Showing papers by "Walter Paulus published in 2011"

Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment

Abstract: Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality in HFpEF are similar to values observed in patients with HF and reduced EF, yet no effective treatment has been identified. While early research focused on the importance of diastolic dysfunction in the pathophysiology of HFpEF, recent studies have revealed that multiple non-diastolic abnormalities in cardiovascular function also contribute. Diagnosis of HFpEF is frequently challenging and relies upon careful clinical evaluation, echo-Doppler cardiography, and invasive haemodynamic assessment. In this review, the principal mechanisms, diagnostic approaches, and clinical trials are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future.

Transcranial electrical stimulation (tES – tDCS; tRNS, tACS) methods

Abstract: Weak transcranial direct current stimulation (tDCS) with a homogenous DC field at intensities of around 1 mA induces long-lasting changes in the brain. tDCS can be used to manipulate brain excitability via membrane polarisation: cathodal stimulation hyperpolarises, while anodal stimulation depolarises the resting membrane potential, whereby the induced after-effects depend on polarity, duration and intensity of the stimulation. A variety of other parameters influence tDCS effects; co-application of neuropharmacologically active drugs may most impressively prolong or even reverse stimulation effects. Transcranial alternating stimulation (tACS) and random noise stimulation (tRNS) are used to interfere with ongoing neuronal oscillations and also finally produce neuroplastic effects if applied with appropriate parameters.

Transcranial direct current stimulation--update 2011.

Abstract: Non-invasive brain stimulation with weak direct currents (transcranial direct current stimulation (tDCS)) has emerged as one of the major tools to induce neuroplastic cortical excitability alterations in humans since its (re-) introduction to the arsenal of plasticity-inducing brain stimulation tools. In this review, we gather newly emerged knowledge about the effect of tDCS on brain function in both, basic and applied research. This overview will deliver an update of the last two years of research, because especially during this time numerous important studies were published covering the above-mentioned fields.

Modulating functional connectivity patterns and topological functional organization of the human brain with transcranial direct current stimulation

Abstract: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that alters cortical excitability and activity in a polarity-dependent way. Stimulation for few minutes has been shown to induce plastic alterations of cortical excitability and to improve cognitive performance. These effects might be caused by stimulation-induced alterations of functional cortical network connectivity. We aimed to investigate the impact of tDCS on cortical network function through functional connectivity and graph theoretical analysis. Single recordings in healthy volunteers with 62 electroencephalography channels were acquired before and after 10 min of facilitatory anodal tDCS over the primary motor cortex (M1), combined with inhibitory cathodal tDCS of the contralateral frontopolar cortex, in resting state and during voluntary hand movements. Correlation matrices containing all 62 pairwise electrode combinations were calculated with the synchronization likelihood (SL) method and thresholded to construct undirected graphs for the θ, α, β, low-γ and high-γ frequency bands. SL matrices and undirected graphs were compared before and after tDCS. Functional connectivity patterns significantly increased within premotor, motor, and sensorimotor areas of the stimulated hemisphere during motor activity in the 60-90 Hz frequency range. Additionally, tDCS-induced significant intrahemispheric and interhemispheric connectivity changes in all the studied frequency bands. In summary, we show for the first time evidence for tDCS-induced changes in brain synchronization and topological functional organization.

Time course of the induction of homeostatic plasticity generated by repeated transcranial direct current stimulation of the human motor cortex.

Abstract: Several mechanisms have been proposed that control the amount of plasticity in neuronal circuits and guarantee dynamic stability of neuronal networks. Homeostatic plasticity suggests that the ease ...

Diabetes Mellitus Worsens Diastolic Left Ventricular Dysfunction in Aortic Stenosis Through Altered Myocardial Structure and Cardiomyocyte Stiffness

Abstract: Background—Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adverse...

Cathodal transcranial direct current stimulation of the visual cortex in the prophylactic treatment of migraine.

Abstract: Background: The purpose of this study was to determine whether transcranial direct current stimulation (tDCS) can be an effective prophylactic therapy for migraine and migraine-associated pain. Method: This painless and non-invasive method was applied for 6 weeks over the visual cortex (V1), delivered three times per week. Thirty patients were assigned to cathodal or to sham stimulation, and 26 patients participated in the final analyses (cathodal: n ¼ 13, sham: n ¼ 13). During the first 3 weeks both groups received only placebo stimulation. Measures of attack frequency and duration, intensity of pain and number of migraine-related days were recorded 2 months before, during and 2 months post-treatment. Results: Patients treated by cathodal tDCS showed a significant reduction in the duration of attacks, the intensity of pain and the number of migraine-related days post-treatment as compared to the baseline period, but not in the frequency of the attacks. However, compared to the sham group, only the intensity of the pain was significantly reduced poststimulation. No patients experienced severe adverse effects. Conclusion: Our results suggest that the application of cathodal stimulation over the V1 might be an effective prophylactic therapy in migraine, at least with regard to pain control.

Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1.

Abstract: Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.

Frequency Specific Modulation of Human Somatosensory Cortex

Abstract: Oscillatory neuronal activities are commonly observed in response to sensory stimulation. However, their functional roles are still the subject of debate. One-way to probe the roles of oscillatory neural activities is to deliver alternating current to the cortex at biologically relevant frequencies and examine whether such stimulation influences perception and cognition. In this study, we tested whether transcranial alternating current stimulation (tACS) over the primary somatosensory cortex (SI) could elicit tactile sensations in humans in a frequency-dependent manner. We tested the effectiveness of tACS over SI at frequency bands ranging from 2 to 70 Hz. Our results show that stimulation in alpha (10-14 Hz) and high gamma (52-70 Hz) frequency range produces a tactile sensation in the contralateral hand. A weaker effect was also observed for beta (16-20 Hz) stimulation. These findings highlight the frequency dependency of effective tACS over SI with the effective frequencies corresponding to those observed in previous electroencephalography/magnetoencephalography studies of tactile perception. Our present study suggests that tACS could be used as a powerful online stimulation technique to reveal the causal roles of oscillatory brain activities.

Individual voxel-based subtype prediction can differentiate progressive supranuclear palsy from idiopathic Parkinson syndrome and healthy controls.

Abstract: Voxel-based morphometry (VBM) shows a differentiated pattern in patients with atypical Parkinson syndrome but so far has had little impact in individual cases. It is desirable to translate VBM findings into clinical practice and individual classification. To this end, we examined whether a support vector machine (SVM) can provide useful accuracies for the differential diagnosis. We acquired a volumetric 3D T1-weighted MRI of 21 patients with idiopathic Parkinson syndrome (IPS), 11 multiple systems atrophy (MSA-P) and 10 progressive supranuclear palsy (PSP), and 22 healthy controls. Images were segmented, normalized, and compared at group level with SPM8 in a classical VBM design. Next, a SVM analysis was performed on an individual basis with leave-one-out cross-validation. VBM showed a strong white matter loss in the mesencephalon of patients with PSP, a putaminal grey matter loss in MSA, and a cerebellar grey matter loss in patients with PSP compared with IPS. The SVM allowed for an individual classification in PSP versus IPS with up to 96.8% accuracy with 90% sensitivity and 100% specificity. In MSA versus IPS, an accuracy of 71.9% was achieved; sensitivity, however, was low with 36.4%. Patients with IPS could not be differentiated from controls. In summary, a voxel-based SVM analysis allows for a reliable classification of individual cases in PSP that can be directly clinically useful. For patients with MSA and IPS, further developments like quantitative MRI are needed.

Transcranial alternating current stimulation in the low kHz range increases motor cortex excitability.

Abstract: Purpose: External transcranial electric and magnetic stimulation techniques allow for the fast induction of sus- tained and measurable changes in cortical excitability. Here we aim to develop a paradigm using transcranial alternating current (tACS) in a frequency range higher than 1 kHz, which potentially interferes with membrane excitation, to shape neuroplastic processes in the human primary motor cortex (M1). Methods: Transcranial alternating current stimulation was applied at 1, 2 and 5 kHz over the left primary motor cortex with a reference electrode over the contralateral orbit in 11 healthy volunteers for a duration of 10 min at an intensity of 1 mA. Monophasic single- pulse transcranial magnetic stimulation (TMS) was used to measure changes in corticospinal excitability, both during and after tACS in the low kHz range, in the right hand muscle. As a control inactive sham stimulation was performed. Results: All frequencies of tACS increased the amplitudes of motor- evoked potentials (MEPs) up to 30-60 min post stimu- lation, compared to the baseline. Two and 5 kHz stimulations were more efficacious in inducing sustained changes in cortical excitability than 1 kHz stimulation, compared to sham stimulation. Conclusions: Since tACS in the low kHz range appears too fast to interfere with network oscillations, this technique opens a new possibility to directly interfere with cortical excitability, probably via neuronal membrane activation. It may also potentially replace more conventional repetitive transcranial magnetic stimulation (rTMS) techniques for some applications in a clinical setting.

Left-Ventricular Remodeling After Myocardial Infarction Is Associated with a Cardiomyocyte-Specific Hypothyroid Condition

Abstract: Similarities in cardiac gene expression in hypothyroidism and left ventricular (LV) pathological remodeling after myocardial infarction (MI) suggest a role for impaired cardiac thyroid hormone (TH) signaling in the development of heart failure. Increased ventricular activity of the TH-degrading enzyme type 3 deiodinase (D3) is recognized as a potential cause. In the present study, we investigated the cardiac expression and activity of D3 over an 8-wk period after MI in C57Bl/6J mice. Pathological remodeling of the noninfarcted part of the LV was evident from cardiomyocyte hypertrophy, interstitial fibrosis, and impairment of contractility. These changes were maximal and stable from the first week onward, as was the degree of LV dilation. A strong induction of D3 activity was found, which was similarly stable for the period examined. Plasma T(4) levels were transiently decreased at 1 wk after MI, but T(3) levels remained normal. The high D3 activity was associated with increased D3 mRNA expression at 1 but not at 4 and 8 wk after MI. Immunohistochemistry localized D3 protein to cardiomyocytes. In vivo measurement of TH-dependent transcription activity in cardiomyocytes using a luciferase reporter assay indicated a 48% decrease in post-MI mice relative to sham-operated animals, and this was associated with a 50% decrease in LV tissue T(3) concentration. In conclusion, pathological ventricular remodeling after MI in the mouse leads to high and stable induction of D3 activity in cardiomyocytes and a local hypothyroid condition.

Evaluating Aftereffects of Short-Duration Transcranial Random Noise Stimulation on Cortical Excitability

Abstract: A 10-minute application of highfrequency (100–640 Hz) transcranial random noise stimulation (tRNS) over the primary motor cortex (M1) increases baseline levels of cortical excitability, lasting around 1 hr poststimulation Terney et al. (2008). We have extended previous work demonstrating this effect by decreasing the stimulation duration to 4, 5, and 6 minutes to assess whether a shorter duration of tRNS can also induce a change in cortical excitability. Single-pulse monophasic transcranial magnetic stimulation (TMS) was used to measure baseline levels of cortical excitability before and after tRNS. A 5- and 6-minute tRNS application induced a significant facilitation. 4-minute tRNS produced no significant aftereffects on corticospinal excitability. Plastic after effects after tRNS on corticospinal excitability require a minimal stimulation duration of 5 minutes. However, the duration of the aftereffect of 5-min tRNS is very short compared to previous studies using tRNS. Developing different transcranial stimulation techniques may be fundamental in understanding how excitatory and inhibitory networks in the human brain can be modulated and how each technique can be optimised for a controlled and effective application.

Isometric contraction interferes with transcranial direct current stimulation (tDCS) induced plasticity: evidence of state-dependent neuromodulation in human motor cortex.

Abstract: Background and Purpose: Neuroplastic alterations of cortical excitability and activity represent the likely neuro- physiological foundation of learning and memory formation. Beyond their induction, alterations of these processes by subsequent modification of cortical activity, termed metaplasticity, came into the focus of interest recently. Animal slice experiments demon- strated that neuroplastic excitability enhancements, or diminutions, can be abolished by consecutive subthreshold stimulation. These processes, termed de-potentiation, and de-depression, have so far not been explored in humans. Methods: We combined neuroplasticity induction by transcranial direct current stimulation (tDCS) applied to the hand area of primary motor cortex (M1), which can be used to induce long-lasting excitability enhancements or reductions, dependent on the polarity of stimulation, with short-lasting voluntary muscle contraction (VMC), which itself does not induce plastic cortical excitability changes. Corticospinal and intra-cortical M1 excitability were monitored by different transcranial magnetic stimulation (TMS) protocols. Results: VMC reduced or tended to reverse the anodal tDCS-driven motor cortical excitability enhancement and the cathodal tDCS-induced excitability diminution. Our findings thus demonstrate de-potentiation- and de-depression-like phenomena at the system level in the human motor cortex. Conclusion: This neurophysiological study may contribute to a better understanding of the balance between induction and reversal of plasticity associated with motor learning and rehabilitation processes.

Heart failure and cognitive function in the general population: the Hoorn Study

Abstract: Aim To examine whether reduced cognitive functioning can be observed in early stages of left ventricular (LV) dysfunction and heart failure. Methods and results In 313 individuals aged 59–87 years from the longitudinal non-demented population-based Hoorn Study, echocardiography was performed to measure markers of LV systolic and diastolic function at baseline (2000–01) and follow-up (2005–09), together with standardized physical examinations and brain natriuretic peptide (BNP) measurements. Heart failure was assessed echocardiographically at the follow-up examination only. Cognitive tests for information processing speed, memory, and attention and executive functioning were administered at follow-up. Linear regression analyses showed that baseline markers of LV diastolic function, but not LV systolic function, were associated with lower scores on attention and executive functioning at follow-up. Individuals with higher baseline BNP had lower scores on all three cognitive domains: standardized regression coefficients were −0.16 (–0.26 to −0.05), −0.17 (–0.28 to −0.05), and −0.28 (–0.37 to −0.19). Worse LV systolic and diastolic function at follow-up were associated with a worse performance on attention and executive functioning. Furthermore, individuals with heart failure at follow-up had lower scores on attention and executive functioning: −0.21 (–0.41 to −0.00). Higher BNP at follow-up was also associated with worse attention and executive functioning, even after adjustment for baseline BNP. Conclusions Worse cognitive functioning can already be observed in early stages of LV dysfunction and heart failure. BNP is a target for further investigation as a risk factor for cognitive decline in the general population.

Dose-dependent nonlinear effect of L-DOPA on paired associative stimulation-induced neuroplasticity in humans.

Abstract: Dopamine is one of the major neuromodulators in the CNS, which is involved in learning and memory processes. A nonlinear, inverted U-shaped dose–response curve of its effects on cognition has been observed in animal studies. The basis for this nonlinear effect might be a similar effect of dopamine on neuroplasticity. Whereas it has been shown that dopamine affects paired associative stimulation (PAS)-induced plasticity, which might reflect learning-related processes to a larger degree than other noninvasive plasticity induction protocols in the human motor cortex in principle, its dose-dependency has not been explored previously. We studied the effect of different dosages of the dopamine precursor l-DOPA on motor cortex plasticity induced by facilitatory and inhibitory PAS of the motor cortex in 12 healthy humans. They received 25, 100, or 200 mg of l-DOPA or placebo medication combined with either excitability-enhancing or -diminishing PAS. Cortical excitability level was monitored before and for up to 2 d after plasticity induction by assessment of transcranial magnetic stimulation-induced motor-evoked potentials. Low-dose l-DOPA abolished the aftereffects of PAS and medium-dose l-DOPA prolonged facilitatory plasticity. High-dose l-DOPA reversed the excitability enhancement accomplished by facilitatory PAS to diminution. Thus, the results show a clear nonlinear effect of l-DOPA dosage on associative plasticity, different from that on nonfocal plasticity. This might help to explain dopaminergic effect on cognition and could be relevant for understanding the pathophysiology and treatment of neuropsychiatric diseases accompanied by alterations of the dopaminergic system.

Differentiation of Typical and Atypical Parkinson Syndromes by Quantitative MR Imaging

Abstract: BACKGROUND AND PURPOSE: The differential diagnosis of Parkinson syndromes remains a major challenge. Quantitative MR imaging can aid in this classification, but it is unclear which of the proposed techniques is best suited for this task. We, therefore, conducted a head-to-head study with different quantitative MR imaging measurements in patients with IPS, MSA-type Parkinson, PSP, and healthy elderly controls. MATERIALS AND METHODS: Thirty-one patients and 13 controls underwent a comprehensive quantitative MR imaging protocol including R2*-, R2- and R1-mapping, magnetization transfer, and DTI with manual region-of-interest measurements in basal ganglia regions. Group differences were assessed with a post hoc ANOVA with a Bonferroni error correction and an ROC. RESULTS: The best separation of MSA from IPS in patients and controls could be achieved with R2*-mapping in the PU, with an ROC AUC of ≤0.96, resulting in a sensitivity of 77.8% (with a specificity 100%). MD was increased in patients with PSP compared with controls and to a lesser extent compared with those with IPS and MSA in the SN. CONCLUSIONS: Among the applied quantitative MR imaging methods, R2*-mapping seems to have the best predictive power to separate patients with MSA from those with IPS, and DTI for identifying PSP.

Circadian Modulation of GABA-Mediated Cortical Inhibition

Abstract: Circadian rhythms exert powerful influence on various aspects of human physiology and behavior. Here, we tested changes of human cerebral cortex excitability over the course of the day with transcranial magnetic stimulation (TMS). At different times of the day, intracortical and corticospinal excitability of the primary motor cortex (M1) was evaluated in 15 healthy subjects by TMS of left M1. While motor thresholds, short-interval intracortical inhibition and facilitation and input/output curves remained unchanged, we found that a specific form of γ-aminobutyric acid (GABA)-mediated intracortical inhibition, revealed by long-interval intracortical inhibition and cortical silent periods, progressively decreased during the course of the day. Additional experiments demonstrated that morning inhibition persisted irrespective of previous sleep or sleep deprivation. Corticotropin-releasing hormone (CRH) infusions in the evening lead to morning cortisol levels but did not restore levels of morning inhibition, whereas suppression of endogenous CRH release by repeated oral dexamethasone intake over 24 h prevented morning inhibition. The findings suggest a specific modulation of GABAergic motor cortex inhibition within the circadian cycle, possibly linked to the CRH system, and may indicate a neurobiological basis for variable neuroplasticity over the course of the day.

Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload

Abstract: Chronic pressure-overload and diabetes mellitus are two frequent disorders affecting the heart. We aimed to characterize myocardial structural and functional changes induced by both conditions. Pressure-overload was established in Wistar-han male rats by supra-renal aortic banding. Six-weeks later, diabetes was induced by streptozotocin (65 mg/kg,ip), resulting in four groups: SHAM, banding (BA), diabetic (DM) and diabetic-banding (DB). Six-weeks later, pressure–volume loops were obtained and left ventricular samples were collected to evaluate alterations in insulin signalling pathways, extracellular matrix as well as myofilament function and phosphorylation. Pressure-overload increased cardiomyocyte diameter (BA 22.0 ± 0.4 μm, SHAM 18.2 ± 0.3 μm) and myofilament maximal force (BA 25.7 ± 3.6 kN/m2, SHAM 18.6 ± 1.4 kN/m2), Ca2+ sensitivity (BA 5.56 ± 0.02, SHAM 5.50 ± 0.02) as well as MyBP-C, Akt and Erk phosphorylation, while decreasing rate of force redevelopment (K tr; BA 14.9 ± 1.1 s−1, SHAM 25.2 ± 1.5 s−1). At the extracellular matrix level, fibrosis (BA 10.8 ± 0.9%, SHAM 5.3 ± 0.6%), pro-MMP-2 and MMP-9 activities increased and, in vivo, relaxation was impaired (τ; BA 14.0 ± 0.9 ms, SHAM 12.9 ± 0.4 ms). Diabetes increased cardiomyocyte diameter, fibrosis (DM 21.4 ± 0.4 μm, 13.9 ± 1.8%, DB 20.6 ± 0.4 μm, 13.8 ± 0.8%, respectively), myofilament Ca2+sensitivity (DM 5.57 ± 0.02, DB 5.57 ± 0.01), advanced glycation end-product deposition (DM 4.9 ± 0.6 score/mm2, DB 5.1 ± 0.4 score/mm2, SHAM 2.1 ± 0.3 score/mm2), and apoptosis, while decreasing K tr (DM 13.5 ± 1.9 s−1, DB 15.2 ± 1.4 s−1), Akt phosphorylation and MMP-9/TIMP-1 and MMP-1/TIMP-1 ratios. Diabetic hearts were stiffer (higher end-diastolic-pressure: DM 7.0 ± 1.2 mmHg, DB 6.7 ± 0.7 mmHg, SHAM 5.3 ± 0.4 mmHg, steeper end-diastolic-pressure–volume relation: DM 0.59 ± 0.18, DB 0.83 ± 0.17, SHAM 0.41 ± 0.10), and hypo-contractile (decreased end-systolic-pressure-volume-relation). DB animals presented further pulmonary congestion (Lungs/body-weight: DB 5.23 ± 0.21 g/kg, SHAM 3.80 ± 0.14 g/kg) as this group combined overload-induced relaxation abnormalities and diabetes-induced stiffness. Diabetes mellitus and pressure overload led to distinct diastolic dysfunction phenotypes: while diabetes promoted myocardial stiffening, pressure overload impaired relaxation. The association of these damages accelerates the progression of diastolic heart failure progression in diabetic-banded animals.

Electrical stimulation and visual network plasticity

Abstract: The visual system has the most complex circuitry of all the sensory systems and it also possesses the ability to undergo induced and spontaneous neuroplastic changes. Most of what we know about the functional organization of the visual system is derived from animal experiments or by correlating circumscribed anatomical lesions in patients and their visual perceptual deficits or dysfunctions. However, in the past years, significant achievements have been made in characterizing visual information processing in the human using non-invasive neurophysiological techniques, such as electrical stimulation of the brain. Transcranial direct (tDCS) and alternating current stimulation (tACS) applied through the skull was shown to directly modulate the excitability of the motor and visual cortices in human subjects. This review article focuses on these stimulation methods and summarizes the latest results with regard to the application of these method over the visual areas in healthy subjects and clinical populations.

Transcranial direct current stimulation effects on I-wave activity in humans

Abstract: Transcranial direct current stimulation (tDCS) of the human cerebral cortex modulates cortical excitability noninvasively in a polarity-specific manner: anodal tDCS leads to lasting facilitation an...