Modulation of respiratory sinus arrhythmia in rats with central pattern generator hardware

Nogaret, Alain; Zhao, Le; Moraes, Deovaldo de; Paton, Julian F. R.

doi:10.1016/j.jneumeth.2012.09.024

Cited by 12 publications

(19 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Daily pacing commenced the following day (8 h per day for 2 weeks) and was set above the intrinsic HR at rest. Rats were divided into three groups: (i) respiratory-modulated heart rate paced (RMH; n = 5) using our previously described biofeedback device (Nogaret et al 2013;J Physiol 598.3 O'Callaghan et al 2016); (ii) monotonically paced (n = 5) with an isolated, constant voltage stimulator (DS2A, Digitimer Ltd, UK) triggered by a TTL output generated by a digital-analogue converter output, controlled by Spike2 software; (iii) unpaced (n = 7) for a time-matched control. The RMH waveform was tuned at the start of day 1 such that the minimum HR was above the average intrinsic HR at rest and the peak-trough amplitude of RMH was 20-30 bpm, with peak HR occurring with inspiration ( Fig.…”

Section: Pacing Protocolmentioning

confidence: 99%

Enhancing respiratory sinus arrhythmia increases cardiac output in rats with left ventricular dysfunction

O’Callaghan

Lataro

Roloff

et al. 2019

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Key points Respiratory sinus arrhythmia is physiological pacing of the heart that disappears in cardiovascular disease and is associated with poor cardiac prognosis. In heart failure, cardiac pacing has little, if any, variation in rate at rest. We proposed that reinstatement of respiratory sinus arrhythmia would improve cardiac function in rats with heart failure. Heart failure rats were paced daily for 2 weeks with either respiratory sinus arrhythmia or paced monotonically at a matched heart rate; cardiac function was measured using non‐invasive echocardiography. Cardiac output and stroke volume were increased in rats paced with respiratory sinus arrhythmia compared to monotonic pacing, via improvement in systolic function that persisted beyond the pacing treatment period. We propose that respiratory sinus arrhythmia pacing reverse‐remodels the heart in heart failure and is worth considering as a new form of cardiac pacemaking. Abstract Natural pacing of the heart results in heart rate variability, an indicator of good health and cardiac function. A contributor to heart rate variability is respiratory sinus arrhythmia or RSA – an intrinsic respiratory modulated pacing of heart rate. The loss of RSA is associated with poor cardiac prognosis and sudden cardiac death. We tested if reinstatement of respiratory‐modulated heart rate (RMH) would improve cardiac performance in heart failure. Heart failure was induced in Wistar rats by ligation of the left anterior descending coronary artery. Rats were unpaced, monotonically paced and RMH paced; the latter had the same average heart rate as the monotonically paced animals. Cardiac function was assessed non‐invasively using echocardiography before and after 2 weeks of daily pacing at a time when pacing was turned off. RMH increased cardiac output by 20 ± 8% compared to monotonic pacing (−3 ± 5%; P < 0.05). This improvement in cardiac output was associated with an increase in stroke volume compared to monotonic pacing (P = 0.03) and improvement in circumferential strain (P = 0.02). Improvements in ejection fraction (P = 0.08) and surrogate measures of left ventricle compliance did not reach significance. Increases in contractility (P < 0.05) and coronary blood flow (P < 0.05) were seen in vitro during variable pacing to mimic RMH. Thus, in rats with left ventricular dysfunction, chronic RMH pacing improved cardiac function through improvements in systolic function. As these improvements were made with pacing switched off, we propose the novel idea that RMH pacing causes reverse‐remodelling.

show abstract

Section: Pacing Protocolmentioning

confidence: 99%

Enhancing respiratory sinus arrhythmia increases cardiac output in rats with left ventricular dysfunction

O’Callaghan

Lataro

Roloff

et al. 2019

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The neuronal hCPG we have built is based on analog neurons which integrate the Hodgkin–Huxley equations in real time that is suitable for neuro‐stimulation (Nogaret, ; Nogaret et al . ; Fig. ).…”

Section: An Unmet Clinical Needmentioning

confidence: 93%

“…For the simplest networks such parameters can be obtained by trial and error (Nogaret et al . ). For more complicated networks such as the mammalian respiratory CPG in Fig.…”

Section: An Unmet Clinical Needmentioning

confidence: 97%

Silicon central pattern generators for cardiac diseases

Nogaret

O’Callaghan

Lataro

et al. 2015

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Cardiac rhythm management devices provide therapies for both arrhythmias and resynchronisation but not heart failure, which affects millions of patients worldwide. This paper reviews recent advances in biophysics and mathematical engineering that provide a novel technological platform for addressing heart disease and enabling beat-to-beat adaptation of cardiac pacing in response to physiological feedback. The technology consists of silicon hardware central pattern generators (hCPGs) that may be trained to emulate accurately the dynamical response of biological central pattern generators (bCPGs). We discuss the limitations of present CPGs and appraise the advantages of analog over digital circuits for application in bioelectronic medicine. To test the system, we have focused on the cardio-respiratory oscillators in the medulla oblongata that modulate heart rate in phase with respiration to induce respiratory sinus arrhythmia (RSA). We describe here a novel, scalable hCPG comprising physiologically realistic (Hodgkin-Huxley type) neurones and synapses. Our hCPG comprises two neurones that antagonise each other to provide rhythmic motor drive to the vagus nerve to slow the heart. We show how recent advances in modelling allow the motor output to adapt to physiological feedback such as respiration. In rats, we report on the restoration of RSA using an hCPG that receives diaphragmatic electromyography input and use it to stimulate the vagus nerve at specific time points of the respiratory cycle to slow the heart rate. We have validated the adaptation of stimulation to alterations in respiratory rate. We demonstrate that the hCPG is tuneable in terms of the depth and timing of the RSA relative to respiratory phase. These pioneering studies will now permit an analysis of the physiological role of RSA as well as its any potential therapeutic use in cardiac disease. Abbreviations ADC, analog-to-digital converter; bCPG, biological central pattern generator; BötC, Bötzinger complex; CPG, central pattern generator; CPU, central processing unit; CRT, cardiac resynchronisation therapy; cVN, central vagus nerve; DAC, digital-to-analog converter; hCPG, hardware central pattern generator; HR, heart rate; GPN, glossopharyngeal nerve; LBBB, left bundle branch block; NHS, National Health Service (UK); PN, phrenic nerve; r.m.s, root mean square; RSA, respiratory sinus arrhythmia; RTN, retro-trapezoid nucleus; RVLM, rostral ventro lateral medulla; sCPG, software central pattern generator; SN, sympathetic nerve; τ AV , atrioventricular delay; τ VV , interventricular delay; VN, vagus nerve; VRG, ventral respiratory group.Alain Nogaret is a physicist with interest in building and studying artificial neurons and networks that make constructive use of the principles of nonlinear science to develop novel therapies for chronic diseases. He has demonstrated enhanced transmission of electric pulses by stochastic resonance in semiconductor neurons that have dendrites, soma and axon compartments. He has also demonstrated the coexistenc...

show abstract

“…The device consists of physiologically realistic (Hodgkin-Huxley-type) semiconductor neurons that are reciprocally connected via inhibitory synapses to generate alternating, phasic motor patterns (Nogaret et al 2012) with an analog circuit capable of integrating physiological inputs in real time to provide outputs to end-organs. Paton talked about the development of a silicon brain (or central pattern generator) to control or pace the heart on a breath-by-breath basis.…”

Section: Introduction Introductionmentioning

confidence: 99%

“…Paton talked about the development of a silicon brain (or central pattern generator) to control or pace the heart on a breath-by-breath basis. The device consists of physiologically realistic (Hodgkin-Huxley-type) semiconductor neurons that are reciprocally connected via inhibitory synapses to generate alternating, phasic motor patterns (Nogaret et al 2012) with an analog circuit capable of integrating physiological inputs in real time to provide outputs to end-organs. He described how this device couples heart rate to respiration in order to augment respiratory sinus arrhythmia (Nogaret et al 2015), a phenomenon for which the functional significance is controversial, but it may serve to save cardiac energy and optimize pumping efficiency (Ben-Tal et al 2012, 2014.…”

Section: Introduction Introductionmentioning

confidence: 99%