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The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) has been firmly established; however, the entity of diabetic myocardial disorder (previously called diabetic cardiomyopathy) remains a matter of debate. Diabetic myocardial disorder was originally described as the occurrence of myocardial structural/functional abnormalities associated with T2DM in the absence of coronary heart disease, hypertension and/or obesity. However, supporting evidence has been derived from experimental and small clinical studies. Only a minority of T2DM patients are recognized as having this condition in the absence of contributing factors, thereby limiting its clinical utility. Therefore, this concept is increasingly being viewed along the evolving HF trajectory, where patients with T2DM and asymptomatic structural/functional cardiac abnormalities could be considered as having pre‐HF. The importance of recognizing this stage has gained interest due to the potential for current treatments to halt or delay the progression to overt HF in some patients. This document is an expert consensus statement of the Heart Failure Association of the ESC and the ESC Working Group on Myocardial & Pericardial Diseases. It summarizes contemporary understanding of the association between T2DM and HF and discuses current knowledge and uncertainties about diabetic myocardial disorder that deserve future research. It also proposes a new definition, whereby diabetic myocardial disorder is defined as systolic and/or diastolic myocardial dysfunction in the presence of diabetes. Diabetes is rarely exclusively responsible for myocardial dysfunction, but usually acts in association with obesity, arterial hypertension, chronic kidney disease and/or coronary artery disease, causing additive myocardial impairment. [ABSTRACT FROM AUTHOR]

The article discusses heart failure with preserved ejection fraction has become increasingly prevalent, accounting for 56% of all cases of heart failure. Topics include the pharmacologic treatment of the latter, the treatment of heart failure with preserved ejection fraction has disappointing; and microvascular inflammation uncouples endothelial nitric oxide synthase, leading to lower levels of nitric oxide and higher levels of reactive oxygen species.

Key points Chronic administration of the selective noradrenaline reuptake inhibitor (NRI) reboxetine (RBX) increased and prolonged the long-term potentiation-like plasticity induced by anodal transcranial direct current stimulation (tDCS) for over 24 h., Chronic administration of RBX converted cathodal tDCS-induced long-term depression-like plasticity into facilitation for 120 min., Chronic noradrenergic activity enhancement on plasticity of the human brain might partially explain the delayed therapeutic impact of selective NRIs in depression and other neuropsychiatric diseases., Abstract Noradrenaline affects cognition and motor learning processes via its impact on long-term potentiation (LTP) and depression (LTD). We aimed to explore the impact of single dose and chronic administration of the selective noradrenaline reuptake inhibitor (NRI) reboxetine (RBX) on plasticity induced by transcranial direct current stimulation (tDCS) in healthy humans via a double-blinded, placebo-controlled, randomized crossover study. Sixteen healthy volunteers received placebo or single dose RBX (8 mg) before anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took RBX (8 mg day−1) consecutively for 21 days. During this period, two additional interventions were performed (RBX with anodal or cathodal tDCS), to explore the impact of chronic RBX treatment on plasticity. Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic administration of RBX increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h. Chronic RBX significantly converted cathodal tDCS-induced LTD-like plasticity into facilitation, as compared to the single dose condition, for 120 min after stimulation. The results show a prominent impact of chronic noradrenergic enhancement on plasticity of the human brain that might partially explain the delayed therapeutic impact of selective NRIs in depression and other neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

An introduction is presented for the article "A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure with Preserved Ejection Fraction" by Y.N.V. Reddy, R.E. Carter, M. Obokata, and others which was published in the same issue which examined a diagnostic algorithm in evaluating heart failure.

Activation of neurons not only changes their membrane potential and firing rate but as a secondary action reduces membrane resistance. This loss of resistance, or increase of conductance, may be of central importance in non-invasive magnetic or electric stimulation of the human brain since electrical fields cause larger changes in transmembrane voltage in resting neurons with low membrane conductances than in active neurons with high conductance. This may explain why both the immediate effects and after-effects of brain stimulation are smaller or even reversed during voluntary activity compared with rest. Membrane conductance is also increased during shunting inhibition, which accompanies the classic GABAA IPSP. This short-circuits nearby EPSPs and is suggested here to contribute to the magnitude and time course of short-interval intracortical inhibition and intracortical facilitation. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the significance of pulse configurations and current direction for corticospinal activation using transcranial magnetic stimulation (TMS). In 11 healthy subjects (8 female), a motor map for the motor evoked potentials (MEPs) recorded from the first dorsal interosseus (FDI), abductor digiti minimi (ADM), extensor carpi radialis, and biceps brachii (BB) muscles of the dominant side was established. Starting from a manually determined hot spot of the FDI representation, we measured MEPs at equal oriented points on an hexagonal grid, with 7 MEPs recorded at each point, using the following pulse configurations: posteriorly directed monophasic (Mo-P), anteriorly directed monophasic (Mo-A), biphasic with the more relevant second cycle oriented posteriorly (Bi-P) as well as a reversed biphasic condition (Bi-A). For each pulse configuration, a hot spot was determined and a center of gravity (CoG) was calculated. We found that the factor current direction had an effect on location of the CoG-adjusted hot spot in the cranio-caudal axis but not in the latero-medial direction with anteriorly directed pulses locating the CoG more anteriorly and vice versa. In addition, the CoG for the FDI was more laterally than the cortical representations for the abductor digiti minimi (ADM) and extensor carpi radialis (ECR) which were registered as well. The results indicate that direction of the current pulse should be taken into account for determination of the motor representation of a muscle by TMS. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) causes a complex spatial distribution of the electric current flow in the head which hampers the accurate localization of the stimulated brain areas. In this study we show how various anatomical features systematically shape the electric field distribution in the brain during tDCS. We constructed anatomically realistic finite element (FEM) models of two individual heads including conductivity anisotropy and different skull layers. We simulated a widely employed electrode montage to induce motor cortex plasticity and moved the stimulating electrode over the motor cortex in small steps to examine the resulting changes of the electric field distribution in the underlying cortex. We examined the effect of skull thickness and composition on the passing currents showing that thinner skull regions lead to higher electric field strengths. This effect is counteracted by a larger proportion of higher conducting spongy bone in thicker regions leading to a more homogenous current over the skull. Using a multiple regression model we could identify key factors that determine the field distribution to a significant extent, namely the thicknesses of the cerebrospinal fluid and the skull, the gyral depth and the distance to the anode and cathode. These factors account for up to 50% of the spatial variation of the electric field strength. Further, we demonstrate that individual anatomical factors can lead to stimulation “hotspots” which are partly resistant to electrode positioning. Our results give valuable novel insights in the biophysical foundation of tDCS and highlight the importance to account for individual anatomical factors when choosing an electrode montage. [ABSTRACT FROM AUTHOR]

The neuromodulator dopamine plays an important role in synaptic plasticity. The effects are determined by receptor subtype specificity, concentration level, and the kind of neuroplasticity induced. D1-like receptors have been proposed to be involved in cognitive processes via their impact on plasticity. Cognitive studies in humans and animals revealed a dosage-dependent effect of D1-like receptor activation on task performance. In humans, D1-like receptor activation re-establishes plasticity under D2 receptor block. However, a dosagedependent effect has not been explored so far. To determine the impact of the amount of D1-like receptor activation on neuroplasticity in humans,we combined sulpiride, a selective D2 receptor antagonist,withthe dopamine precursor L-DOPA (25, 100, and 200mg) or applied placebo medication. The impact on plasticity induced by anodal and cathodal transcranial direct current stimulation (tDCS) was compared withthe impact on plasticity induced by excitatory and inhibitory paired associative stimulation (PAS) atthe primary motor cortex of healthy humans. Stimulation-generated cortical excitability alterations were monitored bytranscranial magnetic stimulation-induced motor-evoked potential amplitudes. D1-like receptor activation produced an inverted U-shaped dose–response curve on plasticity induced by both facilitatory tDCS and PAS. For excitability-diminishing tDCS and PAS, aftereffects were abolished or converted trendwise into facilitation. These data extend findings of dose-dependent inverted U-shaped effects of D1 receptor activation on neuroplasticity of the motor cortex. [ABSTRACT FROM AUTHOR]

Background Functional Electrical Stimulation (FES) can electrically activate paretic muscles to assist movement for post-stroke neurorehabilitation. Here, sensory-motor integration may be facilitated by triggering FES with residual electromyographic (EMG) activity. However, muscle activity following stroke often suffers from delays in initiation and termination which may be alleviated with an adjuvant treatment at the central nervous system (CNS) level with transcranial direct current stimulation (tDCS) thereby facilitating re-learning and retaining of normative muscle activation patterns. Methods This study on 12 healthy volunteers was conducted to investigate the effects of anodal tDCS of the primary motor cortex (M1) and cerebellum on latencies during isometric contraction of tibialis anterior (TA) muscle for myoelectric visual pursuit with quick initiation/termination of muscle activation i.e. 'ballistic EMG control' as well as modulation of EMG for 'proportional EMG control'. Results The normalized delay in initiation and termination of muscle activity during post-intervention 'ballistic EMG control' trials showed a significant main effect of the anodal tDCS target: cerebellar, M1, sham (F(2) = 2.33, p < 0.1), and interaction effect between tDCS target and step-response type: initiation/termination of muscle activation (F(2) = 62.75, p < 0.001), but no significant effect for the step-response type (F(1) = 0.03, p = 0.87). The post-intervention population marginal means during 'ballistic EMG control' showed two important findings at 95% confidence interval (critical values from Scheffe's S procedure): 1. Offline cerebellar anodal tDCS increased the delay in initiation of TA contraction while M1 anodal tDCS decreased the same when compared to sham tDCS, 2. Offline M1 anodal tDCS increased the delay in termination of TA contraction when compared to cerebellar anodal tDCS or sham tDCS. Moreover, online cerebellar anodal tDCS decreased the learning rate during 'proportional EMG control' when compared to M1 anodal and sham tDCS. Conclusions The preliminary results from healthy subjects showed specific, and at least partially antagonistic effects, of M1 and cerebellar anodal tDCS on motor performance during myoelectric control. These results are encouraging, but further studies are necessary to better define how tDCS over particular regions of the cerebellum may facilitate learning of myoelectric control for brain machine interfaces. [ABSTRACT FROM AUTHOR]

Abstract: Neuroplasticity, which is the dynamic structural and functional reorganization of central nervous system connectivity due to environmental and internal demands, is recognized as a major physiological basis for adaption of cognition, and behavior, and thus of utmost importance for normal brain function. Pathological alterations of plasticity are increasingly explored as pathophysiological foundation of diverse neurological and psychiatric diseases. Non-invasive brain stimulation techniques (NIBS), such as repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS), are able to induce and modulate neuroplasticity in humans. Therefore, they have potential to alter pathological plasticity on the one hand, and foster physiological plasticity on the other, in neuropsychiatric diseases to reduce symptoms, and enhance rehabilitation. tDCS is an emerging NIBS tool, which induces glutamatergic plasticity via application of relatively weak currents through the scalp in humans. In the last years its efficacy to treat neuropsychiatric diseases has been explored increasingly. In this review, we will give an overview of pathological alterations of plasticity in neuropsychiatric diseases, gather clinical studies involving tDCS to ameliorate symptoms, and discuss future directions of application, with an emphasis on optimizing stimulation effects. [Copyright &y& Elsevier]

Serotonin modulates diverse brain functions. Beyond its clinical antidepressant effects, it improves motor performance, learning and memory formation. These effects might at least be partially caused by the impact of serotonin on neuroplasticity, which is thought to be an important foundation of the respective functions. In principal accordance, selective serotonin reuptake inhibitors enhance long-term potentiation-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. As other neuromodulators have discernable effects on different kinds of plasticity in humans, here we were interested to explore the impact of serotonin on paired associative stimulation (PAS)-induced plasticity, which induces a more focal kind of plasticity, as compared with tDCS, shares some features with spike timing-dependent plasticity, and is thought to be relative closely related to learning processes. In this single-blinded, placebo-controlled, randomized crossover study, we administered a single dose of 20 mg citalopram or placebo medication and applied facilitatory- and excitability-diminishing PAS to the left motor cortex of 14 healthy subjects. Cortico-spinal excitability was explored via single-pulse transcranial magnetic stimulation-elicited MEP amplitudes up to the next evening after plasticity induction. After citalopram administration, inhibitory PAS-induced after-effects were abolished and excitatory PAS-induced after-effects were enhanced trendwise, as compared with the respective placebo conditions. These results show that serotonin modulates PAS-induced neuroplasticity by shifting it into the direction of facilitation, which might help to explain mechanism of positive therapeutic effects of serotonin in learning and medical conditions characterized by enhanced inhibitory or reduced facilitatory plasticity, including depression and stroke. [ABSTRACT FROM AUTHOR]

Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity. [Copyright &y& Elsevier]

The authors reflect on a study which establishes myocardial titin and collagen in order to sufficiently compromise diastolic left ventricular (LV) function in inducing heart failure with preserved ejection fraction (HFPEF). They offer information about high myocardial diastolic stiffness as well as myocardial collagen deposition. Other critical topics such as protein kinase, phosphorylation, and oxidation are discussed.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been shown to alter cortical excitability and activity via application of weak direct currents. Beyond intracortical effects, functional imaging as well as behavioral studies are suggesting additional tDCS-driven alterations of subcortical areas, however, direct evidence for such effects is scarce. We aimed to investigate the impact of tDCS on cortico-subcortical functional networks by seed functional connectivity analysis of different striatal and thalamic regions to prove tDCS-induced alterations of the cortico-striato-thalamic circuit. fMRI resting state data sets were acquired immediately before and after 10 min of bipolar tDCS during rest, with the anode/cathode placed over the left primary motor cortex (M1) and the cathode/anode over the contralateral frontopolar cortex. To control for possible placebo effects, an additional sham stimulation session was carried out. Functional coupling between the left thalamus and the ipsilateral primary motor cortex (M1) significantly increased following anodal stimulation over M1. Additionally, functional connectivity between the left caudate nucleus and parietal association cortices was significantly strengthened. In contrast, cathodal tDCS over M1 decreased functional coupling between left M1 and contralateral putamen. In summary, in this study, we show for the first time that tDCS modulates functional connectivity of cortico-striatal and thalamo-cortical circuits. Here we highlight that anodal tDCS over M1 is capable of modulating elements of the cortico-striato-thalamo-cortical functional motor circuit. Hum Brain Mapp 33:2499-2508, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The temporal maintenance and subsequent retrieval of information that no longer exists in the environment is called working memory. It is believed that this type of memory is controlled by the persistent activity of neuronal populations, including the prefrontal, temporal, and parietal cortex. For a long time, it has been controversially discussed whether, in working memory, the PFC stores past sensory events or, instead, its activation is an extra-mnemonic source of top-down control over posterior regions. Recent animal studies suggest that specific information about the contents of working memory can be decoded from population activity in prefrontal areas. However, it has not been shown whether the contents of working memory during the delay periods can be decoded from EEG recordings in the human brain. We show that by analyzing the nonlinear dynamics of EEG oscillatory patterns it is possible to noninvasively decode with high accuracy, during encoding and maintenance periods, the contents of visual working memory information within high-gamma oscillations in the human PFC. These results are thus in favor of an active storage function of the human PFC in working memory; this, without ruling out the role of PFC in top-down processes. The ability to noninvasively decode the contents of working memory is promising in applications such as brain computer interfaces, together with computation of value function during planning and decision making processes. [ABSTRACT FROM AUTHOR]

The primary motor cortex (M1) is the main effector structure implicated in the generation of voluntary movements and is directly involved in motor learning. The intrinsic horizontal neuronal connections of M1 exhibit short-term and long-term plasticity, which is a strong substrate for learning-related map reorganization. Transcranial direct current stimulation (tDCS) applied for few minutes over M1 has been shown to induce relatively long-lasting plastic alterations and to modulate motor performance. Here we test the hypothesis that the relatively long-lasting synaptic modification induced by tDCS over M1 results in the alteration of associations among populations of M1 neurons which may be reflected in changes of its functional architecture. fMRI resting-state datasets were acquired immediately before and after 10 minutes of tDCS during rest, with the anode/cathode placed over the left M1. For each functional dataset, grey-matter voxels belonging to Brodmann area 4 (BA4) were labelled and afterwards BA4 voxel-based synchronization matrices were calculated and thresholded to construct undirected graphs. Nodal network parameters which characterize the architecture of functional networks (connectivity degree, clustering coefficient and characteristic path-length) were computed, transformed to volume maps and compared before and after stimulation. At the dorsolateral-BA4 region cathodal tDCS boosted local connectedness, while anodal-tDCS enhanced long distance functional communication within M1. Additionally, the more efficient the functional architecture of M1 was at baseline, the more efficient the tDCS-induced functional modulations were. In summary, we show here that it is possible to non-invasively reorganize the intrinsic functional architecture of M1, and to image such alterations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Abstract: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability and activity in a polarity-dependent way. Stimulation for a few minutes has been shown to induce plastic alterations of cortical excitability and to improve cognitive performance. These effects might be related to stimulation-induced alterations of functional cortical network connectivity. We aimed to investigate the impact of tDCS on cortical network function by functional connectivity and graph theoretical analysis of the BOLD fMRI spontaneous activity. fMRI resting-state datasets were acquired immediately before and after 10-min bipolar tDCS during rest, with the anode placed over the left primary motor cortex (M1) and the cathode over the contralateral frontopolar cortex. For each dataset, grey matter voxel-based synchronization matrices were calculated and thresholded to construct undirected graphs. Nodal connectivity degree and minimum path length maps were calculated and compared before and after tDCS. Nodal minimum path lengths significantly increased in the left somatomotor (SM1) cortex after anodal tDCS, which means that the number of direct functional connections from the left SM1 to topologically distant grey matter voxels significantly decreased. In contrast, functional coupling between premotor and superior parietal areas with the left SM1 significantly increased. Additionally, the nodal connectivity degree in the left posterior cingulate cortex (PCC) area as well as in the right dorsolateral prefrontal cortex (right DLPFC) significantly increased. In summary, we provide initial support that tDCS-induced neuroplastic alterations might be related to functional connectivity changes in the human brain. Additionally, we propose our approach as a powerful method to track for neuroplastic changes in the human brain. [Copyright &y& Elsevier]

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 after effects on corticospinal excitability. Plastic after effects after tRNS on corticospinal excitability require a minimal stimulation duration of 5 minutes. However, the duration of the after effect 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. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Externally induced neuroplasticity may be of therapeutic value in several neuro-psychiatric disorders. To facilitate research on mechanisms and to make possible the design of prospective, advanced stimulation protocols without exposing human subjects to risk, we have developed a primate model which allows us to assess changes of motor cortical excitability using transcranial magnetic stimulation (TMS). Methods: TMS hand muscle representation and cortical excitability were determined in two awake trained rhesus monkeys. Neuroplastic changes of cortical excitability were established by 13min of paired associative stimulation (PAS) with interstimulus intervals of either 15 or 5ms. Results: The representational areas of FDI and APB muscles (3.02–4.96cm2) were located between the spur of the arcuate and the superior precentral sulcus, indicating the potential to carry out spatially selective cortical stimulation. PAS with an interstimulus interval of 15ms strongly increased cortical excitability for up to two hours, while 5ms interval had no effect. Conclusions: This first systematic TMS and PAS primate study demonstrates that the trained rhesus monkeys represent an exceptional animal model that allows cortical TMS mapping as well as non–invasive assessment and induction of cortical neuroplasticity. Significance: This animal model offers additional advantageous options not possible with humans, namely an alternative to invasive, morphological or molecular analyses, making it highly suitable for preclinical development of advanced neuroplasticity paradigms without exposing human subjects to risk. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is formed from arginine by the enzyme nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) can inhibit NO production by competing with arginine for NOS binding. Therefore, the net amount of NO might be indicated by the arginine/ADMA ratio. In turn, arginine can be metabolized by the enzyme arginase, and ADMA by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). While ADMA has been implicated as a cardiovascular risk factor, arginine supplementation has been indicated as a treatment in cardiac diseases. This review discusses the roles of ADMA and arginine in the failing heart and its vasculature. Furthermore, it proposes nutritional therapies to improve NO availability. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Controlled blinded studies using transcranial electrical stimulation (tES) paradigms need a validated sham stimulation paradigm since an itching or tingling sensation on the skin surface under the electrode can be associated with current flow. Methods: Here we investigated the skin perception thresholds of transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS) for current intensities ranging from 200 to 2000μA and additional non-stimulation trials using a motor cortex–contralateral orbit montage in three different healthy subject groups: subjects naïve to tES methods, subjects with previous experience with these techniques and investigators, who use these methods in their research. Results: Taking the whole sample into consideration the 50% perception threshold for both tDCS conditions was at 400μA while this threshold was at 1200μA in the case of tRNS. Anodal and cathodal tDCS are indistinguishable regarding sites of perception. Experienced investigators show a significantly higher anodal stimulation detection rate when compared to the naïve group, furthermore investigators performed significantly better than naïve subjects in non-stimulation discrimination. Conclusions: tRNS has the advantage of higher cutaneous perception thresholds and lower response rates in when compared with tDCS. Further investigation in blinding methods (such as placebo itching) is warranted in order to improve sham control. Significance: As tRNS has been shown to have similar aftereffects as anodal tDCS, this finding points to the application of tRNS as a possible alternative with a better blinding control. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Recent developments in transcranial alternating current stimulation (tACS) provide a powerful approach to establish the functional roles of neuronal oscillatory activities in the human brain. Here, we investigated whether tACS can reach and modulate the excitability of the visual cortex in a frequency-dependent manner. Methods: We measured the cortical excitability of the visual cortex using single pulse transcranial magnetic stimulation (TMS) while delivering tACS to the occipital region at different frequencies (5, 10, 20 and 40Hz). Results: We found that tACS at 20Hz decreased TMS–phosphene threshold (i.e., increased the excitability of the visual cortex) during the stimulation, whereas other frequencies did not affect TMS–phosphene thresholds. Conclusions: Our findings demonstrate direct interactions of tACS with the visual cortex in a frequency-dependent manner. Significance: Our present work provides further demonstration of the potential of tACS as a method to selectively modulate the excitability of the visual cortex. [ABSTRACT FROM AUTHOR]

Transcranial stimulation of the primary motor cortex (M1) for the treatment of pain has attracted much interest in recent years. Non-invasive low frequency and high frequency repetitive transcranial magnetic stimulation (rTMS) over the M1 was reported to reduce both experimentally induced acute and chronic pain. In this paper we summarize the results of several studies from our laboratory and report the antinociceptive effects of a special rTMS paradigm, theta-burst stimulation (TBS). We have applied excitatory (iTBS) and inhibitory (cTBS) paradigms over two cortical locations (M1 and the primary somatosensory cortex (S1)). As evaluation criteria a pain rating scale and the recording of laser evoked potentials (LEPs) were used. Reduced subjective pain perception after cTBS could be objectified by alterations of LEPs that reflect pain related activations in the pain processing in the operculo-insular and anterior cingulate cortex. The stimulation of S1 had physiological effects (LEPs), but did not induce significant reduction in acute pain perception. We believe that the application of cTBS over M1 in pain research has a great potential and as a method it can contribute to a more efficient manipulation of the brain plasticity for therapeutic purposes, for example in chronic pain. Nevertheless, the effectiveness of other types of TBS paradigms should also be tested. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is a somatosensory network disorder that is clinically diagnosed according to four main criteria: an urge to move the legs, usually associated with unpleasant leg sensations; induction or exacerbation of symptoms by rest; symptom relief on activity; and diurnal fluctuations in symptoms with worsening in the evening and at night. Genetic variants in four chromosomal regions have been identified that increase the risk of RLS. In addition, various different lesions, ranging from peripheral neuropathies to spinal cord lesions or alterations of brain metabolism, are implicated in RLS. In most cases, sleep disorders with frequent sleep fragmentation and characteristic periodic limb movements during sleep can be identified during a polysomnographic recording. The first-line drugs for RLS are dopaminergic agents, which are effective in low to moderate doses. Alternative or additional treatments include opioids and anticonvulsants. Augmentation-paradoxical worsening of symptoms by dopaminergic treatment-is the main problem encountered in difficult-to-treat patients. Iron deficiency must be identified and treated by supplementation, both to improve RLS symptoms and to potentially lower the risk of augmentation. Here, we review the latest studies pertaining to the pathophysiology, clinical presentation and management of RLS. [ABSTRACT FROM AUTHOR]

Despite use of similar drugs, outcomes of recent heart failure (HF) trials were frequently neutral in heart failure with normal left ventricular ejection fraction (HFNEF) and positive in heart failure with reduced left ventricular ejection fraction (HFREF). The neutral outcomes of HFNEF trials were often attributed to deficient HFNEF patient recruitment with inclusion of many HFREF or noncardiac patients. Patient recruitment criteria of 21 HFNEF trials were therefore reviewed in reference to diagnostic guidelines for HFNEF. In the 4 published sets of guidelines, a definite diagnosis of HFNEF required the simultaneous and obligatory presence of signs and/or symptoms of HF and evidence of normal systolic left ventricular (LV) function and of diastolic LV dysfunction. In 3 of 4 sets of guidelines, normal systolic LV function comprised both a left ventricular ejection fraction (LVEF) >50% and an absence of LV dilation. Among the 21 HFNEF trials, LVEF cutoff values ranged from 35% to 50%, with only 8 trials adhering to an LVEF >50%. Furthermore, only 1 trial specified a normal LV end-diastolic dimension as an enrollment criterion and only 7 trials required evidence of diastolic LV dysfunction. Nonadherence to diagnostic guidelines induced excessive enrollment into HFNEF trials of HF patients with eccentric LV remodeling and ischemic heart disease compared with HF patients with concentric LV remodeling and arterial hypertension. Nonadherence to guidelines also led to underpowered HFNEF trials with a low incidence of outcome events such as death or HF hospitalizations. Future HFNEF trials should therefore adhere to diagnostic guidelines for HFNEF. [Copyright &y& Elsevier]

The article discusses aortic stenosis, its epidemiology, causes, pathophysiology, diagnosis, and medical and surgical treatments. The management of mild, severe asymptomatic, and far advanced aortic stenosis is discussed. Causes for the disease include calcific aortic stenosis, congential aortic stenosis, and rheumatic valve disease. The pathophysiology related to symptoms such as dyspnoea and syncope is examined. Diagnosis includes a physical examination and diagnostic studies using echocardiogram. Brain natriuretic peptide is described as a potential useful marker in predicting the onset of symptoms. The use of statins to slow the progression of coronary disease is also examined. Aortic valve replacement for patients with severe symptomatic and asymptomatic disease is also discussed.

Transcranial magnetic stimulation (TMS) transports a short (about 100 µs) high intensity (∼ 2 Tesla) magnetic field painless through the skull into the brain and induces an electric current flow. This in turn excites neurons or fiber tracts. TMS can only induce tangential current flow. Its intensity declines exponentially; thus mainly cortical areas closed to the surface are targeted. The best available data are those obtained at the motor cortex (M1). M1 stimulation allows easy quantification of effects by recording electromyographic muscle activity. When stimulating the visual cortex phosphenes can be induced. Computational models allocate the lowest threshold elements into terminals of the axon collaterals. The dependence of threshold and polarization on spatial and temporal stimulation parameters are strongly affected by morphological features of the axonal arbor, including myelination, diameter, and branching. The thresholds for current flow are directionally sensitive, with lower threshold from the back to the front as vice versa. Intensity dependent a D-wave and several I-waves with 1.5 ms intervals are induced, which can be recorded in man invasively at the cervical spinal cord. In psychology it allows to induce short virtual lesions which provide data on cortical functions arising in the area stimulated. TMS is clinically used to quantify central motor conduction time in particular in patients with multiple sclerosis. Reliable information on amplitude changes e.g. in cervical myelopathy can be obtained by the triple stimulation technique. [ABSTRACT FROM AUTHOR]

Non-invasive brain stimulation started in the antiquity by treating headache with electric fishes (∼ 1 A, ∼ 700 V). Transcranial direct current stimulation dominated research in the 19th century after the invention of the voltaic pile (∼ 1 mA, ∼10 V). At present the main applications involve either weak electric stimulation of many different types (transcranial direct, alternating, random noise or combinations) of currents or high energy pulsed stimulations (∼8 kA, ∼ 10 µs) mediated by transcranial magnetic energy transfer (transcranial magnetic stimulation: TMS). Inhibitory or excitatory after-effects are guided by stimulus intensity, duration and intervals (cf. theta burst, quadripulse and others). In general, lower intensities lead to inhibition and higher intensities to excitation. There is no linear correlation between the duration of stimulation and the size of the after-effects, prolongation of stimulus duration may lead to an oscillating pattern of inhibition or excitation. Missing the right windows in time or in amplitude may lead to no or opposite results explaining the variability and conflicting data in the field. Intracellular calcium increase may be a key leader for deciding between LTD- or LTP-like after-effects. Uncontrolled consumption of nicotine and caffeine increase variability further. Co-application of drugs may guide after-effects in terms of selectivity and duration of after-effects. Current developments encompass new physical techniques such as varying TMS pulse widths, multi-electrode stimulation, interference fields, ultrasound or near infrared stimulation, hypothesis driven protocols based on neurophysiological features of cortical neurons, optimized techniques on realistic individual head models for targeting current flow to predefined areas and others. Clinical applications targeting cortical excitability increases (e.g. depression, pain) or decreases (e.g. epilepsy, migraine) seem to be more rewarding than those requiring structural repair (e.g. stroke). [ABSTRACT FROM AUTHOR]

Abstract: Objective: Comparative assessment of best conventional with best theta burst repetitive transcranial magnetic stimulation (rTMS) protocols on human motor cortex excitability. Methods: Stimulation of dominant hand abductor digiti minimi muscle representation of motor cortex in nine healthy right-handed subjects utilising two different MagPro stimulators to generate TMS pulses of distinct monophasic, half sine and biphasic shape with anteriorly or posteriorly directed current flow, measuring resting and active motor threshold and motor-evoked potential (MEP) amplitude. Comparison of two different conventional rTMSs and eight different theta burst stimulation (TBS) protocols. Results: Continuous TBS (cTBS) yielded an inhibition, and intermittent TBS (iTBS) a facilitation of MEP amplitudes. These effects were not significantly influenced by waveform or current orientation. Compared to conventional rTMS paradigms, neither cTBS nor iTBS showed significantly stronger effects. In addition and confirming earlier findings, the asymmetric monophasic pulse and a posteriorly directed current flow yielded a higher threshold than all other TMS types. The less asymmetric half-sine pulse had a lower threshold for postero-anterior current than in the opposite direction. The biphasic stimuli yielded the lowest motor threshold particularly with an antero-posterior current direction. Conclusions: TBS did not depend on current direction or on pulse configuration in this sample of healthy subjects. In addition, TBS effect size was not clearly superior to conventional rTMS protocols. Significance: This systematic comparison of three waveforms, two current directions and two different interventional protocols allows a better understanding of the mechanisms of TMS on human motor cortex. [Copyright &y& Elsevier]

Membrane potentials and spike sequences represent the basic modes of cerebral information processing. Both can be externally modulated in humans by quite specific techniques: transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). These methods induce reversible circumscribed cortical excitability changes, either excitatory or inhibitory, outlasting stimulation in time. Experimental pharmacological interventions may selectively enhance the duration of the aftereffects. Whereas rTMS induces externally triggered changes in the neuronal spiking pattern and interrupts or excites neuronal firing in a spatially and temporally restricted fashion, tDCS modulates the spontaneous firing rates of neurons by changing resting-membrane potential. The easiest and most common way of evaluating the cortical excitability changes is by applying TMS to the motor cortex, since it allows reproducible quantification through the motor-evoked potential. Threshold determinations at the visual cortex or psychophysical methods usually require repeated and longer measurements and thus more time for each data set. Here, results derived from the use of tDCS in visual perception, including contrast as well as motion detection and visuo – motor coordination and learning, are summarised. It is demonstrated that visual functions can be transiently altered by tDCS, as has been shown for the motor cortex previously. Up- and down-regulation of different cortical areas by tDCS is likely to open a new branch in the field of visual psychophysics. [ABSTRACT FROM AUTHOR]

Pathophysiological concepts of restless legs syndrome (RLS) are based mainly on neuroimaging and on neurophysiological data. Furthermore treatment effects contribute essentially to the present understanding of the disease, unless the genetic progress expected in the near future will clarify substantially open issues. The concept agreed on assumes a dysfunction of the dopaminergic system, possibly on the level of striatal and/or spinal dopamine receptors, and the A11 neuron group localized in the hypothalamus as an integrated part of the system. These neurons modulate spinal excitability, alterations of which in turn affect sensory processing predominantly of leg afferents in brain stem structures. Neurophysiologically excitability alterations can be measured by a variety of methods such as determination of pain thresholds, H-reflex testing, and quantitative sensory testing. [ABSTRACT FROM AUTHOR]

The Restless Legs Syndrome (RLS) is a heterogeneous disease. Symptomatic or secondary forms encompass iron deficiency, uremia, pregnancy, polyneuropathy, and other causes. The so-called idiopathic RLS syndrome preferentially affects patients with a younger onset before the age of 30. Here we summarize pathophysiological results along the anatomical route, beginning at the cortex and followed by the basal ganglia, thalamus, A11 neurones, substantia nigra, brainstem nuclei, and spinal cord. Genetic risk variants for RLS have recently been identified in two genes, one of them the homeobox gene MEIS1, known to be involved in embryonic development and variants in a second locus containing the genes encoding mitogen-activated protein kinase MAP2K5, and the transcription factor LBXCOR1. A third one, the BTBD9 gene with unknown function encodes a BTB(POZ) domain. Accordingly, new concepts on pathophysiology have to bridge conventional knowledge with possible consequences deriving from these findings. Furthermore, this may create a framework to help understand why dopamine, opioid, and some anticonvulsant therapies are effective in RLS patients. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Summary: Therapy-related augmentation of the symptoms of restless legs syndrome (RLS) is an important clinical problem reported in up to 60% of patients treated with levodopa and, to a lesser extent, with dopamine agonists. The efficacy of low-dose dopaminergic drugs for RLS has been established, but the mode of action is unknown. Here, we review the existing data and conclude that augmentation is a syndrome characterised by a severely increased dopamine concentration in the CNS; overstimulation of the dopamine D1 receptors compared with D2 receptors in the spinal cord may lead to D1-related pain and generate periodic limb movements; iron deficiency may be a main predisposing factor of augmentation, probably caused by a reduced function of the dopamine transporter; therapy with levodopa or dopamine agonists should remain at low doses and; iron supplementation and opiates are the therapy of choice to counter augmentation. [Copyright &y& Elsevier]

Summary: The restless legs syndrome is a common disorder that encompasses an idiopathic form of genetic or unknown origin and symptomatic forms associated with many causes. Symptomatic forms occur during pregnancy and are coincident with uraemia, iron depletion, polyneuropathy, spinal disorders, and rheumatoid arthritis. For the hereditary forms, at least three gene loci, located on chromosomes 12, 14, and 9, have been traced so far. Prevalence in the general population is between 3% and 9%, increases with age, and is higher in women than in men. Treatment is needed only in the moderate to severe forms of the disorder and mostly in elderly people. Pathophysiology and treatment may be closely linked to the dopaminergic system and iron metabolism. Dopaminergic treatment with levodopa and dopamine agonists is the first choice in idiopathic restless legs syndrome, but augmentation and rebound should be monitored in long-term treatment. Various other drugs, such as opioids, gabapentin, and benzodiazepines, provide alternative treatment possibilities. [Copyright &y& Elsevier]

Beneficial actions of nitric oxide (NO) in failing myocardium have frequently been overshadowed by poorly documented negative inotropic effects mainly derived from in vitro cardiac preparations. NO's beneficial actions include control of myocardial energetics and improvement of left ventricular (LV) diastolic distensibility. In isolated cardiomyocytes, administration of NO increases their diastolic cell length consistent with a rightward shift of the passive length-tension relation. This shift is explained by cGMP-induced phosphorylation of troponin I, which prevents calcium-independent diastolic cross-bridge cycling and concomitant diastolic stiffening of the myocardium. Similar improvements in diastolic stiffness have been observed in isolated guinea pig hearts, in pacing-induced heart failure dogs, and in patients with dilated cardiomyopathy or aortic stenosis and have been shown to result in higher LV preload reserve and stroke work. NO also controls myocardial energetics through its effects on mitochondrial respiration, oxygen consumption, and substrate utilization. The effects of NO on diastolic LV performance appear to be synergistic with its effects on myocardial energetics through prevention of myocardial energy wastage induced by LV contraction against late-systolic reflected arterial pressure waves and through prevention of diastolic LV stiffening, which is essential for the maintenance of adequate subendocardial coronary perfusion. A drop in these concerted actions of NO on diastolic LV distensibility and on myocardial energetics could well be instrumental for the relentless deterioration of failing myocardium. [ABSTRACT FROM AUTHOR]

Examines the hypothesis of Tourette's disorder. Diagnostic features of Tourette's disorder; Investigation of motor cortex excitability; Comparison of patients with Tourette's disorder and healthy subjects.

Pressure and volume overload results in concentric and eccentric hypertrophy of cardiac ventricular chambers with, respectively, parallel and series replication of sarcomeres. These divergent patterns of hypertrophy were related 40 years ago to disparate wall stresses in both conditions, with systolic wall stress eliciting parallel replication of sarcomeres and diastolic wall stress, series replication. These observations are relevant to clinical practice, as they relate to the excessive hypertrophy and contractile dysfunction regularly observed in patients with aortic stenosis. Stress-sensing mechanisms in cardiomyocytes and activation of cardiomyocyte death by elevated wall stress continue to intrigue cardiovascular scientists. [ABSTRACT FROM AUTHOR]

The authors present their views on the relationship between diabetes mellitus and diastolic dysfunction (DADD). They refer to a study by Christina Jarnert et al., published in this issue of the "European Journal of Heart Failure." They believe that the negative outcome of the DADD clinical trial can be attributed to the exclusive enrolment of patients in whom diastolic left ventricle (LV) dysfunction was traced to diabetes mellitus. The role of hyperglycemia in the diastolic LV dysfunction is also discussed by the authors.