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Researchers at Monash University have isolated the electrical activity of single neurons from recordings of human vagus nerves and identified a subset that have cardiovascular function.
The vagus nerves contain the axons of neurons that monitor or modify the function of the cardiovascular system. This includes both vagal sensory neurons and vagal motor neurons. Alterations in the activity of both are implicated in cardiovascular disease.
Vagal sensory neurons detect changes in blood pressure and blood volume. In patients with cardiovascular disease, reflexes evoked by activation of these receptors (such as the baroreflex) are “blunted”, with greater increases in blood pressure required to evoke them.
It is not known whether this occurs due to changes in the excitability of sensory neurons, or to changes in the way these inputs are processed by the brain. This has never been directly tested in humans.
With regards to vagal motor neurons, an important subset of these neurons acts to slow the heart. In health, their activity waxes and wanes with respiration, giving rise to the “respiratory sinus arrhythmia”, which is a corresponding waxing and waning of heart rate that occurs with breathing. This coordination between heart rate and breathing appears to be extremely important for cardiac health.
In patients with cardiovascular disease, the magnitude of the respiratory sinus arrhythmia is reduced, presumably because the corresponding magnitude of fluctuations in the activity of heart rate-slowing vagal neurons is also reduced. As with sensory neurons, this has never been directly measured in humans.
Our laboratory has been making direct recordings of the electrical activity of the human vagus nerve. This raises a question: what can we learn about the neural control of the cardiovascular system from these recordings?
Direct measurement of human vagal nerve activity by microneurography
Over the past 5 years, our laboratory has been carrying out direct recordings of the electrical activity of the human vagus nerve. This is done by directly inserting a tungsten microelectrode (200 µm in diameter) into the neck and guiding the tip into the vagus nerve. Ultrasound imaging is used to visualise the electrode’s trajectory towards the vagus nerve, and to aid us in avoiding the major blood vessels (the carotid artery and internal jugular vein) that are adjacent to the nerve.
To date, we have examined the gross electrical activity of the cervical vagus nerve, which is the summed activity of many neuronal signals. This includes both those going to, and those coming from, the heart, lungs, airways and the gut. Recently, we set out to do two things: first, extract the activity of single neurons within the nerve by tapping into their axons; second, identify those with a cardiovascular function.
First, we used a process called “spike sorting” to analyse the electrical activity of the vagus nerve and identify the firing of single neurons by their characteristic shape (spikes). Once identified, we examined the firing pattern of each neuron to see if it fired with a cardiac rhythm, as this is a signature of cardiovascular function.
Once a neuron had been identified as possessing cardiac rhythmicity, we further examined the relationships between its firing, the heart rate, and the respiratory cycle to categorise it as a particular type of neuron with cardiovascular function.
For example, cardiac vagal motor neurons were categorised as those that were cardiac rhythmic and that were most active when the participant was breathing out.
Other neurons were classified using the temporal relationship between their peak firing frequency and the R wave of the electrocardiogram, and this approach yielded a cohort of mostly cardiopulmonary sensory neurons of various subtypes (eg, atrial receptors, ventricular receptors).
Significance
The recording, isolation and classification of vagal cardiovascular neurons in humans represents a first. We believe that it is an important one as this approach enables the direct study of these neurons in the human, which is a significant advance in our understanding of the operation of this cranial nerve.
We have done this in a healthy cohort of participants, but these recordings can now be extended to those with cardiovascular disease.
This will enable us to determine if sensory neurons (baroreceptors and cardiopulmonary receptors) show altered activity in cardiovascular disease. Similarly, the neurons that give rise to respiratory sinus arrhythmia, which is depressed in cardiovascular disease, may be directly studied.
We have learned a great deal about the vagus nerve and the neural control of the cardiovascular system from approximately 150 years of experimentation in animals, and crucial work in this space continues to provide unique mechanistic insights.
However, the human cardiovascular system differs in important ways from that of the most commonly used experimental animals, not least in that humans are upright. As a result, our cardiovascular systems need to deal with the hydrostatic pressure difference between the head and the feet, while those of experimental animals such as rats and mice do not. It would be surprising if there were not some important differences in the neural organisation of the reflexes that regulate blood pressure between bipedal and quadrupedal animals, particularly with respect to the importance of blood volume receptors in detecting changes in volume with changes in posture. Through these recordings, we have already started to tease out these differences.
The future
With regards to the technique, we believe that there is room for improvement. We have shown, in principle, that neurons of the vagus nerve that are involved in cardiovascular control can be identified; however, this process could be improved.
The combination of vagus nerve recordings with procedures that selectively modulate the activity of particular vagal sensory neurons (such as the application of lower body negative pressure or passive head-up tilt while lying down) would enable a more rigorous means of identifying these neurons.
This approach would also provide an exciting means of studying the electrophysiology of identified neurons, that is, the relationship between their firing rate and the magnitude of the cardiovascular reflexes that result from their firing could be quantified.
Finally, through the application of statistical analysis or signal processing, it may be possible to more systematically examine the relationship between a given neuron’s firing and the cardiac cycle, and so more rigorously classify it as a sensory or motor neuron, further refining this important technique.
David GS Farmer is a research fellow in the Department of Neuroscience within the School of Translational Medicine at Monash University.
Vaughan G Macefield is a Professor of Neuroscience at the same.
The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.
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