Ashok S. Chauhan

A paradox in neuroscience is the large number of oscillations of small neural networks compared with the few oscillations observed in the conscious brain. It remains unclear what is the maximum number of synchronized oscillations a network can support and whether all or some of these oscillations would survive in noisy heterogenous circuits. Here, we attempt to answer these questions through a comprehensive study of local inhibitory networks of Hodgkin-Huxley neurons. We use a neuromorphic platform combining electronic noise and device-specific heterogeneity with tuneable extrinsic noise, tuneable network connectivity, and controlled initial conditions. As in the brain, stimuli are instantaneously integrated by analog circuits. This gives us the computing power needed to map the network dynamics over the entire phase space and demonstrate the full complement of limit cycles, basins of attraction, and dependence on network parameters. Our main finding is that the maximum number of limit cycles is equal to the combinatorial number of activation pathways through the network, allowing for coincident action potentials, and that all limit cycles are equally robust to noise and mild heterogeneity but highly dependent on inhibition delay and the timing of stimuli. We established the robustness of individual limit cycles by computing the detailed balance of bifurcations between attractors. This accounts for all transitions in a system where Lyapunov exponents are both positive and negative depending on phase space coordinates and noise intensity. Another interesting finding is the unexpected resilience of limit cycles to mild network heterogeneity. This occurs as stochastic processes recruit quiescent neurons whose subthreshold periodic oscillations help maintain the synchronization of limit cycles against heterogeneity.

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. 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.

During cognitive tasks cortical microcircuits synchronize to bind stimuli into unified perception. The emergence of coherent rhythmic activity is thought to be inhibition-driven and stimulation-dependent. However, the exact mechanisms of synchronization remain unknown. Recent optogenetic experiments have identified two neuron sub-types as the likely inhibitory vectors of synchronization. Here, we show that local networks mimicking the soma-targeting properties observed in fast-spiking interneurons and the dendrite-projecting properties observed in somatostatin interneurons synchronize through different mechanisms which may provide adaptive advantages by combining flexibility and robustness. We probed the synchronization phase diagrams of small all-to-all inhibitory networks in-silico as a function of inhibition delay, neurotransmitter kinetics, timings and intensity of stimulation. Inhibition delay is found to induce coherent oscillations over a broader range of experimental conditions than high-frequency entrainment. Inhibition delay boosts network capacity (ln2)^−N-fold by stabilizing locally coherent oscillations. This work may inform novel therapeutic strategies for moderating pathological cortical oscillations.

We experimentally and theoretically demonstrate ultrafast pressure sensing with transient tunnelling currents in thin composite films.

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 analogue 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 (an indicator of cardiac health), we have explored the versatility and efficiency of the CPG for producing respiratory modulation of heart rate in anaesthetised, 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.

We report on a hCPG device, which is a network of silicon neurons, and its applications to cardiorespiratory therapy. We study the chaotic dynamics of neurons that compete through mutually inhibitory synapses and demonstrate the emergence of multistable behavior. We were able to select the spatio-temporal sequences associated with stable modes of oscillation by imparting different initial conditions with timed current steps mimicking delayed stimuli. We constructed the phase lag maps of the hCPG for various connectivities of the network. We also describe a simpler two neuron hCPG which generates a two-phase rhythmic pattern for vagus nerve stimulation and modulation of heart rate by respiration to obtain artificial respiratory sinus-arrhythmia (RSA).