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The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of [Cav.sub.3.1] T-type [Ca.sup.2+] channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4-to 10-Hz synchronous neuronal activities arose from the 10 and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking [Cav.sub.3.1] gene. Intracellular recordings in brain-stem slices revealed that the [Cav.sub.3.1]-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of [Cav.sub.3.1] gene in the inferior olive by shRNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate [Cav.sub.3.1] channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, [Cav.sub.3.1] is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor. subthreshold oscillation | T-type calcium channel | harmaline doi/ 10.1073/pnas.1002995107

Entrainment of the circadian pacemaker to the light:dark cycle is necessary for rhythmic physiological functions to be appropriately timed over the 24-h day. Nonentrainment results in sleep, endocrine, and neurobehavioral impairments. Exposures to intermittent bright light pulses have been reported to phase shift the circadian pacemaker with great efficacy. Therefore, we tested the hypothesis that a modulated light exposure (MLE) with bright light pulses in the evening would entrain subjects to a light:dark cycle 1 h longer than their own circadian period ([tau]). Twelve subjects underwent a 65-day inpatient study. Individual subject's circadian period was determined in a forced desynchrony protocol. Subsequently, subjects were released into 30 Ionger-than-24-h days (daylength of [tau] + 1 h) in one of three light:dark conditions: (i) [approximately equal to]25 lux; (ii) [approximately equal to]100 lux; and (iii) MLE: [approximately equal to]25 lux followed by [approximately equal to]100 lux, plus two 45-rain bright light pulses of [approximately equal to]9,500 lux near the end of scheduled wakefulness. We found that lighting levels of [approximately equal to]25 lux were insufficient to entrain all subjects tested. Exposure to [approximately equal to]100 lux was sufficient to entrain subjects, although at a significantly wider phase angle compared with baseline. Exposure to MLE was able to entrain the subjects to the imposed sleep--wake cycles but at a phase angle comparable to baseline. These results suggest that MLE can be used to entrain the circadian pacemaker to non-24-h days. The implications of these findings are important because they could be used to treat circadian misalignment associated with space flight and circadian rhythm sleep disorders such as shiftwork disorder. light | melatonin | phase angle of entrainment | phase response curve | sleep

This paper presents a digital hardware implementation of a novel wavelet-based event detector suitable for the next generation of cardiac pacemakers. Significant power savings are achieved by introducing a second operation mode that shuts down 2/3 of the hardware for long time periods when the pacemaker patient is not exposed to noise, while not degrading performance. Due to a 0.13-[micro]m CMOS technology and the low clock frequency of 1 kHz, leakage power becomes the dominating power source. By introducing sleep transistors in the power-supply rails, leakage power of the hardware being shut off is reduced by 97%. Power estimation on RTL-level shows that the overall power consumption is reduced by 67% with a dual operation mode. Under these conditions, the detector is expected to operate in the sub-[micro]W region. Detection performance is evaluated by means of databases containing electrograms to which five types of exogenic and endogenic interferences are added. The results show that reliable detection is obtained at moderate and low signal to noise-ratios (SNRs). Average detection performance in terms of detected events and false alarms for 25-dB SNR is [P.sub.D] = 0.98 and [P.sub.FA] = 0.014, respectively. Index Terms--Cardiac pacemaker, event detector, gated supply, sleep transistors, wavelet filter.

A low-power front end for a pacemaker atrial sensing channel based on level detection is presented. The very tight system specifications in terms of power consumption and output noise, the need to operate with a supply voltage decreasing from 2.8 to 2 V during the battery lifetime, and additional functionalities with respect to standard front ends, like gain programmability and early sensing, make the design of this system a challenge. The front end includes a preamplifier and a third-order switched capacitor filter, and it is fabricated in a 0.8-[micro]m CMOS technology. It features a 1-[micro]. A current consumption at a supply voltage of 2.7 V, and an input referred total noise of 6.9 [mu][V.sub.rms]. Index Terms--Low power, pacemaker, switched-capacitor (SC) filter.

Human exposure to external 50/60-Hz electric and magnetic fields induces electric fields within the body. These induced fields can cause interference with implanted pacemakers. In the case of exposure to magnetic fields, the pacemaker leads are subject to induced electromotive forces, with current return paths being provided by the conducting body tissues. Modern computing resources used in conjunction with millimeter-scale human body conductivity models make numerical modeling a viable technique for examining any such interference. In this paper, an existing well-verified scalar-potential finite-difference frequency-domain code is modified to handle thin conducting wires embedded in the body. The effects of each wire can be included numerically by a simple modification to the existing code. Results are computed for two pacemaker lead insertion paths, terminating at either atrial or ventricular electrodes in the heart. Computations are performed for three orthogonal 60-Hz magnetic field orientations. Comparison with simplified estimates from Faraday's law applied directly to extracorporeal loops representing unipolar leads underscores problems associated with this simplified approach. Numerically estimated electromagnetic interference (EMI) levels under the worst case scenarios are about 40 [mu]T for atrial electrodes, and 140 [mu]T for ventricular electrodes. These methods could also be applied to studying EMI with other implanted devices such as cardiac defibrillators. Index Terms--Cardiac pacemaker, electromagnetic interference, modeling, power lines.

Experimental analysis of the behavioral theory of timing in which pulses from a hypothetical Poisson pacemaker generate shifts between states that correlate to adjunctive behavior. Interreinforcer intervals influence the average interpulse time of the pacemaker. Variations in temporal discrimination as a function of interreinforcer interval are unaffected by the discrimination of reinforce occurrence.

The electrical interaction between the heart and an artificial pacemaker is often complex. Because of the sophistication and diversity of dual-chamber device algorithms, even experienced cardiologists can have difficulty interpreting paced electrocardiograms (ECG's). In order to study heart-pacemaker interaction (HPI), a computer model of the cardiac conduction system has been developed which includes the effects of artificial pacemaker function and failure. The stochastic network model of cardiac conduction consists of five vertices, each representing a functional electrophysiologic element. Electrophysiologic multidimensional conditional probability functions determine the depolarization status of each vertex. The atrioventricular (AV) node is emulated using a mathematical model which includes the influence of past cycle lengths on AV nodal conduction time. Twenty-three classes of arrhythmias may be simulated and, for pacing simulation, one of 12 antibradycardia pacing modes may be chosen. Random effects of pacemaker malfunction including oversensing, undersensing, or failure-to-capture may be simulated through the use of probability distribution functions. This model should prove useful in the development of pacemaker algorithms, determining patient-specific pacemaker therapy, and predicting causes for apparent pacemaker malfunction. The model has been used in the development of an expert system to analyze paced ECG's for pacemaker function and malfunction.

The possibility of interference by low-frequency external electric fields with cardiac pacemakers is a matter of practical concern. For pragmatic reasons, experimental investigations into such interference have used contact electrode current sources. However, the applicability to the external electric field problem remains unclear. The recent development of anatomically based electromagnetic models of the human body, together with progress in computational electromagnetics, enable the use of numerical modeling to quantify the relationship between external field and contact electrode excitation. This paper presents a comparison between the computed fields induced in a 3.6-mm-resolution conductivity model of the human body by an external electric field and by several electrode source configurations involving the feet and either the head or shoulders. The application to cardiac pacemaker interference is also indicated. Index Terms--Cardiac pacemaker, electromagnetic interference, modeling, power lines.

Heart failure is the most common cause of hospitalization and death in adults over age 55 in the United States and is fast becoming a leading cause of death worldwide [...]

A 10 year old boy with severe learning disabilities had a permanent subpectoral endocardial pacemaker for intermittent heart block. Twenty three months later, he presented with an episode of collapse [...]

In the present work I have focused on some aspects of the dynamics of a simulated neural network consisting of excitatory neurons with a small number of embedded endogenous oscillators. [...]