Our next talk will be presented by Hussain Shaquille, and he'll be talking to us this afternoon about compensation for neuropathic hyperexcitability in peripheral nerves and how this ultimately fails. Thank you. Hi. My name is Hussain, and today I'll be discussing, as mentioned, about compensation within peripheral nerves and the fact that it must ultimately fail if we have this phenomenon of neuropathic hyperexcitability. Can I just click to ... Click that. So I'll begin by describing the hyperexcitability that we know occurs within peripheral nerves, and then go on to describe how the compensation that we also know occurs within these nerves, how it might ultimately fail and result in pathological hyperexcitability. And then finally, I'll finish off with some ... I should actually say number three, but I'll finish off by describing some future directions and bigger picture ideas that I've been thinking of based on this work. So first off, neuropathic pain, as we know, is a very debilitating condition that's associated with dysfunction of the nervous system. And really, it's associated with the nervous system reacting to something which it shouldn't be. So it's kind of like these pain processing neurons are over-responsive to this innocuous stimulation or no stimulation at all. It affects a sizable portion of the population, and as mentioned previously, is notoriously difficult to treat. Neuropathic pain is associated with hyperexcitability that occurs at many points along the near axis. However, I will be focusing specifically on peripheral nerves, and more specifically, on the primary afferent neurons that make up these peripheral nerves. Now, we know that literature within neuropathic research shows that these peripheral neurons display hyperexcitability patterns, which is seen as repetitive firing patterns. And under normal conditions, when you have a specific stimulation, these peripheral neurons are only supposed to have this onset-only spiking pattern. But with nerve injury animal models, we find this repetitive spiking pattern. And research has shown that this can occur through distinct molecular changes. Some people have found that changes in potassium ion channels are able to switch these peripheral neurons from onset-only to repetitive spiking. Other research shows that sodium channels, things like NAV1.7 channels, can be upregulated and cause this switch to neuropathic excitability. And further, other research shows that it's probably a combination of these two channels, which is resulting in the switch. So this really shows that you can have distinct ion channel changes, which can bring you to the same set point of neuropathic excitability. And this imparts this idea of degeneracy between the ion channels. So changes in both potassium or sodium, or a combination of the two, are really degenerate in that they're both resulting in the same endpoint of neuropathic hyperexcitability. So whenever you have degeneracy between different ion channels, you can talk about this property of compensation. So if we consider this sort of parameter space of ion channels, where you can consider this to be potassium ion channel expression and sodium ion channel expression, if you measure different levels of excitability, you can compensate for changes within one channel by changes in another. So for instance, if you had a peripheral neuron and you wanted to maintain a given level of excitability, the exact value is not important. But if you change the concentration of potassium channels within these cells, this can be offset by changes within the sodium channel, which really is what the compensation is referring to. And this has been seen in actual studies of these peripheral nerves, which show that you can have adjustments in the expression of both these channels when you do things like certain types of stimulation. Now throughout this talk, I'll be referring to these types of figures. So when I speak of parameter space, I'm just describing the sets of combinations of these ion channels and for each combination, the value of excitability for that. And these contour lines really represent the compensation that is occurring between these two ion channels. So if we have this system that's able to compensate for different types of changes, but we know that neuropathic hyperexcitability ultimately develops, then this compensation must somehow be failing. And my question is related to how might this be occurring? My hypothesis was that although these compensatory changes are able to offset certain measures of excitability, they ultimately fail to do so when you look at other aspects of excitability. So more specifically, within a primary afferent neuron, if you look at compensation between sodium and potassium channel conductances, they're able to maintain one measure such as RayoBase. But if you look at other measures such as ATP use per spike, the actual firing rate at that RayoBase and the stability of the neuron, these might actually change. So the methods that I used are computational. So these were simulations involving a Morisot-Carr model of a primary afferent neuron. And the way I simulated these two ion channels was using these Hodgkin-Huxley style ion channels that had been previously published. So these are the results that I had. So along this axis, we have what can be considered as potassium ion channel expression. And this would be sodium ion channel expression. And for these different combinations, you have different types of excitability. So as mentioned before, onset-only spiking represents normal physiological patterns of action potentials within these peripheral nerves. And this would represent your neuropathic type of activity. If you take a specific kind of contour line, as mentioned, then you know that this represents sort of compensatory behaviors. As you change potassium, as you change, sorry, sodium, you can offset this change by a change in potassium to maintain this specific level of RayoBase, which is what's being looked at over here. Now, if you take the same parameter space and plot for at each point the ATP use per spike, you see that these are quite different in their landscape. And if you take these same contour lines, which are a mathematical representation of compensation, and for each point, you plot out what is the ATP use per spike, you see that along this line, as this compensation is occurring between sodium and potassium, although RayoBase is being maintained, this ATP use per spike is actually changing. And then if you look at other measures, like the actual, so if you look at the contour line within normal excitability, you see that this change is also occurring. And then finally, if you look at another measure, which is the actual firing rate of these neurons, this is also changing as well. So the next thing I looked at is stability of the actual system. So stability can be considered as the distance from which a specific kind of set of parameters are from a transition between excitability. So as mentioned, there was a boundary between normal type of excitability and neuropathic repetitive firing excitability. If we look at the distance between this boundary between these two along this contour line, what do we see? And just as before, as you move along this contour line, although RayoBase is being maintained, you actually have a change in the distance of this boundary. So the stability of these neurons are actually changing. So in summary, compensation between sub-threshold sodium and potassium channels, although they're able to maintain a fixed level of RayoBase, these other measure of excitability, like action potential per spike, the distance to the boundary or the stability, and the actual firing rate of these neurons is changing. So what sorts of things did this make me think of moving forward? So if you have these other properties of the neurons changing, then we might have a condition where you reach a critical point, where once the ATP use per spike passes this critical point, you have this sort of decompensation in the system, and it changes from this physiological onset-only spiking to this hyper-excitable repetitive spiking pattern. And we know in nerve injury models that we actually see a behavior that's similar to this in that directly after nerve injury, often the lesioned animals don't display neuropathic behavior, but abruptly a few days after, they'll suddenly decline and decompensate and display this neuropathic phenotype. Further, I was having a question about whether things like neuromodulation are actually pushing the system past this critical point, so that you're moving yourself beyond this neuropathic state back towards regular physiological spiking patterns. So thank you, everyone, for giving me the opportunity to speak today. I'd like to thank my supervisor, Dr. Prescott, as well as the different members of my lab, and of course ANS and the organizers of this pain session for allowing me the opportunity to speak. Thank you very much.

compensation

neuropathic hyperexcitability

peripheral nerves

potassium ion channels

sodium ion channels