Abstract
In an emerging bioelectronics era, there is a clinical need for physiological devices incorporating biofeedback that permits natural and demand-dependent control in real time. Here, we describe a novel device termed a central pattern generator (CPG) that uses cutting edge analog circuitry producing temporally controlled, electrical stimulus outputs based on the real time integration of physiological feedback. Motivated by the fact that respiratory sinus arrhythmia (RSA), which is the cyclical changes in heart rate every breath, is an essential component of heart rate variability (HRV) (an indicator of cardiac health), we have explored the versatility and efficiency of the CPG for producing respiratory modulation of heart rate in anesthetized, spontaneously breathing rats. Diaphragmatic electromyographic activity was used as the input to the device and its output connected to either the right cervical vagus nerve or the right atrium for pacing heart rate. We found that the CPG could induce respiratory related heart rate modulation that closely mimicked RSA. Whether connected to the vagus nerve or right atrium, the versatility of the device was demonstrated by permitting: (i) heart rate modulation in any phase of the respiratory cycle, (ii) control of the magnitude of heart rate modulation, and (iii) instant adaptation to changes in respiratory frequency. Vagal nerve pacing was only possible following transection of the nerve limiting its effective use chronically. Pacing via the right atrium permitted better flexibility and control of heart rate above its intrinsic level. This investigation now lays the foundation for future studies using this biofeedback technology permitting closer analysis of both the function and dysfunction of RSA.
Highlights
Respiratory sinus arrhythmia (RSA) is the physiological phenomenon whereby heart accelerates during inspiration and decelerates during expiration (Anrep et al, 1936)
The gain of the hCPG for vagal nerve stimulation (VN-CPG) input was finely adjusted to tune the diaphragmatic electromyogram (dEMG) signal of each rat such that two distinct bursting phases were generated from the Vagus Nerve (VN)-CPG outputs neuron 1 (N1) and neuron 2 (N2) (Figure 3A)
N1 intra-burst interval is shortest during peak dEMG activity (Figure 3A inset)
Summary
Respiratory sinus arrhythmia (RSA) is the physiological phenomenon whereby heart accelerates during inspiration and decelerates during expiration (Anrep et al, 1936). Increasing heart rate variability (HRV) by reinstating RSA may improve outcome in patients with cardiovascular diseases such as heart failure. Cyclic modulation of heart rate (HR) within each breath is not possible with existing medical device technology. Such technology must be a closed-loop system that generates a physiologically-appropriate stimulus in response to a biological input, such as respiration, in real time. We have developed a novel analog-hardware central pattern generator (hCPG) that integrates Hodgkin-Huxley equations in real time to recapitulate the outputs and dynamics of neurons. The advantage of hCPG neurons is that their firing sequence is extremely stable but both highly sensitive and fast to respond (microseconds) to changes in input signal. Functional circuits have been simulated (Briggman and Kristan, 2008) but it this the first time their principles are being implemented in hardware for the application of neurostimulation in vivo
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