Showing papers by "Walter Paulus published in 2015"

Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes.

Abstract: Diabetes mellitus-related cardiomyopathy (DMCMP) was originally described as a dilated phenotype with eccentric left ventricular (LV) remodelling and systolic LV dysfunction. Recently however, clinical studies on DMCMP mainly describe a restrictive phenotype with concentric LV remodelling and diastolic LV dysfunction. Both phenotypes are not successive stages of DMCMP but evolve independently to respectively heart failure with preserved left ventricular ejection fraction (HFPEF) or reduced left ventricular ejection fraction (HFREF). Phenotype-specific pathophysiological mechanisms were recently proposed for LV remodelling and dysfunction in HFPEF and HFREF consisting of coronary microvascular endothelial dysfunction in HFPEF and cardiomyocyte cell death in HFREF. A similar preferential involvement of endothelial or cardiomyocyte cell compartments explains DMCMP development into distinct restrictive/HFPEF or dilated/HFREF phenotypes. Diabetes mellitus (DM)-related metabolic derangements such as hyperglycaemia, lipotoxicity, and hyperinsulinaemia favour development of DMCMP with restrictive/HFPEF phenotype, which is more prevalent in obese type 2 DM patients. In contrast, autoimmunity predisposes to a dilated/HFREF phenotype, which manifests itself more in autoimmune-prone type 1 DM patients. Finally, coronary microvascular rarefaction and advanced glycation end-products deposition are relevant to both phenotypes. Diagnosis of DMCMP requires impaired glucose metabolism and exclusion of coronary, valvular, hypertensive, or congenital heart disease and of viral, toxic, familial, or infiltrative cardiomyopathy. In addition, diagnosis of DMCMP with restrictive/HFPEF phenotype requires normal systolic LV function and diastolic LV dysfunction, whereas diagnosis of DMCMP with dilated/HFREF phenotype requires systolic LV dysfunction. Treatment of DMCMP with restrictive/HFPEF phenotype is limited to diuretics and lifestyle modification, whereas DMCMP with dilated/HFREF phenotype is treated in accordance to HF guidelines.

Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease

Abstract: Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7, 8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.

Transcranial random noise stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive.

Abstract: Background: Application of transcranial random noise stimulation (tRNS) between 0.1 and 640 Hz of the primary motor cortex (M1) for 10 minutes induces a persistent excitability increase lasting for at least 60 minutes. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS) was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1mA for 10mins stimulation duration and a pharmacological agent (or sham) on 8 healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency towards inhibiting MEPs 5-60 mins poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0-20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS. Conclusions: In contrast to transcranial direct current stimulation (tDCS), aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms.

Reproducibility of the Structural Brain Connectome Derived from Diffusion Tensor Imaging.

Abstract: Rationale Disruptions of brain anatomical connectivity are believed to play a central role in several neurological and psychiatric illnesses. The structural brain connectome is typically derived from diffusion tensor imaging (DTI), which may be influenced by methodological factors related to signal processing, MRI scanners and biophysical properties of neuroanatomical regions. In this study, we evaluated how these variables affect the reproducibility of the structural connectome. Methods Twenty healthy adults underwent 3 MRI scanning sessions (twice in the same MRI scanner and a third time in a different scanner unit) within a short period of time. The scanning sessions included similar T1 weighted and DTI sequences. Deterministic or probabilistic tractography was performed to assess link weight based on the number of fibers connecting gray matter regions of interest (ROI). Link weight and graph theory network measures were calculated and reproducibility was assessed through intra-class correlation coefficients, assuming each scanning session as a rater. Results Connectome reproducibility was higher with data from the same scanner. The probabilistic approach yielded larger reproducibility, while the individual variation in the number of tracked fibers from deterministic tractography was negatively associated with reproducibility. Links connecting larger and anatomically closer ROIs demonstrated higher reproducibility. In general, graph theory measures demonstrated high reproducibility across scanning sessions. Discussion Anatomical factors and tractography approaches can influence the reproducibility of the structural connectome and should be factored in the interpretation of future studies. Our results demonstrate that connectome mapping is a largely reproducible technique, particularly as it relates to the geometry of network architecture measured by graph theory methods.

Restless legs syndrome-current therapies and management of augmentation.

Abstract: Restless legs syndrome that reduces quality of life and disturbs sleep requires pharmacological intervention. In the context of current guidelines and diagnostic criteria, Claudia Trenkwalder and colleagues summarize the treatments that are currently approved and used in clinical practice, including combination therapies. They also draw on their clinical experience to discuss and advise on the management of augmentation induced by dopaminergic drugs. Idiopathic restless legs syndrome (RLS) can severely affect quality of life and disturb sleep, so that pharmacological treatment is necessary, especially for elderly patients. Treatment guidelines recommend initiation of therapy with dopamine agonists (pramipexole, ropinirole or the rotigotine transdermal patch, all approved in most countries) or α-2-δ ligands (gabapentin enacarbil, approved in the USA and Japan), depending on the country and availability. Where approved, opioids (prolonged release oxycodone–naloxone, approved in Europe) are also recommended as a second-line therapy for severe RLS. Several iron formulations can be effective but are not yet approved for RLS therapy, whereas benzodiazepines and other anticonvulsants are not recommended or approved. Less is known about effective management of RLS that is associated with other conditions, such as uraemia or pregnancy. Furthermore, very little data are available on the management of RLS when first-line treatment fails or patients experience augmentation. In this Review, we summarize state-of-the-art therapies for RLS in the context of the diagnostic criteria and available guidelines, based on knowledge ranging from Class I evidence for the treatment of idiopathic RLS to Class IV evidence for the treatment of complications such as augmentation. We consider therapies, including combination therapies, that are used in clinical practice for long-term management of RLS, despite a lack of trials and approval, and highlight the need for practical long-term evaluation of current trials.

Speech dynamics are coded in the left motor cortex in fluent speakers but not in adults who stutter

Abstract: The precise excitability regulation of neuronal circuits in the primary motor cortex is central to the successful and fluent production of speech. Our question was whether the involuntary execution of undesirable movements, e.g. stuttering, is linked to an insufficient excitability tuning of neural populations in the orofacial region of the primary motor cortex. We determined the speech-related time course of excitability modulation in the left and right primary motor tongue representation. Thirteen fluent speakers (four females, nine males; aged 23–44) and 13 adults who stutter (four females, nine males, aged 21–55) were asked to build verbs with the verbal prefix ‘auf’. Single-pulse transcranial magnetic stimulation was applied over the primary motor cortex during the transition phase between a fixed labiodental articulatory configuration and immediately following articulatory configurations, at different latencies after transition onset. Bilateral electromyography was recorded from self-adhesive electrodes placed on the surface of the tongue. Off-line, we extracted the motor evoked potential amplitudes and normalized these amplitudes to the individual baseline excitability during the fixed configuration. Fluent speakers demonstrated a prominent left hemisphere increase of motor cortex excitability in the transition phase (P = 0.009). In contrast, the excitability of the right primary motor tongue representation was unchanged. Interestingly, adults afflicted with stuttering revealed a lack of left-hemisphere facilitation. Moreover, the magnitude of facilitation was negatively correlated with stuttering frequency. Although orofacial midline muscles are bilaterally innervated from corticobulbar projections of both hemispheres, our results indicate that speech motor plans are controlled primarily in the left primary speech motor cortex. This speech motor planning-related asymmetry towards the left orofacial motor cortex is missing in stuttering. Moreover, a negative correlation between the amount of facilitation and stuttering severity suggests that we discovered a main physiological principle of fluent speech production and its role in stuttering.

Double dissociation of working memory and attentional processes in smokers and non-smokers with and without nicotine.

Abstract: Nicotine has been shown to affect cortical excitability measured using transcranial magnetic stimulation in smoking and non-smoking subjects in different ways. In tobacco-deprived smokers, administration of nicotine restores compromised cortical facilitation while in non-smokers, it enhances cortical inhibition. As cortical excitability and activity are closely linked to cognitive processes, we aimed to explore whether nicotine-induced physiological alterations in non-smokers and smokers are associated with cognitive changes. Specifically, we assessed the impact of nicotine on working memory performance (n-back letter task) and on attentional processes (Stroop interference test) in healthy smokers and non-smokers. Both tasks have been shown to rely on prefrontal areas, and nicotinic receptors are relevantly involved in prefrontal function. Sixteen smoking and 16 non-smoking subjects participated in the 3-back letter task and 21 smoking and 21 non-smoking subjects in the Stroop test after the respective application of placebo or nicotine patches. The results show that working memory and attentional processes are compromised in nicotine-deprived smokers compared to non-smoking individuals. After administration of nicotine, working memory performance in smokers improved, while non-smoking subjects displayed decreased accuracy with increased number of errors. The effects have been shown to be more apparent for working memory performance than attentional processes. In summary, cognitive functions can be restored by nicotine in deprived smokers, whereas non-smokers do not gain additional benefit. The respective changes are in accordance with related effects of nicotine on cortical excitability in both groups.

Parietal transcranial direct current stimulation modulates primary motor cortex excitability

Abstract: The posterior parietal cortex is part of the cortical network involved in motor learning and is structurally and functionally connected with the primary motor cortex (M1). Neuroplastic alterations of neuronal connectivity might be an important basis for learning processes. These have however not been explored for parieto-motor connections in humans by transcranial direct current stimulation (tDCS). Exploring tDCS effects on parieto-motor cortical connectivity might be functionally relevant, because tDCS has been shown to improve motor learning. We aimed to explore plastic alterations of parieto-motor cortical connections by tDCS in healthy humans. We measured neuroplastic changes of corticospinal excitability via motor evoked potentials (MEP) elicited by single-pulse transcranial magnetic stimulation (TMS) before and after tDCS over the left posterior parietal cortex (P3), and 3 cm posterior or lateral to P3, to explore the spatial specificity of the effects. Furthermore, short-interval intracortical inhibition/intracortical facilitation (SICI/ICF) over M1, and parieto-motor cortical connectivity were obtained before and after P3 tDCS. The results show polarity-dependent M1 excitability alterations primarily after P3 tDCS. Single-pulse TMS-elicited MEPs, M1 SICI/ICF at 5 and 7 ms and 10 and 15 ms interstimulus intervals (ISIs), and parieto-motor connectivity at 10 and 15 ms ISIs were all enhanced by anodal stimulation. Single pulse-TMS-elicited MEPs, and parieto-motor connectivity at 10 and 15 ms ISIs were reduced by cathodal tDCS. The respective corticospinal excitability alterations lasted for at least 120 min after stimulation. These results show an effect of remote stimulation of parietal areas on M1 excitability. The spatial specificity of the effects and the impact on parietal cortex-motor cortex connections suggest a relevant connectivity-driven effect.

Is sham cTBS real cTBS? The effect on EEG dynamics.

Abstract: Increasing sensitivity of modern evaluation tools allows for the study of weaker electric stimulation effects on neural populations. In the current study we examined the effects of sham continuous theta burst (cTBS) transcranial magnetic stimulation to the left dorsolateral prefrontal cortex (DLPFC) upon somatosensory evoked potentials (SEP) and frontal-parietal phase coupling of alpha and beta bands. Sham TMS results in an induced electric field amplitude roughly 5% that of real TMS with a similar spatial extent in cortex. Both real and sham cTBS reduced the amplitude of the frontal P14-N30 SEP and increased local phase coupling in the alpha-beta frequency bands of left frontal cortex. In addition, both sham and real cTBS increased frontal-parietal phase coupling in the alpha-beta bands concomitant with an increase in amplitude of parietal P50-N70 complex. These data suggest that weak electric fields from sham cTBS can affect both local and downstream neuronal circuits, though in a different manner than high strength TMS.

Separating recognition processes of declarative memory via anodal tDCS: boosting old item recognition by temporal and new item detection by parietal stimulation.

Abstract: There is emerging evidence from imaging studies that parietal and temporal cortices act together to achieve successful recognition of declarative information; nevertheless, the precise role of these regions remains elusive. To evaluate the role of these brain areas in declarative memory retrieval, we applied bilateral tDCS, with anode over the left and cathode over the right parietal or temporal cortices separately, during the recognition phase of a verbal learning paradigm using a balanced old-new decision task. In a parallel group design, we tested three different groups of healthy adults, matched for demographic and neurocognitive status: two groups received bilateral active stimulation of either the parietal or the temporal cortex, while a third group received sham stimulation. Accuracy, discriminability index (d’) and reaction times of recognition memory performance were measurements of interest. The d’ sensitivity index and accuracy percentage improved in both active stimulation groups, as compared with the sham one, while reaction times remained unaffected. Moreover, the analysis of accuracy revealed a different effect of tDCS for old and new item recognition. While the temporal group showed enhanced performance for old item recognition, the parietal group was better at correctly recognising new ones. Our results support an active role of both of these areas in memory retrieval, possibly underpinning different stages of the recognition process.

Transcranial Direct Current Stimulation: Protocols and Physiological Mechanisms of Action

Abstract: Tonic stimulation with direct currents (transcranial direct current stimulation [tDCS]) was reintroduced about a decade ago as a method to modulate cortical excitability, activity, and to elicit neuroplasticity in the human brain. tDCS alters cortical excitability for up to hours after the end of stimulation, depending on its duration and intensity. While anodal stimulation increases excitability, cathodal stimulation reduces it. Beyond these local effects under the electrodes, an impact of tDCS on cortical networks was revealed recently. During the last 12 years, tDCS has been demonstrated to modify perceptual, motor, and cognitive functions reversibly in healthy subjects. Moreover, the results of clinical pilot studies suggest its suitability as a treatment in neurological and psychiatric diseases. This review will give an overview of the principles of tDCS. It will be discussed how specific stimulation parameters, like stimulation intensity, duration, electrode size, and configuration, including recently developed new stimulation protocols, determine the direction, magnitude, and duration of effects. Moreover, an overview of the main putative regional and network physiological mechanisms will be given.

Effect of the Nicotinic α4β2-receptor Partial Agonist Varenicline on Non-invasive Brain Stimulation-Induced Neuroplasticity in the Human Motor Cortex

Abstract: Nicotine alters cognitive functions in animals and humans most likely by modification of brain plasticity. In the human brain, it alters plasticity induced by transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS), probably by interference with calcium-dependent modulation of the glutamatergic system. We aimed to test this hypothesis further by exploring the impact of the α4β2-nicotinic receptor partial agonist varenicline on focal and non-focal plasticity, induced by PAS and tDCS, respectively. We administered low (0.1 mg), medium (0.3 mg), and high (1.0 mg) single doses of varenicline or placebo medication before PAS or tDCS on the left motor cortex of 25 healthy non-smokers. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor evoked potential amplitudes up to 36 h after plasticity induction. Whereas low-dose varenicline had no impact on stimulation-induced neuroplasticity, medium-dose abolished tDCS-induced facilitatory after-effects, favoring focal excitatory plasticity. High-dose application preserved cathodal tDCS-induced excitability diminution and focal excitatory PAS-induced facilitatory plasticity. These results are comparable to the impact of nicotine receptor activation and might help to further explain the involvement of specific receptor subtypes in the nicotinic impact on neuroplasticity and cognitive functions in healthy subjects and patients with neuropsychiatric diseases.

Atrial fibrillation coincides with the advanced glycation end product N(ε)-(carboxymethyl)lysine in the atrium.

Abstract: Presence of advanced glycation end products (AGEs) in the heart induces a proinflammatory phenotype. However, the presence of AGEs within atrial tissue of atrial fibrillation (AF) patients is unknown and was analyzed here. Left atrial appendage tissue from 33 AF patients and 9 controls was analyzed for the presence of the major AGEs N(e)-(carboxymethyl)lysine (CML), VCAM-1, neutrophilic granulocytes, lymphocytes, and macrophages in both the fat tissue and myocardium separately. The total amount of fibrosis was also analyzed. Presence of CML was significantly higher in blood vessels of the left atrial appendage in AF patients as compared to controls, independent of diabetes mellitus. In AF patients, VCAM-1 expression in blood vessels and the numbers of infiltrated neutrophilic granulocytes, lymphocytes, and macrophages significantly increased compared to controls, and were highest in the fat tissue; there was no significant difference in fibrosis compared to controls. Interestingly, total amount of CML and fibrosis in AF and control patients correlated positively. Finally, there was no difference between AF patients based on AF type or surgical indication in the presence of CML, VCAM-1 expression, inflammatory cells, and fibrosis. Our results indicate that in AF the intramyocardial blood vessels of the left atrial appendage have an increased CML presence and proinflammatory status coinciding with a local increase in the number of inflammatory cells.

Mechanisms of Nicotinic Modulation of Glutamatergic Neuroplasticity in Humans.

Abstract: The impact of nicotine (NIC) on plasticity is thought to be primarily determined via calcium channel properties of nicotinic receptor subtypes, and glutamatergic plasticity is likewise calcium-dependent. Therefore glutamatergic plasticity is likely modulated by the impact of nicotinic receptor-dependent neuronal calcium influx. We tested this hypothesis for transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity, which is abolished by NIC in nonsmokers. To reduce calcium influx under NIC, we blocked N-methyl-d-aspartate (NMDA) receptors. We applied anodal tDCS combined with 15 mg NIC patches and the NMDA-receptor antagonist dextromethorphan (DMO) in 3 different doses (50, 100, and 150 mg) or placebo medication. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor-evoked potential amplitudes after plasticity induction. NIC abolished anodal tDCS-induced motor cortex excitability enhancement, which was restituted under medium dosage of DMO. Low-dosage DMO did not affect the impact of NIC on tDCS-induced plasticity and high-dosage DMO abolished plasticity. For DMO alone, the low dosage had no effect, but medium and high dosages abolished tDCS-induced plasticity. These results enhance our knowledge about the proposed calcium-dependent impact of NIC on plasticity in humans and might be relevant for the development of novel nicotinic treatments for cognitive dysfunction.

Bi-frontal transcranial alternating current stimulation in the ripple range reduced overnight forgetting

Abstract: High frequency oscillations in the hippocampal structures recorded during sleep have been proved to be essential for long-term episodic memory consolidation in both animals and in humans. The aim of this study was to test if transcranial Alternating Current Stimulation (tACS) of the dorsolateral prefrontal cortex (DLPFC) in the hippocampal ripple range, applied bi-frontally during encoding, could modulate declarative memory performance, measured immediately after encoding, and after a night's sleep. An associative word-pair learning test was used. During an evening encoding phase, participants received 1 mA 140 Hz tACS or sham stimulation over both DLPFCs for 10 min while being presented twice with a list of word-pairs. Cued recall performance was investigated 10 min after training and the morning following the training session. Forgetting from evening to morning was observed in the sham condition, but not in the 140 Hz stimulation condition. 140 Hz tACS during encoding may have an effect on the consolidation of declarative material.

Increased HCN channel driven inward rectification in benign cramp fasciculation syndrome

Abstract: Muscle cramps are a common complaint associated with sudden painful involuntary contractions of a muscle. The mechanisms responsible for muscle cramps are still not clear. Axonal excitability and multi-unit electromyography studies were performed in 20 patients suffering from benign cramp fasciculation syndrome, not currently on medication. The measures of axonal excitability suggested greater inward rectification, indicative of an increase in Ih. Mathematical modelling suggested that the data were best explained by depolarization of the voltage dependence of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Parameters associated with polarization of resting membrane potential were not changed. These findings suggest that a role for HCN channels may become apparent during the rhythmic discharge associated with a voluntary contraction. Consistent with this view, patients had higher motor unit discharge rates than healthy controls during maximal voluntary effort.

Neuroplastic effects of transcranial near-infrared stimulation (tNIRS) on the motor cortex.

Abstract: Near-infrared light stimulation of the brain has been claimed to improve deficits caused by traumatic brain injury and stroke. Here, we exploit the effect of transcranial near-infrared stimulation (tNIRS) as a tool to modulate cortical excitability in the healthy human brain. tNIRS was applied at a wavelength of 810 nm for 10 minutes over the hand area of the primary motor cortex (M1). Both single-pulse and paired-pulse measures of transcranial magnetic stimulation (TMS) were used to assess levels of cortical excitability in the corticospinal pathway and intracortical circuits. The serial reaction time task (SRTT) was used to investigate the possible effect of tNIRS on implicit learning. By evaluating the mean amplitude of single-pulse TMS elicited motor-evoked-potentials (MEPs) a significant decrease of the amplitude was observed up to 30 minutes post-stimulation, compared to baseline. Furthermore, the short interval cortical inhibition (SICI) was increased and facilitation (ICF) decreased significantly after tNIRS. The results from the SRTT experiment show that there was no net effect of stimulation on the performance of the participants. Results of a study questionnaire demonstrated that tNIRS did not induce serious side effects apart from light headache and fatigue. Nevertheless, 66% were able to detect the difference between active and sham stimulation conditions. In this study we provide further evidence that tNIRS is suitable as a tool for influencing cortical excitability and activity in the healthy human brain.

Ultrasound and microbubble-induced local delivery of microrna-based therapeutics

Abstract: MicroRNAs are involved in many pathologic processes and are a promising target for therapeutic intervention. However, successful, localized delivery of microRNA-based therapeutics is lacking. In this study, cationic ultrasound-responsive microbubbles (MBs) were used to deliver microRNA blockers and mimics in vitro and in vivo. Cationic MBs successfully delivered microRNA blockers to human endothelial cells on ultrasound (US) exposure in vitro. This in vitro US protocol did not successfully deliver microRNA mimics to skeletal muscle of mice, whereas an US protocol that is routinely used for contrast imaging did. Additionally, we used cationic MBs and US to locally deliver antimiR and antagomiR molecules with US causing inertial cavitation. Delivery of antimiR to the extracellular compartments of the muscle was only slightly increased, whereas delivery of antagomiR to the capillaries, myocytes and extracellular space was significantly increased. AntagomiR seems to be a more suitable microRNA blocker than antimiR for use in combination with MBs and US for local delivery.

Pathophysiological rationale and diagnostic targets for diastolic stress testing

Abstract: Cardiopulmonary functional reserve measured as peak oxygen uptake is predicted better at rest by measures of cardiac diastolic function than by systolic function. Normal adaptations in the trained heart include resting bradycardia, increased LV end-diastolic volume and augmented early diastolic suction on exercise. In normal populations early diastolic relaxation declines with age and end-diastolic stiffness increases, but in healthy older subjects who have exercised throughout their lives diastolic function can be well preserved. The mechanisms by which LV diastolic filling and pressures can be impaired during exercise include reduced early diastolic recoil and suction (which can be exacerbated by increased late systolic loading), increased preload and reduced compliance. Abnormal ventricular-arterial coupling and enhanced ventricular interaction may contribute in particular circumstances. One common final pathway that causes breathlessness is an increase in LV filling pressure and left atrial pressure. Testing elderly subjects with breathlessness of unknown aetiology in order to detect worsening diastolic function during stress is proposed to diagnose heart failure with preserved EF. In invasive studies, the most prominent abnormality is an early and rapid rise in pulmonary capillary wedge pressure. A systematic non-invasive diagnostic strategy would use validated methods to assess different mechanisms of inducible diastolic dysfunction and not just single parameters that offer imprecise estimates of mean LV filling pressure. Protocols should assess early diastolic relaxation and filling as well as late diastolic filling and compliance, as these may be affected separately. Better refined diagnostic targets may translate to more focused treatment.

Normal resting pulmonary artery wedge pressure: a diagnostic trap for heart failure with preserved ejection fraction

Abstract: This article refers to ‘Exercise haemodynamics may unmask the diagnosis of diastolic dysfunction among patients with pulmonary hypertension’ by E. Maor et al., published in this issue on page 151 The diagnosis of heart failure with preserved ejection fraction (HFPEF) remains challenging. A correct diagnosis requires the presence of signs or symptoms of congestion, normal LV systolic function, and evidence of diastolic LV dysfunction.1 Failure to establish the diagnosis of HFPEF correctly can be related to omission of evidence of diastolic LV dysfunction,2 to exclusive reliance on elevated natriuretic peptides,3 which are only modestly raised in HFPEF,4 and to the fortuitous presence of a hypovolaemic status at the time of diagnostic evaluation,5 which necessitates a repeat assessment during exercise6 or saline infusion.7 The latter was convincingly demonstrated in the current issue of the journal by the study of Maor et al., who performed a limited upper body exercise stress test mimicking daily living activities during right heart catheterization in patients with pulmonary hypertension (PHT) [mean pulmonary artery pressure (mPAP) >25 mmHg] and normal resting pulmonary artery wedge pressure (PAWP <15 mmHg).8 Despite attaining a rise in heart rate of 10%, which was only 62% of the age-predicted maximal heart rate, one-third of the patients had a substantial rise of PAWP from 11.4± 3.3 to 28.0± 6.5 mmHg. Without exercise stress testing, their HFPEF-induced post-capillary (group 2) PHT would have remained unnoticed and these patients would have been erroneously classified as pre-capillary (group 1) PHT in accordance with the Dana Point PHT criteria.9 Significant predictors of an exercise-induced rise in PAWP were a borderline resting PAWP (12< PAWP<15 mmHg), a high body mass index (BMI), presence of obesity, and a dilated left atrium.

When battery exhaustion lets the lame walk: a case report on the importance of long-term stimulator monitoring in deep brain stimulation

Abstract: Deep brain stimulation is increasingly used in the treatment of advanced Parkinson’s disease. While its short-term effectiveness is well documented, there are only few reports on long-term outcomes, and the need to repeatedly reprogram the stimulator is seldom reported. We present a 74-year-old man with gait impairment, which had been mistaken for worsening of the disease and only remitted when the stimulator battery was exhausted indicating that the stimulator itself had been the cause. This case highlights the need to repeatedly monitor not only battery capacity, but also stimulator-related side-effects for an extended period after implantation and, if necessary, to refer to centres capable of systematically reprogramming the device.

Vascular safety of brain plasticity induction via transcranial direct currents

Abstract: Experience alters the strength of neuronal connections as a fundamental feature of brain physiology. This process, termed neuroplasticity, appears crucially involved in cognitive processes such as learning, memory formation, and adaptive behavior. Neuroplasticity is increasingly implicated in not only a number of neurologic diseases, but also in restitution after brain injury. Noninvasive brain stimulation can induce and modulate neuroplasticity in humans.1 In accordance with the functional relevance of neuroplasticity, noninvasive brain stimulation not only modulates psychological processes and behavior in healthy humans, but also reduces symptoms, and improves rehabilitation, in patients with neurologic diseases, including stroke.2–4