Showing papers by "Walter Paulus published in 2020"
Paris 12 Val de Marne University1, University Medical Center Groningen2, Eindhoven University of Technology3, University Hospital of Lausanne4, French Institute of Health and Medical Research5, Università Campus Bio-Medico6, University of Belgrade7, University of Cologne8, Ludwig Maximilian University of Munich9, École Polytechnique Fédérale de Lausanne10, Turku University Hospital11, University of Regensburg12, Università telematica San Raffaele13, Paris Descartes University14, Paracelsus Private Medical University of Salzburg15, University of Bern16, Universidade Nova de Lisboa17, Medical Park18, University of Göttingen19, University of Messina20, Central European Institute of Technology21, University of Siena22, University of Turku23, University of Tübingen24
TL;DR: These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018, and are based on the differences reached in therapeutic efficacy of real vs. sham rT MS protocols.
822 citations
Barrow Neurological Institute1, King's College London2, Royal Victoria Infirmary3, Peking Union Medical College Hospital4, University of Lisbon5, University of British Columbia6, Beaumont Hospital7, University of Queensland8, University of Chile9, Columbia University10, University of Göttingen11, University of Sydney12, Queen Mary University of London13, University of Oxford14, Fukushima Medical University15, Utrecht University16, Universidad del Desarrollo17, Royal Prince Alfred Hospital18
TL;DR: This is an open access article under the CC BY-NC-ND license and the paper has been approved for publication by the International Federation of Clinical Neurophysiology.
210 citations
Paris 12 Val de Marne University1, University Medical Center Groningen2, Eindhoven University of Technology3, University Hospital of Lausanne4, French Institute of Health and Medical Research5, Università Campus Bio-Medico6, University of Belgrade7, University of Cologne8, Ludwig Maximilian University of Munich9, École Polytechnique Fédérale de Lausanne10, Turku University Hospital11, University of Regensburg12, Università telematica San Raffaele13, Paris Descartes University14, Paracelsus Private Medical University of Salzburg15, University of Bern16, Universidade Nova de Lisboa17, Medical Park18, University of Göttingen19, University of Messina20, Central European Institute of Technology21, University of Siena22, University of Turku23, University of Tübingen24
TL;DR: Jean-Pascal Lefaucheur, André Aleman, Chris Baeken, David H. Benninger, Jérôme Brunelin, Vincenzo Di Lazzaro, Saša R. Filipovic, Emmanuel Poulet, Angelo Quartarone, Irena Rektorová, Simone Rossi, Hanna Sahlsten, Martin Schecklmann, David Szekely, Ulf Ziemann.
77 citations
TL;DR: TDCS‐induced excitability changes correlated more strongly with perfusion changes in the left sensorimotor region compared to the targeted hand‐knob region and with the predicted electric field, as simulated with finite element modeling.
Abstract: Transcranial direct current stimulation (tDCS) induces polarity- and dose-dependent neuroplastic aftereffects on cortical excitability and cortical activity, as demonstrated by transcranial magnetic stimulation (TMS) and functional imaging (fMRI) studies. However, lacking systematic comparative studies between stimulation-induced changes in cortical excitability obtained from TMS, and cortical neurovascular activity obtained from fMRI, prevent the extrapolation of respective physiological and mechanistic bases. We investigated polarity- and intensity-dependent effects of tDCS on cerebral blood flow (CBF) using resting-state arterial spin labeling (ASL-MRI), and compared the respective changes to TMS-induced cortical excitability (amplitudes of motor evoked potentials, MEP) in separate sessions within the same subjects (n = 29). Fifteen minutes of sham, 0.5, 1.0, 1.5, and 2.0-mA anodal or cathodal tDCS was applied over the left primary motor cortex (M1) in a randomized repeated-measure design. Time-course changes were measured before, during and intermittently up to 120-min after stimulation. ROI analyses indicated linear intensity- and polarity-dependent tDCS after-effects: all anodal-M1 intensities increased CBF under the M1 electrode, with 2.0-mA increasing CBF the greatest (15.3%) compared to sham, while all cathodal-M1 intensities decreased left M1 CBF from baseline, with 2.0-mA decreasing the greatest (-9.3%) from sham after 120-min. The spatial distribution of perfusion changes correlated with the predicted electric field, as simulated with finite element modeling. Moreover, tDCS-induced excitability changes correlated more strongly with perfusion changes in the left sensorimotor region compared to the targeted hand-knob region. Our findings reveal lasting tDCS-induced alterations in cerebral perfusion, which are dose-dependent with tDCS parameters, but only partially account for excitability changes.
60 citations
TL;DR: Three Ways to Break His Heart There are two established causes of high diastolic left ventricular stiffness: fibrosis and the rigidification of titin.
Abstract: Three Ways to Break His Heart There are two established causes of high diastolic left ventricular stiffness: fibrosis and the rigidification of titin. A recent scientific study of a mouse model poi...
45 citations
TL;DR: There is an urgent need to more accurately define the syndrome of HFpEF to inform diagnosis, patient selection for clinical trials, and, ultimately, future therapeutic approaches, according to current knowledge gaps and existing diagnostic tools and algorithms.
Abstract: There is a lack of consensus on how we define heart failure with preserved ejection fraction (HFpEF), with wide variation in diagnostic criteria across society guidelines. This lack of uniformity in disease definition stems in part from an incomplete understanding of disease pathobiology, phenotypic heterogeneity, and natural history. We review current knowledge gaps and existing diagnostic tools and algorithms. We present a simple approach to implement these tools within the constraints of the current knowledge base, addressing separately (1) hospitalized individuals with rest congestion, where diagnosis is more straightforward; and (2) individuals with exercise intolerance, where diagnosis is more complex. Here, a potential role for advanced or provocative testing, including evaluation of hemodynamic responses to exercise is considered. More importantly, we propose focus areas for future studies to develop accurate and feasible diagnostic tools for HFpEF, including animal models that recapitulate human HFpEF, and human studies that both address a fundamental understanding of HFpEF pathobiology, and new diagnostic approaches and tools, as well. In sum, there is an urgent need to more accurately define the syndrome of HFpEF to inform diagnosis, patient selection for clinical trials, and, ultimately, future therapeutic approaches.
31 citations
TL;DR: RTMS can induce immediate electrophysiological effects at much weaker electric field strengths than previously thought and is consistently found to increase neural synchronization in the posterior alpha frequency band when measured simultaneously with scalp electroencephalography.
Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a potent tool for modulating endogenous oscillations in humans. The current standard method for rTMS defines the stimulation intensity based on the evoked liminal response in the visual or motor system (e.g., resting motor threshold). The key limitation of the current approach is that the magnitude of the resulting electric field remains elusive. A better characterization of the electric field strength induced by a given rTMS protocol is necessary in order to improve the understanding of the neural mechanisms of rTMS. In this study we used a novel approach, in which individualized prospective computational modeling of the induced electric field guided the choice of stimulation intensity. We consistently found that rhythmic rTMS protocols increased neural synchronization in the posterior alpha frequency band when measured simultaneously with scalp electroencephalography. We observed this effect already at electric field strengths of roughly half the lowest conventional field strength, which is 80% of the resting motor threshold. We conclude that rTMS can induce immediate electrophysiological effects at much weaker electric field strengths than previously thought.
29 citations
06 Aug 2020
TL;DR: The results suggest that cognitive control depends on the phase specificity of the θ-γ CFC, which is designed to stimulate the frontal and cingulate cortices in humans through transcranial alternating current stimulation.
Abstract: Cognitive control is a mental process, which underlies adaptive goal-directed decisions. Previous studies have linked cognitive control to electrophysiological fluctuations in the theta band and theta-gamma cross-frequency coupling (CFC) arising from the cingulate and frontal cortices. Yet, to date the behavioral consequences of different forms of theta-gamma CFC remain elusive. Here, we studied the behavioral effects of the theta-gamma CFC via transcranial alternating current stimulation (tACS) designed to stimulate the frontal and cingulate cortices in humans. Using a double-blind, randomized, repeated measures study design, 24 healthy participants were subjected to three active and one control CFC-tACS conditions. In the active conditions, 80 Hz gamma tACS was coupled to 4 Hz theta tACS. Specifically, in two of the active conditions, short gamma bursts were coupled to the delivered theta cycle to coincide with either its peaks or troughs. In the third active condition, the phase of a theta cycle modulated the amplitude of the gamma oscillation. In the fourth, control protocol, 80 Hz tACS was continuously superimposed over the 4 Hz tACS, therefore lacking any phase-specificity in the CFC. During the 20-minute of stimulation, the participants performed a Go/NoGo monetary reward- and punishment-based instrumental learning task. A Bayesian hierarchical logistic regression analysis revealed that relative to the control, the peak-coupled tACS had no effects on the behavioral performance, whereas the trough-coupled tACS and, to a lesser extent, amplitude-modulated tACS reduced performance in conflicting trials. Our results suggest that cognitive control depends on the phase-specificity of the theta-gamma CFC.Statement of significance This study investigated the behavioral effects of different forms of theta-gamma cross-frequency coupling in cognitive control. To this aim, we delivered cross-frequency transcranial alternating current stimulation over the cingulate and frontal cortices in humans. We found that when gamma tACS was coupled to the trough of theta tACS, the stimulation worsened the ability of healthy participants to employ cognitive control. Our findings highlight the role of theta-gamma cross frequency coupling in complex goal-directed behavior in humans.
23 citations
University of Lorraine1, University of Porto2, Universidad Pública de Navarra3, Norwegian University of Science and Technology4, Oslo University Hospital5, University of Perugia6, Maastricht University7, The Heart Research Institute8, Queen Mary University of London9, Katholieke Universiteit Leuven10, University of Eastern Piedmont11, St. Michael's GAA, Sligo12, French Institute of Health and Medical Research13, University of Debrecen14, University of Amsterdam15
TL;DR: It was demonstrated that biomarkers associated with the high- risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolism, which may help select high-risk HFpEF patients most likely to respond to the selected mechanistically targeted therapies.
Abstract: Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes.Methods: Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression.Results: Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 vs. 1. Patients in cluster 2 vs. those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12-3.32, p = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism.Conclusion: Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significanceMore insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolismBiomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials.Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.
22 citations
TL;DR: The transition from asymptomatic pre-HFpEF to symptomatic HFpEF also involves left atrial failure, pulmonary hypertension and right ventricular dysfunction, and renal failure, and ultimately the currently accepted driver—systemic inflammation.
Abstract: To better understand heart failure with preserved ejection fraction (HFpEF), we need to better characterize the transition from asymptomatic pre-HFpEF to symptomatic HFpEF. The current emphasis on left ventricular diastolic dysfunction must be redirected to microvascular inflammation and endothelial dysfunction that leads to cardiomyocyte remodeling and enhanced interstitial collagen deposition. A pre-HFpEF patient lacks signs or symptoms of heart failure (HF), has preserved left ventricular ejection fraction (LVEF) with incipient structural changes similar to HFpEF, and possesses elevated biomarkers of cardiac dysfunction. The transition from pre-HFpEF to symptomatic HFpEF also involves left atrial failure, pulmonary hypertension and right ventricular dysfunction, and renal failure. This review focuses on the non-left ventricular mechanisms in this transition, involving the atria, right heart cavities, kidneys, and ultimately the currently accepted driver-systemic inflammation. Impaired atrial function may decrease ventricular hemodynamics and significantly increase left atrial and pulmonary pressure, leading to HF symptoms, irrespective of left ventricle (LV) systolic function. Pulmonary hypertension and low right-ventricular function are associated with the incidence of HF. Interstitial fibrosis in the heart, large arteries, and kidneys is key to the pathophysiology of the cardiorenal syndrome continuum. By understanding each of these processes, we may be able to halt disease progression and eventually extend the time a patient remains in the asymptomatic pre-HFpEF stage.
21 citations
TL;DR: The right posterior parietal cortex is an essential node that promotes the encoding of long-term memories and it is found that single-trial low theta power in this region predicts subsequent long- term recognition.
TL;DR: This work searched for highly significant mutational burden in candidate genes to identify putatively causative genes at genetic risk loci in restless legs syndrome.
Abstract: Objective Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. Methods We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. Results Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. Interpretation Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.
University of Lorraine1, University of Porto2, Universidad Pública de Navarra3, Oslo University Hospital4, Norwegian University of Science and Technology5, University of Perugia6, Maastricht University7, The Heart Research Institute8, University of Eastern Piedmont9, St. Michael's GAA, Sligo10, French Institute of Health and Medical Research11, University of Debrecen12, Charité13, University of Amsterdam14
TL;DR: Assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients, which may help further investigations into potential pathophysiological processes contributing to HFpEF.
Abstract: Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce. A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models. We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83–2.63), p = 0.18. In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.
TL;DR: This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB).
Abstract: Aim Diagnosing Heart Failure with Preserved Ejection Fraction (HFpEF) in the non-acute setting remains challenging Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB) Methods and results A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until April 21, 2020 Those without diagnostic performance measures reported, or performed in an acute HF population were excluded, leading to a total of 28 studies For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing At least one domain with a high ROB was present in all studies Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants Due to the high ROB and different patient populations no meta-analysis was performed Conclusion The majority of current diagnostic HFpEF biomarker studies have a high risk of bias, reducing the reproducibility and the potential for clinical care Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF
TL;DR: Another possibility in which bursting of CST neurons is produced by dendritic Ca2+-spikes is proposed, in which backpropagation of the initial action potential from the soma interacts with synaptic input in the dendrites to initiate a dendrite calcium spike.
TL;DR: TACS over the visual cortex has the potential to terminate migraine attacks, but the high drop-out rate due to compliance problems suggests that this method is impeded by its complexity and time-consuming setup.
Abstract: Background: Low intensity, high-frequency transcranial alternating current stimulation (tACS) applied over the motor cortex decreases the amplitude of motor evoked potentials. This double-blind, placebo-controlled parallel group study aimed to test the efficacy of this method for acute management of migraines. Methods: The patients received either active (0.4 mA, 140 Hz) or sham stimulation for 15 min over the visual cortex with the number of terminated attacks two hours post-stimulation as the primary endpoint, as a home therapy option. They were advised to treat a maximum of five migraine attacks over the course of six weeks. Results: From forty patients, twenty-five completed the study, sixteen in the active and nine in the sham group with a total of 102 treated migraine attacks. The percentage of terminated migraine attacks not requiring acute rescue medication was significantly higher in the active (21.5%) than in the sham group (0%), and the perceived pain after active stimulation was significantly less for 2-4 h post-stimulation than after sham stimulation. Conclusion: tACS over the visual cortex has the potential to terminate migraine attacks. Nevertheless, the high drop-out rate due to compliance problems suggests that this method is impeded by its complexity and time-consuming setup.
24 Oct 2020
TL;DR: A consensus conference on the application of transcranial magnetic stimulation (TMS) in research and clinical settings was held in Siena (Italy) in 2018 as discussed by the authors, with a focus on safety issues of recently developed stimulation devices and pulse configurations.
Abstract: This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.
TL;DR: A stratified treatment approach, using dapagliflozin in heart failure patients with preserved ejection fraction without evidence of significant myocardial fibrosis is investigated, using SGLT2 inhibition as a viable therapeutic option.
Abstract: Aims High myocardial stiffness in heart failure with preserved ejection fraction (HFpEF) is attributed to comorbidity-induced structural and functional remodelling through inflammation and oxidative stress affecting coronary microvascular endothelial cells and cardiomyocytes, which augments interstitial fibrosis and cardiomyocyte stiffness. In murine and human HFpEF myocardium, sodium glucose co-transporter 2 (SGLT2) inhibition ameliorates cardiac microvascular endothelial cell and cardiomyocyte oxidative stress, while enhancing myocardial protein kinase G activity and lowering titin-based cardiomyocyte stiffness. Failure of previous HFpEF outcome trials refocuses attention to improving pathophysiological insight and trial design with better phenotyping of patients and matching of therapeutic targets to prevailing pathogenetic mechanisms. SGLT2 inhibition could represent a viable therapeutic option especially in HFpEF patients in whom high diastolic left ventricular (LV) stiffness is predominantly caused by elevated cardiomyocyte stiffness and associated endothelial dysfunction, whereas HFpEF patients with extensive myocardial fibrosis might be less responsive. This study aims to investigate a stratified treatment approach, using dapagliflozin in heart failure patients with preserved ejection fraction without evidence of significant myocardial fibrosis. Methods and results The Stratified Treatment to Ameliorate DIAstolic left ventricular stiffness in early Heart Failure with preserved Ejection Fraction (STADIA-HFpEF) is a Phase II, randomized, 2 × 2 crossover trial, evaluating the efficacy of 13 weeks of treatment with dapagliflozin 10 mg od in 26 patients with HFpEF, with normal cardiac magnetic resonance imaging-derived extracellular volume. The co-primary endpoint is echocardiographically derived change in E/e'/LV end-diastolic volume index and change in mean LV e'. Conclusions The STADIA-HFpEF trial will be the first study to evaluate the direct effects of dapagliflozin on amelioration of LV stiffness, using histological phenotyping to discern early HFpEF.
TL;DR: Despite the heterogeneity of the included studies, this review supported the current multivariable-based approach for the diagnosis of HFpEF and LVDD and showed a potential diagnostic role for exercise echocardiography and left atrial strain.
Abstract: This study aimed to evaluate the diagnostic performance of echocardiographic markers of heart failure with preserved ejection fraction (HFpEF) and left ventricular diastolic dysfunction (LVDD) in comparison with the gold standard of cardiac catheterization. Diagnosing HFpEF is challenging, as symptoms are non-specific and often absent at rest. A clear need exists for sensitive echocardiographic markers to diagnose HFpEF. We systematically searched for studies testing the diagnostic value of novel echocardiographic markers for HFpEF and LVDD. Two investigators independently reviewed the studies and assessed the risk of bias. Results were meta-analysed when four or more studies reported a similar diagnostic measure. Of 353 studies, 20 fulfilled the eligibility criteria. The risk of bias was high especially in the patients’ selection domain. The highest diagnostic performance was demonstrated by a multivariable model combining echocardiographic, clinical and arterial function markers with an area under the curve of 0.95 (95% CI, 0.89–0.98). A meta-analysis of four studies indicated a reasonable diagnostic performance for left atrial strain with an AUC of 0.83 (0.70–0.95), a specificity of 93% (95% CI, 90–97%) and a sensitivity of 77% (95% CI, 59–96%). Moreover, the addition of exercise E/e′ improved the sensitivity of HFpEF diagnostic algorithms up to 90%, compared with 60 and 34% of guidelines alone. Despite the heterogeneity of the included studies, this review supported the current multivariable-based approach for the diagnosis of HFpEF and LVDD and showed a potential diagnostic role for exercise echocardiography and left atrial strain. Larger well-designed studies are needed to evaluate the incremental value of novel diagnostic tools to current diagnostic algorithms.
03 Dec 2020
TL;DR: D diagnosis and treatment of functional movement disorders and specifically functional tremor is challenging and should include a combination of intensive clinical examination and targeted addition of standardized testing, especially electrophysiological methods.
Abstract: Diagnosis of functional movement disorders and specifically functional tremor (FT) (representing 50% of them) remains demanding. Additionally, due to heterogeneity of the disorders, structured concepts and guidelines for diagnosis and therapy are difficult to establish. Ascertaining the state of knowledge to derive instructions for operating procedures is the aim of this review. Based on a standardized systematic literature research using the term “psychogenic tremor” in the MEDLINE database dating back ten years, 76 studies were evaluated. Conventional features of FT are variability of frequency and amplitude. Further, response to distraction by motor and cognitive tasks is a key diagnostic feature in differentiation between organic and functional origin. A variety of electrophysiological tests have been evaluated including surface electromyography and accelerometry to establish laboratory-supported criteria for diagnosing tremor. Also, finger tapping tests have been used to identify FT, showing positive potential as supplementary evidence. Imaging studies in general are mostly underpowered and imaging cannot be used on an individual basis. Therapeutic studies in FT often have a diagnostic component. Cognitive behavioral therapy should be the preferred psychological treatment independent of additional psychiatric symptoms. Other psychotherapeutic methods show lack of evidence concerning FT. Relaxation techniques and physiotherapy are an important additional feature, especially in children and adolescents. In regard to drug therapy, randomized and blinded trials are not available. A significant decrease in rating scales could be detected after active, not sham repetitive transcranial magnetic stimulation with a long-lasting effect. Also root magnetic stimulation seems to be effective. The clinical feature of tremor entrainment in FT can be used in combination with biofeedback as so-called tremor retrainment, using self-modulation of frequency and severity, to bring the movements under volitional control. Diagnosis and treatment of FT is challenging and should include a combination of intensive clinical examination and targeted addition of standardized testing, especially electrophysiological methods. Often therapeutic effects have a diagnostic component. A multimodal strategy, considering psychological factors as a potential origin as well as maintaining effects seems to be most effective.
TL;DR: It is concluded that low intensity, rhythmic rTMS can synchronize mu-alpha rhythm and modulate the corticospinal excitability in M1.
Abstract: Sensorimotor mu-alpha rhythm reflects the state of cortical excitability. Repetitive transcranial magnetic stimulation (rTMS) can modulate neural synchrony by inducing periodic electric fields (E-fields) in the cortical networks. We hypothesized that the increased synchronization of mu-alpha rhythm would inhibit the corticospinal excitability reflected by decreased motor evoked potentials (MEP). In seventeen healthy participants, we applied rhythmic, arrhythmic, and sham rTMS over the left M1. The stimulation intensity was individually adapted to 35 mV/mm using prospective E-field estimation. This intensity corresponded to ca. 40% of the resting motor threshold. We found that rhythmic rTMS increased the synchronization of mu-alpha rhythm, increased mu-alpha/beta power, and reduced MEPs. On the other hand, arrhythmic rTMS did not change the ongoing mu-alpha synchronization or MEPs, though it increased the alpha/beta power. We concluded that low intensity, rhythmic rTMS can synchronize mu-alpha rhythm and modulate the corticospinal excitability in M1.
TL;DR: Structural and functional connectivity of the sensorimotor integration and inhibitory control network shape speech motor learning, and a heightened negative correlation between stuttering severity and fractional anisotropy in the superior longitudinal fasciculus is found.
Abstract: Developmental stuttering is a fluency disorder with anomalies in the neural speech motor system. Fluent speech requires multifunctional network formations. Currently, it is unclear which functional domain is targeted by speech fluency interventions. Here, we tested the impact of fluency-shaping on resting-state fMRI connectivity of the speech planning, articulatory convergence, sensorimotor integration, and inhibitory control network. Furthermore, we examined white matter metrics of major speech tracts. Improved fluency was accompanied by an increased synchronization within the sensorimotor integration network. Specifically, two connections were strengthened, left laryngeal motor cortex and right superior temporal gyrus showed increased connectivity with the left inferior frontal gyrus. The integration of the command-to-execution and auditory-motor pathway was strengthened. Since we investigated task-free brain activity, we assume that our findings are not biased to network activity involved in compensation. No alterations were found within white matter microstructure. But, brain-behavior relationships changed. We found a heightened negative correlation between stuttering severity and fractional anisotropy in the superior longitudinal fasciculus, and a heightened positive correlation between the psycho-social impact of stuttering and fractional anisotropy in the right frontal aslant tract. Taken together, structural and functional connectivity of the sensorimotor integration and inhibitory control network shape speech motor learning.
TL;DR: It is concluded that there is no major difference in the movement patterns of a fluent-sounding utterance in both groups, which encourages studies looking at state rather than trait markers of speech dysfluency.
Abstract: Whether fluent-sounding utterances of adults who stutter (AWS) are normally articulated is unclear. We asked 15 AWS and 17 matched adults who do not stutter (ANS) to utter the pseudoword "natscheitideut" 15 times in a 3 T MRI scanner while recording real-time MRI videos at 55 frames per per second in a mid-sagittal plane. All stuttered or otherwise dysfluent runs were discarded. We used sophisticated analyses to model the movement of the tip of the tongue, lips and velum. We observed reproducible movement patterns of the inner and outer articulators which were similar in both groups. Speech duration was similar in both groups and decreased over repetitions, more so in ANS than in AWS. The variability of the movement patterns of tongue, lips and velum decreased over repetitions. The extent of variability decrease was similar in both groups. Across all participants, this repetition effect on movement variability for the lips and the tip of the tongue was less pronounced in severely as compared to mildly stuttering individuals. We conclude that there is no major difference in the movement patterns of a fluent-sounding utterance in both groups. This encourages studies looking at state rather than trait markers of speech dysfluency.
29 Jan 2020
TL;DR: In this article, Bicoronary infusion of the NO-donor sodium nitroprusside, reduced LV peak and end-systolic pressures through a relaxation-hastening effect and increased LV diastolic distensibility.
Abstract: Endothelial release of nitric oxide (NO) is an important control mechanism of vascular tone. Nitric oxide released from the endothelial lining of the coronary vasculature also influences myocardial performance. In isolated papillary muscles and in ejecting guinea-pig hearts, substance P, which releases NO from endothelial cells, shortened myocardial contraction through a relaxation hastening effect. Similar findings were observed with exogenous NO-donor substances such as sodium nitroprusside.
These observations were recently extended to the clinical setting because of demonstration in man of myocardial contractile effects of both exogenous and endogenous NO. In healthy control subjects, bicoronary infusion of the NO-donor sodium nitroprusside, reduced LV peak and end-systolic pressures through a relaxation-hastening effect and increased LV diastolic distensibility. Similar observations were made in transplant recipients and in patients with aortic stenosis. The occasional observation of a larger LV end-diastolic volume during intravenous NO-donor infusion supports the presence of direct myocardial relaxant effects of NO even during intravenous administration of NO-donors. Direct myocardial effects of NO could not be demonstrated in normal subjects or in heart failure patients during inhalation of NO probably because of rapid inactivation of NO by hemoglobin in the pulmonary circulation. In healthy control subjects and in transplant recipients, bicoronary infusion of substance P influenced LV performance in a similar way as bicoronary infusion of sodium nitroprusside by reducing LV peak and end-systolic pressures, by hastening the onset of LV relaxation and by increasing LV diastolic distensibility. These effects were attributed to a paracrine myocardial action of NO, released by substance P from the coronary endothelium and were potentiated in transplant recipients by simultaneous intracoronary infusion of L-arginine or by intravenous infusion of dobutamine. Because of recent demonstration of myocardial expression of inducible NO-synthase in certain cardiomyopathies, the cardiodepression observed in these conditions was linked to myocardial production of NO. The functional consequence of NO produced by inducible NO-synthase remains however unclear because, in contrast to NO derived from NO-donor or endothelial cells, expression of inducible NO-synthase impairs myocardial relaxation.
Myocardial relaxant effects of endothelially released NO are relevant to diastolic LV performance both acutely and chronically. Acute increases in LV workload augment coronary flow and increase endothelial release of NO, which through its paracrine myocardial action lowers LV filling pressures to promote subendocardial perfusion and hasten the onset of LV relaxation to prolong diastolic coronary perfusion time. Chronic enhancement of coronary endothelial release of NO as a result of chronic exercise or pacing could relate to the increased LV diastolic distensibility observed in athlete’s heart or in tachycardia-induced cardiomyopathy. Chronic reduction of coronary endothelial release of NO, as occurs with aging or after transplantation, could explain reduced diastolic LV distensibility in the elderly or in transplant recipients.