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Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally located in cortex-basal ganglia (BG) circuits. Increasing evidence suggests that motor impairments in untreated PD patients are linked to an excessive synchronization of cortex-BG activity at beta frequencies (13–30 Hz). Levodopa and subthalamic nucleus deep brain stimulation (STN-DBS) suppress pathological beta-band reverberation and improve the motor symptoms in PD. Yet a dynamic tuning of beta oscillations in BG-cortical loops is fundamental for movement-timing and synchronization, and the impact of PD therapies on sensorimotor functions relying on neural transmission in the beta frequency-range remains controversial. Here, we set out to determine the differential effects of network neuromodulation through dopaminergic medication (ON and OFF levodopa) and STN-DBS (ON-DBS, OFF-DBS) on tapping synchronization and accompanying cortical activities. To this end, we conducted a rhythmic finger-tapping study with high-density EEG-recordings in 12 PD patients before and after surgery for STN-DBS and in 12 healthy controls. STN-DBS significantly ameliorated tapping parameters as frequency, amplitude and synchrony to the given auditory rhythms. Aberrant neurophysiologic signatures of sensorimotor feedback in the beta-range were found in PD patients: their neural modulation was weaker, temporally sluggish and less distributed over the right cortex in comparison to controls. Levodopa and STN-DBS boosted the dynamics of beta-band modulation over the right hemisphere, hinting to an improved timing of movements relying on tactile feedback. The strength of the post-event beta rebound over the supplementary motor area correlated significantly with the tapping asynchrony in patients, thus indexing the sensorimotor match between the external auditory pacing signals and the performed taps. PD patients showed an excessive interhemispheric coherence in the beta-frequency range during the finger-tapping task, while under DBS-ON the cortico-cortical connectivity in the beta-band was normalized. Ultimately, therapeutic DBS significantly ameliorated the auditory-motor coupling of PD patients, enhancing the electrophysiological processing of sensorimotor feedback-information related to beta-band activity, and thus allowing a more precise cued-tapping performance.

IntroductionInterpersonal synchronization involves the alignment of behavioral, affective, physiological, and brain states during social interactions. It facilitates empathy, emotion regulation, and prosocial commitment. Mental disorders characterized by social interaction dysfunction, such as Autism Spectrum Disorder (ASD), Reactive Attachment Disorder (RAD), and Social Anxiety Disorder (SAD), often exhibit atypical synchronization with others across multiple levels. With the introduction of the “second-person” neuroscience perspective, our understanding of interpersonal neural synchronization (INS) has improved, however, so far, it has hardly impacted the development of novel therapeutic interventions.MethodsTo evaluate the potential of INS-based treatments for mental disorders, we performed two systematic literature searches identifying studies that directly target INS through neurofeedback (12 publications; 9 independent studies) or brain stimulation techniques (7 studies), following PRISMA guidelines. In addition, we narratively review indirect INS manipulations through behavioral, biofeedback, or hormonal interventions. We discuss the potential of such treatments for ASD, RAD, and SAD and using a systematic database search assess the acceptability of neurofeedback (4 studies) and neurostimulation (4 studies) in patients with social dysfunction.ResultsAlthough behavioral approaches, such as engaging in eye contact or cooperative actions, have been shown to be associated with increased INS, little is known about potential long-term consequences of such interventions. Few proof-of-concept studies have utilized brain stimulation techniques, like transcranial direct current stimulation or INS-based neurofeedback, showing feasibility and preliminary evidence that such interventions can boost behavioral synchrony and social connectedness. Yet, optimal brain stimulation protocols and neurofeedback parameters are still undefined. For ASD, RAD, or SAD, so far no randomized controlled trial has proven the efficacy of direct INS-based intervention techniques, although in general brain stimulation and neurofeedback methods seem to be well accepted in these patient groups.DiscussionSignificant work remains to translate INS-based manipulations into effective treatments for social interaction disorders. Future research should focus on mechanistic insights into INS, technological advancements, and rigorous design standards. Furthermore, it will be key to compare interventions directly targeting INS to those targeting other modalities of synchrony as well as to define optimal target dyads and target synchrony states in clinical interventions.

Abstract To explore the influence of bilateral subthalamic deep brain stimulation (STN-DBS) on car driving ability in patients with Parkinson’s disease (PD), we prospectively examined two age-matched, actively driving PD patient groups: one group undergone DBS-surgery (PD-DBS, n = 23) and one group that was eligible for DBS but did not undergo surgery (PD-nDBS, n = 29). In PD-DBS patients, investigation at Baseline was done just prior and at Follow-up 6–12 month after DBS-surgery. In PD-nDBS patients, time interval between Baseline and Follow-up was aimed to be comparable. To assess the general PD driving level, driving was assessed once in 33 age-matched healthy controls at Baseline. As results, clinical and driving characteristics of PD-DBS, PD-nDBS and controls did not differ at Baseline. At Follow-up, PD-DBS patients drove unsafer than PD-nDBS patients. This effect was strongly driven by two single PD-DBS participants (9%) with poor Baseline and disastrous Follow-up driving performance. Retrospectively, we could not identify any of the assessed motor and non-motor clinical Baseline characteristics as predictive for this driving-deterioration at Follow-up. Excluding these two outliers, comparable driving performance between PD-DBS and PD-nDBS patients not only at Baseline but also at Follow-up was demonstrated. Age, disease duration and severity as well as Baseline driving insecurity were associated with poorer driving performance at Follow-up. This first prospective study on driving safety in PD after DBS surgery indicates that DBS usually does not alter driving safety but might increase the risk for driving deterioration, especially in single subjects with already unsafe driving prior to DBS surgery.

Abstract Connectivity studies have significantly extended the knowledge on motor network alterations after stroke. Compared to interhemispheric or ipsilesional networks, changes in the contralesional hemisphere are poorly understood. Data obtained in the acute stage after stroke and in severely impaired patients are remarkably limited. This exploratory, preliminary study aimed to investigate early functional connectivity changes of the contralesional parieto-frontal motor network and their relevance for the functional outcome after severe motor stroke. Resting-state functional imaging data were acquired in 19 patients within the first 2 weeks after severe stroke. Nineteen healthy participants served as a control group. Functional connectivity was calculated from five key motor areas of the parieto-frontal network on the contralesional hemisphere as seed regions and compared between the groups. Connections exhibiting stroke-related alterations were correlated with clinical follow-up data obtained after 3–6 months. The main finding was an increase in coupling strength between the contralesional supplementary motor area and the sensorimotor cortex. This increase was linked to persistent clinical deficits at follow-up. Thus, an upregulation in contralesional motor network connectivity might be an early pattern in severely impaired stroke patients. It might carry relevant information regarding the outcome which adds to the current concepts of brain network alterations and recovery processes after severe stroke.

Abstract Background Unpredictable vegetative deteriorations made the treatment of patients with acute COVID-19 on intensive care unit particularly challenging during the first waves of the pandemic. Clinical correlates of dysautonomia and their impact on the disease course in critically ill COVID-19 patients are unknown. Methods We retrospectively analyzed data collected during a single-center observational study (March 2020–November 2021) which was performed at the University Medical Center Hamburg-Eppendorf, a large tertiary medical center in Germany. All patients admitted to ICU due to acute COVID-19 disease during the study period were included (n = 361). Heart rate variability (HRV) and blood pressure variability (BPV) per day were used as clinical surrogates of dysautonomia and compared between survivors and non-survivors at different time points after admission. Intraindividual correlation of vital signs with laboratory parameters were calculated and corrected for age, sex and disease severity. Results Patients who deceased in ICU had a longer stay (median days ± IQR, survivors 11.0 ± 27.3, non-survivors 14.1 ± 18.7, P = 0.85), in contrast time spent under invasive ventilation was not significantly different (median hours ± IQR, survivors 322 ± 782, non-survivors 286 ± 434, P = 0.29). Reduced HRV and BPV predicted lethal outcome in patients staying on ICU longer than 10 days after adjustment for age, sex, and disease severity. Accordingly, HRV was significantly less correlated with inflammatory markers (e.g. CRP and Procalcitonin) and blood carbon dioxide in non-survivors in comparison to survivors indicating uncoupling between autonomic function and inflammation in non-survivors. Conclusions Our study suggests autonomic dysfunction as a contributor to mortality in critically ill COVID-19 patients during the first waves of the pandemic. Serving as a surrogate for disease progression, these findings could contribute to the clinical management of COVID-19 patients admitted to the ICU. Furthermore, the suggested measure of dysautonomia and correlation with other laboratory parameters is non-invasive, simple, and cost-effective and should be evaluated as an additional outcome parameter in septic patients treated in the ICU in the future.

Abstract The accurate assessment of cerebrospinal fluid opening pressure during spinal puncture provides important medical information in diagnosis, prognosis and therapy of several neurological conditions. However, purpose-specific spinal needle choice is debated. While atraumatic needles are associated with lower incidence of post-puncture headache and re-hospitalisation, some clinicians believe that they lack in accuracy of CSF opening pressure assessment. Our primary objective was to investigate different needle types on correctly assessing CSF opening pressure. We compared typical clinically utilised traumatic (0.9 mm outer diameter) and atraumatic (0.7 mm; 0.45 mm) spinal needles with regards to the assessment of the opening pressure in an experimental spinal puncture model testing experimental and cerebrospinal fluids in predefined pressures. Our goal was to measure the time until indicated pressure levels were correctly shown. Atraumatic needles of at least 0.7 mm diameter had a similar accuracy as traumatic needles without significant differences in time-to-equilibrium. These results were independent of protein and glucose concentration and the presence of haemoglobin. This study demonstrates that atraumatic needles can be used to accurately measure CSF opening pressure. This knowledge might guide clinicians in their choice of needle and help to reduce post-puncture headaches and re-hospitalisation.

Abstract Background Patients with a left (LHS) or right hemispheric stroke (RHS) differ in terms of clinical symptoms due to lateralization of specific cortical functions. Studies on functional outcome after stroke and endovascular thrombectomy (EVT) comparing both hemispheres showed conflicting results so far. The impact of stroke laterality on patient-reported health-related quality of life (HRQoL) after EVT has not yet been adequately addressed and still remains unclear. Methods Consecutive stroke thrombectomy patients, derived from a multi-center, prospective registry (German Stroke Registry) between June 2015 and December 2019, were included in this study. At 90 days, outcome after EVT was assessed by the modified Rankin scale (mRS) and HRQoL using the European QoL-five dimensions questionnaire utility-index (EQ-5D-I; higher values indicate better HRQoL) in patients with LHS and RHS. Adjusted regression analysis was applied to evaluate the influence of stroke laterality on outcome after EVT. Results In total, 5683 patients were analyzed. Of these, 2953 patients (52.8%) had LHS and 2637 (47.2%) RHS. LHS patients had a higher baseline NIHSS (16 vs. 13, p

Abstract Background Previous studies have demonstrated that purinergic receptors could be therapeutic targets to modulate the inflammatory response in multiple models of brain diseases. However, tools for the selective and efficient targeting of these receptors are lacking. The development of new P2X7-specific nanobodies (nbs) has enabled us to effectively block the P2X7 channel. Methods Temporary middle cerebral artery occlusion (tMCAO) in wild-type (wt) and P2X7 transgenic (tg) mice was used to model ischemic stroke. Adenosine triphosphate (ATP) release was assessed in transgenic ATP sensor mice. Stroke size was measured after P2X7-specific nbs were injected intravenously (iv) and intracerebroventricularly (icv) directly before tMCAO surgery. In vitro cultured microglia were used to investigate calcium influx, pore formation via 4,6-diamidino-2-phenylindole (DAPI) uptake, caspase 1 activation and interleukin (IL)-1β release after incubation with the P2X7-specific nbs. Results Transgenic ATP sensor mice showed an increase in ATP release in the ischemic hemisphere compared to the contralateral hemisphere or the sham-treated mice up to 24 h after stroke. P2X7-overexpressing mice had a significantly greater stroke size 24 h after tMCAO surgery. In vitro experiments with primary microglial cells demonstrated that P2X7-specific nbs could inhibit ATP-triggered calcium influx and the formation of membrane pores, as measured by Fluo4 fluorescence or DAPI uptake. In microglia, we found lower caspase 1 activity and subsequently lower IL-1β release after P2X7-specific nb treatment. The intravenous injection of P2X7-specific nbs compared to isotype controls before tMCAO surgery did not result in a smaller stroke size. As demonstrated by fluorescence-activated cell sorting (FACS), after stroke, iv injected nbs bound to brain-infiltrated macrophages but not to brain resident microglia, indicating insufficient crossing of the blood–brain barrier of the nbs. Therefore, we directly icv injected the P2X7-specific nbs or the isotype nbs. After icv injection of 30 µg of P2X7 specific nbs, P2X7 specific nbs bound sufficiently to microglia and reduced stroke size. Conclusion Mechanistically, we can show that there is a substantial increase of ATP locally after stroke and that blockage of the ATP receptor P2X7 by icv injected P2X7-specific nbs can reduce ischemic tissue damage.

Abstract Technological advances of Deep Brain Stimulation (DBS) within the subthalamic nucleus (STN) for Parkinson’s disease (PD) provide increased programming options with higher programming burden. Reducing the effort of DBS optimization requires novel programming strategies. The objective of this study was to evaluate the feasibility of a semi-automatic algorithm-guided-programming (AgP) approach to obtain beneficial stimulation settings for PD patients with directional DBS systems. The AgP evaluates iteratively the weighted combination of sensor and clinician assessed responses of multiple PD symptoms to suggested DBS settings until it converges to a final solution. Acute clinical effectiveness of AgP DBS settings and DBS settings that were found following a standard of care (SoC) procedure were compared in a randomized, crossover and double-blind fashion in 10 PD subjects from a single center. Compared to therapy absence, AgP and SoC DBS settings significantly improved (p = 0.002) total Unified Parkinson’s Disease Rating Scale III scores (median 69.8 interquartile range (IQR) 64.6|71.9% and 66.2 IQR 58.1|68.2%, respectively). Despite their similar clinical results, AgP and SoC DBS settings differed substantially. Per subject, AgP tested 37.0 IQR 34.0|37 settings before convergence, resulting in 1.7 IQR 1.6|2.0 h, which is comparable to previous reports. Although AgP long-term clinical results still need to be investigated, this approach constitutes an alternative for DBS programming and represents an important step for future closed-loop DBS optimization systems.

Non-communicable diseases (NCDs), including coronary heart disease, stroke, hypertension, type 2 diabetes, dementia, depression and cancers, are on the rise worldwide and are often associated with a lack of physical activity (PA). Globally, the levels of PA among individuals are below WHO recommendations. A lack of PA can increase morbidity and mortality, worsen the quality of life and increase the economic burden on individuals and society. In response to this trend, numerous organisations came together under one umbrella in Hamburg, Germany, in April 2021 and signed the ‘Hamburg Declaration’. This represented an international commitment to take all necessary actions to increase PA and improve the health of individuals to entire communities. Individuals and organisations are working together as the ‘Global Alliance for the Promotion of Physical Activity’ to drive long-term individual and population-wide behaviour change by collaborating with all stakeholders in the community: active hospitals, physical activity specialists, community services and healthcare providers, all achieving sustainable health goals for their patients/clients. The ‘Hamburg Declaration’ calls on national and international policymakers to take concrete action to promote daily PA and exercise at a population level and in healthcare settings.

Abstract The aim of this study was to assess the effects of novel stimulation algorithms of deep brain stimulation (short pulse and directional stimulation) in the ventrointermediate thalamus and posterior subthalamic area (VIM/PSA-DBS) on tremor in Parkinson’s disease (PD) and to compare the effects with those in essential tremor (ET). We recruited six PD patients (70.8 ± 10.4 years) and seven ET patients (64.4 ± 9.9 years) with implanted VIM/PSA-DBS in a stable treatment condition (> 3 months postoperatively). Tremor severity and ataxia were assessed in four different stimulation conditions in a randomized order: DBS switched off (STIM OFF), omnidirectional stimulation with 60 µs (oDBS60), omnidirectional stimulation with 30 µs (oDBS30), directional stimulation at the best segment with 60 µs (dDBS60). In both patient groups, all three DBS stimulation modes reduced the total tremor score compared to STIM OFF, whereas stimulation-induced ataxia was reduced by oDBS30 and partially by dDBS60 compared to oDBS60. Tremor reduction was more pronounced in PD than in ET due to a limited DBS effect on intention and action-specific drawing tremor in ET. In PD and ET tremor, short pulse or directional VIM/PSA-DBS is an effective and well tolerated therapeutic option. Trial registration: The study was registered in the DRKS (ID DRKS00025329, 18.05.2021, German Clinical Trials Register, DRKS—Deutsches Register Klinischer Studien).

Abstract Cerebral small vessel disease (CSVD) is a common cause of morbidity and cognitive decline in the elderly population. However, characterizing the disease pathophysiology and its association with potential clinical sequelae in early stages is less well explored. We applied fixel-based analysis (FBA), a novel framework of investigating microstructural white matter integrity by diffusion-weighted imaging, to data of 921 participants of the Hamburg City Health Study, comprising middle-aged individuals with increased cerebrovascular risk in early stages of CSVD. In individuals in the highest quartile of white matter hyperintensity loads (n = 232, median age 63 years; IQR 15.3 years), FBA detected significantly reduced axonal density and increased atrophy of transcallosal fiber tracts, the bilateral superior longitudinal fasciculus, and corticospinal tracts compared to participants in the lowest quartile of white matter hyperintensities (n = 228, mean age 55 years; IQR 10 years). Analysis of all participants (N = 921) demonstrated a significant association between reduced fiber density and worse executive functions operationalized by the Trail Making Test. Findings were confirmed by complementary analysis of diffusion tensor metrics.

Summary: Background: The National Institutes of Health Stroke Scale (NIHSS) is the most frequently applied clinical rating scale for standardized assessment of neurological deficits in acute stroke in both clinical and research settings. Notwithstanding this prominent role, important questions regarding its validity remain insufficiently addressed: Investigations of the underlying dimensional structure of the NIHSS yielded inconsistent results that are largely not generalizable across studies. Neurobiological validations by linking measured deficit dimensions to brain anatomy and function are missing. Methods: We, therefore, employ advanced machine learning to identify an optimal representation of the dimensional structure of the NIHSS across two independent and heterogeneous stroke datasets (N = 503 and N = 690). Associated lesion locations are identified by multivariate lesion-deficit mapping (LDM) and their functional relevance is profiled based on a-priori task activation meta-data analysis, to provide an independent link to the behavioural level. Findings: A five-factor structure of the NIHSS was identified as the most robust and generalizable representation of stroke deficit dimensions across study populations, settings, and clinical phenotypes. Specifically, the identified dimensions comprised NIHSS items for (F1) left motor deficits, (F2) right motor deficits, (F3) dysarthria and facial palsy, (F4) language, and (F5) deficits in spatial attention and gaze. LDM linked four of these factors to differentially localized, eloquent neuroanatomical areas. Functional characterization of LDM results aligned with detected deficit dimensions, revealing associations with motor functions, language processing, and various functions in the perception domain. Interpretation: By cross-validating machine learning in heterogeneous multi-site stroke cohorts, we report evidence on the validity of the NIHSS: We identified an overarching structure of the NISHS containing a five-dimensional representation of stroke deficits. We provide an anatomical map of the NIHSS that is of value for future applications of individualized stroke treatment and rehabilitation. Funding: This research was supported by the National Key R&D Program of China (Grant No. 2021YFC2502200), the National Human Brain Project of China (Grant No. 2022ZD0214000)”, the German Research Foundation (Deutsche Forschungsgemeinschaft), Project 178316478 (A1, C1, C2), and Project 454012190 of the SPP 2041, the Helmholtz Portfolio Theme “Supercomputing and Modelling for the Human Brain” and Helmholtz Imaging Platform grant NimRLS (ZT-I-PF-4-010).

Abstract Background Impaired motor functions after stroke are common and negatively affect patients' activities of daily living and quality of life. In particular, hand motor function is essential for daily activities, but often returns slowly and incompletely after stroke. However, few data are available on the long-term dynamics of motor recovery and self-reported health status after stroke. The Interdisciplinary Platform for Rehabilitation Research and Innovative Care of Stroke Patients (IMPROVE) project aims to address this knowledge gap by studying the clinical course of recovery after inpatient rehabilitation. Methods In this prospective observational longitudinal multicenter study, patients were included towards the end of inpatient rehabilitation after ischemic or hemorrhagic stroke. Follow-up examination was performed at three, six, and twelve months after enrollment. Motor function was assessed by the Upper Extremity Fugl-Meyer Assessment (FMA), grip and pinch strength, and the nine-hole peg test. In addition, Patient-Reported Outcomes Measurement Information System 10-Question Short Form (PROMIS-10) was included. Linear mixed effect models were fitted to analyze change over time. To study determinants of hand motor function, patients with impaired hand function at baseline were grouped into improvers and non-improvers according to hand motor function after twelve months. Results A total of 176 patients were included in the analysis. Improvement in all motor function scores and PROMIS-10 was shown up to 1 year after inpatient rehabilitation. FMA scores improved by an estimate of 5.0 (3.7–6.4) points per year. In addition, patient-reported outcome measures increased by 2.5 (1.4–3.6) and 2.4 (1.4–3.4) per year in the physical and mental domain of PROMIS-10. In the subgroup analysis non-improvers showed to be more often female (15% vs. 55%, p = 0.0155) and scored lower in the Montreal Cognitive Assessment (25 [23–27] vs. 22 [20.5–24], p = 0.0252). Conclusions Continuous improvement in motor function and self-reported health status is observed up to 1 year after inpatient stroke rehabilitation. Demographic and clinical parameters associated with these improvements need further investigation. These results may contribute to the further development of the post-inpatient phase of stroke rehabilitation. Trial registration: The trial is registered at ClinicalTrials.gov (NCT04119479).

Age-related cortical atrophy, approximated by cortical thickness measurements from magnetic resonance imaging, follows a characteristic pattern over the lifespan. Although its determinants remain unknown, mounting evidence demonstrates correspondence between the connectivity profiles of structural and functional brain networks and cortical atrophy in health and neurological disease. Here, we performed a cross-sectional multimodal neuroimaging analysis of 2633 individuals from a large population-based cohort to characterize the association between age-related differences in cortical thickness and functional as well as structural brain network topology. We identified a widespread pattern of age-related cortical thickness differences including “hotspots” of pronounced age effects in sensorimotor areas. Regional age-related differences were strongly correlated within the structurally defined node neighborhood. The overall pattern of thickness differences was found to be anchored in the functional network hierarchy as encoded by macroscale functional connectivity gradients. Lastly, the identified difference pattern covaried significantly with cognitive and motor performance. Our findings indicate that connectivity profiles of functional and structural brain networks act as organizing principles behind age-related cortical thinning as an imaging surrogate of cortical atrophy.

Abstract Background Lymphocytes have dichotomous functions in ischemic stroke. Regulatory T cells are protective, while IL-17A from innate lymphocytes promotes the infarct growth. With recent advances of T cell-subtype specific transgenic mouse models it now has become possible to study the complex interplay of T cell subpopulations in ischemic stroke. Methods In a murine model of experimental stroke we analyzed the effects of IL-10 on the functional outcome for up to 14 days post-ischemia and defined the source of IL-10 in ischemic brains based on immunohistochemistry, flow cytometry, and bone-marrow chimeric mice. We used neutralizing IL-17A antibodies, intrathecal IL-10 injections, and transgenic mouse models which harbor a deletion of the IL-10R on distinct T cell subpopulations to further explore the interplay between IL-10 and IL-17A pathways in the ischemic brain. Results We demonstrate that IL-10 deficient mice exhibit significantly increased infarct sizes on days 3 and 7 and enlarged brain atrophy and impaired neurological outcome on day 14 following tMCAO. In ischemic brains IL-10 producing immune cells included regulatory T cells, macrophages, and microglia. Neutralization of IL-17A following stroke reversed the worse outcome in IL-10 deficient mice and intracerebral treatment with recombinant IL-10 revealed that IL-10 controlled IL-17A positive lymphocytes in ischemic brains. Importantly, IL-10 acted differentially on αβ and γδ T cells. IL-17A producing CD4+ αβ T cells were directly controlled via their IL-10-receptor (IL-10R), whereas IL-10 by itself had no direct effect on the IL-17A production in γδ T cells. The control of the IL-17A production in γδ T cells depended on an intact IL10R signaling in regulatory T cells (Tregs). Conclusions Taken together, our data indicate a key function of IL-10 in restricting the detrimental IL-17A-signaling in stroke and further supports that IL-17A is a therapeutic opportunity for stroke treatment.

Background and aims: We aimed to determine the association of carotid intima media thickness (CIMT), carotid plaques, and heart function with peak systolic velocity (PSV) of the common (CCA) and internal carotid artery (ICA) in a cross-sectional study. Methods: In the population-based Hamburg-City-Health-Study participants between 45 and 74 years were recruited. Cardio-vascular risk factors were assessed by history, blood samples, and clinical examination. CIMT, plaques, and PSV were determined by carotid ultrasound. Serum N-terminal brain natriuretic peptide (NT-proBNP) was determined as a biomarker for cardiac dysfunction, and left ventricular ejection fraction (LVEF) was quantified by echocardiography. Participants with carotid stenosis were excluded. Data were analyzed by multivariate linear regression. Results: We included 8567 participants, median age was 62 years, 51.8% were women. Median CIMT was 0.75 mm, NT-proBNP 80 pg/ml, LVEF 58.5%, and 30.4% had carotid plaques. For women PSV decreased in decades from 89 to 73 cm/s in CCAs and 78 to 66 cm/s in ICAs, and for men from 91 to 76 cm/s in CCAs and from 70 to 66 cm/s in ICAs. Corrected for age, sex, red blood cell count, and blood pressure, in CCAs lower PSV was associated with carotid plaques (p

IntroductionThis study assesses the association of comorbidity burden and polypharmacy with self-reported quality of life after stroke.Patients and methodsWe performed a post-hoc analysis of a prospective, single-center, observational study of outcome evaluation by patient-reported outcome measures in stroke clinical practice. Consecutive patients with acute ischemic stroke (AIS) were enrolled and self-reported health–related quality of life (HrQoL) was assessed 90 days after acute stroke using the Patient-reported Outcomes Measurement Information System 10-Question Short-Form (PROMIS-10). Comorbidities at baseline were assessed by the Charlson Comorbidity Index (CCI). Polypharmacy was defined as medication intake of ≥5 at baseline. We used linear regression analysis to study the association of CCI, polypharmacy and other clinical covariates with HrQoL after stroke.ResultsOf 781 patients (median age 76 years, 48.4% female) enrolled, 30.2% had a CCI Score ≥2, and 31.5% presented with polypharmacy. At follow up, 71 (9.1%) had died. In 409 (52.4%) reached for outcome evaluation, Global Physical Health T-Score was 43.8 ± 10 and Global Mental Health T-Score was 43.5 ± 8.76, indicating lower HrQoL than the average population. A CCI Score ≥2, higher NIHSS Score, female sex, dependency on others for dressing, toileting and mobility before index stroke, atrial fibrillation and hypertension were independent predictors of worse physical and mental health outcomes, while polypharmacy was not.ConclusionIn patients with AIS, high comorbidity burden and polypharmacy are frequent. Comorbidity burden at admission is independently associated with worse self-reported physical and mental health three months after stroke.

Homoarginine is associated with cardio- and cerebrovascular morbidity and mortality. However, the underlying pathomechanisms remain elusive. Here, we evaluated the association of homoarginine with adverse events (i.e., death, stroke, and myocardial infarction) and carotid intima-media thickness (cIMT) in stroke patients. In the prospective bioMARKers in STROKE (MARK-STROKE) cohort, patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled. Plasma homoarginine concentrations were analyzed and associated with clinical phenotypes in cross-sectional (374 patients) and prospective (273 patients) analyses. Adjustments for possible confounders were evaluated. A two-fold increase in homoarginine was inversely associated with the National Institutes of Health Stroke Scale (NIHSS) score at admission, cIMT, and prevalent atrial fibrillation (mean factor −0.68 [95% confidence interval (CI): −1.30, −0.07], −0.14 [95% CI: −0.22, −0.05]; and odds ratio 0.57 [95% CI: 0.33, 0.96], respectively). During the follow-up (median 284 [25th, 75th percentile: 198, 431] days), individuals with homoarginine levels in the highest tertile had fewer incident events compared with patients in the lowest homoarginine tertile independent of traditional risk factors (hazard ratio 0.22 [95% CI: 0.08, 0.63]). A lower prevalence of atrial fibrillation and a reduced cIMT pinpointed potential underlying pathomechanisms.

Abstract Background We aimed to identify groups of patients with similar health status after stroke, assessed by patient reported outcome measures (PROMs), to improve initial risk stratification. Methods In a prospective study, inpatients were recruited during acute stroke treatment. Demographics, history, and cardio-vascular risk factors were assessed at baseline. Self-reported functional status, physical and mental health as well as anxiety and depressive symptoms were assessed 3 and 12 months after stroke and used to identify latent classes. The association of patient characteristics with latent class membership was investigated with multinomial logistic regression. Results Of the 650 patients included with a mean age of 75 years and 48% female, 70% had ischemic, 6% hemorrhagic strokes, and 24% transient ischemic attacks. Median NIHSS on admission was 2 (IQR:0,5). Values of PROMs remained comparable at 3 and 12 months. A three-class model was developed, differentiating between patients with mildly (75%), moderately (17%), and severely (8%) impaired self-reported health status. Adjusted for univariately significant baseline characteristics, initial NIHSS distinguished mild- from moderate-, and moderate- from severe-class-membership (p

Abstract Background Idiopathic intracranial hypertension (IIH) is defined by an increased cerebrospinal fluid pressure in the absence of inflammation, structural obstructions, or mass lesions. Although the underlying pathogenesis of IIH is not fully understood, associations with specific risk factors as obesity, obstruction of cerebral venous sinuses, medications, endocrine or systemic conditions and chronic kidney disease have been described. Immune-complex glomerulonephritis as IgA-nephropathy is a frequent cause of chronic kidney failure, which was reported previously in one IIH patient. To date, there is no knowledge about the variable relation of immune-complex nephritis, kidney function and the course of IIH. Case presentation We report three cases (two females) of concurrent diagnosis of IIH and immune-complex glomerulonephritis. All patients presented with typical IIH symptoms of headache and visual disturbances. Two patients had been diagnosed with IgA-nephropathy only few weeks prior to IIH diagnosis. The third patient had been diagnosed earlier with terminal kidney failure due to a cryoglobulin glomerulonephritis. Conclusion We propose a possible link between renal deposition of immune-complexes and increased cerebrospinal fluid pressure. Pathophysiological hypotheses and clinical implications are discussed. We recommend clinical awareness and further systematic research to obtain more information on the association of IIH and immune-complex glomerulonephritis.

Abstract The aging of the nervous system is a heterogeneous process. It remains a significant challenge to identify relevant markers of pathological and healthy brain aging. A central aspect of aging are decreased sensory acuities, especially because they correlate with the decline in higher cognitive functioning. Sensory and higher cognitive processing relies on information flow between distant brain areas. Aging leads to disintegration of the underlying white matter tracts. While this disintegration is assumed to contribute to higher cognitive decline, data linking structural integrity and sensory function are sparse. The investigation of their interrelation may provide valuable insight into the mechanisms of brain aging. We used a combined behavioral and neuroimaging approach and investigated to what extent changes in microstructural white matter integrity reflect performance declines in tactile pattern recognition with aging. Poor performance in older participants was related to decreased integrity in the anterior corpus callosum. Probabilistic tractography showed that this structure is connected to the prefrontal cortices. Our data point to decreased integrity in the anterior corpus callosum as a marker for advanced brain aging. The correlation between impaired tactile recognition and disintegration in frontal brain networks could provide an explanation why the decrease of sensory function predicts cognitive decline.

Abstract Stroke has a deleterious impact on quality of life. However, it is less well known if stroke lesions in different brain regions are associated with reduced quality of life (QoL). We therefore investigated this association by multivariate lesion-symptom mapping. We analyzed magnetic resonance imaging and clinical data from the WAKE-UP trial. European Quality of Life 5 Dimensions (EQ-5D) 3 level questionnaires were completed 90 days after stroke. Lesion symptom mapping was performed using a multivariate machine learning algorithm (support vector regression) based on stroke lesions 22–36 h after stroke. Brain regions with significant associations were explored in reference to white matter tracts. Of 503 randomized patients, 329 were included in the analysis (mean age 65.4 years, SD 11.5; median NIHSS = 6, IQR 4–9; median EQ-5D score 90 days after stroke 1, IQR 0–4, median lesion volume 3.3 ml, IQR 1.1–16.9 ml). After controlling for lesion volume, significant associations between lesions and EQ-5D score were detected for the right putamen, and internal capsules of both hemispheres. Multivariate lesion inference analysis revealed an association between injuries of the cortico-spinal tracts with worse self-reported quality of life 90 days after stroke in comparably small stroke lesions, extending previous reports of the association of striato-capsular lesions with worse functional outcome. Our findings are of value to identify patients at risk of impaired QoL after stroke.

Abstract Gait disorders in patients with Parkinson’s disease (PD) impact their mobility and self-dependence. Gait training and dual-task (DT)-training improve gait quality. This study aims to assess the feasibility of a specific, gradually intensified DT-training for PD patients with a special focus on gait performance under single task (ST) and DT conditions. Correlations to Freezing of Gait (FoG) were examined. 17 PD patients (70.1 ± 7.4 years, H&Y Stadium 2–3, FoG-Q 9.0 ± 5.5) participated in a four-week DT-training (1x/week, 60 min) with progressively increasing task difficulty and number of tasks. Gait performance (spatiotemporal parameters) was assessed during ST and DT conditions. The training improved DT gait performance, especially gait velocity + 0.11 m/s; (F(2,16) = 7.163; p = .0171; η2part = .309) and step length (+ 5.73 cm). Also, physical well-being and absolved walking distance improved significantly. Correlation analyses of the FoG score at baseline with relative change of gait metrics post-training revealed significant correlations with training-induced changes of step length and improvement of gait velocity. Overall, the developed DT-training was feasible and effective. Further studies should examine the long-term benefits and the optimal setting to achieve the highest impact. The study was registered in the DRKS (ID DRKS00018084, 23.1.20).

Abstract Background We report the case of a patient with recurrent episodes of disturbed memory suggestive of transient epileptic amnesia, and a focal hippocampal lesion typically associated with transient global amnesia. We argue how careful consideration of clinical, electrophysiological and imaging findings can resolve this apparent contradiction and lead to a diagnosis of early symptomatic post-stroke seizures that links brain structure to function in a new, clinically relevant way. Case presentation A 70-year-old patient was identified in clinical practice in our tertiary care centre and was evaluated clinically as well as by repeated electroencephalography and magnetic resonance imaging. The presenting complaint were recurrent episodes of short-term memory disturbance which manifested as isolated anterograde amnesia on neurocognitive evaluation. EEG and MRI revealed predominantly right frontotemporal spikes and a punctate diffusion-restricted lesion in the left hippocampus, respectively. Both symptoms and EEG changes subsided under anticonvulsant treatment with levetiracetam. Conclusions Our report contributes to the current discussion of clinical challenges in the differential diagnosis of transient memory disturbance. It suggests that focal diffusion-restricted hippocampal lesions, as seen in TGA, might be ischemic and thus highlights the importance of considering post-stroke seizures as a possible cause of transient memory disturbance.

IntroductionHigher white blood cell (WBC) count is associated with poor functional outcome in acute ischemic stroke (AIS). However, little is known about whether the association is modified by treatment with intravenous alteplase.MethodsWAKE-UP was a randomized controlled trial of the efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in unknown onset stroke. WBC count was measured on admission and again at 22–36 h after randomization to treatment (follow-up). Favorable outcome was defined by a score of 0 or 1 on the modified Rankin scale (mRS) 90 days after stroke. Further outcome were stroke volume and any hemorrhagic transformation (HT) that were assessed on follow-up CT or MRI. Multiple logistic regression analysis was used to assess the association between outcome and WBC count and treatment group.ResultsOf 503 randomized patients, WBC count and baseline parameters were available in 437 patients (μ = 64.7 years, 35.2% women) on admission and 355 patients (μ = 65.1 years, 34.1% women) on follow-up. Median WBC count on admission was 7.6 × 109/L (interquartile range, IQR, 6.1–9.4 × 109/L) and 8.2 × 109/L (IQR, 6.7–9.7 × 109/L) on follow-up. Higher WBC count both on admission and follow-up was associated with lower odds of favorable outcome, adjusted for age, National Institutes of Health (NIH) Stroke Scale Score, temperature, and treatment (alteplase vs. placebo, adjusted odds ratio, aOR 0.85, 95% confidence interval [CI] 0.78–0.94 and aOR 0.88, 95% CI 0.79–0.97). No interaction between WBC count and treatment group was observed (p = 0.11). Furthermore, WBC count on admission and follow-up was significantly associated with HT (aOR 1.14, 95% CI 1.05–1.24 and aOR 1.13, 95% CI 1.00–1.26). Finally, WBC count on follow-up was associated with larger stroke volume (aOR 2.57, 95% CI 1.08–6.07).ConclusionHigher WBC count is associated with unfavorable outcome, an increased risk of HT, and larger stroke volume, independent of treatment with alteplase. Whether immunomodulatory manipulation of WBC count improves stroke outcome needs to be tested.Trial RegistrationClinicalTrials.gov Identifier: NCT01525290.

The effects of thrombolysis therapy in stroke on structural connectivity are not well understood. Here, the authors show with causal mediation analysis that the clinical benefits of thrombolysis in anterior circulation stroke are mediated via structural connectivity.

Abstract Introduction Stroke has a long-term impact on functional status and quality of life in multiple health domains. A well-coordinated managed care program for stroke patients is crucial for ameliorating patients’ health and cost-efficient use of resources. The aim of this study is the implementation and evaluation of an optimised cross-sectoral, coordinated and managed care program for stroke patients bridging secondary and tertiary care. Methods In this multi-center mixed method sequentially controlled intervention study, stroke patients with ischemic stroke (I63), transient ischemic attack and related syndromes (G45), or intracerebral haermorrhage (I64) will be invited to participate. For a 12-months period, 235 consecutive patients are expected to be enrolled and assigned standard of care treatment as an active control group. During the following 12 months, 235 consecutive patients will be enrolled and assigned to a post stroke intervention program. The StroCare intervention consists of repeated outpatient visits with specialized stroke teams, the implementation of a case manager, the use of an electronical tool for communication between acute care, rehabilitation facilities, and out-patient care, and the definition of individualized treatment targets. Patients will be followed up for 24 months. The primary outcome is health-related quality of life measured by the Patient-Reported Outcomes Measurement Information System 10-Question Short Form (PROMIS-10) at 12 months after the index event, i.e. stroke or TIA. For the qualitative survey of the implementation process, 21 patients in the intervention group will be interviewed after implementation of the interventions. In addition, 20 health care providers and staff members will be interviewed before and after implementation. Additionally, economic outcomes will be evaluated after 6 and 12 months. Perspective The study will not only provide information about the tested intervention but is likely to be helpful for clinicians, suppliers of reimbursement, and researchers in implementing and evaluating complex interventions in stroke care in general. With this program, the health care system will have a reference model at its disposal for transfer to other regions and settings. Trial registration The trial is registered at ClinicalTrials.gov ( NCT04159324 ). Approval of the local ethics committee (Ethik-Kommission der Ärztekammer Hamburg, Niedersachsen, Schleswig-Holstein) has been obtained.

Abstract While there is evidence that sensory processing and multisensory integration change with age, links between these alterations and their relation to cognitive status remain unclear. In this study, we assessed sensory thresholds and performance of healthy younger and older adults in a visuotactile delayed match-to-sample task. Using Bayesian structural equation modelling (BSEM), we explored the factors explaining cognitive status in the group of older adults. Additionally, we applied transcranial alternating current stimulation (tACS) to a parieto-central network found to underlie visuotactile interactions and working memory matching in our previous work. Response times and signal detection measures indicated enhanced multisensory integration and enhanced benefit from successful working memory matching in older adults. Further, tACS caused a frequency-specific speeding (20 Hz) and delaying (70 Hz) of responses. Data exploration suggested distinct underlying factors for sensory acuity and sensitivity d’ on the one side, and multisensory and working memory enhancement on the other side. Finally, BSEM showed that these two factors labelled ‘sensory capability’ and ‘information integration’ independently explained cognitive status. We conclude that sensory decline and enhanced information integration might relate to distinct processes of ageing and discuss a potential role of the parietal cortex in mediating augmented integration in older adults.

Hyperscanning studies have begun to unravel the brain mechanisms underlying social interaction, indicating a functional role for interpersonal neural synchronization (INS), yet the mechanisms that drive INS are poorly understood. The current study, thus, addresses whether INS is functionally-distinct from synchrony in other systems – specifically the autonomic nervous system and motor behavior. To test this, we used concurrent functional near-infrared spectroscopy - electrocardiography recordings, while N = 34 mother-child and stranger-child dyads engaged in cooperative and competitive tasks. Only in the neural domain was a higher synchrony for mother-child compared to stranger-child dyads observed. Further, autonomic nervous system and neural synchrony were positively related during competition but not during cooperation. These results suggest that synchrony in different behavioral and biological systems may reflect distinct processes. Furthermore, they show that increased mother-child INS is unlikely to be explained solely by shared arousal and behavioral similarities, supporting recent theories that postulate that INS is higher in close relationships.

Ischemic stroke leads to excitability changes of the motor network as probed by means of transcranial magnetic stimulation (TMS). There is still limited data that shows to what extent structural alterations of the motor network might be linked to excitability changes. Previous results argue that the microstructural state of specific corticofugal motor tracts such as the corticospinal tract associate with cortical excitability in chronic stroke patients. The relationship between changes of cortical anatomy after stroke, as operationalized by means of decreases or increases in local cortical thickness (CT), has scarcely been addressed. In the present study, we re-analyzed TMS data and recruitment curve properties of motor evoked potentials and CT data in a group of 14 well-recovered chronic stroke patients with isolated supratentorial subcortical lesions. CT data of the stroke patients were compared to CT data of 17 healthy controls. Whole-brain and region-of-interest based analyses were conducted to relate CT data to measures of motor cortical excitability and clinical data. We found that stroke patients exhibited significantly reduced CT not only in the ipsilesional primary motor cortex but also in numerous secondary motor and non-motor brain regions, particularly in the ipsilesional hemisphere including areas along the central sulcus, the inferior frontal sulcus, the intraparietal sulcus, and cingulate cortices. We could not detect any significant relationship between the extent of CT reduction and stroke-related excitability changes of the motor network or clinical scores.

BackgroundThe preferable position of Deep Brain Stimulation (DBS) electrodes is proposed to be located in the dorsolateral subthalamic nucleus (STN) to improve general motor performance. The optimal DBS electrode localization for the post-operative improvement of balance and gait is unknown.MethodsIn this single-center, retrospective analyses, 66 Parkinson’s disease (PD) patients (24 female, age 63 ± 7 years) were assessed pre- and post-operatively (8.45 ± 4.2 months after surgery) by using MDS-UPDRS, freezing of gait (FoG) score, Giladi’s gait and falls questionnaire and Berg balance scale. The clinical outcome was related to the DBS electrode coordinates in x, y, z plane as revealed by image-based reconstruction (SureTune™). Binomial generalized linear mixed models with fixed-effect variables electrode asymmetry, parkinsonian subtype, medication, age class and clinical DBS induced changes were analyzed.ResultsSubthalamic nucleus-deep brain stimulation improved all motor, balance and FoG scores in MED OFF condition, however there were heterogeneous results in MED ON condition. DBS electrode reconstructed coordinates impacted the responsiveness of axial symptoms. FoG and balance responders showed slightly more medially located STN electrode coordinates and less medio-lateral asymmetry of the electrode reconstructed coordinates across hemispheres compared to non-responders.ConclusionDeep brain stimulation electrode reconstructed coordinates, particularly electrode asymmetry on the medio-lateral axis affected the post-operative responsiveness of balance and FoG symptoms in PD patients.

Abstract Background One quarter to one third of patients eligible for systemic thrombolysis are on antiplatelet therapy at presentation. In this study, we aimed to assess the safety and efficacy of intravenous thrombolysis in stroke patients on prescribed antiplatelet therapy in the WAKE-UP trial. Methods WAKE-UP was a multicenter, randomized, double-blind, placebo-controlled clinical trial to study the efficacy and safety of MRI-guided intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time. The medication history of all patients randomized in the WAKE-UP trial was documented. The primary safety outcome was any sign of hemorrhagic transformation on follow-up MRI. The primary efficacy outcome was favorable functional outcome defined by a score of 0–1 on the modified Rankin scale at 90 days after stroke, adjusted for age and baseline stroke severity. Logistic regression models were fitted to study the association of prior antiplatelet treatment with outcome and treatment effect of intravenous alteplase. Results Of 503 randomized patients, 164 (32.6%) were on antiplatelet treatment. Patients on antiplatelet treatment were older (70.3 vs. 62.8 years, p

Abstract Background The anatomical distribution of acute lacunar infarcts has mainly been studied for supratentorial lesions. In addition, little is known about the association with distinct stroke symptoms, not summarized as classical lacunar syndromes. We aimed to describe the spatial lesion distribution of acute supra- and infratentorial lacunar infarcts and their association with stroke symptoms in patients eligible for thrombolysis. Methods All patients enrolled in the WAKE-UP trial (efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in wake-up stroke) were screened for lacunar infarcts on diffusion-weighted imaging (DWI). The relationship between the anatomical distribution of supra- and infratentorial lacunar infarcts, their demographic characteristics and acute stroke symptoms, defined by the National Institutes of Health Stroke Scale (NIHSS) score, were correlated and compared. Results Maps of lesion distribution from 224 lacunar infarct patients (76 [33.9%] females, mean age [standard deviation] of 63.4 [11.5] years) were generated using computational image mapping methods. Median infarct volume was 0.73 ml (interquartile range [IQR] 0.37–1.15 ml). Median NIHSS sum score on hospital arrival was 4 (IQR 3–6). 165 (73.7%) patients had lacunar infarcts in the supratentorial deep white or grey matter, while 59 (26.3%) patients had infratentorial lacunar infarcts. Patients with supratentorial lacunar infarcts presented with a significantly lower occurrence of deficits in the NIHSS items gaze (p

Abstract Objectives Dysphagia is a frequent and highly relevant symptom in Parkinson's disease (PD) due to high associated morbidity and mortality. To compare the effect of simultaneous stimulation of the subthalamic nucleus (STN) and substantia nigra (SNr) with conventional STN‐stimulation on swallowing function in Parkinson's disease. Methods In this controlled, randomized, double‐blind, cross‐over clinical trial, 15 PD patients were assessed with DBS switched off (STIM OFF), STN‐DBS, STN + SNr‐DBS. Patients and 32 age‐matched healthy controls were examined clinically and by flexible‐endoscopic evaluation of swallowing (FEES) to evaluate the swallowing function. The primary endpoint was the assessment of residues, secondary endpoints were penetration/aspiration, leakage, retained pharyngeal secretions, drooling, and assessments of the patient’s self‐perception of swallowing on a visual analog scale. Results Compared with healthy controls PD patients showed significantly more pharyngeal residues in STIM OFF and both DBS modes. Residues or aspiration events were found in 80% of the patients under STN‐stimulation. Simultaneous STN + SNr‐stimulation had no additional positive effect on objective dysphagia and self‐reported swallowing function compared to STN‐DBS. Interpretation Simultaneous STN + SNr‐stimulation seems to have no additional beneficial effects on dysphagia when compared with conventional STN‐stimulation, but did not deteriorate the swallowing function. If STN + SNr‐stimulation is planned to be applied for the improvement of axial symptoms and gait disorders in PD patients, it can be considered safe in terms of dysphagia.

Abstract Introduction Stroke and its long-term consequences pose major challenges for the lives of those affected and healthcare systems. Neurological rehabilitation therefore primarily attempts to improve function in order to increase independence in activities of daily living, and to enable social participation. There is only scarce data on dynamics of functional recovery after patients discharge from inpatient neurological rehabilitation. Even less is known about the patient’s perspective on long-term recovery from stroke. The Interdisciplinary Platform for Rehabilitation Research and Innovative Care of Stroke Patients (IMPROVE) aims to address this knowledge gap by providing new insights into the dynamics and extent of functional recovery from stroke beyond inpatient rehabilitation treatment. Methods We provide the protocol for an observational, longitudinal, multicenter study conducted in an Universitary Stroke Center in cooperation with five Neurological Rehabilitation Centers in Northern Germany. Patients who suffered from ischemic or hemorrhagic stroke will be enrolled by the end of inpatient rehabilitation and followed up to 1 year. In addition, a group of chronic stroke patients and a group of craniocerebral trauma patients will be enrolled as a comparison group. Data on stroke characteristics, vascular risk factors, co-morbidities, social support, and demographics will be recorded. Comprehensive clinical evaluation will be performed at baseline, three, six, and twelve months after enrollment. The assessments and scores used reflect the three components of the International Classification of Functioning, Disability and Health (ICF), some of them are tests regularly used in rehabilitation settings. Tests of motor function, cognition, and mood are included, as are tests of self-reported health-related quality of life. Primary outcome measure is a hand motor score, built by the sum of the hand items of the Fugl-Meyer Assessment as an objective measurement of hand function at 12 months after enrollment. Predictors of the primary outcome will be analyzed using linear regression analysis. Perspective The results of IMPROVE will inform about the long-term dynamics of functional stroke recovery after patients’ discharge from inpatient rehabilitation and will provide insights into the association of clinical and demographic factors with recovery of function. Trial registration The protocol is registered at ClinicalTrials.gov ( NCT04119479 ).

Abstract Background Randomized controlled trials (RCTs) demonstrated efficacy and safety of endovascular treatment (ET) in anterior circulation large vessel occlusions (LVO). We aimed at investigating how stroke patients treated by thrombectomy in clinical practice and their outcome compare to cohorts and results of thrombectomy trials. Methods In a prospective study, we consecutively included stroke patients treated by thrombectomy (2015–2017). Baseline characteristics, procedural and outcome data were analyzed. Outcome was assessed by modified Rankin Scale (mRS) at 90 days. Ordinal regression analysis was performed to identify predictors of outcome. Results Thrombectomy was applied in 264 patients (median 75 years, 49.6% female). Median baseline National Institutes of Health Stroke Scale (NIHSS) was 16, 58.0% received concomitant intravenous thrombolysis, 62.1% were referred from external hospitals. Median Alberta Stroke Program Early CT Score (ASPECTS) was 7. Successful recanalization (modified Thrombolysis in Cerebral Infarction Score, mTICI 2b/3) was achieved in 72.0%. Symptomatic intracranial hemorrhage (sICH) occurred in 4.5%. Independent outcome (mRS 0–2) was achieved in 26.2%, poor outcome (mRS 5–6) in 49.2%. Only 33.5% met the stringent enrolment criteria of previous RCTs. Lower age, baseline NIHSS, pre-stroke mRS, higher ASPECTS, and successful recanalization were independent predictors of favourable outcome. Conclusions The majority of stroke patients treated by ET in clinical practice would not have qualified for randomization in prior RCTs. Outcome in real-life patient cohorts is worse than in the highly selected cohorts from randomized trials, while rates of successful recanalization, sICH and outcome predictors are the same. Our findings support ET in broader patient populations than in the RCTs and may improve treatment decision in individual stroke patients with LVO in clinical practice.

Aging is accompanied by structural brain changes that are thought to underlie cognitive decline and dementia. Yet little is known regarding the association between increasing age, structural brain damage, and alterations of functional brain connectivity. The aim of this study was to evaluate whether cortical thickness and white matter damage as markers of age-related structural brain changes are associated with alterations in functional connectivity in non-demented healthy middle-aged to older adults. Therefore, we reconstructed functional connectomes from resting-state functional magnetic resonance imaging (MRI) (rsfMRI) data of 976 subjects from the Hamburg City Health Study, a prospective population-based study including participants aged 45–74 years from the metropolitan region Hamburg, Germany. We performed multiple linear regressions to examine the association of age, cortical thickness, and white matter damage quantified by the peak width of skeletonized mean diffusivity (PSMD) from diffusion tensor imaging on whole-brain network connectivity and four predefined resting state networks (default mode, dorsal, salience, and control network). In a second step, we extracted subnetworks with age-related decreased functional connectivity from these networks and conducted a mediation analysis to test whether the effect of age on these networks is mediated by decreased cortical thickness or PSMD. We observed an independent association of higher age with decreased functional connectivity, while there was no significant association of functional connectivity with cortical thickness or PSMD. Mediation analysis identified cortical thickness as a partial mediator between age and default subnetwork connectivity and functional connectivity within the default subnetwork as a partial mediator between age and executive cognitive function. These results indicate that, on a global scale, functional connectivity is not determined by structural damage in healthy middle-aged to older adults. There is a weak association of higher age with decreased functional connectivity which, for specific subnetworks, appears to be mediated by cortical thickness.

BackgroundFreezing of gait (FoG) is a disabling burden for Parkinson’s disease (PD) patients with poor response to conventional therapies. Combined deep brain stimulation of the subthalamic nucleus and substantia nigra (STN+SN DBS) moved into focus as a potential therapeutic option to treat the parkinsonian gait disorder and refractory FoG. The mechanisms of action of DBS within the cortical-subcortical-basal ganglia network on gait, particularly at the cortical level, remain unclear.MethodsTwelve patients with idiopathic PD and chronically-implanted DBS electrodes were assessed on their regular dopaminergic medication in a standardized stepping in place paradigm. Patients executed the task with DBS switched off (STIM OFF), conventional STN DBS and combined STN+SN DBS and were compared to healthy matched controls. Simultaneous high-density EEG and kinematic measurements were recorded during resting-state, effective stepping, and freezing episodes.ResultsClinically, STN+SN DBS was superior to conventional STN DBS in improving temporal stepping variability of the more affected leg. During resting-state and effective stepping, the cortical activity of PD patients in STIM OFF was characterized by excessive over-synchronization in the theta (4–8 Hz), alpha (9–13 Hz), and high-beta (21–30 Hz) band compared to healthy controls. Both active DBS settings similarly decreased resting-state alpha power and reduced pathologically enhanced high-beta activity during resting-state and effective stepping compared to STIM OFF. Freezing episodes during STN DBS and STN+SN DBS showed spectrally and spatially distinct cortical activity patterns when compared to effective stepping. During STN DBS, FoG was associated with an increase in cortical alpha and low-beta activity over central cortical areas, while with STN+SN DBS, an increase in high-beta was prominent over more frontal areas.ConclusionsSTN+SN DBS improved temporal aspects of parkinsonian gait impairment compared to conventional STN DBS and differentially affected cortical oscillatory patterns during regular locomotion and freezing suggesting a potential modulatory effect on dysfunctional cortical-subcortical communication in PD.

Background: The Parkinsonian [i.e., Parkinson's disease (PD)] gait disorder represents a therapeutical challenge with residual symptoms despite the use of deep brain stimulation of the subthalamic nucleus (STN DBS) and medical and rehabilitative strategies. The aim of this study was to assess the effect of different DBS modes as combined stimulation of the STN and substantia nigra (STN+SN DBS) and environmental rehabilitative factors as footwear on gait kinematics.Methods: This single-center, randomized, double-blind, crossover clinical trial assessed shod and unshod gait in patients with PD with medication in different DBS conditions (i.e., STIM OFF, STN DBS, and STN+SN DBS) during different gait tasks (i.e., normal gait, fast gait, and gait during dual task) and compared gait characteristics to healthy controls. Notably, 15 patients participated in the study, and 11 patients were analyzed after a dropout of four patients due to DBS-induced side effects.Results: Gait was modulated by both factors, namely, footwear and DBS mode, in patients with PD. Footwear impacted gait characteristics in patients with PD similarly to controls with longer step length, lower cadence, and shorter single-support time. Interestingly, DBS exerted specific effects depending on gait tasks with increased cognitive load. STN+SN DBS was the most efficient DBS mode compared to STIM OFF and STN DBS with intense effects as step length increment during dual task.Conclusion: The PD gait disorder is a multifactorial symptom, impacted by environmental factors as footwear and modulated by DBS. DBS effects on gait were specific depending on the gait task, with the most obvious effects with STN+SN DBS during gait with increased cognitive load.

Introduction: Chronic cerebral hypoperfusion caused by asymptomatic high-grade stenosis of the internal carotid artery (ICA) has been associated with impaired cognitive function. Only few studies exist on underlying changes of functional connectivity (FC). Methods: 20 patients with unilateral high-grade ICA stenosis without MRI lesions and 25 aged-match controls underwent resting-state functional MRI (rsfMRI) and neuropsychological assessment. Patients were examined within ten days before and 6–10 weeks after surgical or interventional revascularization of carotid stenosis. We examined mean resting-state FC ipsi- and contralateral to stenosis and network topology using graph-theoretical measures. Results: At baseline, intrahemispheric FC was similar for patients and healthy controls. After revascularization mean FC increased moderately without an effect on network topology. Patients performed worse in TMT B and Stroop test, while performance in global screening tests for dementia (Mini Mental Status Examination, DemTect) were comparable. Test results did not improve after revascularization. Conclusion: In our study population, we find no effect of chronic hypoperfusion on FC and global cognitive function, although we observe minor impairments in processing speed and mental flexibility. The subtle increase of FC after revascularization could indicate excessive upregulation after restoration of perfusion. However, it might as well be a coincidental finding due to the limited sample size.

IntroductionThe preoperative evaluation of Parkinson's Disease (PD) patients for subthalamic nucleus deep brain stimulation (STN-DBS) includes the assessment of the neuropsychological status of the patient. A widely used preoperative test is the Mattis Dementia rating scale (MDRS). However, the Montreal cognitive assessment (MoCA) has also been proven to be a sensitive, time-sparing tool with high diagnostic validity in PD. We evaluate the utility of the MoCA as a preoperative screening test for PD patients undergoing bilateral STN-DBS.MethodsIn this single-centre, retrospective study, we analysed pre- and postoperative assessments of MoCA, MDRS, Movement disorder society-Unified PD Rating Scale-motor examination, PD Questionnaire-39 and levodopa equivalent daily dose. Longitudinal outcome changes were analysed using paired t-test, Pearson's correlation coefficient, linear regression and CHAID (chi-square automatic interaction detector) regression tree model.ResultsClinical motor and cognitive scores of 59 patients (61.05±7.73 years, 24 females) were analysed. The MoCA, but not the MDRS, identified significant postoperative cognitive decline in PD patients undergoing STN-DBS. The preoperative MoCA score correlated with postoperative quality of life improvement, whereas the MDRS did not. PD patients with a MoCA score ≤ 23 points had a significant decline of quality of life after DBS surgery compared to patients > 23 points.ConclusionThis study identifies the MoCA as an alternative test within the preoperative evaluation of PD patients for the detection of neuropsychological deficits and prediction of the postoperative improvement of quality of life.

Objective: Several guidelines recommend oral administration of nimodipine as vasospasm prophylaxis after aneurysmal subarachnoid hemorrhage (SAH). However, in clinical practice, the drug is administered orally and intravenously (i.v.), depending on clinical conditions and local treatment regimens. We have therefore investigated the safety and clinical effects of switching from i.v. to oral nimodipine therapy.Methods: Patients with aneurysmal SAH between January 2014 and April 2018 and initial i.v. nimodipine therapy, which was subsequently switched to oral administration, were included in this retrospective study. Transcranial Doppler sonography (TCD) of the vessels of the anterior circulation was performed daily. The occurrence of vasospasm and infarction during the overall course of the treatment was recorded. Statistical level of significance was set to p < 0.05.Results: A total of 133 patients (mean age 55.8 years, 65% female) initially received nimodipine i.v. after aneurysmal SAH, which was subsequently switched to oral administration after a mean of 12 days. There were no significant increases in mean flow velocities on TCD after the switch from i.v. to oral nimodipine administration regarding the anterior cerebral artery. For the middle cerebral artery, an increase from 62.36 to 71.78 cm/sec could only be detected in the subgroup of patients with infarction. There was no clustering of complicating events such as new-onset vasospasm or infarction during or after the switch.Conclusions: Our results do not point to any safety concerns when switching nimodipine from initial i.v. to oral administration. Switching was neither associated with clinically relevant increases in TCD velocities nor other relevant adverse events.

Background Randomized controlled clinical trials (RCT) have demonstrated the efficacy of endovascular treatment in anterior circulation large vessel occlusions. However, outcome of patients treated in daily practice differs from the results of the clinical trials. We hypothesize that this is attributable to the study criteria and that application of the criteria on patients undergoing endovascular therapy in daily routine would improve their outcome. Methods and Results Data from a multicenter prospective registry of GSR‐ET (German Stroke Registry – Endovascular Treatment) was used. Inclusion criteria and selectivity of SWIFT‐PRIME (Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment trial), MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands trial), ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times trial), DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake‐Up and Late Presenting Strokes Undergoing Neurointervention with Trevo trial) and DEFUSE‐3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke trial) trials were analyzed. Baseline characteristics, procedural and outcome data of patients from GSR‐ET before and after selection were compared with the results of the RCTs. Furthermore, outcome of patients who underwent endovascular treatment despite not fulfilling the RCT criteria was analyzed. A total of 2611 patients were included (median age, 75 years; 49.6% women; median National Institute of Health Stroke Scale, 16). A minority of patients met all inclusion criteria, ranging from 3% (DEFUSE‐3 criteria) to 35% (MR CLEAN criteria). Of the patients fulfilling the MR CLEAN criteria, 41% of patients had a good clinical outcome, compared with 34% of patients that did not fulfill MR CLEAN criteria. Conclusions The RCTs represent a selected population with higher rates of good clinical outcome compared with daily practice. The good outcomes of RCTs can be reproduced in clinical routine in patients who fulfill the RCT inclusion criteria. Furthermore, patients who did not meet the criteria of the RCT still had substantial rates of good clinical outcome.

A better understanding of motor recovery after stroke requires large-scale, longitudinal trials applying suitable assessments. Currently, there is an abundance of upper limb assessments used to quantify recovery. How well various assessments can describe upper limb function change over 1 year remains uncertain. A uniform and feasible standard would be beneficial to increase future studies' comparability on stroke recovery. This review describes which assessments are common in large-scale, longitudinal stroke trials and how these quantify the change in upper limb function from stroke onset up to 1 year. A systematic search for well-powered stroke studies identified upper limb assessments classifying motor recovery during the initial year after a stroke. A metaregression investigated the association between assessments and motor recovery within 1 year after stroke. Scores from nine common assessments and 4,433 patients were combined and transformed into a standardized recovery score. A mixed-effects model on recovery scores over time confirmed significant differences between assessments (P < 0.001), with improvement following the weeks after stroke present when measuring recovery using the Action Research Arm Test (β = 0.013), Box and Block test (β = 0.011), Fugl–Meyer Assessment (β = 0.007), or grip force test (β = 0.023). A last-observation-carried-forward analysis also highlighted the peg test (β = 0.017) and Rivermead Assessment (β = 0.011) as additional, valuable long-term outcome measures. Recovery patterns and, thus, trial outcomes are dependent on the assessment implemented. Future research should include multiple common assessments and continue data collection for a full year after stroke to facilitate the consensus process on assessments measuring upper limb recovery.

Abstract Introduction The impact of stroke-related impairment on activities of daily living may vary between patients, and can only be estimated by applying patient-reported outcome measures. The International Consortium for Health Outcome Measurement has developed a standard set of instruments that combine clinical and longitudinal patient-reported outcome measures for stroke. The present study was designed (1) to implement and evaluate the feasibility of the use of it as a consistent outcome measure in clinical routine at the stroke center of a German university hospital, (2) to characterize impairment in everyday life caused by stroke, and (3) to identify predictive factors associated with patient-relevant outcomes. Methods We plan to enroll 1040 consecutive patients with the diagnosis of acute ischemic stroke, transient ischemic attack, or intracerebral hemorrhage in a prospective observational study. Demographics, cardiovascular risk factors, and living situation are assessed at inpatient surveillance. At 90 days and 12 months after inclusion, follow-up assessments take place including the Patient-reported Outcomes Measurement Information System 10-Question Short Form (PROMIS-10), the Patient- Health Questionnaire-4, and the simplified modified Ranking Scale questionnaire. The acceptance and feasibility (1) will be assessed by a process evaluation through qualitative semi-structured interviews with clinical staff and patients and quantitative analyses of the data quality evaluating practicability, acceptance, adoption, and fidelity to protocol. The primary outcome of objective 2 and 3 is health-related quality of life measured with the PROMIS-10. Additional outcomes are depressive and anxiety symptoms and patient participation in their social roles. Patient-reported outcomes will be assessed in their longitudinal course using (generalized) mixed regressions. Exploratory descriptive and inference statistical analyses will be used to find patterns of patient characteristics and predictive factors of the outcome domains. Perspective The results will describe and further establish the evaluation of stroke patients of a stroke center by standardized PROMs in everyday life. Trial registration The trial is registered at ClinicalTrials.gov (NCT03795948). Approval of the local ethics committee (Ethik-Kommission der Ärztekammer Hamburg) has been obtained.

Abstract Background We investigated changes of cortical thickness and its association with cognitive performance in patients with high-grade carotid artery stenosis without ischemic brain lesions. Methods We studied 25 patients with unilateral carotid artery stenosis ≥50% and 25 age-matched controls. All subjects underwent T1-weighted MRI, and cortical thickness was measured in 33 regions of interest in each hemisphere, as well as in brain regions belonging to the vascular territory of the middle cerebral artery (MCA). General linear mixed models were fitted to the dependent variable cortical thickness. Cognitive assessment comprised the Stroop Test and Trail Making Test B. Results In the linear mixed model, presence of carotid stenosis had no effect on cortical thickness. There was a significant interaction of stenosis and region with a trend towards lower cortical thickness in the MCA region on the side of carotid stenosis. Patients with carotid stenosis performed significantly worse on the Stroop test than controls, but there was no correlation with cortical thickness. Conclusion In patients with carotid stenosis without ischemic brain lesions, neither a clear pattern of reduced cortical thickness nor an association of cortical thickness with cognitive function was observed. Our data do not support the hypothesized association of cortical thinning and cognitive impairment in carotid stenosis.

Background and Aims: Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial.Methods: One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median

Somatosensory deficits after ischaemic stroke are common and can occur in patients with lesions in the anterior parietal cortex and subcortical nuclei. It is less clear to what extent damage to white matter tracts within the somatosensory system may contribute to somatosensory deficits after stroke. We compared the roles of cortical damage and disruption of subcortical white matter tracts as correlates of somatosensory deficit after ischaemic stroke.Clinical and imaging data were assessed in incident stroke patients. Somatosensory deficits were measured using a standardized somatosensory test. Remote effects were quantified by projecting the MRI-based segmented stroke lesions onto a predefined atlas of white matter connectivity. Direct ischaemic damage to grey matter was computed by lesion overlap with grey matter areas. The association between lesion impact scores and sensory deficit was assessed statistically.In 101 patients, median sensory score was 188/193 (97.4%). Lesion volume was associated with somatosensory deficit, explaining 23.3% of variance. Beyond this, the stroke-induced grey and white matter disruption within a subnetwork of the postcentral, supramarginal, and transverse temporal gyri explained an additional 14% of the somatosensory outcome variability. On mutual comparison, white matter network disruption was a stronger predictor than grey matter damage.Ischaemic damage to both grey and white matter are structural correlates of acute somatosensory disturbance after ischaemic stroke. Our data suggest that white matter integrity of a somatosensory network of primary and secondary cortex is a prerequisite for normal processing of somatosensory inputs and might be considered as an additional parameter for stroke outcome prediction in the future.

The quality of crossmodal perception hinges on two factors: The accuracy of the independent unimodal perception and the ability to integrate information from different sensory systems. In humans, the ability for cognitively demanding crossmodal perception diminishes from young to old age. Here, we propose a new approach to research to which degree the different factors contribute to crossmodal processing and the age-related decline by replicating a medical study on visuo-tactile crossmodal pattern discrimination utilizing state-of-the-art tactile sensing technology and artificial neural networks (ANN). We implemented two ANN models to specifically focus on the relevance of early integration of sensory information during the crossmodal processing stream as a mechanism proposed for efficient processing in the human brain. Applying an adaptive staircase procedure, we approached comparable unimodal classification performance for both modalities in the human participants as well as the ANN. This allowed us to compare crossmodal performance between and within the systems, independent of the underlying unimodal processes. Our data show that unimodal classification accuracies of the tactile sensing technology are comparable to humans. For crossmodal discrimination of the ANN the integration of high-level unimodal features on earlier stages of the crossmodal processing stream shows higher accuracies compared to the late integration of independent unimodal classifications. In comparison to humans, the ANN show higher accuracies than older participants in the unimodal as well as the crossmodal condition, but lower accuracies than younger participants in the crossmodal task. Taken together, we can show that state-of-the-art tactile sensing technology is able to perform a complex tactile recognition task at levels comparable to humans. For crossmodal processing, human inspired early sensory integration seems to improve the performance of artificial neural networks. Still, younger participants seem to employ more efficient crossmodal integration mechanisms than modeled in the proposed ANN. Our work demonstrates how collaborative research in neuroscience and embodied artificial neurocognitive models can help to derive models to inform the design of future neurocomputational architectures.