Undoubtedly unaware of homonymous hemianopia: The contribution of overconfidence to anosognosia of hemianopia.

A new functional deficit caused by a stroke can be understood as a situation of uncertainty that has to prompt deficit discovery and subsequent incorporation into an altered self-perception. Anosognosia for visual field deficits is frequent after stroke. For hemiplegia, patients' performance in a riddle test provided evidence that the inability to generate and adjust beliefs in face of uncertainty contributes to anosognosia for hemiplegia. In this prospective study, the same riddles are used in patients with homonymous hemianopia due to a first-ever stroke in the posterior cerebral artery territory and in an age-matched control cohort. The riddles create a situation of uncertainty that is resolved with five successive clues which progressively delimit the target word. After each clue, patients have to guess the target word and rate their confidence in the answer's correctness. Patients were tested once during the hospital stay. According to the Bisiach score for anosognosia, 12 out of 29 patients were unaware of their visual field deficits. All patients with anosognosia for hemianopia had right hemisphere lesions. Patients with and without anosognosia did not differ significantly in global cognitive impairment, mental flexibility or memory function. Importantly, patients with anosognosia showed higher confidence ratings than patients without anosognosia and controls in the first two clues (situations of uncertainty). This was demonstrated by a significant interaction effect in a mixed ANOVA with the factors group (anosognosia, nosognosia, controls) and riddle clues. An exploratory lesion subtraction analysis showed a high proportion of deficit unawareness in patients with lesions in the right fusiform and (para)hippocampal gyri. Our findings suggest that overconfidence in situations of uncertainty might contribute to the appearance of anosognosia for hemianopia. Because this has been demonstrated before in anosognosia for hemiplegia, we suggest that overconfidence is a supra-modal contributor to deficit unawareness.

Preserved White Matter Integrity and Recovery After Brain Tumor Surgery: A Prospective Pilot Study on the Frontal Aslant Tract.

Introduction: Damage to white matter tracts can cause severe neurological deficits, which are often hardly predictable before brain tumor surgery. To explore the possibility of assessing white matter integrity and its preservation, we chose the frontal aslant tract (FAT) due to its involvement in multiple neurological functions such as speech and movement initiation. Methods: Right-handed patients with left hemispheric intracerebral tumors underwent FAT tractography within 7 days before and 3 days after surgery. Neurological performance score and aphasia score were assessed within 7 days before and after surgery, as well as at follow-up 3 months postoperatively. Results: Fifteen patients were prospectively analyzed. After multivariate analysis and receiver operating characteristic analysis, we found that preoperative fractional anisotropy (FA) of the left FAT indicated the preoperative aphasia score (cutoff 0.40, p = 0.015). Aphasia scores 3 months postoperatively were predicted by both postoperative FA of the left FAT (cutoff 0.35, p = 0.005) and postoperatively preserved FA of the left FAT (cutoff 95.8%, p = 0.017). Postoperatively preserved right FAT FA inversely predicted postoperative aphasia score (cutoff 95.1%, p = 0.016). Discussion: Assessment of white matter integrity preservation is possible and correlates with outcome after brain tumor surgery. It may be useful for patient counseling and assessment of rehabilitation potential, as well as to investigate relevant brain networks in the future. Clinical Trial Registration: The trial was prospectively registered at ClinicalTrials.gov (NCT04302857).

Associations of lesion location, structural disconnection, and functional diaschisis with depressive symptoms post stroke.

Introduction: Post-stroke depressive symptoms (PSDS) are common and relevant for patient outcome, but their complex pathophysiology is ill understood. It likely involves social, psychological and biological factors. Lesion location is a readily available information in stroke patients, but it is unclear if the neurobiological substrates of PSDS are spatially localized. Building on previous analyses, we sought to determine if PSDS are associated with specific lesion locations, structural disconnection and/or localized functional diaschisis. Methods: In a prospective observational study, we examined 270 patients with first-ever stroke with the Hospital Anxiety and Depression Scale (HADS) around 6 months post-stroke. Based on individual lesion locations and the depression subscale of the HADS we performed support vector regression lesion-symptom mapping, structural-disconnection-symptom mapping and functional lesion network-symptom-mapping, in a reanalysis of this previously published cohort to infer structure-function relationships. Results: We found that depressive symptoms were associated with (i) lesions in the right insula, right putamen, inferior frontal gyrus and right amygdala and (ii) structural disconnection in the right temporal lobe. In contrast, we found no association with localized functional diaschisis. In addition, we were unable to confirm a previously described association between depressive symptom load and a network damage score derived from functional disconnection maps. Discussion: Based on our results, and other recent lesion studies, we see growing evidence for a prominent role of right frontostriatal brain circuits in PSDS.

Tissue Outcome Prediction in Patients with Proximal Vessel Occlusion and Mechanical Thrombectomy Using Logistic Models.

Perfusion CT is established to aid selection of patients with proximal intracranial vessel occlusion for thrombectomy in the extended time window. Selection is mostly based on simple thresholding of perfusion parameter maps, which, however, does not exploit the full information hidden in the high-dimensional perfusion data. We implemented a multiparametric mass-univariate logistic model to predict tissue outcome based on data from 405 stroke patients with acute proximal vessel occlusion in the anterior circulation who underwent mechanical thrombectomy. Input parameters were acute multimodal CT imaging (perfusion, angiography, and non-contrast) as well as basic demographic and clinical parameters. The model was trained with the knowledge of recanalization status and final infarct localization. We found that perfusion parameter maps (CBF, CBV, and Tmax) were sufficient for tissue outcome prediction. Compared with single-parameter thresholding-based models, our logistic model had comparable volumetric accuracy, but was superior with respect to topographical accuracy (AUC of receiver operating characteristic). We also found higher spatial accuracy (Dice index) in an independent internal but not external cross-validation. Our results highlight the value of perfusion data compared with non-contrast CT, CT angiography and clinical information for tissue outcome-prediction. Multiparametric logistic prediction has high potential to outperform the single-parameter thresholding-based approach. In the future, the combination of tissue and functional outcome prediction might provide an individual biomarker for the benefit from mechanical thrombectomy in acute stroke care.

Involvement of Thalamocortical Networks in Patients With Poststroke Thalamic Aphasia.

BACKGROUND AND OBJECTIVE: Theories assume that thalamic stroke may cause aphasia because of dysfunction in connected cortical networks. This takes into account that brain functions are organized in distributed networks, and in turn, localized damage may result in a network disorder such as thalamic aphasia. With this study, we investigate whether the integration of the thalamus into specific thalamocortical networks underlies symptoms after thalamic stroke. We hypothesize that thalamic lesions in patients with language impairments are functionally connected to cortical networks for language and cognition. METHODS: We combined nonparametric lesion mapping methods in a retrospective cohort of patients with acute or subacute first-ever thalamic stroke. A relationship between lesion location and language impairments was assessed using nonparametric voxel-based lesion-symptom mapping. This method reveals regions more frequently damaged in patients with compared with those without a symptom of interest. To test whether these symptoms are linked to a common thalamocortical network, we additionally performed lesion-network-symptom mapping. This method uses normative connectome data from resting-state fMRI of healthy participants (n = 65) for functional connectivity analyses, with lesion sites serving as seeds. Resulting lesion-dependent network connectivity of patients with language impairments was compared with those with motor and sensory deficits as baseline. RESULTS: A total of 101 patients (mean [SD] age 64.1 [14.6] years, 57 left, 42 right, and 2 bilateral lesions) were included in the study. Voxel-based lesion-symptom mapping showed an association of language impairments with damage to left mediodorsal thalamic nucleus lesions. Lesion-network-symptom mapping revealed that language compared with sensory deficits were associated with higher normative lesion-dependent network connectivity to left frontotemporal language networks and bilateral prefrontal, insulo-opercular, midline cingular, and parietal domain-general networks. Lesions related to motor and sensory deficits showed higher lesion-dependent network connectivity within the sensorimotor network spanning prefrontal, precentral, and postcentral cortices. DISCUSSION: Thalamic aphasia relates to lesions in the left mediodorsal thalamic nucleus and to functionally connected left cortical language and bilateral cortical networks for cognitive control. This suggests that dysfunction in thalamocortical networks contributes to thalamic aphasia. We propose that inefficient integration between otherwise undamaged domain-general and language networks may cause thalamic aphasia.

Association of Lesion Location and Depressive Symptoms Poststroke.

BACKGROUND: Depressive symptoms are a common stroke sequela, yet their neurobiological substrates are still unclear. We sought to determine if they are associated with specific lesion locations. METHODS: In a prospective observational study, 270 patients with stroke were tested twice with the Hospital Anxiety and Depression Scale around day 6 and again 6 months poststroke and voxel-based lesion behavior mapping was performed. RESULTS: Frequency of depressive symptoms (depression subscale of the Hospital Anxiety and Depression Scale >7) after 6 months was 19.6 %. Higher Hospital Anxiety and Depression Scale scores for depression around day 6 were the only variable associated with depressive symptoms after 6 months in a multiple logistic regression. Lesions in the right putamen were significantly associated with depressive symptoms after 6 months in the voxel-based lesion behavior mapping. CONCLUSIONS: Lesions in the right basal ganglia might increase the risk of depressive symptoms 6 months poststroke.

fMRI informed voxel-based lesion analysis to identify lesions associated with right-hemispheric activation in aphasia recovery.

Several mechanisms have been attributed to post-stroke loss and recovery of language functions. However, the significance and timing of domain-general and homotopic right-hemispheric activation is controversial. We aimed to examine the effect of left-hemispheric lesion location and time post-stroke on right-hemispheric activation. Voxel-based lesion analyses were informed by auditory language-related fMRI activation of 71 patients with left middle cerebral artery stroke examined longitudinally in the acute, subacute and early chronic phase. Language activation was determined in several right-hemispheric regions of interest and served as regressor of interest for voxel-based lesion analyses. We found that an acute to chronic increase of language activation in the right supplementary motor area was associated with lesions to the left extreme capsule as part of the ventral language pathway. Importantly, this activation increase correlated significantly with improvement of out-of-scanner comprehension abilities. We interpret our findings in terms of successful domain-general compensation in patients with critical left frontotemporal disconnection due to damage to the ventral language pathway but relatively spared cortical language areas.

Voxelwise structural disconnection mapping: Methodological validation and recommendations.

Voxelwise disconnection mapping is a novel approach to disclose lesion-symptom relationships for symptoms caused by white matter disconnection. It uses MRI-based fiber tracking in healthy subjects seeded from patient's focal brain lesions. Resulting individual disconnection maps can then be statistically associated with symptoms. Despite increasing use in the recent years, the validity of this approach remains to be investigated. In this study, we validated both, our own implementation and the implementation provided within BCBtoolkit. For technical validation, we used simulated symptoms based on overlap of 70 real stroke lesions with tracts from a white matter atlas. For clinical validation, paresis scores and lesions from 316 patients with stroke were used. We found that voxelwise disconnection mapping is technically valid and outperforms the standard voxel-based lesion-symptom mapping approach for symptoms caused by white matter disconnection. Supporting its clinical validity and utility, we were able to reproduce the known association between corticospinal tract damage and contralateral hemiparesis. In addition, we demonstrate that the validity can be substantially diminished by relatively minor methodological changes. Based on these results, we derive methodological recommendations for the future use of voxelwise disconnection mapping. Our study highlights the importance of validating novel methodological approaches in the rapidly evolving field of neuroimaging.

Resolution of diaschisis contributes to early recovery from post-stroke aphasia.

Diaschisis is a phenomenon observed in stroke that is defined as neuronal dysfunction in regions spared by the infarction but connected to the lesion site. We combined lesion network mapping and task-based functional MRI in 71 patients with post-stroke aphasia to investigate, whether diaschisis and its resolution contribute to early loss and recovery of language functions. Language activation acquired in the acute, subacute and chronic phase was analyzed in compartments with high and low normative resting-state functional connectivity to the lesion site on an individual basis. Regions with high compared to regions with low lesion connectivity showed a steeper increase in language reactivation from the acute to the subacute phase. This finding is compatible with the assumption of resolution of diaschisis. Additionally, language performance in the subacute phase and improvement from the subacute to the chronic phase significantly correlated with the diaschisis effect and its resolution, respectively, suggesting a behavioral relevance of this effect. We therefore assume that undamaged but functionally connected regions become dysfunctional due to missing input from the lesion contributing to the aphasic deficit. Since these regions are structurally intact, dysfunction resolves over time contributing to the rapid early behavioral improvement observed in aphasic stroke patients. Our results demonstrate that diaschisis and its resolution might be a relevant mechanism of early loss and recovery of language function in acute stroke patients.

Temporo-cerebellar connectivity underlies timing constraints in audition.

The flexible and efficient adaptation to dynamic, rapid changes in the auditory environment likely involves generating and updating of internal models. Such models arguably exploit connections between the neocortex and the cerebellum, supporting proactive adaptation. Here, we tested whether temporo-cerebellar disconnection is associated with the processing of sound at short timescales. First, we identify lesion-specific deficits for the encoding of short timescale spectro-temporal non-speech and speech properties in patients with left posterior temporal cortex stroke. Second, using lesion-guided probabilistic tractography in healthy participants, we revealed bidirectional temporo-cerebellar connectivity with cerebellar dentate nuclei and crura I/II. These findings support the view that the encoding and modeling of rapidly modulated auditory spectro-temporal properties can rely on a temporo-cerebellar interface. We discuss these findings in view of the conjecture that proactive adaptation to a dynamic environment via internal models is a generalizable principle.

Pathological laughter and crying: insights from lesion network-symptom-mapping.

The study of pathological laughter and crying (PLC) allows insights into the neural basis of laughter and crying, two hallmarks of human nature. PLC is defined by brief, intense and frequent episodes of uncontrollable laughter or crying provoked by trivial stimuli. It occurs secondary to CNS disorders such as stroke, tumours or neurodegenerative diseases. Based on case studies reporting various lesions locations, PLC has been conceptualized as dysfunction in a cortico-limbic-subcortico-thalamo-ponto-cerebellar network. To test whether the heterogeneous lesion locations are indeed linked in a common network, we applied 'lesion network-symptom-mapping' to 70 focal lesions identified in a systematic literature search for case reports of PLC. In lesion network-symptom-mapping normative connectome data (resting state functional MRI, n = 100) is used to identify the brain regions that are likely affected by diaschisis based on the lesion locations. With lesion network-symptom-mapping we were able to identify a common network specific for PLC when compared with a control cohort (n = 270). This bilateral network is characterized by positive connectivity to the cingulate and temporomesial cortices, striatum, hypothalamus, mesencephalon and pons, and negative connectivity to the primary motor and sensory cortices. In the most influential pathophysiological model of PLC, a centre for the control and coordination of facial expressions, respiration and vocalization in the periaqueductal grey is assumed, which is controlled via two pathways: an emotional system that exerts excitatory control of the periaqueductal grey descending from the temporal and frontal lobes, basal ganglia and hypothalamus; and a volitional system descending from the lateral premotor cortices that can suppress laughter or crying. To test whether the positive and negative PLC subnetworks identified in our analyses can indeed be related to an emotional system and a volitional system, we identified lesions causing emotional (n = 15) or volitional facial paresis (n = 46) in a second literature search. Patients with emotional facial paresis show preserved volitional movements but cannot trigger emotional movements in the affected hemiface, while the reverse is true for volitional facial paresis. Importantly, these lesions map differentially onto the PLC subnetworks: the 'positive PLC subnetwork' is part of the emotional system and the 'negative PLC subnetwork' overlaps with the volitional system for the control of facial movements. Based on this network analysis we propose a two-hit model of PLC: a combination of direct lesion and indirect diaschisis effects cause PLC through the loss of inhibitory cortical control of a dysfunctional emotional system.

Hippocampal gray matter volume in the long-term course after transient global amnesia.

OBJECTIVE: In this retrospective, cross-sectional study we aimed to examine long-term memory deficits and gray matter volumes (GMV) in the hippocampus after transient global amnesia (TGA). METHODS: 20 patients with a history of TGA (TGA+, mean 6.5 years after TGA) and 20 age-matched healthy controls (TGA-) underwent neurocognitive assessment (i.e. Mini-Mental State Examination (MMSE), visuospatial, verbal and episodic autobiographical memory and visuospatial learning/navigation ["human water maze"]) in combination with structural cerebral MRI. Voxel-based morphometry (VBM) was used to detect GMV in the hippocampus in TGA+ versus TGA-. RESULTS: Besides slight differences in MMSE and visuo-spatial learning/navigation measured with a human water maze in TGA+ vs. TGA-, no other tests of visuo-spatial, verbal and autobiographical long-term memory differed between groups. VBM analyses yielded a statistically significant difference in bilateral hippocampal GMV with TGA+ compared to TGA- showing greater GMV in a region corresponding to bilateral CA1. However, none of the hippocampus-dependent cognitive measures correlated with hippocampal GMV. CONCLUSION: In the long-term course after TGA, only subtle neurocognitive deficits without microstructural damage of the hippocampus could be detected. Greater GMV in bilateral hippocampus in TGA+ vs. TGA- may indicate that TGA triggers hippocampal GMV increase rather than atrophy.

Association of Lesion Location and Depressive Symptoms Poststroke.

BACKGROUND AND PURPOSE: Poststroke depression is a common stroke sequel, yet its neurobiological substrates are still unclear. We sought to determine whether specific lesion locations are associated with depressive symptoms after stroke. METHODS: In a prospective study, 270 patients with first ever stroke were repeatedly tested with the depression subscale of the Hospital Anxiety and Depression Scale within the first 4 weeks and 6 months after stroke. Voxel-based lesion behavior mapping based on clinical imaging was performed to test for associations between symptoms of depression and lesion locations. RESULTS: Frequency of poststroke depression (Hospital Anxiety and Depression Scale-D score >7) after 6 months was 19.6%. Higher Hospital Anxiety and Depression Scale-D scores for depression within the first 4 weeks were the only independent predictor for poststroke depression after 6 months in a multiple logistic regression also including age, sex, lesion volume, stroke severity, Barthel-Index, and the anxiety subscale of the Hospital Anxiety and Depression Scale. Nonparametric permutation-test based voxel-based lesion behavior mapping identified a cluster of voxels mostly within the left ventrolateral prefrontal cortex where lesions were significantly associated with more depressive symptoms after 6 months. No such association was observed within the right hemisphere despite better lesion coverage. CONCLUSIONS: Lesions in the left ventrolateral prefrontal cortex increase the risk of depressive symptoms 6 months poststroke. Lesions within the right hemisphere are unrelated to depressive symptoms. Recognition of left frontal lesions as a risk factor should help in the early diagnosis of poststroke depression through better risk stratification. The results are in line with evidence from functional imaging and noninvasive brain stimulation in patients without focal brain damage indicating that dysfunction in the left lateral prefrontal cortex contributes to depressive disorders.

Short-term modulation of the lesioned language network.

Language is sustained by large-scale networks in the human brain. Stroke often severely affects function and network dynamics. However, the adaptive potential of the brain to compensate for lesions is poorly understood. A key question is whether upregulation of the right hemisphere is adaptive for language recovery. Targeting the potential for short-term reorganization in the lesioned brain, we applied 'virtual lesions' over left anterior or posterior inferior frontal gyrus (IFG) in post-stroke patients with left temporo-parietal lesions prior to functional neuroimaging. Perturbation of the posterior IFG selectively delayed phonological decisions and decreased phonological activity. The individual response delay was correlated with the upregulation of the lesion homologue, likely reflecting compensation. Moreover, stronger individual tract integrity of the right superior longitudinal fascicle was associated with lesser disruption. Our results provide evidence for functional and structural underpinnings of plasticity in the lesioned language network, and a compensatory role of the right hemisphere.

Dynamics of language reorganization after left temporo-parietal and frontal stroke.

The loss and recovery of language functions are still incompletely understood. This longitudinal functional MRI study investigated the neural mechanisms underlying language recovery in patients with post-stroke aphasia putting particular emphasis on the impact of lesion site. To identify patterns of language-related activation, an auditory functional MRI sentence comprehension paradigm was administered to patients with circumscribed lesions of either left frontal (n = 17) or temporo-parietal (n = 17) cortex. Patients were examined repeatedly during the acute (≤1 week, t1), subacute (1-2 weeks, t2) and chronic phase (>6 months, t3) post-stroke; healthy age-matched control subjects (n = 17) were tested once. The separation into two patient groups with circumscribed lesions allowed for a direct comparison of the contributions of distinct lesion-dependent network components to language reorganization between both groups. We hypothesized that activation of left hemisphere spared and perilesional cortex as well as lesion-homologue cortex in the right hemisphere varies between patient groups and across time. In addition, we expected that domain-general networks serving cognitive control independently contribute to language recovery. First, we found a global network disturbance in the acute phase that is characterized by reduced functional MRI language activation including areas distant to the lesion (i.e. diaschisis) and subsequent subacute network reactivation (i.e. resolution of diaschisis). These phenomena were driven by temporo-parietal lesions. Second, we identified a lesion-independent sequential activation pattern with increased activity of perilesional cortex and bilateral domain-general networks in the subacute phase followed by reorganization of left temporal language areas in the chronic phase. Third, we observed involvement of lesion-homologue cortex only in patients with frontal but not temporo-parietal lesions. Fourth, irrespective of lesion location, language reorganization predominantly occurred in pre-existing networks showing comparable activation in healthy controls. Finally, we detected different relationships of performance and activation in language and domain-general networks demonstrating the functional relevance for language recovery. Our findings highlight that the dynamics of language reorganization clearly depend on lesion location and hence open new perspectives for neurobiologically motivated strategies of language rehabilitation, such as individually-tailored targeted application of neuro-stimulation.

Motor Performance But Neither Motor Learning Nor Motor Consolidation Are Impaired in Chronic Cerebellar Stroke Patients.

The capacity to acquire and retain new motor skills is essential for everyday behavior and a prerequisite to regain functional independence following impairments of motor function caused by brain damage, e.g., ischemic stroke. Learning a new motor skill requires repeated skill practice and passes through different online and offline learning stages that are mediated by specific dynamic interactions between distributed brain regions including the cerebellum. Motor sequence learning is an extensively studied paradigm of motor skill learning, yet the role of the cerebellum during online and offline stages remains controversial. Here, we studied patients with chronic cerebellar stroke and healthy control participants to further elucidate the role of the cerebellum during acquisition and consolidation of sequential motor skills. Motor learning was assessed by an ecologically valid explicit sequential finger tapping paradigm and retested after an interval of 8 h to assess consolidation. Compared to healthy controls, chronic cerebellar stroke patients displayed significantly lower motor sequence performance independent of whether the ipsilesional or contralesional hand was used for task execution. However, the ability to improve performance during training (i.e., online learning) and to consolidate training-induced skill formation was similar in patients and controls. Findings point to an essential role of the cerebellum in motor sequence production that cannot be compensated, while its role in online and offline motor sequence learning seems to be either negligible or amenable to compensatory mechanisms. This further suggests that residual functional impairments caused by cerebellar stroke may be mitigated even months later by additional skill training.

Hippocampal diaschisis contributes to anosognosia for hemiplegia: Evidence from lesion network-symptom-mapping.

Anosognosia for hemiplegia (AHP) is known to be associated with lesions to the motor system combined with varying lesions to the right insula, premotor cortex, parietal lobe or hippocampus. Due to this widespread cortical lesion distribution, AHP can be understood best as a network disorder. We used lesion maps and behavioral data (n â€‹= â€‹49) from two previous studies on AHP and performed a lesion network-symptom-mapping (LNSM) analysis. This new approach permits the identification of relationships between behavior and regions connected to the lesion site based on normative functional connectome data. In a first step, using ordinary voxel-based lesion-symptom mapping, we found an association of AHP with lesions in the right posterior insula. This is in accordance with previous studies. Applying LNSM, we were able to additionally identify a region in the right posterior hippocampus where AHP was associated with significantly higher normative lesion connectivity. Notably, this region was spared by infarction in all patients. We therefore argue that remote neuronal dysfunction caused by disrupted functional connections between the lesion site and the hippocampus (i.e. diaschisis) contributed to the phenotype of AHP. An indirect affection of the hippocampus may lead to memory deficits which, in turn, impair the stable encoding of updated beliefs on the bodily state thus contributing to the multifactorial phenomenon of AHP.

Implicit learning of artificial grammatical structures after inferior frontal cortex lesions.

OBJECTIVE: Previous research associated the left inferior frontal cortex with implicit structure learning. The present study tested patients with lesions encompassing the left inferior frontal gyrus (LIFG; including Brodmann areas 44 and 45) to further investigate this cognitive function, notably by using non-verbal material, implicit investigation methods, and by enhancing potential remaining function via dynamic attending. Patients and healthy matched controls were exposed to an artificial pitch grammar in an implicit learning paradigm to circumvent the potential influence of impaired language processing. METHODS: Patients and healthy controls listened to pitch sequences generated within a finite-state grammar (exposure phase) and then performed a categorization task on new pitch sequences (test phase). Participants were not informed about the underlying grammar in either the exposure phase or the test phase. Furthermore, the pitch structures were presented in a highly regular temporal context as the beneficial impact of temporal regularity (e.g. meter) in learning and perception has been previously reported. Based on the Dynamic Attending Theory (DAT), we hypothesized that a temporally regular context helps developing temporal expectations that, in turn, facilitate event perception, and thus benefit artificial grammar learning. RESULTS: Electroencephalography results suggest preserved artificial grammar learning of pitch structures in patients and healthy controls. For both groups, analyses of event-related potentials revealed a larger early negativity (100-200 msec post-stimulus onset) in response to ungrammatical than grammatical pitch sequence events. CONCLUSIONS: These findings suggest that (i) the LIFG does not play an exclusive role in the implicit learning of artificial pitch grammars, and (ii) the use of non-verbal material and an implicit task reveals cognitive capacities that remain intact despite lesions to the LIFG. These results provide grounds for training and rehabilitation, that is, learning of non-verbal grammars that may impact the relearning of verbal grammars.

Rheologically Essential Surfactant Proteins of the CSF Interacting with Periventricular White Matter Changes in Hydrocephalus Patients - Implications for CSF Dynamics and the Glymphatic System.

Surfactant proteins (SP) are multi-systemic proteins playing crucial roles in the regulation of rheological properties of physiological fluids, host defense, and the clearance of potentially harmful metabolites. Hydrocephalus patients suffer from disturbed central nervous system (CNS) fluid homeostasis and exhibit remarkably altered SP concentrations within the cerebrospinal fluid (CSF). A connection between CSF-SPs, CSF flow, and ventricular dilatation, a morphological hallmark of hydrocephalus, has been reported previously. However, currently there are no studies investigating the link between rheologically active SPs and periventricular white matter changes caused by impaired CSF microcirculation in hydrocephalic conditions. Thus, the aim of this study was to assess their possible relationships. The present study included 47 individuals (27 healthy subjects and 20 hydrocephalus patients). CSF specimens were analyzed for concentrations of SP-A, SP-C, and SP-D by using enzyme-linked immunosorbent assays (ELISAs). Axial T2w turbo inversion recovery magnitude (TIRM) magnetic resonance imaging was employed in all cases. Using a custom-made MATLAB-based tool for quantification of magnetic resonance signal intensities in the brain, parameters related to disturbed deep white matter CSF microcirculation were estimated (TIRM signal intensity (SI)-mean, minimum, maximum, median, mode, standard deviation, and percentiles, p10th, p25th, p75th, p90th, as well as kurtosis, skewness, and entropy of the SI distribution). Subsequently, statistical analysis was performed (IBM SPSS 24™) to identify differences between hydrocephalic patients and healthy individuals and to further investigate the connections between CSF-SP changes and deep white matter signal intensities. SP-A (0.38 ± 0.23 vs. 0.76 ± 0.49 ng/ml) and SP-C (0.54 ± 0.28 vs. 1.27 ± 1.09 ng/ml) differed between healthy controls and hydrocephalus patients in a statistically significant manner. Also, corresponding quantification of white matter signal intensities revealed statistically significant differences between hydrocephalus patients and healthy individuals: SImean (370.41 ± 188.15 vs. 222.27 ± 99.86, p = 0.001), SImax (1115.30 ± 700.12 vs. 617.00 ± 459.34, p = 0.005), SImedian (321.40 ± 153.17 vs. 209.52 ± 84.86, p = 0.001), SImode (276.55 ± 125.63 vs. 197.26 ± 78.51, p = 0.011), SIstd (157.09 ± 110.07 vs. 81.71 ± 64.94, p = 0.005), SIp10 (229.10 ± 104.22 vs. 140.00 ± 63.12, p = 0.001), SIp25 (266.95 ± 122.62 vs. 175.63 ± 71.42, p = 0.002), SIp75 (428.80 ± 226.88 vs. 252.19 ± 110.91, p = 0.001), SIp90 (596.47 ± 345.61 vs. 322.06 ± 176.00, p = 0.001), skewness (1.19 ± 0.68 vs. 0.43 ± 1.19, p = 0.014), and entropy (5.36 ± 0.37 vs. 4.92 ± 0.51, p = 0.002). There were no differences regarding SP-D levels in hydrocephalus patients vs. healthy controls. In the acute hydrocephalic subgroup, correlations were as follows: SP-A showed a statistically significant correlation with SImax (r = 0.670, p = 0.024), SIstd (r = 0.697, p = 0.017), SIp90 (r = 0.621, p = 0.041), and inverse correlation with entropy (r = - 0.700, p = 0.016). SP-C correlated inversely with entropy (r = - 0.686, p = 0.020). For the chronic hydrocephalus subgroup, the following correlations were identified: SP-A correlated with kurtosis of the TIRM histogram (r = - 0.746, p = 0.021). SP-C correlated with SImean (r = - 0.688, p = 0.041), SImax (r = - 0.741, p = 0.022), SImedian (r = - 0.716, p = 0.030), SImode (r = - 0.765, p = 0.016), SIstd (r = - 0.671, p = 0.048), SIp25 (r = - 0.740, p = 0.023), SIp75 (r = - 0.672, p = 0.048), and SIp90 (r = - 0.667, p = 0.050). SP-D apparently does not play a major role in CSF fluid physiology. SP-A and SP-C are involved in different aspects of CNS fluid physiology. SP-A appears to play an essential compensatory role in acute hydrocephalus and seems less involved in chronic hydrocephalus. In contrary, SP-C profile and white matter changes are remarkably connected in CSF of chronic hydrocephalus patients. Considering the association between CSF flow phenomena, white matter changes, and SP-C profiles, the latter may especially contribute to the regulation of paravascular glymphatic physiology.

Resting-state functional connectivity: An emerging method for the study of language networks in post-stroke aphasia.

Aphasia results both from direct effects of focal damage to eloquent cortical areas as well as dysfunction of interconnected remote areas within the language network. Resting-state functional MRI (rsfMRI) can be used to examine functional connectivity (FC) within these networks. Herein we review publications, which applied rsfMRI to understand network pathology in post stroke aphasia. A common finding in this research is an acute disruption of connectivity within the language network, which is correlated with loss of language function and tends to resolve with recovery from aphasia. All studies are limited by small sample sizes, heterogeneous patient characteristics and a wide range of analytical approaches, which further hinder deduction of common patterns across studies. One recent large-scale study examining FC and behavior across various cognitive domains, however, has made substantial progress with the description of a "network phenotype of stroke injury", which consists of a disruption of interhemispheric connectivity and reduced segregation of intrahemispheric networks. Unlike in other domains, language functions showed substantial dependence on intact left intrahemispheric connectivity (Siegel, Ramsey et al., 2016). In the future, such analyses of network pathology might support prognosis and development of effective treatment strategies in individual patients with aphasia.