the care pathway for stroke. A holistic approach to rehabilitation and care provision, that includes targeted sleep interventions, is likely to enhance long-term outcome and quality of live in those living with chronic deficits after stroke.

Although post-stroke cognitive deficit can significantly limit patient independence and social re-integration, clinical routine predictors for this condition are lacking. ‘Cognitive reserve’ limits the detrimental effects of slowly developing neurodegeneration. We aimed to determine whether comparable effects also exist in acute stroke. Using 'years of education' as a proxy, we investigated whether cognitive reserve beneficially influences cognitive performance and disability after stroke, whilst controlling for age and lesion size as measure of stroke pathology. Within the first week of ischemic right hemisphere stroke, 36 patients were assessed for alertness, working memory, executive functions, spatial neglect, global cognition and motor deficit at 4.9 ± 2.1 days post-stroke, in addition to routine clinical tests (NIH Stroke Scale, modified Rankin Scale on admission

Objective Spatial neglect can either spontaneously resolve or persist after stroke; the latter is associated with a poorer outcome. We aimed to investigate the neural correlates and predictors of favorable versus poor recovery from neglect in acute stroke. Methods In addition to neuropsychological testing, we explored task-related functional magnetic resonance imaging activation and functional connectivity in 34 patients with neglect and/or extinction. Patients were examined at 2 to 3 days (acute phase I) and 8 to 10 days (acute phase II), and some of them at 4 to 6 months (chronic phase) poststroke. Results Course of recovery was predicted by the strength of functional connectivity between the right parietal and left prefrontal and parietal regions, as early as acute phase I. During acute phase II, favorable recovery from neglect was associated with increased activation in the left prefrontal and right parietal regions, an effect not observed at any time point in patients with poor acute recovery. The extent of neglect amelioration correlated with activation gain in the right attention centers; stronger activation of their left functional homologues correlated with better spatial processing in the neglected hemispace during both of the acute examination phases. Interpretation System excitability and early recruitment of contralesional functional homologues represented specific features of favorable recovery in acute stroke. In severe strokes leading to neglect, contralesional functional homologues support recovery by modulating the preserved ipsilesional network, and initial functional connectivity between them might predict recovery course and help to identify patients with potentially poor recovery requiring more intensive early rehabilitation.

Previous lesion studies suggest that semantic and phonological fluency are differentially subserved by distinct brain regions in the left temporal and the left frontal cortex, respectively. However, as of yet, this often implied double dissociation has not been explicitly investigated due to mainly two reasons: (i) the lack of sufficiently large samples of brain-lesioned patients that underwent assessment of the two fluency variants and (ii) the lack of tools to assess interactions in factorial analyses of non-normally distributed behavioral data. In addition, previous studies did not control for task resource artifacts potentially introduced by the generally higher task difficulty of phonological compared to semantic fluency.We addressed these issues by task-difficulty adjusted assessment of semantic and phonological fluency in 85 chronic patients with ischemic stroke of the left middle cerebral artery. For classical region-based lesion-behavior mapping patients were grouped with respect to their primary lesion location. Building on the extension of the non-parametric Brunner-Munzel rank-order test to multi-factorial designs, ANOVA-type analyses revealed a significant two-way interaction for cue type (semantic vs. phonological) by lesion location (left temporal vs. left frontal vs. other as stroke control group). Subsequent contrast analyses further confirmed the proposed double dissociation by demonstrating that (i) compared to stroke controls, left temporal lesions led to significant impairments in semantic but not in phonological fluency, whereas left frontal lesions led to significant impairments in phonological but not in semantic fluency, and that (ii) patients with frontal lesions showed significantly poorer performance in phonological than in semantic fluency, whereas patients with temporal lesions showed significantly poorer performance in semantic than in phonological fluency.The anatomical specificity of these findings was further assessed in voxel-based lesion-behavior mapping analyses using the multi-factorial extension of the Brunner-Munzel test. Voxel-wise ANOVA-type analyses identified circumscribed parts of left inferior frontal gyrus and left superior and middle temporal gyrus that significantly double-dissociated with respect to their differential contribution to phonological and semantic fluency, respectively. Furthermore, a main effect of lesion with significant impairments in both fluency types was found in left inferior frontal regions adjacent to but not overlapping with those showing the differential effect for phonological fluency.The present study hence not only provides first explicit evidence for the anatomical double dissociation in verbal fluency at the group level but also clearly underlines that its formulation constitutes an oversimplification as parts of left frontal cortex appear to contribute to both semantic and phonological fluency. Keywords: Verbal fluency, Brain lesion, Frontal lobe, Temporal lobe, Double dissociation

Behavioral deficits after stroke like apraxia can be related to structural lesions and to a functional state of the underlying network – three factors, reciprocally influencing each other. Combining lesion data, behavioral performance and passive functional activation of the network-of-interest, this study aims to disentangle those mutual influences and to identify 1) activation patterns associated with the presence or absence of acute apraxia in tool-associated actions and 2) the specific impact of lesion location on those activation patterns. Brain activity of 48 patients (63.31 ± 13.68 years, 35 male) was assessed in a fMRI paradigm with observation of tool-related actions during the acute phase after first-ever left-hemispheric stroke (4.83 ± 2.04 days). Behavioral assessment of apraxia in tool-related tasks was obtained independently. Brain activation was compared between patients versus healthy controls and between patient with versus without apraxia. Interaction effects of lesion location (frontal vs parietal) and behavioral performance (apraxia vs no apraxia) were assessed in a 2 × 2 factorial design. Action observation activated the ventro-dorsal parts of the network for cognitive motor function; activation was globally downregulated after stroke. Apraxic compared to non-apraxic patients showed relatively increased activity in bilateral posterior middle temporal gyrus and middle frontal gyrus/superior frontal sulcus. Altered activation occurred in regions for tool-related cognition, corroborating known functions of the ventro-dorsal and ventral streams for praxis, and comprised domain-general areas, functionally related to cognitive control. The interaction analyses revealed different levels of activation in the left anterior middle temporal gyrus in the ventral stream in apraxic patients with frontal compared to parietal lesions, suggesting a modulation of network activation in relation to behavioral performance and lesion location as separate factors. By detecting apraxia-specific activation patterns modulated by lesion location, this study underlines the necessity to combine structural lesion information, behavioral parameters and functional activation to comprehensively examine cognitive functions in acute stroke patients.

Questionnaire studies suggest that stroke patients experience sustained problems with sleep and daytime sleepiness, but physiological sleep studies focussing specifically on the chronic phase of stroke are lacking. Here we report for the first time physiological data of sleep and daytime sleepiness obtained through the two gold-standard methods, nocturnal polysomnography and the Multiple Sleep Latency Test. Data from community-dwelling patients with chronic right-hemispheric stroke (>12 months) were compared to sex- and age-matched controls. Behavioural and physiological measures suggested that stroke patients had poorer sleep with longer sleep latencies and lower sleep efficiency. Patients further spent more time awake during the night, and showed greater high-frequency power during nonREM sleep than controls. At the same time the Multiple Sleep Latency Test revealed greater wake efficiency in patients than controls. Importantly these findings were not due to group differences in sleep disordered breathing or periodic limb movements. Post-stroke insomnia is presently not adequately addressed within the care pathway for stroke. A holistic approach to rehabilitation and care provision, that includes targeted sleep interventions, is likely to enhance long-term outcome and quality of live in those living with chronic deficits after stroke.

Studies on verbal learning in patients with impaired verbal short-term memory (vSTM) have revealed dissociations among types of verbal information. Patients with impaired vSTM are able to learn lists of known words but fail to acquire new word forms. This suggests that vSTM is involved in new word learning. The present study assessed both new word learning and the learning of digit sequences in two patients with impaired vSTM. In two experiments, participants were required to learn people's names, ages and professions, or their four digit 'phone numbers'. The STM patients were impaired on learning unknown family names and phone numbers, but managed to acquire other verbal information. In contrast, a patient with a severe verbal episodic memory impairment was impaired across information types. These results indicate verbal STM involvement in the learning of digit sequences.

Stroke patients frequently display spatial neglect, an inability to report, or respond to, relevant stimuli in the contralesional space. Although this syndrome is widely considered to result from the dysfunction of a large-scale attention network, the individual contributions of damaged grey and white matter regions to neglect are still being disputed. Moreover, while the neuroanatomy of neglect in right hemispheric lesions is well studied, the contributions of left hemispheric brain regions to visuospatial processing are less well understood. To address this question, 128 left hemisphere acute stroke patients were investigated with respect to left- and rightward spatial biases measured as severity of deviation in the line bisection test and as Center of Cancellation (CoC) in the Bells Test. Causal functional contributions and interactions of nine predefined grey and white matter regions of interest in visuospatial processing were assessed using Multi-perturbation Shapley value Analysis (MSA). MSA, an inference approach based on game theory, constitutes a robust and exact multivariate mathematical method for inferring functional contributions from multi-lesion patterns. According to the analysis of performance in the Bells test, leftward attentional bias (contralesional deficit) was associated with contributions of the left superior temporal gyrus and rightward attentional bias with contributions of the left inferior parietal lobe, whereas the arcuate fascicle was contributed to both contra- and ipsilesional bias. Leftward and rightward deviations in the line bisection test were related to contributions of the superior longitudinal fascicle and the inferior parietal lobe, correspondingly. Thus, Bells test and line bisection tests, as well as ipsi- and contralesional attentional biases in these tests, have distinct neural correlates. Our findings demonstrate the contribution of different grey and white matter structures to contra- and ipsilesional spatial biases as revealed by left hemisphere stroke. The results provide new insights into the role of the left hemisphere in visuospatial processing.

Visual neglect results from dysfunction within the spatial attention network. The structural connectivity in undamaged brain tissue in neglect has barely been investigated until now. In the present study, we explored the microstructural white matter characteristics of the contralesional hemisphere in relation to neglect severity and recovery in acute stroke patients. We compared age-matched healthy subjects and three groups of acute stroke patients (9 ± 0.5 days after stroke): (i) patients with nonrecovered neglect (n = 12); (ii) patients with rapid recovery from initial neglect (within the first week post-stroke, n = 7), (iii) stroke patients without neglect (n = 17). We analyzed the differences between groups in grey and white matter density and fractional anisotropy (FA) and used fiber tracking to identify the affected fibers. Patients with nonrecovered neglect differed from those with rapid recovery by FA-reduction in the left inferior parietal lobe. Fibers passing through this region connect the left-hemispheric analogues of the ventral attention system. Compared with healthy subjects, neglect patients with persisting neglect had FA-reduction in the left superior parietal lobe, optic radiation, and left corpus callosum/cingulum. Fibers passing through these regions connect centers of the left dorsal attention system. FA-reduction in the identified regions correlated with neglect severity. The study shows for the first time white matter changes within the spatial attention system remote from the lesion and correlating with the extent and persistence of neglect. The data support the concept of neglect as disintegration within the whole attention system and illustrate the dynamics of structural-functional correlates in acute stroke. Hum Brain Mapp 35:4678–4692, 2014. © 2014 Wiley Periodicals, Inc.

By implementing a task that closely resembled a clinical test for diagnosing spatial neglect in stroke patients, Himmelbach et al. (: Neuroimage 32:1747-1759) found significantly increased activation during active exploration in those cortical areas in healthy subjects that are known to induce spatial neglect in case of a lesion. The present study investigated whether direct intra-hemispheric cortico-cortical connections could be found between these activated clusters using a probabilistic fiber-tracking approach in 52 healthy subjects. We found that parts of the extreme capsule (EmC) and the middle longitudinal fascicle (MdLF) connected the functional cluster in the prefrontal cortex with the superior temporal cortex and the temporo-parietal junction (TPJ) area in both hemispheres. The activation peak in the TPJ was additionally connected to the inferior frontal cortex by parts of the arcuate fascicle and the superior longitudinal fascicle (SLF II) in the right hemisphere. Our study elucidates the connections constituting the perisylvian network for spatial orienting and attention. Hence, we complement the knowledge from patients suffering from spatial neglect by giving first empirical evidence for the complete postulated network in healthy subjects.

Visual neglect after left-hemispheric lesion is thought to be less frequent, less severe, and shorter lived than visuospatial attention deficits resulting from right-hemispheric lesions. However, reports exist opposing this assumption, and it is unclear how these findings fit into the current theories of visuospatial processing. Furthermore, only little is known about the exact structure-function relationship between visuospatial attention deficits and left-hemispheric stroke. We investigated neglect in 121 patients with acute left-hemispheric ischemic stroke by following clinical development from within the first 24 h of stroke onset until hospital discharge. Visuospatial attention deficits occurred in 17.4 % (n = 21). Voxel-based lesion-symptom mapping associated visual neglect to the right with lesion in the left superior and middle temporal gyrus, temporal pole, frontal operculum, and insula. Neglect severity, captured by the Center of Cancellation Score of the Bells test, was associated with lesion in the left anterior temporal lobe and the left frontal operculum. The left-hemispheric lesion pattern of neglect thus involves areas of the ventral attention system and partly mirrors the critical regions of the right hemisphere known to be associated with neglect. Based on our prospective analysis on a large cohort of patients with left-hemispheric stroke, this study shows that in a remarkable number of patients, the left hemisphere essentially contributes to an intact representation of space and clarifies the impact of the distinct left-hemispheric structures involved in visuospatial processing.

There are a number of studies concerning difference of postural control following left or right hemisphere lesions. Few studies, however, compare the role of the right and left hemisphere in learning new postural tasks. This study aimed to address this question. Twenty patients with hemiparesis after ischemic stroke in the middle cerebral artery territory (11 with a right and 9 with a left hemispheric lesion) were investigated. All subjects were trained using two different tasks during ten training sessions. In both tasks, the subjects stood on a force platform and were taught to change the position of the center of pressure (COP) presented as a cursor on a monitor screen in front of the patient. The subjects were instructed to align the COP with the target and then move the target by shifting the COP in the indicated direction. In the "Balls" task, the position of the target (a ball) varied randomly, so the subject had to learn a general strategy of voluntary COP control. In "Bricks", the subject always had to move the target in a single direction (downward) from the top to the bottom of the screen, so that a precise postural coordination had to be learned. The number of correctly performed trials for a session was scored. The task performance and its rate were analyzed and compared with respect to the lesion lateralization between two patient groups. The voluntary control of the COP position and learning course were initially impaired in all groups of patients in both tasks. In "Balls", there were no differences between the two groups of patients. In contrast, in "Bricks", there was a greater initial deficit in patients with right hemisphere lesions, while the rate of postural learning and the final performance level did not differ between the groups. With a lower initial deficit and similar rate of learning, the maximal level of the task performance was reached earlier (on the 5th day of training) in patients with left hemisphere lesions. This group stopped improving its performance during follow-up training. The results suggest that the motor structures of the right hemisphere are more involved in the precise control of COP trajectory, but not in learning. There is no difference between hemispheres in the initial performance and learning of the general strategy of voluntary COP control. Possibly, the control of specific COP trajectory needs more sensory feedback that is associated with greater involvement of the right hemisphere. This might be a reason for the greater initial impairment of this task after lesions in the right hemisphere.

Spatial neglect can either spontaneously resolve or persist after stroke; the latter is associated with a poorer outcome. We aimed to investigate the neural correlates and predictors of favorable versus poor recovery from neglect in acute stroke.In addition to neuropsychological testing, we explored task-related functional magnetic resonance imaging activation and functional connectivity in 34 patients with neglect and/or extinction. Patients were examined at 2 to 3 days (acute phase I) and 8 to 10 days (acute phase II), and some of them at 4 to 6 months (chronic phase) poststroke.Course of recovery was predicted by the strength of functional connectivity between the right parietal and left prefrontal and parietal regions, as early as acute phase I. During acute phase II, favorable recovery from neglect was associated with increased activation in the left prefrontal and right parietal regions, an effect not observed at any time point in patients with poor acute recovery. The extent of neglect amelioration correlated with activation gain in the right attention centers; stronger activation of their left functional homologues correlated with better spatial processing in the neglected hemispace during both of the acute examination phases.System excitability and early recruitment of contralesional functional homologues represented specific features of favorable recovery in acute stroke. In severe strokes leading to neglect, contralesional functional homologues support recovery by modulating the preserved ipsilesional network, and initial functional connectivity between them might predict recovery course and help to identify patients with potentially poor recovery requiring more intensive early rehabilitation.

Impaired tool use despite preserved basic motor functions occurs after stroke in the context of apraxia, a cognitive motor disorder. To elucidate the neuroanatomical underpinnings of different tool use deficits, prospective behavioral assessments of 136 acute left-hemisphere stroke patients were combined with lesion delineation on magnetic resonance imaging (MRI) images for voxel-based lesion-symptom mapping. Deficits affecting both the selection of the appropriate recipient for a given tool (ToolSelect, e.g., choosing the nail for the hammer), and the performance of the typical tool-associated action (ToolUse, e.g., hammering in the nail) were associated with ventro-dorsal stream lesions, particularly within inferior parietal lobule. However, ToolSelect compared with ToolUse deficits were specifically related to damage within ventral stream regions including anterior temporal lobe. Additional retrospective error dichotomization based on the videotaped performances of ToolUse revealed that spatio-temporal errors (movement errors) were mainly caused by inferior parietal damage adjacent to the intraparietal sulcus while content errors, that is, perplexity, unrecognizable, or semantically incorrect movements, resulted from lesions within supramarginal gyrus and superior temporal lobe. In summary, our results suggest that in the use of tools, conceptual and production-related aspects can be differentiated and are implemented in anatomically distinct streams.

This study is the first to compare in the same subjects the specific spatial distribution and the functional and anatomical connectivity of the neuronal resources that activate and integrate syntactic representations during music and language processing. Combining functional magnetic resonance imaging with functional connectivity and diffusion tensor imaging-based probabilistic tractography, we examined the brain network involved in the recognition and integration of words and chords that were not hierarchically related to the preceding syntax; that is, those deviating from the universal principles of grammar and tonal relatedness. This kind of syntactic processing in both domains was found to rely on a shared network in the left hemisphere centered on the inferior part of the inferior frontal gyrus (IFG), including pars opercularis and pars triangularis, and on dorsal and ventral long association tracts connecting this brain area with temporo-parietal regions. Language processing utilized some adjacent left hemispheric IFG and middle temporal regions more than music processing, and music processing also involved right hemisphere regions not activated in language processing. Our data indicate that a dual-stream system with dorsal and ventral long association tracts centered on a functionally and structurally highly differentiated left IFG is pivotal for domain–general syntactic competence over a broad range of elements including words and chords.

Processing of multiple or bilateral conditions presented simultaneously in both hemifields reflects the natural mode of perception in our multi-target environment, but is not yet completely understood. While region-of-interest based studies in healthy subjects reported single cortical areas as the right inferior parietal lobe (IPL) or temporoparietal junction (TPJ) to process bilateral conditions, studies in extinction patients with reduced ability in this regard suggested the right superior temporal cortex to hold a key role. The present fMRI study on healthy subjects aimed at resolving these discrepancies by contrasting bilateral versus unilateral visual conditions in a paradigm similar to the bed-side test for patients with visual extinction on a whole brain level. Additionally, reduced attentional capacity in spatial processing was investigated in normal aging. Processing of bilateral conditions compared to unilateral ones showed to require stronger activation of not one single cortical region but the entire right-lateralized ventral attention network, bilateral parietal and visual association areas. These results might suggest a conceptual difference between unilateral and bilateral spatial processing with the latter depending on additional anatomical and functional brain resources. Reduced attentional capacity in elderly subjects was associated with compensatory recruitment of contralateral functional homologues [left IPL, TPJ, frontal eye field (FEF)]. These data reveal the functional anatomy of our ability to visually process and respond to the entity of the environment and improve our understanding of neglect and extinction. Moreover, the data demonstrate that a restriction of the attentional capacity is based on processing limitations in the network of high-level cortical areas and not due to restriction in the primary sensory ones.

The current concept of a dual loop system of brain organization predicts a domain-general dual-pathway architecture involving dorsal and ventral fiber connections. We investigated if a similar dichotomy of brain network organization applies for pantomime (P) and imitation of meaningless gestures (I). Impairments of these tasks occur after left hemispheric brain lesions causing apraxia. Isolated impairments and double-dissociations point towards an anatomical segregation. Frontal and parietal areas seem to contribute differently. A special role of the inferior frontal gyrus and underlying fiber pathways was suggested recently. Using a combined fMRI/DTI-approach, we compared the fiber pathway architecture of left hemispheric frontal, temporal and parietal network components of pantomime and imitation. Thereby, we separated object effects from pantomime-specific effects. P and I both engage a fronto-temporo-parietal network of cortical areas interconnected by a dorsal fiber system (superior longitudinal fascicle) for direct sensory-motor interactions. The pantomime-specific effect additionally involved the triangular part of the inferior frontal gyrus, the middle temporal gyrus, the inferior parietal cortex and the intraparietal sulcus, interconnected by ventral fibers of the extreme capsule, likely related to higher-order conceptual and semantic operations. We discuss this finding in the context of the dual loop model and recent anatomical concepts.

Early diagnosis of different modalities in neglect after right hemisphere ischemic lesion and subsequent adequate therapy is crucial in regard to the clinical outcome (e.g. Buxbaum et al., 2004). Bed-side tests in the acute phase after stroke usually include only clinical examination and paper based cancellation tests (e.g. Ota search task, Bell‘s Cancellation). Additional testing such as recording of deficit in visual exploration by tracking of eye movements and standardized test for diagnosis of representational neglect have so far been only conducted in as non-bed-side tests in sub-acute or chronic stages (Isihai et al., 1989). The present study thus investigates the visual exploration during two different tasks in the acute phase of neglect, using a mobile eye-tracking device. Altogether, 31 acute stroke patients with right hemisphere lesion were included. Out of these, 28 could tolerate the eye-tracking device. The first task was a modified baking tray task in which the patients had to collect (first trial) and redistribute (second trial) 16 "cookies" equally on a tray (modified baking tray Task, Fig. 1a and b; Tham, 1996). For diagnosis of representational deficits a second task consisted of enlisting objects presented on a picture board (third trial, Fig. 2a) and to reproduce the named objects while focussing the white back of the board (fourth trial). The eye movements were tracked during all trials (Fig. 2b and c). Additionally, well-established clinical and paper-based evaluation was carried out. Behavioural results of the modified baking tray task confirm a neglect to the left during collection and redistribution of the cookies ( F =14.710, p F =10.458; p =.004). Enlisting of the objects on the picture board also confirmed a neglect to the left ( F =24.238; p F =48.438; p F =30.221; p Both bedside tests for diagnosis of neglect were proved to be applicable in the very acute phase after ischemic stroke: during collection of the cookies as well as naming and recalling of objects on the picture board, the left space was disregarded. We further demonstrate additional representational deficits in these patients that exceed the deficits in visual neglect. For redistribution of the cookies as well as naming the objects from memory – even though all cookies had been collected before and all objects named before - a stronger deficit to the left was found. Representation of the spatial setup thus seems to be even more biased during intrinsically motivated tasks. Tracking of the visual exploration additionally helped to objectify these results and showed to be, at least partly, applicably in acute bed-side tests. Since the diagnosis of the modality of representational deficits has so far not been investigated in the very acute stage of stroke, only little is known about its development and impact on rehabilitation. Further studies will be necessary on this topic.

Visual neglect results from dysfunction within the spatial attention network. The structural connectivity in undamaged brain tissue in neglect has barely been investigated until now. In the present study, we explored the microstructural white matter characteristics of the contralesional hemisphere in relation to neglect severity and recovery in acute stroke patients. We compared age‐matched healthy subjects and three groups of acute stroke patients (9 ± 0.5 days after stroke): (i) patients with nonrecovered neglect (n = 12); (ii) patients with rapid recovery from initial neglect (within the first week post‐stroke, n = 7), (iii) stroke patients without neglect (n = 17). We analyzed the differences between groups in grey and white matter density and fractional anisotropy (FA) and used fiber tracking to identify the affected fibers. Patients with nonrecovered neglect differed from those with rapid recovery by FA‐reduction in the left inferior parietal lobe. Fibers passing through this region connect the left‐hemispheric analogues of the ventral attention system. Compared with healthy subjects, neglect patients with persisting neglect had FA‐reduction in the left superior parietal lobe, optic radiation, and left corpus callosum/cingulum. Fibers passing through these regions connect centers of the left dorsal attention system. FA‐reduction in the identified regions correlated with neglect severity. The study shows for the first time white matter changes within the spatial attention system remote from the lesion and correlating with the extent and persistence of neglect. The data support the concept of neglect as disintegration within the whole attention system and illustrate the dynamics of structural‐functional correlates in acute stroke. Hum Brain Mapp 35:4678–4692, 2014. © 2014 Wiley Periodicals, Inc.

Complex cognitive abilities such as planning are known to critically rely on activity of bilateral mid-dorsolateral prefrontal cortex (mid-dlPFC). However, the functional relevance of the structural connectivity between left and right mid-dlPFC is yet unknown. Here, we applied global tractography to derive streamline counts as estimates of the structural connectivity between mid-dlPFC homologs and related it to planning performance in the Tower of London task across early to midadulthood, assuming a moderating effect of age. Multiple regression analyses with interaction effects revealed that streamline counts between left and right mid-dlPFC were negatively associated with planning performance specifically in early postadolescence. From the fourth life decade on, there was a trend for a reversed, positive association. These differential findings were corroborated by converging results from fractional anisotropy and white-matter density estimates in the genu of the corpus callosum where fibers connecting mid-dlPFC homologs traversed. Moreover, the results for streamline counts were regionally specific, marking the strength of mid-dlPFC connectivity as critical in predicting interindividual differences in planning performance across different stages of adulthood. Taken together, present findings provide first evidence for nonadditive effects of age on the relation between complex cognitive abilities and the structural connectivity of mid-dlPFC homologs.

Diffusion-weighted magnetic resonance imaging provides information about the nerve fiber bundle geometry of the human brain. While the inference of the underlying fiber bundle orientation only requires single q-shell measurements, the absolute determination of their volume fractions is much more challenging with respect to measurement techniques and analysis. Unfortunately, the usually employed multi-compartment models cannot be applied to single q-shell measurements, because the compartment's diffusivities cannot be resolved. This work proposes an equation for fiber orientation densities that can infer the absolute fraction up to a global factor. This equation, which is inspired by the classical mass preservation law in fluid dynamics, expresses the fiber conservation associated with the assumption that fibers do not terminate in white matter. Simulations on synthetic phantoms show that the approach is able to derive the densities correctly for various configurations. Experiments with a pseudo ground truth phantom show that even for complex, brain-like geometries the method is able to infer the densities correctly. In-vivo results with 81 healthy volunteers are plausible and consistent. A group analysis with respect to age and gender show significant differences, such that the proposed maps can be used as a quantitative measure for group and longitudinal analysis.

Although motor imagery is an entirely cognitive process, it shows remarkable similarity to overt movement in behavioral and physiological studies. In concordance, brain imaging studies reported shared fronto-parietal sensorimotor networks commonly engaged by both tasks. However, differences in prefrontal and parietal regions point toward additional cognitive mechanisms in the context of imagery. Within the perspective of a general dichotomization into dorsal and ventral processing streams in the brain, the question arises whether motor imagery and overt movement could differentially involve the dorsal or ventral system. Therefore, we combined fMRI and DTI data of 20 healthy subjects to analyze the anatomical characteristics of connecting fronto-parietal association pathways of imagined and overt movements. We found a dichotomy of fiber pathways into dorsal and ventral systems: the superior longitudinal fascicle (SLF II-III) was found to connect frontal and parietal regions involved in both overt and imagined movements, whereas a ventral tract via the extreme/external capsule (EmC/EC) connects cortical regions specific for motor imagery that were situated more anteriorly and posteriorly. We suppose that motor imagery-related kinesthetic emulations are embedded into dorsal sensorimotor networks, and imagery-specific cognitive functions are implemented in the ventral system. These findings have implications for models of motor cognition.

The neural mechanisms underlying spatial neglect are still disputed. Abnormal left parietal hyperactivation is proposed to lead to the rightward attentional bias, a clinical hallmark of neglect. Extinction, another deficit of visuospatial attention, is regarded as either a 'mild' form of neglect or a distinct syndrome. Although both neglect and extinction are typical syndromes of acute right hemispheric stroke, all imaging studies investigating these syndromes were conducted at least several weeks after stroke onset, in a phase when brain reorganization has already progressed. The present study aimed at comparing the activation patterns in acute stroke patients with neglect and extinction during visuospatial processing. Using functional magnetic resonance imaging, we examined the functional state of the attention system in 33 patients with a first ever stroke (53 ± 5 h after stroke onset) and age-matched healthy subjects (n = 15). All patients had embolic infarcts within the territory of the right middle cerebral artery. Patients were divided into three groups: (i) normal visuospatial processing (control patients, n = 11); (ii) patients with visual extinction but with no signs of neglect (n = 9); and (iii) patients with visual neglect (n = 13). While undergoing functional magnetic resonance imaging, patients performed a Posner-like task for visuospatial attention with detection of the targets in the left and right visual hemifields. Patients with neglect showed the expected imbalance in the left versus right parietal activation, which however, was present also in control and extinction patients, thus representing an epiphenomenon of the acute structural lesion in the right hemisphere. Compared with control patients, neglect was characterized by reduced activation in the right parietal and lateral occipital cortex, as well as in the left frontal eye field. In contrast, the activation pattern in patients with extinction differed from all other groups by an increased activation of the left prefrontal cortex. In both patients with neglect and extinction, detection of targets in the left hemifield correlated with an activation in the left prefrontal and parietal cortex. Thus at least in acute stroke, a relative hyperactivation of the left parietal cortex is not a particular characteristic of neglect. The specific signature of neglect is represented by the dysfunction of the right parietal and lateral occipital cortex. The function of the left attentional centres might provide a compensatory role after critical right hemisphere lesions and be relevant for the contralesional spatial processing.

In the present study, we identified the most probable trajectories of point-to-point segregated connections between functional attentional centers using a combination of functional magnetic resonance imaging and a novel diffusion tensor imaging-based algorithm for pathway extraction. Cortical regions activated by a visuospatial attention task were subsequently used as seeds for probabilistic fiber tracking in 26 healthy subjects. Combining probability maps of frontal and temporoparietal regions yielded a network that consisted of dorsal and ventral connections. The dorsal connections linked temporoparietal cortex with the frontal eye field and area 44 of the inferior frontal gyrus (IFG). Traveling along superior longitudinal and arcuate fascicles, these fibers are well described in relation to spatial attention. However, the ventral connections, which traveled in the white matter between insula (INS) cortex and putamen parallel to the sylvian fissure, were not previously described for visuospatial attention. Linking temporoparietal cortex with anterior INS and area 45 of IFG, these connections may provide an anatomical substrate for crossmodal cortical integration needed for stimulus perception and response in relation to current intention. The newly anatomically described integral network for visuospatial attention might improve the understanding of spatial attention deficits after white matter lesions.

Built on an analogy between the visual and auditory systems, the following dual stream model for language processing was suggested recently: a dorsal stream is involved in mapping sound to articulation, and a ventral stream in mapping sound to meaning. The goal of the study presented here was to test the neuroanatomical basis of this model. Combining functional magnetic resonance imaging (fMRI) with a novel diffusion tensor imaging (DTI)-based tractography method we were able to identify the most probable anatomical pathways connecting brain regions activated during two prototypical language tasks. Sublexical repetition of speech is subserved by a dorsal pathway, connecting the superior temporal lobe and premotor cortices in the frontal lobe via the arcuate and superior longitudinal fascicle. In contrast, higher-level language comprehension is mediated by a ventral pathway connecting the middle temporal lobe and the ventrolateral prefrontal cortex via the extreme capsule. Thus, according to our findings, the function of the dorsal route, traditionally considered to be the major language pathway, is mainly restricted to sensory-motor mapping of sound to articulation, whereas linguistic processing of sound to meaning requires temporofrontal interaction transmitted via the ventral route.