Long-term health consequences among individuals with SARS-CoV-2 infection compared to individuals without infection: results of the population-based cohort study CoMoLo Follow-up.

BACKGROUND: Most of the previous studies on health sequelae of COVID-19 are uncontrolled cohorts and include a relatively short follow-up. This population-based multi-center cohort study examined health consequences among individuals about 1 to 1.5 years after SARS-CoV-2 infection compared with non-infected. METHODS: The study population consisted of adults (≥ 18 years) from four municipalities particularly affected by the COVID-19 pandemic in the year 2020 who completed a detailed follow-up questionnaire on health-related topics. Exposure was the SARS-CoV-2 infection status (based on IgG antibodies, PCR test, or physician-diagnosis of COVID-19) at baseline (May to December 2020). Outcomes assessed at follow-up (October 2021 to January 2022; mean: 452 days) included recurrent or persistent health complaints, incident diseases, health-related quality of life (PROMIS-29), subjective health, and subjective memory impairment. Logistic and linear regression models were adjusted for baseline sociodemographic and lifestyle characteristics (age, sex, municipality, education, smoking, body mass index), pre-existing health conditions (chronic disease/health problem, health-related activity limitation, depressive/anxiety disorder), and follow-up time. RESULTS: Among 4817 participants, 350 had a SARS-CoV-2 infection at baseline and 4467 had no infection at baseline or during follow-up. Those with an infection statistically significantly more often reported 7 out of 18 recurrent or persistent health complaints at follow-up: smell/taste disorders (12.8% vs. 3.4%, OR 4.11), shortness of breath (23.0% vs. 9.5%, 3.46), pain when breathing (4.7% vs. 1.9%, 2.36), fatigue (36.9% vs. 26.1%, 1.76), weakness in legs (12.8% vs. 7.8%, 1.93), myalgia/joint pain (21.9% vs. 15.1%, 1.53) and cough (30.8% vs. 24.8%, 1.34) and 3 out of 6 groups of incident diseases: liver/kidney (2.7% vs. 0.9%, 3.70), lung (3.2% vs. 1.1%, 3.50) and cardiovascular/metabolic (6.5% vs. 4.0%, 1.68) diseases. Those with an infection were significantly more likely to report poor subjective health (19.3% vs. 13.0%, 1.91), memory impairment (25.7% vs. 14.3%, 2.27), and worse mean scores on fatigue and physical function domains of PROMIS-29 than non-infected. CONCLUSION: Even after more than one year, individuals with SARS-CoV-2 infection showed an increased risk of various health complaints, functional limitations, and worse subjective well-being, pointing toward profound health consequences of SARS-CoV-2 infection relevant for public health.

Delayed Antibody and T-Cell Response to BNT162b2 Vaccination in the Elderly, Germany.

We detected delayed and reduced antibody and T-cell responses after BNT162b2 vaccination in 71 elderly persons (median age 81 years) compared with 123 healthcare workers (median age 34 years) in Germany. These data emphasize that nonpharmaceutical interventions for coronavirus disease remain crucial and that additional immunizations for the elderly might become necessary.

Studying the pathophysiology of coronavirus disease 2019: a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19).

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. METHODS: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. RESULTS: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. CONCLUSION: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00021688).

Mobile electronic versus paper case report forms in clinical trials: a randomized controlled trial.

BACKGROUND: Regulations, study design complexity and amounts of collected and shared data in clinical trials render efficient data handling procedures inevitable. Recent research suggests that electronic data capture can be key in this context but evidence is insufficient. This randomized controlled parallel group study tested the hypothesis that time efficiency is superior when electronic (eCRF) instead of paper case report forms (pCRF) are used for data collection. We additionally investigated predictors of time saving effects and data integrity. METHODS: This study was conducted on top of a clinical weight loss trial performed at a clinical research facility over six months. All study nurses and patients participating in the clinical trial were eligible to participate and randomly allocated to enter cross-sectional data obtained during routine visits either through pCRF or eCRF. A balanced randomization list was generated before enrolment commenced. 90 and 30 records were gathered for the time that 27 patients and 2 study nurses required to report 2025 and 2037 field values, respectively. The primary hypothesis, that eCRF use is faster than pCRF use, was tested by a two-tailed t-test. Analysis of variance and covariance were used to evaluate predictors of entry performance. Data integrity was evaluated by descriptive statistics. RESULTS: All randomized patients were included in the study (eCRF group n = 13, pCRF group n = 14). eCRF, as compared to pCRF, data collection was associated with significant time savings  across all conditions (8.29 ± 5.15 min vs. 10.54 ± 6.98 min, p = .047). This effect was not defined by participant type, i.e. patients or study nurses (F(1,112) = .15, p = .699), CRF length (F(2,112) = .49, p = .609) or patient age (Beta = .09, p = .534). Additional 5.16 ± 2.83 min per CRF were saved with eCRFs due to data transcription redundancy when patients answered questionnaires directly in eCRFs. Data integrity was superior in the eCRF condition (0 versus 3 data entry errors). CONCLUSIONS: This is the first study to prove in direct comparison that using eCRFs instead of pCRFs increases time efficiency of data collection in clinical trials, irrespective of item quantity or patient age, and improves data quality. TRIAL REGISTRATION: Clinical Trials NCT02649907 .

Nonphysiological factors in navigated TMS studies; confounding covariates and valid intracortical estimates.

UNLABELLED: Brain stimulation is used to induce transient alterations of neural excitability to probe or modify brain function. For example, single-pulse transcranial magnetic stimulation (TMS) of the motor cortex can probe corticospinal excitability (CSE). Yet, CSE measurements are confounded by a high level of variability. This variability is due to physical and physiological factors. Navigated TMS (nTMS) systems can record physical parameters of the TMS coil (tilt, location, and orientation) and some also estimate intracortical electric fields (EFs) on a trial-by-trial basis. Thus, these parameters can be partitioned with stepwise regression. PURPOSE: The primary objective was to dissociate variance due to physical parameters from variance due to physiological factors for CSE estimates. The secondary objective was to establish the predictive validity of EF estimates from spherical head models. HYPOTHESIS: Variability of physical parameters of TMS predicts CSE variability. METHODS: Event-related measurements of physical parameters were analyzed in stepwise regression. Partitioned parameter variance and predictive validity were compared for a target-controlled and a nontarget-controlled experiment. A control experiment (preinnervation) confirmed the validity of linear data analysis. A bias-free model quantified the effect of divergence from optimum. RESULTS: Partitioning physical parameter variance reduces CSE variability. EF estimates from spherical models were valid. Post hoc analyses showed that even small physical fluctuations can confound the statistical comparison of CSE measurements. CONCLUSIONS: It is necessary to partition physical and physiological variance in TMS studies to make confounded data interpretable. The spatial resolution of nTMS is <5 mm and the EF-estimates are valid.

Reappraisal of the anatomical landmarks of motor and premotor cortical regions for image-guided brain navigation in TMS practice.

Image-guided navigation systems dedicated to transcranial magnetic stimulation (TMS) have been recently developed and offer the possibility to visualize directly the anatomical structure to be stimulated. Performing navigated TMS requires a perfect knowledge of cortical anatomy, which is very variable between subjects. This study aimed at providing a detailed description of sulcal and gyral anatomy of motor cortical regions with special interest to the inter-individual variability of sulci. We attempted to identify the most stable structures, which can serve as anatomical landmarks for motor cortex mapping in navigated TMS practice. We analyzed the 3D reconstruction of 50 consecutive healthy adult brains (100 hemispheres). Different variants were identified regarding sulcal morphology, but several anatomical structures were found to be remarkably stable (four on dorsoventral axis and five on rostrocaudal axis). These landmarks were used to define a grid of 12 squares, which covered motor cortical regions. This grid was used to perform motor cortical mapping with navigated TMS in 12 healthy subjects from our cohort. The stereotactic coordinates (x-y-z) of the center of each of the 12 squares of the mapping grid were expressed into the standard Talairach space to determine the corresponding functional areas. We found that the regions whose stimulation produced almost constantly motor evoked potentials mainly correspond to the primary motor cortex, with rostral extension to premotor cortex and caudal extension to posterior parietal cortex. Our anatomy-based approach should facilitate the expression and the comparison of the results obtained in motor mapping studies using navigated TMS.

Predictors of non-recovery from fatigue and cognitive deficits after COVID-19: a prospective, longitudinal, population-based study.

Background: Despite the high prevalence and major disability associated with fatigue and cognitive deficits after SARS-CoV-2 infection, little is known about long-term trajectories of these sequelae. We aimed to assess long-term trajectories of these conditions and to identify risk factors for non-recovery. Methods: We analyzed longitudinal data from the population-based COVIDOM/NAPKON-POP cohort in Germany. Participants with confirmed SARS-CoV-2 infection were assessed at least 6 months (baseline) and again at least 18 months (follow-up) after infection using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale (cutoff ≤ 30) and the Montreal Cognitive Assessment (MoCA, cutoff ≤ 25). Predictors of recovery from fatigue or cognitive deficits between assessments were identified through univariate and multivariable logistic regression models. The COVIDOM study is registered at the German registry for clinical studies (DRKS00023742) and at ClinicalTrials.gov (NCT04679584). Findings: Between 15 November 2020 and 9 May 2023, a total of 3038 participants were assessed at baseline (median 9 months after infection) and 83% responded to invitations for follow-up (median 26 months after infection). At baseline, 21% (95% confidence interval (CI) [20%, 23%]) had fatigue and 23% (95% CI [22%, 25%]) had cognitive deficits according to cutoff scores on the FACIT-Fatigue or MoCA. Participants with clinically relevant fatigue (at baseline) showed significant improvement in fatigue scores at follow-up (Hedges' g [95% CI] = 0.73 [0.60, 0.87]) and 46% (95% CI [41%, 50%]) had recovered from fatigue. Participants with cognitive deficits showed a significant improvement in cognitive scores (g [95% CI] = 1.12 [0.90, 1.33]) and 57% (95% CI [50%, 64%]) had recovered from cognitive deficits. Patients with fatigue exhibiting a higher depressive symptom burden and/or headache at baseline were significantly less likely to recover. Significant risk factors for cognitive non-recovery were male sex, older age and <12 years of school education. Importantly, SARS-CoV-2 reinfection had no significant impact on recovery from fatigue or cognitive deficits. Interpretation: Fatigue and cognitive deficits are common sequelae after SARS-CoV-2 infection. These syndromes improved over time and about half of the patients recovered within two years. The identified risk factors for non-recovery from fatigue and cognitive deficits could play an important role in shaping targeted strategies for treatment and prevention. Funding: Funded by the German Federal Ministry of Education and Research (BMBF; grant number 01KX2121) and German Research Foundation (DFG) Excellence Cluster "Position Medicine in Information".

Toward discovery science of human brain function.

Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.

Evidence- and data-driven classification of low back pain via artificial intelligence: Protocol of the PREDICT-LBP study.

In patients presenting with low back pain (LBP), once specific causes are excluded (fracture, infection, inflammatory arthritis, cancer, cauda equina and radiculopathy) many clinicians pose a diagnosis of non-specific LBP. Accordingly, current management of non-specific LBP is generic. There is a need for a classification of non-specific LBP that is both data- and evidence-based assessing multi-dimensional pain-related factors in a large sample size. The "PRedictive Evidence Driven Intelligent Classification Tool for Low Back Pain" (PREDICT-LBP) project is a prospective cross-sectional study which will compare 300 women and men with non-specific LBP (aged 18-55 years) with 100 matched referents without a history of LBP. Participants will be recruited from the general public and local medical facilities. Data will be collected on spinal tissue (intervertebral disc composition and morphology, vertebral fat fraction and paraspinal muscle size and composition via magnetic resonance imaging [MRI]), central nervous system adaptation (pain thresholds, temporal summation of pain, brain resting state functional connectivity, structural connectivity and regional volumes via MRI), psychosocial factors (e.g. depression, anxiety) and other musculoskeletal pain symptoms. Dimensionality reduction, cluster validation and fuzzy c-means clustering methods, classification models, and relevant sensitivity analyses, will classify non-specific LBP patients into sub-groups. This project represents a first personalised diagnostic approach to non-specific LBP, with potential for widespread uptake in clinical practice. This project will provide evidence to support clinical trials assessing specific treatments approaches for potential subgroups of patients with non-specific LBP. The classification tool may lead to better patient outcomes and reduction in economic costs.

Duration of Surgery and Intraoperative Blood Pressure Management Are Modifiable Risk Factors for Postoperative Neurocognitive Disorders After Spine Surgery: Results of the Prospective CONFESS Study.

STUDY DESIGN: Prospective quasi-experimental observational study. OBJECTIVE: The objective of this study was to evaluate whether duration of surgery is a modifiable risk factor for postoperative delirium (POD) after spine surgery and explore further modifiable risk factors. In addition, we sought to investigate the association between POD and postoperative cognitive dysfunction and persistent neurocognitive disorders. SUMMARY OF BACKGROUND DATA: Advances in spine surgery enable technically safe interventions in elderly patients with disabling spine disease. The occurrence of POD and delayed neurocognitive complications ( e.g. postoperative cognitive dysfunction/persistent neurocognitive disorder) remain a concern since these contribute to inferior functional outcomes and long-term care dependency after spine surgery. MATERIALS AND METHODS: This prospective single-center study recruited patients aged 60 years or above and scheduled for elective spine surgery between February 2018 and March 2020. Functional (Barthel Index, BI) and cognitive outcomes [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery; telephone Montréal Cognitive Assessment] were assessed at baseline, three (V3), and 12 months postoperatively. The primary hypothesis was that the duration of surgery predicts POD. Multivariable predictive models of POD included surgical and anesthesiological parameters. RESULTS: Twenty-two percent of patients developed POD (n=22/99). In a multivariable model, duration of surgery [OR adj =1.61/h (95% CI, 1.20-2.30)], age [OR adj =1.22/yr (95% CI, 1.10-1.36)], and baseline deviations of intraoperative systolic blood pressure [25th percentile: OR adj =0.94/mm Hg (95% CI, 0.89-0.99); 90th percentile: OR adj =1.07/mm Hg (95% CI, 1.01-1.14)] were significantly associated with POD. Postoperative cognitive scores generally improved (V3, ΔCERAD total z -score: 0.22±0.63). However, this positive group effect was counteracted by POD [beta: -0.87 (95% CI, -1.31 to 0.42)], older age [beta: -0.03/yr (95% CI, -0.05 to 0.01)], and lack of functional improvement [ΔBI; beta: -0.04/point (95% CI, -0.06 to 0.02)]. Cognitive scores at twelve months remained inferior in the POD group, adjusted for baseline cognition/age. CONCLUSIONS: This study identified distinct neurocognitive effects after spine surgery, which are influenced by perioperative risk factors. Potential cognitive benefits are counteracted by POD, rendering its prevention critical in an aging population.

Protocol of the Berlin Long-term Observation of Vascular Events (BeLOVE): a prospective cohort study with deep phenotyping and long-term follow up of cardiovascular high-risk patients.

INTRODUCTION: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations. METHODS AND ANALYSIS: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes. ETHICS AND DISSEMINATION: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations. STUDY REGISTRATION: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021.

Assessing the functional status of the motor system in brain tumor patients using transcranial magnetic stimulation.

BACKGROUND: Transcranial magnetic stimulation (TMS) is being used in the pre-operative diagnostics of patients with tumors in or near the motor cortex. Although the main purpose of TMS in such patients is to map the functional areas of the motor cortex in spatial relation to the tumor, TMS also provides some numerical neurophysiological measurements of the functional status of the patient's motor system. The aim of this paper is to provide reference values for these neurophysiological measurements from a large and varied clinical sample. METHODS: TMS was used in the pre-operative work-up of patients with various types of tumors in or near the motor cortex during a 3-year period. Data was collected prospectively in 100 patients, yet this is a post hoc report. RESULTS: Patient characteristics had no influence on the neurophysiological parameters. The response latency time was almost never different in the tumorous versus healthy hemisphere, so clinicians should be suspicious if they find interhemispheric differences for latency. A high interhemispheric ratio of resting motor threshold (RMT) or a low interhemispheric ratio of motor evoked potential (MEP) amplitude appear to suggest immanent deterioration of the patient's motor status. CONCLUSION: In addition to topographic cortical mapping, TMS also serves as a neurophysiological assessment of the functional status of the patient's motor system. The results presented here provide clinicians with a set of reference values to contextualize findings in their own tumor patients. Further research is still needed to better understand the full clinical relevance of these neurophysiological parameters.

Non-invasive brain stimulation modulates neural correlates of performance monitoring in patients with obsessive-compulsive disorder.

Overactive performance monitoring, as reflected by enhanced neural responses to errors (the error-related negativity, ERN), is considered a biomarker for obsessive-compulsive disorder (OCD) and may be a promising target for novel treatment approaches. Prior research suggests that non-invasive brain stimulation with transcranial direct current stimulation (tDCS) may reduce the ERN in healthy individuals, yet no study has investigated its efficacy in attenuating the ERN in OCD. In this preregistered, randomized, sham-controlled, crossover study, we investigated effects of tDCS on performance monitoring in patients with OCD (n = 28) and healthy individuals (n = 28). Cathodal and sham tDCS was applied over the presupplementary motor area (pre-SMA) in two sessions, each followed by electroencephalogram recording during a flanker task. Cathodal tDCS reduced the ERN amplitude compared to sham tDCS, albeit this effect was only marginally significant (p = .052; mean difference: 0.86 µV). Additionally, cathodal tDCS reduced the correct-response negativity and increased the error positivity. These neural modulations were not accompanied by behavioral changes. Moreover, we found no evidence that the tDCS effect was more pronounced in the patient group. In summary, our findings indicate that tDCS over the pre-SMA modulates neural correlates of performance monitoring across groups. Therefore, this study represents a valuable starting point for future research to determine whether repeated tDCS application induces a more pronounced ERN attenuation and normalizes aberrant performance monitoring in the long term, thereby potentially alleviating obsessive-compulsive symptoms and providing a psychophysiological intervention strategy for individuals who do not benefit sufficiently from existing interventions.

Neuromodulation through brain stimulation-assisted cognitive training in patients with post-COVID-19 cognitive impairment (Neuromod-COV): study protocol for a PROBE phase IIb trial.

INTRODUCTION: A substantial number of patients diagnosed with COVID-19 experience long-term persistent symptoms. First evidence suggests that long-term symptoms develop largely independently of disease severity and include, among others, cognitive impairment. For these symptoms, there are currently no validated therapeutic approaches available. Cognitive training interventions are a promising approach to counteract cognitive impairment. Combining training with concurrent transcranial direct current stimulation (tDCS) may further increase and sustain behavioural training effects. Here, we aim to examine the effects of cognitive training alone or in combination with tDCS on cognitive performance, quality of life and mental health in patients with post-COVID-19 subjective or objective cognitive impairments. METHODS AND ANALYSIS: This study protocol describes a prospective randomised open endpoint-blinded trial. Patients with post-COVID-19 cognitive impairment will either participate in a 3-week cognitive training or in a defined muscle relaxation training (open-label interventions). Irrespective of their primary intervention, half of the cognitive training group will additionally receive anodal tDCS, all other patients will receive sham tDCS (double-blinded, secondary intervention). The primary outcome will be improvement of working memory performance, operationalised by an n-back task, at the postintervention assessment. Secondary outcomes will include performance on trained and untrained tasks and measures of health-related quality of life at postassessment and follow-up assessments (1 month after the end of the trainings). ETHICS AND DISSEMINATION: Ethical approval was granted by the Ethics Committee of the University Medicine Greifswald (number: BB 066/21). Results will be available through publications in peer-reviewed journals and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04944147.

Fatigue and cognitive impairment after COVID-19: A prospective multicentre study.

Background: Reliable estimates of frequency, severity and associated factors of both fatigue and cognitive impairment after COVID-19 are needed. Also, it is not clear whether the two are distinct sequelae of COVID-19 or part of the same syndrome." Methods: In this prospective multicentre study, frequency of post-COVID fatigue and cognitive impairment were assessed in n = 969 patients (535 [55%] female) ≥6 months after SARS-CoV-2 infection with the FACIT-Fatigue scale (cut-off ≤30) and Montreal Cognitive Assessment (≤25 mild, ≤17 moderate impairment) between November 15, 2020 and September 29, 2021 at University Medical Center Schleswig-Holstein, Campus Kiel and University Hospital Würzburg in Germany. 969 matched non-COVID controls were drawn from a pre-pandemic, randomised, Germany-wide population survey which also included the FACIT-Fatigue scale. Associated sociodemographic, comorbid, clinical, psychosocial factors and laboratory markers were identified with univariate and multivariable linear regression models. Findings: On average 9 months after infection, 19% of patients had clinically relevant fatigue, compared to 8% of matched non-COVID controls (p < 0.001). Factors associated with fatigue were female gender, younger age, history of depression and the number of acute COVID symptoms. Among acute COVID symptoms, altered consciousness, dizziness and myalgia were most strongly associated with long-term fatigue. Moreover, 26% of patients had mild and 1% had moderate cognitive impairment. Factors associated with cognitive impairment were older age, male gender, shorter education and a history of neuropsychiatric disease. There was no significant correlation between fatigue and cognitive impairment and only 5% of patients suffered from both conditions. Interpretation: Fatigue and cognitive impairment are two common, but distinct sequelae of COVID-19 with potentially separate pathophysiological pathways. Funding: German Federal Ministry of Education and Research (BMBF).

Dynamic upper and lower visual field preferences within the human dorsal frontoparietal attention network.

Both in nonhuman primates and in humans, behavioral differences between the upper and lower visual field have been identified in distinct subprocesses of attention. Advantages of the lower field have been explained by its higher spatial resolution; those of the upper field by its higher efficiency in attentional shifting. The physiological basis of visual field asymmetries within in the frontoparietal attention network (FPN) remains unclear. This study investigates the physiological correlates of upper and lower field preferences within the FPN using event-related functional magnetic resonance imaging. The paradigm separated two attentional subprocesses during a visual search task. Whether in the upper or lower field, the attention of subjects was first directed at stationary locations (spatial orienting) and then shifted between locations to search for a target (visual search) in easy or difficult search displays. Depending on the task phase (spatial orienting vs. easy visual search), upper and lower visual field preferences in the FPN changed. The analysis revealed a lower field preference during stationary spatial orienting and an upper field preference during visual search. We conclude that also higher areas represent upper and lower visual field asymmetries depending on distinct subcomponents of visuospatial attentional processing.

Human Premotor Corticospinal Projections Are Engaged in Motor Preparation at Discrete Time Intervals: A TMS-Induced Virtual Lesion Study.

Objectives: The significance of pre-motor (PMC) corticospinal projections in a frontoparietal motor network remains elusive. Temporal activation patterns can provide valuable information about a region's engagement in a hierarchical network. Navigated transcranial magnetic stimulation (nTMS)-induced virtual lesions provide an excellent method to study cortical physiology by disrupting ongoing activity at high temporal resolution and anatomical precision. We use nTMS-induced virtual lesions applied during an established behavioral task demanding pre-motor activation to clarify the temporal activation pattern of pre-motor corticospinal projections. Materials and Methods: Ten healthy volunteers participated in the experiment (4 female, mean age 24 ± 2 years, 1 left-handed). NTMS was used to map Brodmann areae 4 and 6 for primary motor (M1) and PMC corticospinal projections. We then determined the stimulator output intensity required to elicit a 1 mV motor evoked potential (1 mV-MT) through M1 nTMS. TMS pulse were randomly delivered at distinct time intervals (40, 60, 80, 100, 120, and 140 ms) at 1 mV-MT intensity to M1, PMC and the DLPFC (dorsolateral pre-frontal cortex; control condition) before participants had to perform major changes of their trajectory of movement during a tracing task. Each participant performed six trials (20 runs per trial). Task performance and contribution of regions under investigation was quantified through calculating the tracing error induced by the stimulation. Results: A pre-motor stimulation hotspot could be identified in all participants (16.3 ± 1.7 mm medial, 18.6 ± 1.4 mm anterior to the M1 hotspot). NTMS over studied regions significantly affected task performance at discrete time intervals (F(10, 80) = 3.25, p = 0.001). NTMS applied over PMC 120 and 140 ms before changes in movement trajectory impaired task performance significantly more than when applied over M1 (p = 0.021 and p = 0.003) or DLPFC (p = 0.017 and p < 0.001). Stimulation intensity did not account for error size (ß = -0.0074, p = 1). Conclusions: We provide novel evidence that the role of pre-motor corticospinal projections extends beyond that of simple corticospinal motor output. Their activation is crucial for task performance early in the stage of motor preparation suggesting a significant role in shaping voluntary movement. Temporal patterns of human pre-motor activation are similar to that observed in intracortical electrophysiological studies in primates.

Treatment Realities of Headache Disorders in Rural Germany by the Example of the Region of Western Pomerania.

(1) Background: Headache disorders are among the most disabling medical conditions but the supply with experienced providers is outpaced by the demand for service. It is unclear to what extent particularly patients in rural regions are affected by limited access to comprehensive care. Furthermore, it is unknown what role general practitioners (GPs) play in headache care. (2) Methods: First-time consultations to a specialised headache clinic at a tertiary care centre were asked to participate. Their socio-demographic background, general and headache-specific medical history, disability and quality of life (QoL) were assessed. Additionally, 176 GPs in neighbouring districts were contacted regarding headache management. (3) Results: We assessed 162 patients with first-time consultations (age 46.1 ± 17.0 years, 78.1% female), who suffered from migraine (72%), tension type, cluster and secondary headaches (each 5-10%). About 50% of patients received a new headache-diagnosis and 60% had treatment inconsistent with national guidelines. QoL was significantly worse in all domains compared to the general population. About 75% of GPs see headache patients at least several times per week, and mostly treat them by themself. (4) Conclusions: More than every second headache patient was neither correctly diagnosed nor received guideline adherent treatment. Headache-related disability is inferior to what is expected from previous studies. Access to specialised health care is more limited in rural than in urban regions in Germany and GPs request more training.

Transcranial direct current stimulation affects visual perception measured by threshold perimetry.

In this study, we aimed to characterize the effect of anodal and cathodal direct current stimulation (tDCS) on contrast sensitivity inside the central 10 degrees of the visual field in healthy subjects. Distinct eccentricities were investigated separately, since at the cortical level, more central regions of the visual field are represented closer to the occipital pole, i.e. closer to the polarizing electrodes, than are the more peripheral regions. Using a double-blind and sham-controlled within-subject design, we measured the effect of stimulation and potential learning effect separately across testing days. Anodal stimulation of the visual cortex compared to sham stimulation yielded a significant increase in contrast sensitivity within 8° of the visual field. A significant increase in contrast sensitivity between the conditions "pre" and "post" anodal stimulation was only obtained for the central positions at eccentricities smaller than 2°. Cathodal stimulation of the visual cortex did not affect contrast sensitivity at either eccentricity. Perceptual learning across testing days was only observed for threshold perimetry before stimulation. Measuring contrast sensitivity changes after tDCS with a standard clinical tool such as threshold perimetry may provide an interesting perspective in assessing therapeutic effects of tDCS in ophthalmological or neurological defects (e.g. with foveal sparing vs. foveal splitting).

Individualized Template MRI Is a Valid and Reliable Alternative to Individual MRI for Spatial Tracking in Navigated TMS Studies in Healthy Subjects.

Objectives: Navigated transcranial magnetic stimulation (nTMS) provides significant benefits over classic TMS. Yet, the acquisition of individual structural magnetic resonance images (MRIindividual) is a time-consuming, expensive, and not feasible prerequisite in all subjects for spatial tracking and anatomical guidance in nTMS studies. We hypothesize that spatial transformation can be used to adjust MRI templates to individual head shapes (MRIwarped) and that TMS parameters do not differ between nTMS using MRIindividual or MRIwarped. Materials and Methods: Twenty identical TMS sessions, each including four different navigation conditions, were conducted in 10 healthy subjects (one female, 27.4 ± 3.8 years), i.e., twice per subject by two researchers to additionally assess interrater reliabilities. MRIindividual were acquired for all subjects. MRIwarped were obtained through the spatial transformation of a template MRI following a 5-, 9-and 36-point head surface registration (MRIwarped_5, MRIwarped_9, MRIwarped_36). Stimulation hotspot locations, resting motor threshold (RMT), 500 µV motor threshold (500 µV-MT), and mean absolute motor evoked potential difference (MAD) of primary motor cortex (M1) examinations were compared between nTMS using either MRIwarped variants or MRIindividual and non-navigated TMS. Results: M1 hotspots were spatially consistent between MRIindividual and MRIwarped_36 (insignificant deviation by 4.79 ± 2.62 mm). MEP thresholds and variance were also equivalent between MRIindividual and MRIwarped_36 with mean differences of RMT by -0.05 ± 2.28% maximum stimulator output (%MSO; t (19) = -0.09, p = 0.923), 500 µV-MT by -0.15 ± 1.63%MSO (t (19) = -0.41, p = 0.686) and MAD by 70.5 ± 214.38 µV (t (19) = 1.47, p = 0.158). Intraclass correlations (ICC) of motor thresholds were between 0.88 and 0.97. Conclusions: NTMS examinations of M1 yield equivalent topographical and functional results using MRIindividual and MRIwarped if a sufficient number of registration points are used.