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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CResPace (Adaptive Bio-electronics for Chronic Cardiorespiratory Disease)

Teaser

Summary

Worldwide increase in life expectancy is accelerating the shift from prescription drugs to implantable medical devices for the treatment of medical conditions and age related diseases.Biomedical implants, without the long-term side effects of many drugs, have become essential to administer therapies for chronic diseases like Parkinson, cardiac arrhythmias, tremors and chronic pain.Moreover, many diseases i.e congestive heart failure, spinal cord lesions, dystonia, epilepsy, chronic migraine have no or adequate therapy at present.Addressing these challenges is becoming urgent to ease the burden on patients,medical practitioners and National Health resources.

The CResPace consortium answers this challenge by bringing together multidisciplinary academic and industrial research teams from across Europe to develop fit-and-forget medical devices.These devices will be able to adapt to the physiological signals that regulate bodily functions and in this way restore functions that are lost through disease(s).We devise sophisticated mathematical tools and computational techniques that enable bioelectronic implants to read nervous activity in real time and help diseased organs save energy and restore normal function.This vision is embodied in a novel prototype of cardiac resynchronization pacemaker that provides beat-to-beat adaptation of heart rate and heart chamber timings to arterial gas pressure, hemodynamics and respiration.

The main objectives of the project are to develop:
a. large scale data assimilation tools to build quantitative models of medullary neurons and small networks
b. an integrated circuit of the respiratory central pattern generator
c. a central pattern generator designed to reproduce beat-to-beat cardiac resynchronization and an evaluation of its safety envelope
d. an intelligent cardiac resynchronization pacemaker that respond to physiological feedback and its clinical benefits

Work performed

The work done in the first period has focussed on the following:
(i) the construction of optimal models of adaptive bioelectronics,
(ii) the demonstration of a novel therapy for congestive heart failure in rodent animal models,
(iii) the construction of neuronal hardware inspired from medullary central pattern generators accompanied by the extensive probing of their dynamics and safety envelope,
(iv) the design and construction of implant telemetry and sensor platform for the acquisition of physiological data and their integration in the adaptive pacemaker demonstrator.

We have created a database of membrane voltage recordings of medullary neurons under stimulation by complex current protocols.The patch clamp recordings obtained so far have allowed extracting the parameters of analogue neuron models from the assimilation of their membrane voltage oscillations.This has been made possible by developing nonlinear optimization techniques to construct models of neurons and networks.We have incorporated novel mathematical ideas in existing computational framework to increase the speed and accuracy of parameter search, but above all improve convergence towards the global minimum of an objective function.In this way, we have transferred information from the membrane voltage oscillations of respiratory neurons to the Mahowald-Douglas(MD) and the Rasche-Douglas(RD) models that allow the large scale integration of neurons on a silicon chip. The MD model was found to be better than the RD model as it demonstrated superior capability in predicting the oscillations of biological neurons. We have also successfully extended the assimilation method from single neurons to the time series voltages of a ring of three inhibitory neurons. Ultimately we have built an adaptive model of the respiratory central pattern generator. Future work will focus on building models of networks of spiking neurons and transferring this information to hardware.

We have successfully obtained a small central pattern generator made of discrete electronic components on printed circuit board which we used to restore coupling between heart rate and respiration in rodent models of heart failure. A study was conducted on three rat populations comprising sham rats, tonically paced rats and, heart rate modulated rats. This study demonstrated an increase in cardiac output induced by heart rate modulation whilst the tonically paced or sham rats demonstrated no change. This study is extended to longer pacing periods and larger statistical samples but already demonstrate the effects of heart rate variability in congestive heart failure.

The design and construction of neuronal hardware for producing respiratory and cardiac resynchronization rhythms was initiated. Both printed Very Large Scale Integrated neuronal networks and printed circuit board versions have been obtained.The silicon chips are in the process of being conditioned to resynchronize heart chambers. A six-neuron printed board implementation has been extensively investigated over a range of experimental conditions. This demonstrated features of competition dynamics which had so far only been predicted theoretically such as the formation of multiple attractors, and chaotic dynamics. Additionally the hardware gave us a flexibility to tune synaptic kinetics, conductance and neuronal parameters in ways that had not been attempted before. The phase maps and mechanisms underpinning the emergence of synchronization so important to the generation of biological rhythms has been uncovered and have been published in 2 high profile journals. Electrocardiograms of large animal models have been obtained by medical teams. We are assimilating these data to prepare the hardware to resynchronize heart chambers.

Finally, the motherboard built around the pacemaker chip has been designed and manufactured. This is a printed circuit board which incorporates telemetry, sensor electronics, electrode drive, a microcontroller and power

Final results

a. The improvements in cardiac function observed under under heart rate modulation in rats are encouraging results for heart failure patients.The project is already having a socio-economic impact as additional studies in large animal models are being conducted by a private company
b. The technology for miniaturizing arterial gas sensors has matured to the point where these sensors may be translated to a wider range of bioelectronic devices which will increase the quality of life of patients
c. The methods and knowhow we have developed building adaptive bioelectronics in the context of cardiac resynchronization therapy form a body of knowledge that may now be transposed to other fields, for example training neural networks to provide therapies to some of the other diseases mentioned above.
d. The principle of generation of biological rhythms has been demonstrated experimentally for the first time. Fundamental results have been obtained from the mapping of phase portraits of networks, notably phase transitions between different regimes of oscillations induced by the timing of current stimuli. Key results have already been published in high profile journals.