Selective REM sleep restriction in mice using a device designed for tunable somatosensory stimulation.

BACKGROUND: Sleep perturbation is widely used to investigate the physiological mechanisms that mediate sleep-wake dynamics, and to isolate the specific roles of sleep in health and disease. However, state-of-the-art methods to accomplish sleep perturbation in preclinical models are limited in their throughput, flexibility, and specificity. NEW METHOD: A system was developed to deliver vibro-tactile somatosensory stimulation aimed at controlled, selective sleep perturbation. The frequency and intensity of stimulation can be tuned to target a variety of experimental applications, from sudden arousal to sub-threshold transitions between light and deep stages of NREM sleep. This device was activated in closed-loop to selectively interrupt REM sleep in mice. RESULTS: Vibro-tactile stimulation effectively and selectively interrupted REM sleep - significantly reducing the average REM bout duration relative to matched, unstimulated baseline recordings. As REM sleep was repeatedly interrupted, homeostatic mechanisms prompted a progressively quicker return to REM sleep. These effects were dependent on the parameters of stimulation applied. COMPARISON WITH EXISTING METHODS: Existing sleep perturbation systems often require moving parts within the cage and/or restrictive housing. The system presented is unique in that it interrupts sleep without invading the animal's space. The ability to vary stimulation parameters is a great advantage over existing methods, as it allows for adaptation in response to habituation and/or circadian/homeostatic changes in arousal threshold. CONCLUSIONS: The proposed method of stimulation demonstrates feasibility in affecting mouse sleep within a standard home cage environment, thus limiting environmental stress. Furthermore, the ability to tune frequency and intensity of stimulation allows for graded control over the extent of sleep perturbation, which potentially expands the utility of this technology beyond applications related to sleep.

Circumflex to Left Atrial Appendage Fistula Associated With Watchman FLX Closure Device.

An 82-year-old man who had undergone Watchman FLX (Boston Scientific) device implantation presented with dyspnea. Multimodality evaluation demonstrated a small fistula from the proximal circumflex artery to the left atrial appendage. Anatomically, the left circumflex artery is close to the atrial appendage; therefore, it is plausible that fistula formation could be a late complication of implantation of the device.

A pentavalent approach for the evaluation of traumatic brachial plexopathy on MRI: correlation of macropattern and micropattern.

Macropattern analysis of traumatic brachial plexopathy (TBP) by Magnetic Resonance Imaging (MRI) encompasses localization of injured segments and determination of the severity of injury. The micropattern analysis implies the correlation of the MRI features of TBP with Sunderland's grading of the nerve injury, thereby guiding the management protocol. This review article presents a simplified novel pentavalent approach for the radiological anatomy of brachial plexus, MRI acquisition protocol for the evaluation of brachial plexus, cardinal imaging signs of TBP, and their correlation with Sunderland's microanatomical grading.

Lumbar contribution to the trunk forward bending and backward return; age-related differences.

Age-related differences in lumbar contribution to the trunk motion in the sagittal plane were investigated. Sixty individuals between 20-70 years old in five gender-balanced age groups performed forward bending and backward return with slow and fast paces. Individuals older than 50 years old, irrespective of the gender or pace, had smaller lumbar contribution than those younger than this age. The lumbar contribution to trunk motion was also smaller in female participants than male participants, and under fast pace than under the slow pace. Age-related differences in lumbar contributions suggest the synergy between the active and passive lower back tissues is different between those above and under 50 years old, differences that are likely to affect the lower back mechanics. Therefore, detailed modelling should be conducted in future to find the age-related differences in the lower back mechanics for tasks involving large trunk motion. Practitioner Summary: Lumbar contribution to the sagittal trunk motion was observed to be smaller in individuals above 50 years old than those below this age. This could be an indication of a likely change in the synergy between the active and passive lower back tissues, which may disturb the lower back mechanics.

Radiofrequency and Cryo-Ablation Effect on Transvenous Pacing and Defibrillatory Lead Integrity: An In Vitro Study.

INTORDUCTION: Medical societies and cardiac implantable electronic device (CIED) manufacturers recommend avoiding close or direct contact between the body of transvenous leads and ablation catheters used to treat cardiac arrhythmias. These recommendations are made despite the lack of clinical studies. However, the target myocardium for successful ablation can be contiguous to CIED leads. METHODS AND RESULTS: We examine in vitro the effects of direct application of radiofrequency (RF) and cryo-ablation energy on the integrity and functionality of CIED leads (excluding the pacing electrodes and defibrillation coils). A saline bath was created to mimic the body milieu. CIED leads, including all commercially available lead insulation materials, were connected to a CIED pulse generator and placed in direct contact with an ablation catheter in the tissue bath. RF and cryo-ablation energy were delivered under various conditions, including maximal ablation power, temperature, and impedance via the RF generator. CIED lead functionality, reflective of conductor integrity, was evaluated through lead impedance monitoring during ablation. CIED leads were then visually inspected, and examined with optic and electron microscopy as per protocol. A total of 42 leads were studied. All leads showed the absence of insulation damage at the site of ablation visually and with microscopy. Lead functionality was also preserved in all leads. CONCLUSION: Catheter ablation in contact with CIED leads using radiofrequency or cryo-ablation in vitro did not affect lead body integrity and function despite aggressive ablation settings. It may be reasonable to perform ablation in contact with the body of CIED leads when clinically necessary.

Tunable somatosensory stimulation for selective sleep restriction studies in rodents.

Many methods for sleep restriction in rodents have emerged, but most are intrusive, lack fine control, and induce stress. Therefore, a versatile, non-intrusive means of sleep restriction that can alter sleep in a controlled manner could be of great value in sleep research. In previous work, we proposed a novel system for closed-loop somatosensory stimulation based on mechanical vibration and applied it to the task of restricting Rapid Eye Movement (REM) sleep in mice [1]. While this system was effective, it was a crude prototype and did not allow precise control over the amplitude and frequency of stimulation applied to the animal. This paper details the progression of this system from a binary, "all-or-none" version to one that allows dynamic control over perturbation to accomplish graded, state-dependent sleep restriction. Its preliminary use is described in two applications: deep sleep restriction in rats, and REM sleep restriction in mice.

Supernormal Conduction and Suppression of Spatially Discordant Alternans of Cardiac Action Potentials.

Spatially discordant alternans (DA) of action potential durations (APD) is thought to be more pro-arrhythmic than concordant alternans. Super normal conduction (SNC) has been reported to suppress formation of DA. An increase in conduction velocity (CV) as activation rate increases, i.e., a negative CV restitution, is widely considered as hallmark of SNC. Our aim in this study is to show that it is not an increase in CV for faster rates that prevents formation of DA, rather, it is the ratio of the CV for the short relative to the long activation that is critical in DA suppression. To illustrate this subtlety, we simulated this phenomenon using two approaches; (1) by using the standard, i.e., S1S2 protocol to quantify restitution and disabling the slow inactivation gate j of the sodium current (INa), and (2) by using the dynamic, i.e., S1S1 protocol for quantification of restitution and increasing INa at different cycle lengths (CL). Even though both approaches produced similar CV restitution curves, DA was suppressed only during the first approach, where the CV of the short of the long-short action potential (AP) pattern was selectively increased. These results show that negative CV restitution, which is considered characteristic of SNC, per se, is not causal in suppressing DA, rather, the critical factor is a change in the ratio of the velocities of the short and the long APs.

Bachmann's bundle and coronary sinus ostial pacing accentuate left atrial electrical dyssynchrony in an acute canine model.

INTRODUCTION: In patients with intraatrial conduction delay and sinus node (SN) dysfunction, pacing Bachmann's bundle (BBR) and coronary sinus ostium (CSO) has been suggested to achieve atrial resynchronization with potential beneficial impact on atrial fibrillation and diastolic heart failure. Clinical studies have not shown superiority of one approach. METHODS AND RESULTS: We studied electrical activation sequence in an open-chest acute canine model of normal atrial function in 8 mongrel dogs under general anesthesia. Bipolar plunge electrodes were distributed over the surface of the atria during unifocal pacing, and intracardiac activation sequence was observed. SN pacing resulted in near-simultaneous activation at midline sites (BBR and CSO); the left atrium (LA) was activated by anterior and posterior wavefronts simultaneously propagating septally to laterally and meeting at the low-lateral perimitral LA. Right atrial appendage (RAA) pacing created intra-RA conduction delay and delayed onset of LA activation. Pacing from RAA, CSO, and BBR resulted in nonsimultaneous activation at midline sites and produced an anteroposterior gradient of LA activation. This phenomenon was seen to the greatest degree with midline pacing and shifted the site of latest activation away from the low-lateral perimitral LA in all pacing configurations except SN pacing. CONCLUSION: Pacing-induced intra-LA activation dispersion is enhanced with midline atrial pacing, and secondarily shifts the site of latest activation away from the lateral mitral annulus. Measuring atrial activation times to the low-lateral perimitral LA can underestimate the degree of atrial dyssynchrony and be misinterpreted as atrial synchrony. Establishing clinical impact requires evaluation of human data.

Phase Relationship between Alternans of Early and Late Phases of Ventricular Action Potentials.

BACKGROUND: Alternans of early phase and of duration of action potential (AP) critically affect dispersion of refractoriness through their influence on conduction and repolarization. We investigated the phase relationship between the two alternans and its effect on conduction. METHODS AND RESULTS: Transmembrane potentials recorded from ventricles of eight swine and three canines during paced activation intervals of ≤300 ms were used to quantify alternans of maximum rate of depolarization (|dv/dt|(max)) and of action potential duration (APD). Incidence of APD alternans was 62 and 76% in swine and canines. Alternans of APD was frequently accompanied with alternans of |dv/dt|(max). Of these, 4 and 26% were out of phase in swine and canines, i.e., low |dv/dt|(max) preceded long APD. Computer simulations show that out of phase alternans attenuate variation of wavelength and thus minimize formation of spatially discordant alternans. CONCLUSION: The spontaneous switching of phase relationship between alternans of depolarization and repolarization suggests that mechanisms underlying these alternans may operate independent of each other. The phase between these alternans can critically impact spatial dispersion of refractoriness and thus stability of conduction, with the in phase relation promoting transition from concord to discord while out of phase preventing formation of discord.

Effect of rapid delayed rectifier current on hysteresis in restitution of action potential duration in swine.

Electrical stability in the heart depends on two important factors; restitution of action potential duration (APD) and memory. Repolarization currents play an important role in determining APD and also affect memory. We determined the effects of blocking the rapid component of the delayed rectifier (I(Kr)) on a quantifiable measure of memory, i.e. hysteresis in restitution of APD, in swine. Transmembrane potentials were recorded from right ventricular endocardial tissues. Two pacing protocols with explicit control of diastolic interval (DI) were used to change DIs in a sequential and sinusoidal pattern to quantify hysteresis in restitution of APD. E-4031 (5 µM/L) was used to block I(Kr). Measures of memory and restitution were quantified by calculating hysteresis loop thickness, area, overall tilt, and maximum and minimum delays between DIs and APDs. Blocking I(Kr) with E-4031 increased the baseline APD, loop thickness, area, and tilt (p<0.05). However, loop thickness did not increase beyond what could be predicted by the increase in baseline APD after block of I(Kr). The substantial change in APD after blocking I(Kr) suggests that this current plays a major role in repolarization in the swine. Loop thickness is a measure of memory, an increase in which is predicted by theory to reduce instability in activation. In our study, the substantial increase in loop thickness could be accounted for by an equally substantial increase in APD and therefore does not necessarily indicate increased memory after blocking I(Kr). Our results also suggest that factors based on restitution and memory need to be considered in the context of operating point, i.e. baseline APD, when they are used to explore mechanisms that affect electrical stability in the heart.

Importance of performing transesophageal echocardiography in acute stroke patients older than fifty.

BACKGROUND: The purpose of this study was to determine the value of transesophageal echocardiography (TEE) in determining the presence of cardiac manifestations that required anticoagulation in patients presenting with acute stroke. METHODS: Of 626 consecutive stroke patients who underwent TEE, 188 patients with no obvious etiology for stroke were subcategorized according to age. TEE results were analyzed for cardiac findings suggestive of a cause for embolic stroke, including complex atheromas in the arch/ascending aorta, patent foramen ovale (PFO), atrial septal aneurysm (ASA), and intracavitary thrombi. Data were analyzed using Fisher's exact test. RESULTS: Of 188 patients, 66% (125/188) were older than 50 years and 34% (63/188) were younger than 50 years. The incidence of complex atheroma was 12.8% (16/125) in patients older than 50 years as compared to 0% (0/63) in patients who were younger than 50 years (P = 0.002). In patients older than 50 years, findings that indicated a need for anticoagulation based on TEE results were found in 22.4% (28/125) (atheroma = 16, PFO = 12, ASA = 5, thrombus = 3, PFO + ASA = 1) compared to 14.3% (9/63) (atheroma = 0, PFO = 5, ASA = 2, thrombus = 2, PFO + ASA = 1) in patients younger than 50 years. CONCLUSIONS: TEE plays an important role in suspected embolic stroke patients of all age groups. Due to the higher incidence of complex atheromas in patients older than 50 years of age, TEE might be of added importance in identifying the candidates who may benefit from anticoagulation.

A new approach to measure the contribution of restitution to repolarization alternans.

Several studies suggest link between repolarization alternans and arrhythmia. A potential target for minimization of alternans amplitude is pharmacological flattening of restitution function, which links a diastolic interval (DI) and subsequent action potential duration (APD). While our recent studies have shown that DI dependent restitution is not a necessary mechanism for alternans, in circumstances of nearly invariant activation intervals, restitution contributes to alternans. Determination of the degree to which restitution contributes to alternans during stable alternans, which requires determination of the gain between DI and APD, is not possible because it always is unity. We propose that the rate of change of alternans along the length of the tissue may provide an estimate of the degree to which restitution contributes to alternans amplitude. We conducted experiments with swine to demonstrate the above approach. In a linear strand of tissue, we paced such that DIs for successive activations were invariant at one end, which eliminates the restitution dependent mechanism of alternans at this end. Due to conduction delays, at the distal end, both restitution dependent and independent mechanisms manifest. Action potentials recorded from right ventricular endocardial tissue from swine (n = 3) showed an average difference in amplitudes of alternans between the two ends to be 11.99, 25.49, and 39.37 msec. Rates of change of alternans amplitude as a function of distance, computed using linear interpolation, were 0.36, 1.69 and 0.97. We propose that this rate of change may provide an indirect measure of degree of contribution of restitution to alternans and thus may be useful in evaluating therapeutic approaches to minimize its amplitude.

Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development.

Hypertension is a major risk factor for developing cardiac hypertrophy and heart failure. Previous studies show that hypertrophied and failing hearts display alterations in excitation-contraction (E-C) coupling. However, it is unclear whether remodeling of the E-C coupling system occurs before or after heart disease development. We hypothesized that hypertension might cause changes in the E-C coupling system that, in turn, induce hypertrophy. Here we tested this hypothesis by utilizing the progressive development of hypertensive heart disease in the spontaneously hypertensive rat (SHR) to identify a window period when SHR had just developed hypertension but had not yet developed hypertrophy. We found the following major changes in cardiac E-C coupling during this window period. 1) Using echocardiography and hemodynamics measurements, we found a decrease of left ventricular ejection fraction and cardiac output after the onset of hypertension. 2) Studies in isolated ventricular myocytes showed that myocardial contraction was also enhanced at the same time. 3) The action potential became prolonged. 4) The E-C coupling gain was increased. 5) The systolic Ca(2+) transient was augmented. These data show that profound changes in E-C coupling already occur at the onset of hypertension and precede hypertrophy development. Prolonged action potential and increased E-C coupling gain synergistically increase the Ca(2+) transient. Functionally, augmented Ca(2+) transient causes enhancement of myocardial contraction that can partially compensate for the greater workload to maintain cardiac output. The increased Ca(2+) signaling cascade as a molecular mechanism linking hypertension to cardiac hypertrophy development is also discussed.