Local neuronal sleep after stroke: The role of cortical bistability in brain reorganization.

BACKGROUND: Acute cerebral ischemia triggers a number of cellular mechanisms not only leading to excitotoxic cell death but also to enhanced neuroplasticity, facilitating neuronal reorganization and functional recovery. OBJECTIVE: Transferring these cellular mechanisms to neurophysiological correlates adaptable to patients is crucial to promote recovery post-stroke. The combination of TMS and EEG constitutes a promising readout of neuronal network activity in stroke patients. METHODS: We used the combination of TMS and EEG to investigate the development of local signal processing and global network alterations in 40 stroke patients with motor deficits alongside neural reorganization from the acute to the chronic phase. RESULTS: We show that the TMS-EEG response reflects information about reorganization and signal alterations associated with persistent motor deficits throughout the entire post-stroke period. In the early post-stroke phase and in a subgroup of patients with severe motor deficits, TMS applied to the lesioned motor cortex evoked a sleep-like slow wave response associated with a cortical off-period, a manifestation of cortical bistability, as well as a rapid disruption of the TMS-induced formation of causal network effects. Mechanistically, these phenomena were linked to lesions affecting ascending activating brainstem fibers. Of note, slow waves invariably vanished in the chronic phase, but were highly indicative of a poor functional outcome. CONCLUSION: In summary, we found evidence that transient effects of sleep-like slow waves and cortical bistability within ipsilesional M1 resulting in excessive inhibition may interfere with functional reorganization, leading to a less favorable functional outcome post-stroke, pointing to a new therapeutic target to improve recovery of function.

Age- and sex-related changes in motor functions: a comprehensive assessment and component analysis.

Age-related motor impairments often cause caregiver dependency or even hospitalization. However, comprehensive investigations of the different motor abilities and the changes thereof across the adult lifespan remain sparse. We, therefore, extensively assessed essential basic and complex motor functions in 444 healthy adults covering a wide age range (range 21 to 88 years). Basic motor functions, here defined as simple isolated single or repetitive movements in one direction, were assessed by means of maximum grip strength (GS) and maximum finger-tapping frequency (FTF). Complex motor functions, comprising composite sequential movements involving both proximal and distal joints/muscle groups, were evaluated with the Action Research Arm Test (ARAT), the Jebsen-Taylor Hand Function Test (JTT), and the Purdue Pegboard Test. Men achieved higher scores than women concerning GS and FTF, whereas women stacked more pins per time than men during the Purdue Pegboard Test. There was no significant sex effect regarding JTT. We observed a significant but task-specific reduction of basic and complex motor performance scores across the adult lifespan. Linear regression analyses significantly predicted the participants' ages based on motor performance scores (R2 = 0.502). Of note, the ratio between the left- and right-hand performance remained stable across ages for all tests. Principal Component Analysis (PCA) revealed three motor components across all tests that represented dexterity, force, and speed. These components were consistently present in young (21-40 years), middle-aged (41-60 years), and older (61-88 years) adults, as well as in women and men. Based on the three motor components, K-means clustering analysis differentiated high- and low-performing participants across the adult life span. The rich motor data set of 444 healthy participants revealed age- and sex-dependent changes in essential basic and complex motor functions. Notably, the comprehensive assessment allowed for generating robust motor components across the adult lifespan. Our data may serve as a reference for future studies of healthy subjects and patients with motor deficits. Moreover, these findings emphasize the importance of comprehensively assessing different motor functions, including dexterity, force, and speed, to characterize human motor abilities and their age-related decline.

[Quality indicators artificial intelligence]. / Qualitätsindikatoren künstliche Intelligenz.

The ability of some artificial intelligence (AI) systems to autonomously evolve and the sometimes very limited possibilities to comprehend their decision-making processes present new challenges to our legal system. At a European level this has led to reform efforts, of which the proposal for a European AI regulation promises to close regulatory gaps in existing product safety law through cross-sectoral AI-specific safety requirements. A prerequisite, however, would be that the EU legislator does not only avoid duplications and contradictions with existing safety requirements but also refrains from imposing exaggerated and unattainable demands. If this were to be taken into consideration, the new safety requirements could also be used to specify the undefined standard of care in liability law. Nevertheless, challenges in the context of provability continue to remain unresolved, posing a risk of rendering the legal protection efforts of the aggrieved party ineffective. It remains to be seen whether the EU legislator will address this need for reform with the recently proposed reform of product liability law by the Commission.

Interhemispheric Structural Connectivity Underlies Motor Recovery after Stroke.

OBJECTIVE: Although ample evidence highlights that the ipsilesional corticospinal tract (CST) plays a crucial role in motor recovery after stroke, studies on cortico-cortical motor connections remain scarce and provide inconclusive results. Given their unique potential to serve as structural reserve enabling motor network reorganization, the question arises whether cortico-cortical connections may facilitate motor control depending on CST damage. METHODS: Diffusion spectrum imaging (DSI) and a novel compartment-wise analysis approach were used to quantify structural connectivity between bilateral cortical core motor regions in chronic stroke patients. Basal and complex motor control were differentially assessed. RESULTS: Both basal and complex motor performance were correlated with structural connectivity between bilateral premotor areas and ipsilesional primary motor cortex (M1) as well as interhemispheric M1 to M1 connectivity. Whereas complex motor skills depended on CST integrity, a strong association between M1 to M1 connectivity and basal motor control was observed independent of CST integrity especially in patients who underwent substantial motor recovery. Harnessing the informational wealth of cortico-cortical connectivity facilitated the explanation of both basal and complex motor control. INTERPRETATION: We demonstrate for the first time that distinct aspects of cortical structural reserve enable basal and complex motor control after stroke. In particular, recovery of basal motor control may be supported via an alternative route through contralesional M1 and non-crossing fibers of the contralesional CST. Our findings help to explain previous conflicting interpretations regarding the functional role of the contralesional M1 and highlight the potential of cortico-cortical structural connectivity as a future biomarker for motor recovery post-stroke. ANN NEUROL 2023;94:785-797.

Recovered grasping performance after stroke depends on interhemispheric frontoparietal connectivity.

Activity changes in the ipsi- and contralesional parietal cortex and abnormal interhemispheric connectivity between these regions are commonly observed after stroke, however, their significance for motor recovery remains poorly understood. We here assessed the contribution of ipsilesional and contralesional anterior intraparietal cortex (aIPS) for hand motor function in 18 recovered chronic stroke patients and 18 healthy control subjects using a multimodal assessment consisting of resting-state functional MRI, motor task functional MRI, online-repetitive transcranial magnetic stimulation (rTMS) interference, and 3D movement kinematics. Effects were compared against two control stimulation sites, i.e. contralesional M1 and a sham stimulation condition. We found that patients with good motor outcome compared to patients with more substantial residual deficits featured increased resting-state connectivity between ipsilesional aIPS and contralesional aIPS as well as between ipsilesional aIPS and dorsal premotor cortex. Moreover, interhemispheric connectivity between ipsilesional M1 and contralesional M1 as well as ipsilesional aIPS and contralesional M1 correlated with better motor performance across tasks. TMS interference at individual aIPS and M1 coordinates led to differential effects depending on the motor task that was tested, i.e. index finger-tapping, rapid pointing movements, or a reach-grasp-lift task. Interfering with contralesional aIPS deteriorated the accuracy of grasping, especially in patients featuring higher connectivity between ipsi- and contralesional aIPS. In contrast, interference with the contralesional M1 led to impaired grasping speed in patients featuring higher connectivity between bilateral M1. These findings suggest differential roles of contralesional M1 and aIPS for distinct aspects of recovered hand motor function, depending on the reorganization of interhemispheric connectivity.

Prediction of response to lomustine-based chemotherapy in glioma patients at recurrence using MRI and FET PET.

BACKGROUND: We evaluated O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET and MRI for early response assessment in recurrent glioma patients treated with lomustine-based chemotherapy. METHODS: Thirty-six adult patients with WHO CNS grade 3 or 4 gliomas (glioblastoma, 69%) at recurrence (median number of recurrences, 1; range, 1-3) were retrospectively identified. Besides MRI, serial FET PET scans were performed at baseline and early after chemotherapy initiation (not later than two cycles). Tumor-to-brain ratios (TBR), metabolic tumor volumes (MTV), the occurrence of new distant hotspots with a mean TBR >1.6 at follow-up, and the dynamic parameter time-to-peak were derived from all FET PET scans. PET parameter thresholds were defined using ROC analyses to predict PFS of ≥6 months and OS of ≥12 months. MRI response assessment was based on RANO criteria. The predictive values of FET PET parameters and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. RESULTS: After treatment initiation, the median follow-up time was 11 months (range, 3-71 months). Relative changes of TBR, MTV, and RANO criteria predicted a significantly longer PFS (all P ≤ .002) and OS (all P ≤ .045). At follow-up, the occurrence of new distant hotspots (n ≥ 1) predicted a worse outcome, with significantly shorter PFS (P = .005) and OS (P < .001). Time-to-peak changes did not predict a significantly longer survival. Multivariate survival analyses revealed that new distant hotspots at follow-up FET PET were most potent in predicting non-response (P < .001; HR, 8.578). CONCLUSIONS: Data suggest that FET PET provides complementary information to RANO criteria for response evaluation of lomustine-based chemotherapy early after treatment initiation.

Different facets of object-use pantomime: online TMS evidence on the role of the supramarginal gyrus.

BACKGROUND: A key question in apraxia research is which specific cognitive processes in pantomiming the parietal cortex supports. The manipulation-based hypothesis and the technical-reasoning hypothesis ascribe different roles to the inferior parietal lobule (IPL). OBJECTIVE: We elucidated the role of the left supramarginal gyrus (SMG, i.e., part of IPL) during the processing of different aspects of object-use pantomime. METHODS: Thirty-one healthy participants matched pantomimes with the corresponding object (PO) or the corresponding situation (PS) during online transcranial magnetic stimulation (TMS) interference applied to left SMG, compared to a control stimulation (vertex). Notably, the object corresponding to a given pantomime was explicitly not shown in the PS task, excluding the possibility to analyse a physical object. Matching an object to the corresponding situation (OS) served as a control task. RESULTS: TMS interference with left SMG significantly affected response times for both investigated pantomime tasks (PO and PS); the effect in the PO task significantly correlated with that in the PS task. As expected, no TMS effect was observed in the control task (OS). CONCLUSION: Left SMG does not only establish a link between pantomime and a manipulable object but is also involved in pantomime recognition and comprehension. That TMS interfered with both pantomime tasks supports the manipulation-based hypothesis, assuming that the IPL recruits stored gesture engrams whenever pantomimes are processed.

Two Decades of Brain Tumour Imaging with O-(2-[18F]fluoroethyl)-L-tyrosine PET: The Forschungszentrum Jülich Experience.

O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians' rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.

Efficacy and tolerability of regorafenib in pretreated patients with progressive CNS grade 3 or 4 gliomas.

BACKGROUND: The phase 2 REGOMA trial suggested an encouraging overall survival benefit in glioblastoma patients at first relapse treated with the multikinase inhibitor regorafenib. Here, we evaluated the efficacy and side effects of regorafenib in a real-life setting. METHODS: From 2018 to 2021, 30 patients with progressive WHO CNS grade 3 or 4 gliomas treated with regorafenib (160 mg/day; first 3 weeks of each 4-week cycle) with individual dose adjustment depending on toxicity were retrospectively identified. Side effects were evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). MRI was obtained at baseline and after every second cycle. Tumor progression was assessed according to RANO criteria. After regorafenib initiation, the median PFS and OS were calculated. RESULTS: The median number of treatment lines before regorafenib was 2 (range 1-4). Most patients (73%) had two or more pretreatment lines. At first relapse, 27% of patients received regorafenib. A total of 94 regorafenib cycles were administered (median 2 cycles; range 1-9 cycles). Grade 3 and 4 side effects were observed in 47% and 7% of patients, respectively, and were not significantly increased in patients with two or more pretreatments (P > 0.05). The most frequent grade 3 or 4 side effects were laboratory abnormalities (62%). PFS was 2.6 months (range 0.8-8.2 months), and the OS was 6.2 months (range 0.9-24 months). CONCLUSIONS: In patients with progressive WHO grade 3 or 4 gliomas, predominantly with two pretreatment lines or more, regorafenib seems to be effective despite considerable grade 3 or 4 side effects.

Cost Effectiveness of 18F-FET PET for Early Treatment Response Assessment in Glioma Patients After Adjuvant Temozolomide Chemotherapy.

In light of increasing health-care costs, higher medical expenses should be justified socioeconomically. Therefore, we calculated the effectiveness and cost effectiveness of PET using the radiolabeled amino acid O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) compared with conventional MRI for early identification of responders to adjuvant temozolomide chemotherapy. A recently published study in isocitrate dehydrogenase wild-type glioma patients suggested that 18F-FET PET parameter changes predicted a significantly longer survival already after 2 cycles whereas MRI changes were not significant. Methods: To determine the effectiveness and cost effectiveness of serial 18F-FET PET imaging, we analyzed published clinical data and calculated the associated costs from the perspective of the German Statutory Health Insurance system. Based on a decision-tree model, the effectiveness of 18F-FET PET and MRI was calculated-that is, the probability to correctly identify a responder as defined by an overall survival of at least 15 mo. To determine the cost effectiveness, the incremental cost effectiveness ratio (ICER) was calculated-that is, the cost for each additionally identified responder by 18F-FET PET who would have remained undetected by MRI. The robustness of the results was tested by deterministic and probabilistic Monte Carlo sensitivity analyses. Results: Compared with MRI, 18F-FET PET increased the rate of correctly identified responders to chemotherapy by 26%; thus, 4 patients needed to be examined by 18F-FET PET to identify 1 additional responder. Considering the respective costs for serial 18F-FET PET and MRI, the ICER resulted in €4,396.83 for each additional correctly identified responder by 18F-FET PET. Sensitivity analyses confirmed the robustness of the results. Conclusion: In contrast to conventional MRI, the model suggests that 18F-FET PET is cost-effective in terms of ICER values. Considering the high cost of temozolomide, the integration of 18F-FET PET has the potential to avoid premature chemotherapy discontinuation at reasonable cost.

Dynamic connectivity predicts acute motor impairment and recovery post-stroke.

Thorough assessment of cerebral dysfunction after acute lesions is paramount to optimize predicting clinical outcomes. We here built random forest classifier-based prediction models of acute motor impairment and recovery post-stroke. Predictions relied on structural and resting-state fMRI data from 54 stroke patients scanned within the first days of symptom onset. Functional connectivity was estimated via static and dynamic approaches. Motor performance was phenotyped in the acute phase and 6 months later. A model based on the time spent in specific dynamic connectivity configurations achieved the best discrimination between patients with and without motor impairments (out-of-sample area under the curve, 95% confidence interval: 0.67 ± 0.01). In contrast, patients with moderate-to-severe impairments could be differentiated from patients with mild deficits using a model based on the variability of dynamic connectivity (0.83 ± 0.01). Here, the variability of the connectivity between ipsilesional sensorimotor cortex and putamen discriminated the most between patients. Finally, motor recovery was best predicted by the time spent in specific connectivity configurations (0.89 ± 0.01) in combination with the initial impairment. Here, better recovery was linked to a shorter time spent in a functionally integrated configuration. Dynamic connectivity-derived parameters constitute potent predictors of acute impairment and recovery, which, in the future, might inform personalized therapy regimens to promote stroke recovery.

Early motor network connectivity after stroke: An interplay of general reorganization and state-specific compensation.

Motor recovery after stroke relies on functional reorganization of the motor network, which is commonly assessed via functional magnetic resonance imaging (fMRI)-based resting-state functional connectivity (rsFC) or task-related effective connectivity (trEC). Measures of either connectivity mode have been shown to successfully explain motor impairment post-stroke, posing the question whether motor impairment is more closely reflected by rsFC or trEC. Moreover, highly similar changes in ipsilesional and interhemispheric motor network connectivity have been reported for both rsFC and trEC after stroke, suggesting that altered rsFC and trEC may capture similar aspects of information integration in the motor network reflecting principle, state-independent mechanisms of network reorganization rather than state-specific compensation strategies. To address this question, we conducted the first direct comparison of rsFC and trEC in a sample of early subacute stroke patients (n = 26, included on average 7.3 days post-stroke). We found that both rsFC and trEC explained motor impairment across patients, stressing the clinical potential of fMRI-based connectivity. Importantly, intrahemispheric connectivity between ipsilesional M1 and premotor areas depended on the activation state, whereas interhemispheric connectivity between homologs was state-independent. From a mechanistic perspective, our results may thus arise from two distinct aspects of motor network plasticity: task-specific compensation within the ipsilesional hemisphere and a more fundamental form of reorganization between hemispheres.

Translating Functional Connectivity After Stroke: Functional Magnetic Resonance Imaging Detects Comparable Network Changes in Mice and Humans.

Background and Purpose: The translational roadblock has long impeded the implementation of experimental therapeutic approaches for stroke into clinical routine. Considerable interspecies differences, for example, in brain anatomy and function, render comparisons between rodents and humans tricky, especially concerning brain reorganization and recovery of function. We tested whether stroke-evoked changes in neural networks follow similar patterns in mice and patients using a systems-level perspective. Methods: We acquired resting-state functional magnetic resonance imaging data during the early poststroke phase in a sample of human patients and compared the observed network changes with data from 2 mouse stroke models, that is, photothrombosis and distal middle cerebral artery occlusion. Importantly, data were subjected to the same processing steps, allowing a direct comparison of global network changes using graph theory. Results: We found that network parameters computed for both mouse models of stroke and humans follow a similar pattern in the postacute stroke phase. Parameters indicating the global communication structure's facilitation, such as small worldness and characteristic path length, were similarly changed in humans and mice in the first days after stroke. Additionally, small worldness correlated with concurrent motor impairment in humans. Longitudinal observation in the subacute phase revealed a negative correlation between initial small worldness and motor recovery in mice. Conclusions: We show that network measures based on resting-state functional magnetic resonance imaging data after stroke obtained in mice and humans share notable features. The observed network alterations could serve as therapeutic readout parameters for future translational studies in stroke research.

Diagnosis of Pseudoprogression Following Lomustine-Temozolomide Chemoradiation in Newly Diagnosed Glioblastoma Patients Using FET-PET.

PURPOSE: The CeTeG/NOA-09 phase III trial demonstrated a significant survival benefit of lomustine-temozolomide chemoradiation in patients with newly diagnosed glioblastoma with methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. Following lomustine-temozolomide chemoradiation, late and prolonged pseudoprogression may occur. We here evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-l-tyrosine (FET) for differentiating pseudoprogression from tumor progression. EXPERIMENTAL DESIGN: We retrospectively identified patients (i) who were treated off-study according to the CeTeG/NOA-09 protocol, (ii) had equivocal MRI findings after radiotherapy, and (iii) underwent additional FET-PET imaging for diagnostic evaluation (number of scans, 1-3). Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and dynamic FET uptake parameters (e.g., time-to-peak) were calculated. In patients with more than one FET-PET scan, relative changes of TBR values were evaluated, that is, an increase or decrease of >10% compared with the reference scan was considered as tumor progression or pseudoprogression. Diagnostic performances were evaluated using ROC curve analyses and Fisher exact test. Diagnoses were confirmed histologically or clinicoradiologically. RESULTS: We identified 23 patients with 32 FET-PET scans. Within 5-25 weeks after radiotherapy (median time, 9 weeks), pseudoprogression occurred in 11 patients (48%). The parameter TBRmean calculated from the FET-PET performed 10 ± 7 days after the equivocal MRI showed the highest accuracy (87%) to identify pseudoprogression (threshold, <1.95; P = 0.029). The integration of relative changes of TBRmean further improved the accuracy (91%; P < 0.001). Moreover, the combination of static and dynamic parameters increased the specificity to 100% (P = 0.005). CONCLUSIONS: The data suggest that FET-PET parameters are of significant clinical value to diagnose pseudoprogression related to lomustine-temozolomide chemoradiation.

Early Treatment Response Assessment Using 18F-FET PET Compared with Contrast-Enhanced MRI in Glioma Patients After Adjuvant Temozolomide Chemotherapy.

The goal of this study was to compare the value of contrast-enhanced MRI and O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) PET for response assessment in glioma patients after adjuvant temozolomide chemotherapy (TMZ). Methods: After biopsy or resection and completion of radiotherapy with concomitant TMZ, 41 newly diagnosed and histomolecularly characterized glioma patients (glioblastoma, 90%; age range, 20-79 y) were subsequently treated with adjuvant TMZ. MR and 18F-FET PET imaging were performed at baseline and after the second cycle of adjuvant TMZ. We obtained 18F-FET metabolic tumor volumes (MTVs) as well as mean and maximum tumor-to-brain ratios (TBRmean and TBRmax, respectively). Threshold values of 18F-FET PET parameters to predict outcome were established by receiver-operating-characteristic analyses using a median progression-free survival (PFS) of ≥ 9 mo and overall survival (OS) of ≥ 15 mo as reference. MRI response assessment was based on the Response Assessment in Neuro-Oncology (RANO) working group criteria. The predictive value of changes of 18F-FET PET and MRI parameters on survival was evaluated subsequently using univariate and multivariate survival estimates. Results: After 2 cycles of adjuvant TMZ chemotherapy, a treatment-induced reduction of MTV and TBRmax predicted a significantly longer PFS and OS (both P ≤ 0.03; univariate survival analyses) whereas RANO criteria were not significant (P > 0.05). Multivariate survival analysis revealed that TBRmax changes predicted a prolonged PFS (P = 0.012) and changes of MTV a prolonged OS (P = 0.005) independent of O6-methylguanine-DNA-methyltransferase promoter methylation and other strong prognostic factors. Conclusion: Changes of 18F-FET PET parameters appear to be helpful for identifying responders to adjuvant TMZ early after treatment initiation.

Connectivity-Related Roles of Contralesional Brain Regions for Motor Performance Early after Stroke.

Hemiparesis after stroke is associated with increased neural activity not only in the lesioned but also in the contralesional hemisphere. While most studies have focused on the role of contralesional primary motor cortex (M1) activity for motor performance, data on other areas within the unaffected hemisphere are scarce, especially early after stroke. We here combined functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to elucidate the contribution of contralesional M1, dorsal premotor cortex (dPMC), and anterior intraparietal sulcus (aIPS) for the stroke-affected hand within the first 10 days after stroke. We used "online" TMS to interfere with neural activity at subject-specific fMRI coordinates while recording 3D movement kinematics. Interfering with aIPS activity improved tapping performance in patients, but not healthy controls, suggesting a maladaptive role of this region early poststroke. Analyzing effective connectivity parameters using a Lasso prediction model revealed that behavioral TMS effects were predicted by the coupling of the stimulated aIPS with dPMC and ipsilesional M1. In conclusion, we found a strong link between patterns of frontoparietal connectivity and TMS effects, indicating a detrimental influence of the contralesional aIPS on motor performance early after stroke.

Role of the default mode resting-state network for cognitive functioning in malignant glioma patients following multimodal treatment.

BACKGROUND: Progressive cognitive decline following multimodal neurooncological treatment is a common observation in patients suffering from malignant glioma. Alterations of the default-mode network (DMN) represent a possible source of impaired neurocognitive functioning and were analyzed in these patients. METHODS: Eighty patients (median age, 51 years) with glioma (WHO grade IV glioblastoma, n = 57; WHO grade III anaplastic astrocytoma, n = 13; WHO grade III anaplastic oligodendroglioma, n = 10) and ECOG performance score 0-1 underwent resting-state functional MRI (rs-fMRI) and neuropsychological testing at a median interval of 13 months (range, 1-114 months) after initiation of therapy. For evaluation of structural and metabolic changes after treatment, anatomical MRI and amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) were simultaneously acquired to rs-fMRI on a hybrid MR/PET scanner. A cohort of 80 healthy subjects matched for gender, age, and educational status served as controls. RESULTS: The connectivity pattern within the DMN (12 nodes) of the glioma patients differed significantly from that of the healthy subjects but did not depend on age, tumor grade, time since treatment initiation, presence of residual/recurrent tumor, number of chemotherapy cycles received, or anticonvulsive medication. Small changes in the connectivity pattern were observed in patients who had more than one series of radiotherapy. In contrast, structural tissue changes located at or near the tumor site (including resection cavities, white matter lesions, edema, and tumor tissue) had a strong negative impact on the functional connectivity of the adjacent DMN nodes, resulting in a marked dependence of the connectivity pattern on tumor location. In the majority of neurocognitive domains, glioma patients performed significantly worse than healthy subjects. Correlation analysis revealed that reduced connectivity in the left temporal and parietal DMN nodes was associated with low performance in language processing and verbal working memory. Furthermore, connectivity of the left parietal DMN node also correlated with processing speed, executive function, and verbal as well as visual working memory. Overall DMN connectivity loss and cognitive decline were less pronounced in patients with higher education. CONCLUSION: Personalized treatment strategies for malignant glioma patients should consider the left parietal and temporal DMN nodes as vulnerable regions concerning neurocognitive outcome.

Brain responsivity provides an individual readout for motor recovery after stroke.

Promoting the recovery of motor function and optimizing rehabilitation strategies for stroke patients is closely associated with the challenge of individual prediction. To date, stroke research has identified critical pathophysiological neural underpinnings at the cellular level as well as with regard to network reorganization. However, in order to generate reliable readouts at the level of individual patients and thereby realize translation from bench to bedside, we are still in a need for innovative methods. The combined use of transcranial magnetic stimulation (TMS) and EEG has proven powerful to record both local and network responses at an individual's level. To elucidate the potential of TMS-EEG to assess motor recovery after stroke, we used neuronavigated TMS-EEG over ipsilesional primary motor cortex (M1) in 28 stroke patients in the first days after stroke. Twenty-five of these patients were reassessed after >3 months post-stroke. In the early post-stroke phase (6.7 ± 2.5 days), the TMS-evoked EEG responses featured two markedly different response morphologies upon TMS to ipsilesional M1. In the first group of patients, TMS elicited a differentiated and sustained EEG response with a series of deflections sequentially involving both hemispheres. This response type resembled the patterns of bilateral activation as observed in the healthy comparison group. By contrast, in a subgroup of severely affected patients, TMS evoked a slow and simplified local response. Quantifying the TMS-EEG responses in the time and time-frequency domain revealed that stroke patients exhibited slower and simple responses with higher amplitudes compared to healthy controls. Importantly, these patterns of activity changes after stroke were not only linked to the initial motor deficit, but also to motor recovery after >3 months post-stroke. Thus, the data revealed a substantial impairment of local effects as well as causal interactions within the motor network early after stroke. Additionally, for severely affected patients with absent motor evoked potentials and identical clinical phenotype, TMS-EEG provided differential response patterns indicative of the individual potential for recovery of function. Thereby, TMS-EEG extends the methodological repertoire in stroke research by allowing the assessment of individual response profiles.

The differential roles of contralesional frontoparietal areas in cortical reorganization after stroke.

BACKGROUND: Studies examining the contribution of contralesional brain regions to motor recovery after stroke have revealed conflicting results comprising both supporting and disturbing influences. Especially the relevance of contralesional brain regions beyond primary motor cortex (M1) has rarely been studied, particularly concerning the temporal dynamics post-stroke. METHODS: We, therefore, used online transcranial magnetic stimulation (TMS) interference to longitudinally assess the role of contralesional (right) frontoparietal areas for recovery of hand motor function after left hemispheric stroke: contralesional M1, contralesional dorsal premotor cortex (dPMC), and contralesional anterior intraparietal sulcus (IPS). Fourteen stroke patients and sixteen age-matched healthy subjects performed motor tasks of varying complexity with their (paretic) right hand. Motor performance was quantified using three-dimensional kinematic data. All patients were assessed twice, (i) in the first week, and (ii) after more than three months post-stroke. RESULTS: While we did not observe a significant effect of TMS interference on movement kinematics following the stimulation of contralesional M1 and dPMC in the first week post-stroke, we found improvements of motor performance upon interference with contralesional IPS across motor tasks early after stroke, an effect that persisted into the later phase. By contrast, for dPMC, TMS-induced deterioration of motor performance was only evident three months post-stroke, suggesting that a supportive role of contralesional premotor cortex might evolve with reorganization. CONCLUSION: We here highlight time-sensitive and region-specific effects of contralesional frontoparietal areas after left hemisphere stroke, which may influence on neuromodulation regimes aiming at supporting recovery of motor function post-stroke.