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Background Life-space mobility is defined as the size of the area in which a person moves about within a specified period of time. Our study aimed to characterize life-space mobility, identify factors associated with its course, and detect typical trajectories in the first year after ischemic stroke. Methods MOBITEC-Stroke (ISRCTN85999967; 13/08/2020) was a cohort study with assessments performed 3, 6, 9 and 12 months after stroke onset. We applied linear mixed effects models (LMMs) with life-space mobility (Life-Space Assessment; LSA) as outcome and time point, sex, age, pre-stroke mobility limitation, stroke severity (National Institutes of Health Stroke Scale; NIHSS), modified Rankin Scale, comorbidities, neighborhood characteristics, availability of a car, Falls Efficacy Scale-International (FES-I), and lower extremity physical function (log-transformed timed up-and-go; TUG) as independent variables. We elucidated typical trajectories of LSA by latent class growth analysis (LCGA) and performed univariate tests for differences between classes. Results In 59 participants (mean age 71.6, SD 10.0 years; 33.9% women), mean LSA at 3 months was 69.3 (SD 27.3). LMMs revealed evidence (p ≤ 0.05) that pre-stroke mobility limitation, NIHSS, comorbidities, and FES-I were independently associated with the course of LSA; there was no evidence for a significant effect of time point. LCGA revealed three classes: “low stable”, “average stable”, and “high increasing”. Classes differed with regard to LSA starting value, pre-stroke mobility limitation, FES-I, and log-transformed TUG time. Conclusion Routinely assessing LSA starting value, pre-stroke mobility limitation, and FES-I may help clinicians identify patients at increased risk of failure to improve LSA.

Study design Multicentre-observational study. Objectives The 6-minute walk test (6mWT) is an established assessment of walking function in individuals with spinal cord injury (SCI). However, walking 6 min can be demanding for severely impaired individuals. The 2-minute walk test (2mWT) could be an appropriate alternative that has already been validated in other neurological disorders. The aim of this study was to assess construct validity and test-rest reliability of the 2mWT in individuals with SCI. In addition, the influence of walking performance on sensitivity to change of the 2mWT was assessed. Setting Swiss Paraplegic Center Nottwil, Switzerland; Balgrist University Hospital, Zürich, Switzerland. Methods Fifty individuals (aged 18–79) with SCI (neurological level of injury: C1-L3, AIS: A-D) were assessed on two test days separated by 1 to 7 days. The first assessment consisted of a 2mWT familiarization, followed by a 2mWT and 10-meter walk test (10MWT) (including the Walking Index for Spinal Cord Injury (WISCI II)) in randomized order. The second assessment consisted of 2mWT and 6mWT in randomized order. Tests were separated by at least 30 min of rest. Results The interclass correlation coefficient between the 2mWT assessed on the first and second test day was excellent (r = 0.980, p r = 0.992, p r = 0.964, p r = 0.571, p Conclusion The 2mWT is a valid and reliable alternative to the 6mWT to measure walking function in individuals with SCI. Trial registration NCT04555759.

Purpose Glioblastoma is the most common brain tumor in adults and is virtually incurable. Therefore, new therapeutic strategies are urgently needed. Over the last decade, multiple growth-promoting functions have been attributed to CD95, a prototypic death receptor well characterized as an apoptosis mediator upon CD95L engagement. Strategic targeting of non-apoptotic or apoptotic CD95 signaling may hold anti-glioblastoma potential. Due to its antithetic nature, understanding the constitutive role of CD95 signaling in glioblastoma is indispensable. Methods We abrogated constitutive Cd95 and Cd95l gene expression by CRISPR/Cas9 in murine glioma models and characterized the consequences of gene deletion in vitro and in vivo. Results Expression of canonical CD95 but not CD95L was identified in mouse glioma cells in vitro. Instead, a soluble isoform-encoding non-canonical Cd95l transcript variant was detected. In vivo, an upregulation of the membrane-bound canonical CD95L form was revealed. Cd95 or Cd95l gene deletion decreased cell growth in vitro. The growth-supporting role of constitutive CD95 signaling was validated by Cd95 re-transfection, which rescued growth. In vivo, Cd95 or Cd95l gene deletion prolonged survival involving tumor-intrinsic and immunological mechanisms in the SMA-497 model. In the GL-261 model, that expresses no CD95, only CD95L gene deletion prolonged survival, involving a tumor-intrinsic mechanism. Conclusion Non-canonical CD95L/CD95 interactions are growth-promoting in murine glioma models, and glioma growth and immunosuppression may be simultaneously counteracted by Cd95l gene silencing.

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes—and their microstructural underpinnings—remain unclear. Eighteen healthy males received 1 hour of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network.

The identification of a blood marker of brain pathology that is sensitive to substance-induced neurotoxicity and dynamically responds to longitudinal changes in substance intake would substantially improve clinical monitoring in the field of substance use and addiction. Here, we explored the hypothesis that plasma levels of neurofilament light chain (NfL), a promising marker of neuroaxonal pathology, are elevated in chronic cocaine users and longitudinally associated with changes in cocaine use. Plasma NfL levels were determined using single molecule array (SIMOA) technology at baseline and at a 4-month follow-up. Substance use was subjectively assessed with an extensive interview and objectively measured via toxicological analysis of urine and 4-month hair samples. In a generalized linear model corrected for sex, age, and body mass index, NfL plasma levels were elevated in cocaine users (n=35) compared to stimulant-naive healthy controls (n=35). A positive correlation between cocaine hair concentration and NfL levels was also found. Changes in cocaine hair concentration (group analysis of increasers vs. decreasers) over the 4-month interval predicted NfL levels at follow-up, indicating a rise in NfL with increased cocaine use and a reduction with decreased use. No associations between use or change of use of other substances (including the neurotoxic cocaine adulterant levamisole) and NfL levels were found. Our findings demonstrate that NfL is a sensitive marker for assessing cocaine-related neuroaxonal pathology, supporting the utility of blood NfL analysis in addiction research but also suggesting the detailed assessment of substance use in neurological studies and diagnostics., Molecular neurobiology, 60 (7), ISSN:0893-7648, ISSN:1559-1182

ObjectivePreclinical studies have shown that cognitive impairments following spinal cord injury (SCI), such as impaired spatial memory, are linked to inflammation, neurodegeneration, and reduced neurogenesis in the right hippocampus. This cross-sectional study aims to characterize metabolic and macrostructural changes in the right hippocampus and their association to cognitive function in traumatic SCI patients.MethodsWithin this cross-sectional study, cognitive function was assessed in 28 chronic traumatic SCI patients and 18 age-, sex-, and education-matched healthy controls by a visuospatial and verbal memory test. A magnetic resonance spectroscopy (MRS) and structural MRI protocol was performed in the right hippocampus of both groups to quantify metabolic concentrations and hippocampal volume, respectively. Group comparisons investigated changes between SCI patients and healthy controls and correlation analyses investigated their relationship to memory performance.ResultsMemory performance was similar in SCI patients and healthy controls. The quality of the recorded MR spectra was excellent in comparison to the best-practice reports for the hippocampus. Metabolite concentrations and volume of the hippocampus measured based on MRS and MRI were not different between two groups. Memory performance in SCI patients and healthy controls was not correlated with metabolic or structural measures.ConclusionThis study suggests that the hippocampus may not be pathologically affected at a functional, metabolic, and macrostructural level in chronic SCI. This points toward the absence of significant and clinically relevant trauma-induced neurodegeneration in the hippocampus.

Learning new words in an unfamiliar language is a complex endeavor that requires the orchestration of multi-ple perceptual and cognitive functions. Although the neural mechanisms governing word learning are becoming better understood, little is known about the predictive value of resting-state (RS) metrics for foreign word discrim-ination and word learning attainment. In addition, it is still unknown which of the multistep processes involved in word learning have the potential to rapidly reconfigure RS networks. To address these research questions, we used electroencephalography (EEG), measured forty participants, and examined scalp-based power spectra, source-based spectral density maps and functional connectivity metrics before (RS1), in between (RS2) and after (RS3) a series of tasks which are known to facilitate the acquisition of new words in a foreign language, namely word discrimination, word-referent mapping and semantic generalization. Power spectra at the scalp level con-sistently revealed a reconfiguration of RS networks as a function of foreign word discrimination (RS1 vs. RS2) and word learning (RS1 vs. RS3) tasks in the delta, lower and upper alpha, and upper beta frequency ranges. Otherwise, functional reconfigurations at the source level were restricted to the theta (spectral density maps) and to the lower and upper alpha frequency bands (spectral density maps and functional connectivity). Notably, scalp RS changes related to the word discrimination tasks (difference between RS2 and RS1) correlated with word dis-crimination abilities (upper alpha band) and semantic generalization performance (theta and upper alpha bands), whereas functional changes related to the word learning tasks (difference between RS3 and RS1) correlated with word discrimination scores (lower alpha band). Taken together, these results highlight that foreign speech sound discrimination and word learning have the potential to rapidly reconfigure RS networks at multiple functional scales., NeuroImage, 271, ISSN:1053-8119, ISSN:1095-9572

Pericytes are the mural cells of the microvascular network that are in close contact with underlying endothelial cells. Endothelial-secreted PDGFB leads to recruitment of pericytes to the vessel wall, but this is disrupted in Pdgfb(ret/ret) mice when the PDGFB retention motif is deleted. This results in severely reduced pericyte coverage on blood vessels. In this study, we investigated vascular abnormalities and hemodynamics in Pdgfb(ret/ret) mice throughout the cerebrovascular network and in different cortical layers by in vivo two-photon microscopy. We confirmed that Pdgfb(ret/ret) mice are severely deficient in pericytes throughout the vascular network, with enlarged brain blood vessels and a reduced number of vessel branches. Red blood cell velocity, linear density, and tube hematocrit were reduced in Pdgfb(ret/ret) mice, which may impair oxygen delivery to the tissue. We also measured intravascular PO2 and found that concentrations were higher in cortical Layer 2/3 in Pdgfb(ret/ret) mice, indicative of reduced blood oxygen extraction. Finally, we found that Pdgfb(ret/ret) mice had a reduced capacity for vasodilation in response to an acetazolamide challenge during functional MRI imaging. Taken together, these results suggest that severe pericyte deficiency can lead to vascular abnormalities and altered cerebral blood flow, reminiscent of pathologies such as arteriovenous malformations., Journal of Cerebral Blood Flow & Metabolism, 43 (5), ISSN:0271-678X, ISSN:1559-7016

Evidence on associations of lifestyle factors with Alzheimer's pathology and cognition are ambiguous, potentially because they rarely addressed inter-relationships of factors and sex effects. While considering these aspects, we examined the relationships of lifestyle factors with brain amyloid burden and cognition.We studied 178 cognitively normal individuals (women, 49%; 65.0 [7.6] years) and 54 individuals with mild cognitive impairment (women, 35%; 71.3 [8.3] years) enrolled in a prospective study of volunteers who completedOverall, higher cognitive activity was associated with better cognitive performance and higher physical activity was associated with lower amyloid burden. The latter association was weakened to a nonsignificant level after excluding multivariate outliers. Examination of the moderating effect of sex in the model revealed an inverse association of metabolic/vascular risk with cognition in men, whereas in women metabolic/vascular risk trended toward increased amyloid burden. Furthermore, a significant inverse association between physical activity and amyloid burden was found only in men. Inheritance of an APOE4 allele was associated with higher amyloid burden only in women.Sex modifies effects of certain lifestyle-related factors on amyloid burden and cognition. Notably, our results suggest that the negative impact of metabolic/vascular risk influences the risk of cognitive decline and Alzheimer's disease through distinct paths in women and men. ANN NEUROL 2022;92:451-463.

BackgroundFollowing spinal cord injury (SCI), disease processes spread gradually along the spinal cord forming a spatial gradient with most pronounced changes located at the lesion site. However, the dynamics of this gradient in sub-acute SCI patients is not established.ObjectiveThis study tracks the spatiotemporal dynamics of remote anterograde and retrograde spinal tract degeneration in the upper cervical cord following SCI over two years utilizing quantitative MRI.MethodsTwenty-three acute SCI patients (11 paraplegics, 12 tetraplegics) and 21 healthy controls were scanned with a T1-weighted sequence for volumetry and a FLASH sequence for myelin-sensitive magnetization transfer saturation (MTsat) map of the upper cervical cord. We estimated myelin content from MTsat maps within the corticospinal tracts (CST) and dorsal columns (DC) and measured spinal cord atrophy by means of left-right width (LRW) and anterior-posterior width (APW) on the T1-weighted images across cervical levels C1-C3. MTsat in the CST and LRW were considered proxies for retrograde degeneration, while MTsat in the DC and APW provided evidence for anterograde degeneration, respectively. Using regression models, we compared the temporal and spatial trajectories of these MRI readouts between tetraplegics, paraplegics, and controls over a 2-year period and assessed their associations with clinical improvement.ResultsLinear rates and absolute differences in myelin-sensitive MTsat indicated retrograde and anterograde neurodegeneration in the CST and DC, respectively. Changes in MTsat within the CST (change per cervical level: -0.247 p.u./level, p=0.034) and LRW (change per level: -0.323 mm/level, p=0.024) progressively developed over time with a strong gradient towards lower cervical segments specifically in tetraplegics. Within the DC, MTsat was already decreased at all cervical levels at baseline and linear rates in APW were similar across all cervical levels showing no spatial gradient in para- and tetraplegics. The relative improvement in light touch score was correlated with MTsat within the DC at baseline (1.5 months) (rs=0.575, p=0.014).ConclusionRostral and remote to the injury, the CST and DC showed ongoing structural changes, indicative of myelin reductions and atrophy within 2 years after SCI. While anterograde degeneration in the DC was already detectable uniformly at C1-C3 early following SCI, retrograde degeneration in the CST developed over time revealing specific spatial and temporal neurodegenerative gradients. Disentangling and quantifying such dynamic pathological processes may provide biomarkers for regenerative and remyelinating therapies, where antero- and retrograde spinal pathways become specifically affected.

Item does not contain fulltext STUDY DESIGN: Consensus study. OBJECTIVES: The purpose of this study is to define a standardized (network) outcomes set for traumatic spinal cord injury (t-SCI), covering the patient journey from acute to chronic rehabilitation phase, including patient-relevant outcomes, adequate measurement instruments, as well as case-mix and risk factors. SETTING: Acute Spinal Cord Injury (ASCI) Unit Nijmegen, the Netherlands. METHODS: A modified Delphi method was performed, including a multidisciplinary panel of 19 health-care professionals with experience in t-SCI management. Formal consensus was reached after two web-based surveys, a face-to-face meeting, and a final confirmation round (threshold consensus: 70%). RESULTS: In the first two Delphi rounds, 18/19 invited panelists (94.7%) responded and 10 panelists participated in the final meeting. The prefinal set was confirmed by all panelists. The standard set encompasses the three-tiered outcome hierarchy and consists of patient-reported and clinician-reported outcome domains and measurement instruments. Consensus was reached to include survival, degree of health or recovery, time to recovery, and return to normal activities, disutility of care or treatment process, sustainability of health and nature of recurrences, and long-term consequences of therapy. A measurement schedule was defined as well as for proposed casemix and risk factors, including demographics, clinical status, and treatment process. CONCLUSION: A standard set of network outcomes is developed that could be implemented in hospitals and rehabilitation centers involved in the treatment of t-SCI. Using this standard set, comparison of the quality of care is possible and prognostic prediction of outcomes of treatment is feasible, so that each patient receives the right care at the right time in the right place. 01 september 2022

High frequency oscillations (HFO) in scalp EEG are a new and promising epilepsy biomarker. However, considerable fluctuations of HFO rates have been observed through sleep stages and cycles. Here, we aimed to identify the optimal timing within sleep and the minimal data length for sensitive and reproducible HFO detection.We selected 16 whole-night scalp EEG recordings of paediatric patients with a focal structural epilepsy. We used an automated clinically validated HFO detector to determine HFO rates (80-250 Hz). We evaluated the reproducibility of HFO detection across intervals.HFO rates were higher in N3 than in N2 and REM (rapid eye movement) sleep and highest in the first sleep cycle, decreasing with time in sleep. In N3 sleep, the median reliability of HFO detection increased from 67% (interquartile range: iqr 57) to 78% (iqr 59) to 100% (iqr 70%) for 5-, 10-, and 15-min data intervals, improving significantly (p = 0.004, z = 2.9) from 5 to 10 min but not from 10 to 15 min.We identified the first N3 sleep stage as the most sensitive time window for HFO rate detection. At least 10 min N3 data intervals are required and sufficient for reliable measurements of HFO rates.Our study provides a robust and reliable framework for scalp HFO detection that may facilitate their implementation as an EEG biomarker in paediatric epilepsy.

Here we review the paradigm-change from one-size-fits-all psychiatry to more personalized-psychiatry, where we distinguish between 'precision psychiatry' and 'stratified psychiatry'. Using examples in Depression and ADHD we argue that stratified psychiatry, using biomarkers to facilitate patients to best 'on-label' treatments, is a more realistic future for implementing biomarkers in clinical practice.

To test the robustness and signal-to-noise ratio of pain-related evoked potentials following intra-epidermal electrical stimulation (IES) compared to contact heat stimulation in healthy controls, and to explore the feasibility and potential added value of IES in the diagnosis of spinal disorders.Pain-related evoked potentials induced by IES (custom-made, non-invasive, concentric triple pin electrode with steel pins protruding 1 mm from the anode, triangularly separated by 7-10 mm respectively) and contact heat stimulation were compared in 30 healthy subjects. Stimuli were applied to four different body sites. Two IES intensities, i.e., high (individually adapted to contact heat painfulness) and low (1.5 times pain threshold), were used. Additionally, a 40-year-old patient with unilateral dissociated sensory loss due to a multi-segmental syringohydromyelia was assessed comparing IES and contact heat stimulation.Both IES and contact heat stimulation led to robust pain-related evoked potentials recorded in all healthy subjects. Low intensity IES evoked potentials (14.1-38.0 µV) had similar amplitudes as contact heat evoked potentials (11.8-32.3 µV), while pain ratings on the numeric rating scale were lower for IES (0.8-2.5, compared to 1.5-3.9 for contact heat stimulation). High intensity IES led to evoked potentials with higher signal-to-noise ratio than low intensity IES and contact heat stimulation. The patient case showed impaired pain-related evoked potentials in segments with hypoalgesia for both IES modes. IES evoked potentials were preserved, with delayed latencies, while contact heat evoked potentials were abolished.IES evoked robust pain-related cortical potentials, while being less painful in healthy controls. The improved signal-to-noise ratio supports the use of IES for objective segmental testing of nociceptive processing. This was highlighted in a spinal syndrome case, where IES as well as contact heat stimulation reliably detected impaired segmental nociception.

Introduction: The treatment of hydrocephalus has been a topic of intense research ever since the first clinically successful use of a valved cerebrospinal fluid shunt 72 years ago. While ample studies elucidating different phenomena impacting this treatment exist, there are still gaps to be filled. Specifically, how intracranial, intrathecal, arterial, and venous pressures react and communicate with each other simultaneously. Methods: An in-vivo sheep trial (n = 6) was conducted to evaluate and quantify the communication existing within the cranio-spinal, arterial, and venous systems (1 kHz sampling frequency). Standardized intrathecal infusion testing was performed using an automated infusion apparatus, including bolus and constant pressure infusions. Bolus infusions entailed six lumbar intrathecal infusions of 2 mL Ringer’s solution. Constant pressure infusions were comprised of six regulated pressure steps of 3.75 mmHg for periods of 7 min each. Mean pressure reactions, pulse amplitude reactions, and outflow resistance were calculated. Results: All sheep showed intracranial pressure reactions to acute increases of intrathecal pressure, with four of six sheep showing clear cranio-spinal communication. During bolus infusions, the increases of mean pressure for intrathecal, intracranial, arterial, and venous pressure were 16.6 ± 0.9, 15.4 ± 0.8, 3.9 ± 0.8, and 0.1 ± 0.2 mmHg with corresponding pulse amplitude increases of 2.4 ± 0.3, 1.3 ± 0.3, 1.3 ± 0.3, and 0.2 ± 0.1 mmHg, respectively. During constant pressure infusions, mean increases from baseline were 14.6 ± 3.8, 15.5 ± 4.2, 4.2 ± 8.2, and 3.2 ± 2.4 mmHg with the corresponding pulse amplitude increases of 2.5 ± 3.6, 2.5 ± 3.0, 7.7 ± 4.3, and 0.7 ± 2.0 mmHg for intrathecal, intracranial, arterial, and venous pulse amplitude, respectively. Outflow resistances were calculated as 51.6 ± 7.8 and 77.8 ± 14.5 mmHg/mL/min for the bolus and constant pressure infusion methods, respectively—showing deviations between the two estimation methods. Conclusions: Standardized infusion tests with multi-compartmental pressure recordings in sheep have helped capture distinct reactions between the intrathecal, intracranial, arterial, and venous systems. Volumetric pressure changes in the intrathecal space have been shown to propagate to the intraventricular and arterial systems in our sample,and to the venous side in individual cases. These results represent an important step into achieving a more complete quantitative understanding of how an acute rise in intrathecal pressure can propagate and influence other systems., Fluids and Barriers of the CNS, 19 (1), ISSN:2045-8118

Although phenobarbital (PB) is commonly used as a first-line antiseizure medication (ASM) for neonatal seizures, in 2015 we chose to replace it with levetiracetam (LEV), a third-generation ASM. Here, we compared the safety and efficacy of LEV and PB as first-line ASM, considering the years before and after modifying our treatment protocol.We conducted a retrospective cohort study of 108 neonates with electroencephalography (EEG)-confirmed seizures treated with first-line LEV or PB in 2012 to 2020.First-line ASM was LEV in 33 (31%) and PB in 75 (69%) neonates. The etiology included acute symptomatic seizures in 69% of cases (30% hypoxic-ischemic encephalopathy, 32% structural vascular, 6% infectious, otherwise metabolic) and neonatal epilepsy in 22% (5% structural due to brain malformation, 17% genetic). Forty-two of 108 (39%) neonates reached seizure freedom following first-line therapy. Treatment response did not vary by first-line ASM among all neonates, those with acute symptomatic seizures, or those with neonatal-onset epilepsy. Treatment response was lowest for neonates with a higher seizure frequency, particularly for those with status epilepticus versus rare seizures (P 0.001), irrespective of gestational age, etiology, or EEG findings. Adverse events were noted in 22 neonates treated with PB and in only one treated with LEV (P 0.001).Our study suggests a potential noninferiority and a more acceptable safety profile for LEV, which may thus be a reasonable option as first-line ASM for neonatal seizures in place of PB. Treatment should be initiated as early as possible since higher seizure frequencies predispose to less favorable responses.

Stimulus induced repetitive periodic or ictal discharges (SIRPIDs) are a commonly observed EEG pattern in critically ill patients. However, the epileptic significance of SIRPIDs remain unclear. We identified and reviewed 55 cases with SIRPIDs according to the ACNS criteria. SIRPIDs occurred after standardized painful stimuli during a standard 20-minute EEG. These cases were investigated regarding their relation to non-convulsive status epilepticus (NCSE) according to Salzburg Consensus Criteria and in-hospital mortality. In 37/55 patients (67.3%), SIRPIDs were associated with NCSE. In most patients (26/37 cases, 70.3%) with concurrent status epilepticus, SIRPIDs occurred after status epilepticus (on average 4.8 days later), but in 3/37 patients (8.1%) they were observed before a later status epilepticus. In four cases (4/37 cases, 10.8%), SIRPIDs appeared both before and after an episode of NCSE and in other four cases the two patterns coexisted in the same EEG. In 50% of the patients, status epilepticus was refractory, super-refractory or the patient died before its resolution. The overall mortality in the cohort was high at 58.2%. These findings corroborate the hypothesis that SIRPIDs might represent a state with increased epileptogenic potential, commonly co-occurring with NCSE. Furthermore, SIRPIDs are associated with therapy-refractory course of status epilepticus and high mortality.

To improve risk stratification in extracranial internal carotid artery disease (CAD), patients who would benefit maximally from revascularization must be identified. In cardiology, the fractional flow reserve (FFR) has become a reference standard for evaluating the functional severity of coronary artery stenosis, and noninvasive surrogates thereof relying on computational fluid dynamics (CFD) have been developed. Here, we present a CFD-based workflow using digital twins of patients’ carotid bifurcations derived from computed tomography angiography for the noninvasive functional assessment of CAD. We reconstructed patient-specific digital twins of 37 carotid bifurcations. We implemented a CFD model using common carotid artery peak systolic velocity (PSV) acquired with Doppler ultrasound (DUS) as inlet boundary condition and a two-element Windkessel model as oulet boundary condition. The agreement between CFD and DUS on the PSV in the internal carotid artery (ICA) was then compared. The relative error for the agreement between DUS and CFD was 9% ± 20% and the intraclass correlation coefficient was 0.88. Furthermore, hyperemic simulations in a physiological range were feasible and unmasked markedly different pressure drops along two ICA stenoses with similar degree of narrowing under comparable ICA blood flow. Hereby, we lay the foundation for prospective studies on noninvasive CFD-based derivation of metrics similar to the FFR for the assessment of CAD., NeuroImage: Clinical, 38, ISSN:2213-1582

STUDY DESIGN Prospective, multicenter, longitudinal cohort study. OBJECTIVES To describe female-male differences in first-line urological management during spinal cord injury (SCI) rehabilitation. SETTING Inpatient specialized post-acute SCI rehabilitation in Switzerland. METHODS Data on bladder storage medication (antimuscarinic and beta-3 agonist) use, suprapubic catheter placement, demographic and SCI characteristics was collected within 40 days of SCI and at rehabilitation discharge from May 2013-September 2021. Prevalence and indicators of bladder storage medication and suprapubic catheter use at discharge were investigated with sex-stratified descriptive and logistic regression analyses. RESULTS In 748 patients (219 females, 29%), bladder storage medication use at discharge had a prevalence of 24% (95% CI: 18-29%) for females and 30% (95% CI: 26-34%) for males and was indicated by cervical AIS grade A, B, C and traumatic SCI in both sexes. Thoracic AIS grade A, B, C SCI (males), and lumbar/sacral AIS grade A, B, C SCI (females) predicted higher odds of bladder storage medication use (SCI characteristic*sex interaction, p 60 in both sexes. Females with thoracic grade A, B, C SCI tended to have higher odds of suprapubic catheter use (SCI characteristic*sex interaction, p = 0.013). CONCLUSIONS We identified sex differences in urological management especially in persons with AIS grade C or higher sub-cervical SCI. There is scope for well-powered, female-specific research in SCI in order to understand the underlying mechanisms and support patient-tailored management.

After a first episode of major depressive disorder (MDD), there is substantial risk for a long-term remitting-relapsing course. Prevention and early interventions are thus critically important. Various studies have examined the feasibility of detecting at-risk individuals based on out-of-sample predictions about the future occurrence of depression. However, functional magnetic resonance imaging (fMRI) has received very little attention for this purpose so far. Here, we explored the utility of generative models (i.e. different dynamic causal models, DCMs) as well as functional connectivity (FC) for predicting future episodes of depression in never-depressed adults, using a large dataset (N = 906) of task-free ("resting state") fMRI data from the UK Biobank (UKB). Connectivity analyses were conducted using timeseries from pre-computed spatially independent components of different dimensionalities. Over a three-year period, 50% of selected participants showed indications of at least one depressive episode, while the other 50% did not. Using nested cross-validation for training and a held-out test set (80/20 split), we systematically examined the combination of 8 connectivity feature sets and 17 classifiers. We found that a generative embedding procedure based on combining regression DCM (rDCM) with a support vector machine (SVM) enabled the best predictions, both on the training set (0.63 accuracy, 0.66 area under the curve, AUC) and the test set (0.62 accuracy, 0.64 AUC; p < 0.001). However, on the test set, rDCM was only slightly superior to predictions based on FC (0.59 accuracy, 0.61 AUC). Interpreting model predictions based on SHAP (SHapley Additive exPlanations) values suggested that the most predictive connections were widely distributed and not confined to specific networks. Overall, our analyses suggest (i) ways of improving future fMRI-based generative embedding approaches for the early detection of individuals at-risk for depression and that (ii) achieving accuracies of clinical utility may require combination of fMRI with other data modalities., NeuroImage, 273, ISSN:1053-8119, ISSN:1095-9572

Short MRI acquisition time, high signal-to-noise ratio, and high reliability are crucial for image quality when scanning healthy volunteers and patients. Cross-sectional cervical cord area (CSA) has been suggested as a marker of neurodegeneration and potential outcome measure in clinical trials and is conventionally measured on T1-weigthed 3D Magnetization Prepared Rapid Acquisition Gradient-Echo (MPRAGE) images. This study aims to reduce the acquisition time for the comprehensive assessment of the spinal cord, which is typically based on MPRAGE for morphometry and multi-parameter mapping (MPM) for microstructure. The MPRAGE is replaced by a synthetic T1-w MRI (synT1-w) estimated from the MPM, in order to measure CSA. SynT1-w images were reconstructed using the MPRAGE signal equation based on quantitative maps of proton density (PD), longitudinal (R1) and effective transverse (R2*) relaxation rates. The reliability of CSA measurements from synT1-w images was determined within a multi-center test-retest study format and validated against acquired MPRAGE scans by assessing the agreement between both methods. The response to pathological changes was tested by longitudinally measuring spinal cord atrophy following spinal cord injury (SCI) for synT1-w and MPRAGE using linear mixed effect models. CSA measurements based on the synT1-w MRI showed high intra-site (Coefficient of variation [CoV]: 1.43% to 2.71%) and inter-site repeatability (CoV: 2.90% to 5.76%), and only a minor deviation of -1.65 mm2 compared to MPRAGE. Crucially, by assessing atrophy rates and by comparing SCI patients with healthy controls longitudinally, differences between synT1-w and MPRAGE were negligible. These results demonstrate that reliable estimates of CSA can be obtained from synT1-w images, thereby reducing scan time significantly.

Altered brain connectivity between regions of the reading network has been associated with reading difficulties. However, it remains unclear whether connectivity differences between children with dyslexia (DYS) and those with typical reading skills (TR) are specific to reading impairments or to reading experience. In this functional MRI study, 132 children (M = 10.06 y, SD = 1.46) performed a phonological lexical decision task. We aimed to disentangle (1) disorder-specific from (2) experience-related differences in effective connectivity and to (3) characterize the development of DYS and TR. We applied dynamic causal modeling to age-matched (ndys = 25, nTR = 35) and reading-level-matched (ndys = 25, nTR = 22) groups. Developmental effects were assessed in beginning and advanced readers (TR: nbeg = 48, nadv = 35, DYS: nbeg = 24, nadv = 25). We show that altered feedback connectivity between the inferior parietal lobule and the visual word form area (VWFA) during print processing can be specifically attributed to reading impairments, because these alterations were found in DYS compared to both the age-matched and reading-level-matched TR. In contrast, feedforward connectivity from the VWFA to parietal and frontal regions characterized experience in TR and increased with age and reading skill. These directed connectivity findings pinpoint disorder-specific and experience-dependent alterations in the brain's reading network., NeuroImage, 268, ISSN:1053-8119, ISSN:1095-9572

EEG has been the primary diagnostic tool in clinical epilepsy for nearly a century. Its review is performed using qualitative clinical methods that have changed little over time. However, the intersection of higher resolution digital EEG and analytical tools developed in the last decade invites a re-exploration of relevant methodology. In addition to the established spatial and temporal markers of spikes and high frequency oscillations, novel markers involving advanced post-processing and active probing of the interictal EEG are gaining ground. This review provides an overview of the EEG-based passive and active markers of cortical excitability in epilepsy and of the techniques developed to facilitate their identification. Several different emerging tools are discussed in the context of specific EEG applications and the barriers we must overcome to translate these tools into clinical practice.

Theoretical frameworks such as predictive coding suggest that the perception of the body and world – interoception and exteroception – involve intertwined processes of inference, learning, and prediction. In this framework, attention is thought to gate the influence of sensory information on perception. In contrast to exteroception, there is limited evidence for purely attentional effects on interoception. Here, we empirically tested if attentional focus modulates cortical processing of single heartbeats, using a newly-developed experimental paradigm to probe purely attentional differences between exteroceptive and interoceptive conditions in the heartbeat evoked potential (HEP) using EEG recordings. We found that the HEP is significantly higher during interoceptive compared to exteroceptive attention, in a time window of 524–620 ms after the R-peak. Furthermore, this effect predicted self-report measures of autonomic system reactivity. Our study thus provides direct evidence that the HEP is modulated by pure attention and suggests that this effect may provide a clinically relevant readout for assessing interoception., NeuroImage, 186, ISSN:1053-8119, ISSN:1095-9572

Affective disorders are frequent comorbidities of temporal lobe epilepsy (TLE). The endogenous opioid system has been implicated in both epilepsy and affective disorders, and may play a significant role in their bidirectional relationship. In this cross-sectional study, we investigated the association between μ-opioid receptor binding and affective disorders in patients with TLE.Nine patients with TLE and depression/anxiety underwentWe observed widely reduced CFN binding potential (BP) in bilateral frontal lobes and striata in patients with TLE compared to healthy controls. In the TLE group, more severe anxiety and negative affect were associated with decreased CFN BP in the posterior cingulate gyrus.In patients with TLE, interictally reduced binding in the opioid system was associated with higher levels of anxiety and negative affect. We speculate that seizure-related agonist-driven desensitization and downregulation of opioid receptors could be a potential underlying pathomechanism.

Vestibular neuritis is a common neuro-otological entity. Therapeutically, corticosteroids are advised, although the evidence is limited. The objective of this review is to update meta-analyses of clinical trials that address the question of whether patients with vestibular neuritis treated with corticosteroids show better recovery than control patients. The electronic databases Medline, Scopus and Cochrane were searched for clinical trials for the years 1970-2020 without language restriction. Data were extracted, and outcome parameters were subjected to conventional and cumulative meta-analysis using a commercially available software program (www.meta-analysis.com). Finally, 15 trials with 363 participants in the treatment and 489 in the control groups were identified and could be included. Eight studies were judged to be at high risk of bias. The odds ratio (OR) for good outcome in the acute phase was 3.1 (95% CI 1.2-7.8; p = .015) in favour of steroid treatment leading to the number needed to treat (NNT) = 6 (95% CI 4-23). The odds ratio (OR) for restoration of vestibular function in the follow-up was 2.4 (95% CI 1.3-4.4; p = .004) for the benefit of steroid treatment resulting in a NNT = 7 (95% CI 5-18). The results of the cumulative statistics did not differ. The risk of adverse effects was higher in patients treated with steroids with an OR of 10.9 (95% CI 1.3-93.8; p = .015) and an estimated number needed to harm (NNH) = 4 (95% CI 3-19). The advantage for corticosteroids remained when differentiating between patients who participated in randomized or non-randomized clinical trials. Steroid treatment in vestibular neuritis resulted in a statistically significant benefit compared to control therapies. However, broad heterogeneity of the studies, mostly low-grade quality of studies, high risk of bias and broad confidence intervals put the findings into perspective allowing only a careful judgement of some benefit of corticosteroids. The findings, however, support the call for an adequately powered and well-designed randomized controlled trial to re-evaluate the effectiveness of corticosteroids.

The outcomes of five fraction stereotactic radiotherapy (hfSRT) following brain metastasectomy were evaluated and compared with published series. 30 Gy in 5 fractions HfSRT prescribed to the surgical cavity was reduced to 25 Gy if the volume of ‘brain−GTV’ receiving 20 Gy exceeded 20 cm3. Endpoints were local recurrence, nodular leptomeningeal recurrence, new brain metastases and radionecrosis. The literature was searched for reports of clinical and dosimetric outcomes following postoperative hfSRT in 3–5 fractions. 39 patients with 40 surgical cavities were analyzed. Cavity local control rate at 1 year was 33/40 (82.5%). 3 local failures followed 30 Gy/5 fractions and 4 with 25 Gy/5 fractions. The incidence of leptomeningeal disease (LMD) was 7/40 (17.5%). No grade 3–4 toxicities, particularly no radionecrosis, were reported. The incidence of distant brain metastases was 15/40 (37.5%). The median overall survival was 15 months. Across 13 published series, the weighted mean local control was 83.1% (adjusted for sample size), the mean incidence of LMD was 14.9% (7–34%) and the mean rate of radionecrosis was 10.3% (0–20.6%). Postoperative hfSRT can be delivered with 25–30 Gy in 5 fractions with efficacy in excess of 82% and no significant toxicity when the dose to ‘brain−GTV’ does not exceed 20 cm3.

In the CNS, amino acid (AA) neurotransmitters and neurotransmitter precursors are subject to tight homeostatic control mediated by blood-brain barrier (BBB) solute carrier amino acid transporters (AATs). Since the BBB is composed of multiple closely apposed cell types and opportunities for human in vivo studies are limited, we used in vitro and computational approaches to investigate human BBB AAT activity and regulation. Quantitative real-time PCR (qPCR) of the human BBB endothelial cell model hCMEC/D3 (D3) was used to determine expression of selected AAT, tight junction (TJ), and signal transduction (ST) genes under various culture conditions. L-leucine uptake data were interrogated with a computational model developed by our group for calculating AAT activity in complex cell cultures. This approach is potentially applicable to in vitro cell culture drug studies where multiple “receptors” may mediate observed responses. Of 7 Leu AAT genes expressed by D3 only the activity of SLC7A5-SLC3A2/LAT1-4F2HC (LAT1), SLC43A2/LAT4 (LAT4) and sodium-dependent AATs, SLC6A15/B0AT2 (B0AT2), and SLC7A7/y+LAT1 (y+LAT1) were calculated to be required for Leu uptake. Therefore, D3 Leu transport may be mediated by a potentially physiologically relevant functional cooperation between the known BBB AAT, LAT1 and obligatory exchange (y+LAT1), facilitative diffusion (LAT4), and sodium symporter (B0AT2) transporters.

Conduct Disorder (CD) is characterized by severe aggressive and antisocial behavior. The stress hormone system has frequently been investigated as a neurobiological correlate of CD, while other interacting neuroendocrine biomarkers of sex hormone or neuropeptide systems have rarely been studied, especially in females. We examined multiple basal neuroendocrine biomarkers in female and male adolescents with CD compared to healthy controls (HCs), and explored whether they mediate effects of environmental risk factors on CD. Within the FemNAT-CD study, salivary cortisol, alpha-amylase, testosterone, dehydroepiandrosterone-sulfate (DHEA-S), estradiol, progesterone, oxytocin, and arginine-vasopressin were measured under basal conditions in 166 pubertal adolescents with CD, and 194 sex-, age-, and puberty-matched HCs (60% females, 9–18 years). Further, environmental risk factors were assessed. Single hormone analyses showed higher DHEA-S, and lower estradiol and progesterone levels in both females and males with CD relative to HCs. When accounting for interactions between neuroendocrine systems, a male-specific sex hormone factor (testosterone/DHEA-S) predicted male CD, while estradiol and a stress-system factor (cortisol/alpha-amylase) interacting with oxytocin predicted female CD. Estradiol, progesterone, and oxytocin partly explained associations between early environmental risk and CD. Findings provide evidence for sex-specific associations between basal neuroendocrine measures and CD. Especially altered sex hormones (androgen increases in males, estrogen reductions in females) robustly related to CD, while basal stress-system measures did not. Early environmental risk factors for CD may act partly through their effects on the neuroendocrine system, especially in females. Limitations (e.g., basal neuroendocrine assessment, different sample sizes per sex, pubertal participants, exploratory mediation analyses) are discussed.

Deep brain stimulation (DBS) electrodes provide an unparalleled window to record and investigate neuronal activity right at the core of pathological brain circuits. In Parkinson's disease (PD), basal ganglia beta-oscillatory activity (13–35 Hz) seems to play an outstanding role. Conventional DBS, which globally suppresses beta-activity, does not meet the requirements of a targeted treatment approach given the intricate interplay of physiological and pathological effects of beta-frequencies. Here, we wanted to characterise the local field potential (LFP) in the subthalamic nucleus (STN) in terms of beta-burst prevalence, amplitude and length between movement and rest as well as during self-paced as compared to goal-directed motor control. Our electrophysiological recordings from externalised DBS-electrodes in nine patients with PD showed a marked decrease in beta-burst durations and prevalence during movement as compared to rest as well as shorter and less frequent beta-bursts during cued as compared to self-paced movements. These results underline the importance of beta-burst modulation in movement generation and are in line with the clinical observation that cued motor control is better preserved than self-paced movements. Furthermore, our findings motivate the use of adaptive DBS based on beta-bursts, which selectively trim longer beta-bursts, as it is more suitable and efficient over a range of motor behaviours than conventional DBS., Neurobiology of Disease, 172, ISSN:0969-9961, ISSN:1095-953X

Objective: the switch between nonseizure and seizure states involves profound alterations in network excitability and synchrony. In this study, we aimed to identify and compare features of neural excitability and dynamics across multiple zebrafish seizure and epilepsy models. Methods: inspired by video-electroencephalographic recordings in patients, we developed a framework to study spontaneous and photically evoked neural and locomotor activity in zebrafish larvae, by combining high-throughput behavioral tracking and whole-brain in vivo two-photon calcium imaging. Results: our setup allowed us to dissect behavioral and physiological features that are divergent or convergent across multiple models. We observed that spontaneous locomotor and neural activity exhibit great diversity across models. Nonetheless, during photic stimulation, hyperexcitability and rapid response dynamics were well conserved across multiple models, highlighting the reliability of photically evoked activity for high-throughput assays. Intriguingly, in several models, we observed that the initial elevated photic response is often followed by rapid decay of neural activity and a prominent depressed state. Elevated photic response and following depressed state in seizure-prone networks are significantly reduced by the antiseizure medication valproic acid. Finally, rapid decay and depression of neural activity following photic stimulation temporally overlap with slow recruitment of astroglial calcium signals that are enhanced in seizure-prone networks. Significance We argue that fast decay of neural activity and depressed states following photic response are likely due to homeostatic mechanisms triggered by excessive neural activity. An improved understanding of the interplay between elevated and depressed excitability states might suggest tailored epilepsy therapies., European Research Council (ERC); European Union (EU); Horizon 2020; Helse Midt--Norge; Norges Forskningsrad

Effective risk factor modification is the prerequisite to prevent neurovascular disease such as stroke or vascular dementia. Non-traditional vascular risk factors (nt-vrfs) including stress significantly add to the risk of neurovascular disease arising from traditional vascular risk factors (t-vrfs). In order to discover sex-specific changes that may underlie previously reported inclines in the prevalence of neurovascular and cardiovascular disease in women, 10-year trends in the prevalence of vrfs in Switzerland were assessed.Anonymized data from 22,134 participants (51% women) of the governmental Swiss Health Survey, performed every 5 years (2007, 2012 and 2017), were obtained. Epidemiological parameters, t-vrfs and nt-vrfs were analyzed in a cross-sectional study design.Over the observation period, the number of women having full-time jobs increased considerably (2007 38%, 2012 39%, 2017 44%). This was accompanied by a substantial rise in the prevalence of nt-vrfs in women and men including stress at work (2007, not available; 2012 women/men 58%/60%; 2017 women/men 66%/65%), low locus of control (women/men: 2007 21%/19%, 2012 22%/19%, 2017 25%/22%) and sleep disorders (women/men: 2007 30%/22%, 2012 28%/20%, 2017 32%/26%). Amongst t-vrfs, only the prevalence of obesity and hypercholesterolemia increased over time in both sexes, whilst other t-vrfs remained stable (hypertension [27%], diabetes [5%]) or decreased (smoking [9.4 cigarettes/day]).A rise in women's economic participation alongside a higher affection with nt-vrfs in the female Swiss population emphasizes the need to improve vascular risk stratification and implement effective preventive measures for neurovascular and cardiovascular disease.

Psychiatric disorders are among the most common and debilitating illnesses across the lifespan and begin usually during childhood and adolescence, which emphasizes the importance of studying the developing brain. Most of the previous pediatric neuroimaging studies employed traditional univariate statistics on relatively small samples. Multivariate machine learning approaches have a great potential to overcome the limitations of these approaches. On the other hand, the vast majority of existing multivariate machine learning studies have focused on differentiating between children with an isolated psychiatric disorder and typically developing children. However, this line of research does not reflect the real-life situation as the majority of children with a clinical diagnosis have multiple psychiatric disorders (multimorbidity), and consequently, a clinician has the task to choose between different diagnoses and/or the combination of multiple diagnoses. Thus, the goal of the present benchmark is to predict psychiatric multimorbidity in children and adolescents. For this purpose, we implemented two kinds of machine learning benchmark challenges: The first challenge targets the prediction of the seven most prevalent DSM-V psychiatric diagnoses for the available data set, of which each individual can exhibit multiple ones concurrently (i.e. multi-task multi-label classification). Based on behavioral and cognitive measures, a second challenge focuses on predicting psychiatric symptom severity on a dimensional level (i.e. multiple regression task). For the present benchmark challenges, we will leverage existing and future data from the biobank of the Healthy Brain Network (HBN) initiative, which offers a unique large-sample dataset (N = 2042) that provides a wide array of different psychiatric developmental disorders and true hidden data sets. Due to limited real-world practicability and economic viability of MRI measurements, the present challenge will permit only resting state EEG data and demographic information to derive predictive models. We believe that a community driven effort to derive predictive markers from these data using advanced machine learning algorithms can help to improve the diagnosis of psychiatric developmental disorders.

The piriform cortex, at the confluence of the temporal and frontal lobes, generates seizures in response to chemical convulsants and electrical stimulation. Resection of more than 50% of the piriform cortex in anterior temporal lobe resection for refractory temporal lobe epilepsy (TLE) was associated with a 16-fold higher chance of seizure freedom. The objectives of the current study were to implement a robust protocol to measure piriform cortex volumes and to quantify the correlation of these volumes with clinical characteristics of TLE. Sixty individuals with unilateral TLE (33 left) and 20 healthy controls had volumetric analysis of left and right piriform cortex and hippocampi. A protocol for segmenting and measuring the volumes of the piriform cortices was implemented, with good inter-rater and test-retest reliability. The right piriform cortex volume was consistently larger than the left piriform cortex in both healthy controls and patients with TLE. In controls, the mean volume of the right piriform cortex was 17.7% larger than the left, and the right piriform cortex extended a mean of 6 mm (Range: -4 to 12) more anteriorly than the left. This asymmetry was also seen in left and right TLE. In TLE patients overall, the piriform cortices were not significantly smaller than in controls. Hippocampal sclerosis was associated with decreased ipsilateral and contralateral piriform cortex volumes. The piriform cortex volumes, both ipsilateral and contralateral to the epileptic temporal lobe, were smaller with a longer duration of epilepsy. There was no significant association between piriform cortex volumes and the frequency of focal seizures with impaired awareness or the number of anti-seizure medications taken. Implementation of robust segmentation will enable consistent neurosurgical resection in anterior temporal lobe surgery for refractory TLE..

Defined by dysfunction or degeneration of Aδ and C fibers, small fiber neuropathies (SFNs) entail a relevant health burden. In 50% of cases, the underlying cause cannot be identified or treated. In 100 individuals (70% female individuals; mean age: 44.8 years) with an idiopathic, skin biopsy-confirmed SFN, we characterized the symptomatic spectrum and measured markers of oxidative stress (vitamin C, selenium, and glutathione) and inflammation (transforming growth factor beta, tumor necrosis factor alpha), as well as neurotoxic 1-deoxy-sphingolipids. Neuropathic pain was the most abundant symptom (95%) and cause of daily life impairment (72%). Despite the common use of pain killers (64%), the painDETECT questionnaire revealed scores above 13 points in 80% of patients. In the quantitative sensory testing (QST), a dysfunction of Aδ fibers was observed in 70% and of C fibers in 44%, affecting the face, hands, or feet. Despite normal nerve conduction studies, QST revealed Aβ fiber involvement in 46% of patients' test areas. Despite absence of diabetes mellitus or mutations in SPTLC1 or SPTLC2 , plasma 1-deoxy-sphingolipids were significantly higher in the sensory loss patient cluster when compared with those in patients with thermal hyperalgesia ( P0.01) or those in the healthy category ( P0.1), correlating inversely with the intraepidermal nerve fiber density (1-deoxy-SA: P0.05, 1-deoxy-SO: P0.01). Patients with arterial hypertension, overweight (body mass index25 kg/m 2 ), or hyperlipidemia showed significantly lower L-serine (arterial hypertension: P0.01) and higher 1-deoxy-sphingolipid levels (arterial hypertension: P0.001, overweight: P0.001, hyperlipidemia: P0.01). Lower vitamin C levels correlated with functional Aβ involvement ( P0.05). Reduced glutathione was lower in patients with Aδ dysfunction ( P0.05). Idiopathic SFNs are heterogeneous. As a new pathomechanism, plasma 1-deoxy-sphingolipids might link the metabolic syndrome with small fiber degeneration.

Individuals regaining reliable day-to-day walking function after incomplete spinal cord injury (iSCI) report persisting unsteadiness when confronted with walking challenges. However, quantifiable measures of walking capacity lack the sensitivity to reveal underlying impairments of supra-spinal locomotor control. This study investigates the relationship between intramuscular coherence and corticospinal dynamic balance control during a visually guided Target walking treadmill task. In thirteen individuals with iSCI and 24 controls, intramuscular coherence and cumulant densities were estimated from pairs of Tibialis anterior surface EMG recordings during normal treadmill walking and a Target walking task. The approximate center of mass was calculated from pelvis markers. Spearman rank correlations were performed to evaluate the relationship between intramuscular coherence, clinical parameters, and center of mass parameters. In controls, we found that the Target walking task results in increased high-frequency (21–44 Hz) intramuscular coherence, which negatively related to changes in the center of mass movement, whereas this modulation was largely reduced in individuals with iSCI. The impaired modulation of high-frequency intramuscular coherence during the Target walking task correlated with neurophysiological and functional readouts, such as motor-evoked potential amplitude and outdoor mobility score, as well as center of mass trajectory length. The Target walking effect, the difference between Target and Normal walking intramuscular coherence, was significantly higher in controls than in individuals with iSCI [F(1.0,35.0) = 13.042, p < 0.001]. Intramuscular coherence obtained during challenging walking in individuals with iSCI may provide information on corticospinal gait control. The relationships between biomechanics, clinical scores, and neurophysiology suggest that intramuscular coherence assessed during challenging tasks may be meaningful for understanding impaired supra-spinal control in individuals with iSCI.

For patients with symptomatic unilateral internal carotid artery (ICA) occlusion, impaired cerebrovascular reactivity (CVR) indicates increased stroke risk. Here, the role of collateral activation remains a matter of debate, whereas angio-anatomical collateral abundancy does not necessarily imply sufficient compensatory flow provided. We aimed to further elucidate the role of collateral activation in the presence of impaired CVR. From a prospective database, 62 patients with symptomatic unilateral ICA occlusion underwent blood oxygenation-level dependent (BOLD) fMRI CVR imaging and a transcranial Doppler (TCD) investigation for primary and secondary collateral activation. Descriptive statistic and multivariate analysis were used to evaluate the relationship between BOLD-CVR values and collateral activation. Patients with activated secondary collaterals exhibited more impaired BOLD-CVR values of the ipsilateral hemisphere (p = 0.02). Specifically, activation of leptomeningeal collaterals showed severely impaired ipsilateral hemisphere BOLD-CVR values when compared to activation of ophthalmic collaterals (0.05 ± 0.09 vs. 0.12 ± 0.04, p = 0.005). Moreover, the prediction analysis showed leptomeningeal collateral activation as a strong independent predictor for ipsilateral hemispheric BOLD-CVR. In our study, ipsilateral leptomeningeal collateral activation is the sole collateral pathway associated with severely impaired BOLD-CVR in patients with symptomatic unilateral ICA occlusion.

Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) is a significant contributor to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. Prior experimental evidence has suggested cell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) as a pathophysiological driver of SAH-SBI. The aim of this study was to investigate the clinical and pathophysiological association between CSF-Hb and SAH-SBI. We prospectively enrolled 47 consecutive patients and collected daily CSF samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between CSF-Hb and SAH-SBI. The diagnostic accuracy of CSF-Hb for SAH-SBI markedly exceeded that of established methods (area under the curve: 0.89 [0.85-0.92]). Temporal LC-MS/MS CSF proteomics demonstrated that erythrolysis accompanied by an adaptive macrophage response are the two dominant biological processes occurring in the CSF space after aneurysm rupture. To further investigate the pathophysiology between CSF-Hb and SAH-SBI, we explored the vasoconstrictive and lipid peroxidation activities of Hb ex-vivo. These experiments revealed critical inflection points overlapping CSF-Hb concentration thresholds in patients with SAH-SBI. Selective Hb depletion and in-solution neutralization by the Hb-scavenger haptoglobin or the heme-scavenger hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb in patient CSF. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.

Background Whether patients with stroke and cancer exhibit specific characteristics has remained controversial. Methods Medical records of patients with ischemic stroke in 2014 or 2015 registered in the Swiss Stroke Registry of Zurich were retrospectively analyzed and integrated with regional cancer registry data. Associations of clinical and outcome parameters with cancer diagnosed up to 5 years prior to stroke were tested. Results Of 753 patients with ischemic stroke, 59 patients with cancer were identified. History of venous thromboembolism (p p = 0.001), erythrocyte sedimentation rate (p = 0.003), C-reactive protein (CRP) (p p = 0.003) were associated with cancer. For platelets, pathologically low (p = 0.034) or high levels (p p = 0.038 and p = 0.001). Poor post-stroke survival was associated with cancer (HR 2.2, p Conclusions Considering cancer as a cofactor for post-stroke outcome may impact clinical decision making.