Serra
Journal of the Peripheral Nervous System 19(Supplement):S15–S27 (2014)
The role of neurophysiology J Serra Neuroscience Technologies, Ltd., Barcelona, Spain
Assessing the severity of a patient’s pain can be challenging. There are tools that can assist the practitioner in quantifying the level of pain being reported. It is important to first understand the origin (the generator) and the etiologies for neuropathic pain. The origin of
pain may be in the peripheral nervous system (PNS), or in the central nervous system (CNS), or both, and many different etiologies in different parts of the nervous system can cause neuropathic pain. When looking at the PNS, there are a variety of factors that could S22
Serra
Journal of the Peripheral Nervous System 19(Supplement):S15–S27 (2014)
be affecting or making this system dysfunctional in different ways. For example, the generator of pain in a patient with a polyneuropathy is slightly different from the pain or the generator of pain in a patient that may have a radiculopathy. Understanding these differences will guide how we assess the patients and how we treat them. It is important to remember that, in a way, all the symptoms that the patient with neuropathic pain has fall into the category of “negative” or “positive” sensory phenomena. The pathophysiology of negative sensory phenomena is simple: action potentials “do not arrive where they should”, either because there is conduction block, because the neuron has disappeared due to the underlying process, or because there is central modulation with “gating” of the incoming afferent barrage. However, the pathophysiology of positive sensory phenomena is more complex. We know that the information content in the CNS and in the PNS is transmitted through the conduction of action potentials, so if we feel something it is because there are action potentials generated somewhere that arrive into the CNS. Once we acknowledge this, then there are some important questions to be answered. Where are these action potentials being generated? This can be easily answered. The next question is: How are these abnormal action potentials generated? If the action potentials are abnormally generated and we understand why they are generated in this way, then we may be able to design good therapies. The strategies to assess the function of large myelinated fibers are different from those used to probe unmyelinated fibers. The large myelinated fibers are easy to study electrophysiologically because they produce large compound nerve action potentials. These are so large they can be picked up from the surface of the skin via conventional nerve conduction studies. The unmyelinated component and the thinly myelinated component in the PNS are very difficult to study from an electrophysiological point of view because they escape detection with conventional nerve conduction studies. Fortunately, there are a variety of other techniques in addition to nerve conduction studies that have been developed to assess small myelinated and unmyelinated fiber function. Quantitative sensory testing is a commonly used one at the bedside. These sensory examinations can measure mechanical or thermal sensations (e.g., cold detection threshold, warm detection threshold, heat pain, cold pain, etc.). Other electrophysiological techniques such as laser evoked potentials (LEP) and contact heat evoked potentials (CHEPS) may be an option, though sometimes these methods are challenging because patients with certain pathologies sometimes evoke responses
that are difficult to assess. The problem, again, is that you cannot assess positive phenomena. Most of the available tests are actually assessing only the deficit, the negative sensory phenomena. Microneurography is a simple technique that can be used to quantify spontaneous activity in nociceptor fibers and measure both positive and negative phenomena. A microelectrode is placed inside the nerve; the cutaneous receptive field of the nerve is stimulated with another set of electrodes. The recorded signal is not a compound nerve action potential, but a series of action potentials from individual peripheral axons. There are different techniques to visualize these evoked action potentials, but raster plots have proved to be extremely useful. Because we can easily measure the conduction distance between stimulating and recording electrodes, one can calculate the conduction velocity and discern between myelinated and unmyelinated fibers, due to their extremely different conduction velocities. Also, by changing the stimulation rate one can follow the changes in latency that appear because of the phenomenon of activity-dependent slowing of conduction velocity, a property of unmyelinated fibers. If you stimulate the C-fibers, at very low frequencies, conduction velocity settles at a fixed stable latency. By changing the frequency of the stimulating electrode from, for instance, a baseline of 0.25 Hz (one impulse every 4 s), to something like 2 Hz, C-fibers cannot cope and there is a slowing of conduction velocity. By repeating these stimulations with different fibers, different profiles of activity-dependent slowing can be seen. These different profiles correspond to a specific subpopulation of dorsal root ganglion neurons (DRG) and sympathetic neurons (Serra et al., 1999). Identifying different subpopulations of the DRG neurons is important and a very useful method to study unmyelinated fibers in humans and animals. Not only can microneurography identify nociceptors from the rest of the sensory afferents, it can also distinguish between the two big classes of nociceptors that are present in the periphery: the mechano-sensitive and the mechano-insensitive C-nociceptor. The mechano-insensitive nociceptor is probably the nerve growth factor (NGF)-dependent nociceptor which is increasingly being associated with the experience of neuropathic burning or deep-aching pain that we see in our patients. Microneurography has changed a lot over the years. The technique itself is the same as it was in the early 1970s, however, improved software permits us to better analyze the responses. The analysis is quite reliable now. It is fast, standardized, and produces results that can be compared across different trials and across different experiments. Researchers can extract units of interest and analyze different properties such S23
Wallace
Journal of the Peripheral Nervous System 19(Supplement):S15–S27 (2014)
fibromyalgia patients abnormal peripheral C-nociceptor ongoing activity and increased mechanical sensitivity could contribute to the pain (Serra et al., 2014). Spontaneous activity in peripheral nociceptors is a key phenomenon in patients with spontaneous pain. To be clear, pain is not the action potential; but there is a correlation between the presence of action potentials and the occurrence of pain. If we are able to devise machines or devices that can record these correlations in a very systematic way, then we will have a very powerful tool to aid us in research and patient care.
as the conduction velocity, excitability, or presence of pathological behaviors. Comparison of healthy human controls to patients with different pathologies shows pathological findings. One pathological finding in C-nociceptors which is relevant to pain is the occurrence of spontaneous ongoing discharges. Microneurographic raster plots nociceptors which are not discharging spontaneously show latencies that are “flat”. In contrast, spontaneously discharging C-nociceptors produce baselines that are jittering and jumping up and down, in a characteristic “saw-tooth” profile. There are an increasing number of microneurographic studies showing abnormalities in the neuropathic pain patient, from extreme cold sensitivity in patients with cold allodynia, to abnormal discharges in painful small fiber neuropathies (Serra et al., 2009). More strikingly, a study has compared fibromyalgia and small fiber neuropathy patients and shown that in fibromyalgia, the mechano-sensitive nociceptors behave normally, but in 76.6% of the patients the silent, mechano-insensitive ones exhibit abnormalities. Specifically, many silent nociceptors exhibited hyperexcitability resembling that seen in small-fiber neuropathy. These data suggest that in the majority of
References Serra J, Campero M, Ochoa J, Bostock H (1999). Activity-dependent slowing of conduction differentiates functional subtypes of C fibres innervating human skin. J Physiol 515:799–811. Serra J, Solà R, Quiles C, Casanova-Molla J, Pascual V, Bostock H, Valls-Sole J (2009). C-nociceptors sensitized to cold in a patient with small-fiber neuropathy and cold allodynia. Pain 147:46–53. Serra J, Collado A, Solà R, Antonelli F, Torres X, Salgueiro M, Quiles C, Bostock H (2014). Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 75:196–208.
S24
Journal of the Peripheral Nervous System 19(Supplement):S15–S27 (2014)
The role of neurophysiology J Serra Neuroscience Technologies, Ltd., Barcelona, Spain
Assessing the severity of a patient’s pain can be challenging. There are tools that can assist the practitioner in quantifying the level of pain being reported. It is important to first understand the origin (the generator) and the etiologies for neuropathic pain. The origin of
pain may be in the peripheral nervous system (PNS), or in the central nervous system (CNS), or both, and many different etiologies in different parts of the nervous system can cause neuropathic pain. When looking at the PNS, there are a variety of factors that could S22
Serra
Journal of the Peripheral Nervous System 19(Supplement):S15–S27 (2014)
be affecting or making this system dysfunctional in different ways. For example, the generator of pain in a patient with a polyneuropathy is slightly different from the pain or the generator of pain in a patient that may have a radiculopathy. Understanding these differences will guide how we assess the patients and how we treat them. It is important to remember that, in a way, all the symptoms that the patient with neuropathic pain has fall into the category of “negative” or “positive” sensory phenomena. The pathophysiology of negative sensory phenomena is simple: action potentials “do not arrive where they should”, either because there is conduction block, because the neuron has disappeared due to the underlying process, or because there is central modulation with “gating” of the incoming afferent barrage. However, the pathophysiology of positive sensory phenomena is more complex. We know that the information content in the CNS and in the PNS is transmitted through the conduction of action potentials, so if we feel something it is because there are action potentials generated somewhere that arrive into the CNS. Once we acknowledge this, then there are some important questions to be answered. Where are these action potentials being generated? This can be easily answered. The next question is: How are these abnormal action potentials generated? If the action potentials are abnormally generated and we understand why they are generated in this way, then we may be able to design good therapies. The strategies to assess the function of large myelinated fibers are different from those used to probe unmyelinated fibers. The large myelinated fibers are easy to study electrophysiologically because they produce large compound nerve action potentials. These are so large they can be picked up from the surface of the skin via conventional nerve conduction studies. The unmyelinated component and the thinly myelinated component in the PNS are very difficult to study from an electrophysiological point of view because they escape detection with conventional nerve conduction studies. Fortunately, there are a variety of other techniques in addition to nerve conduction studies that have been developed to assess small myelinated and unmyelinated fiber function. Quantitative sensory testing is a commonly used one at the bedside. These sensory examinations can measure mechanical or thermal sensations (e.g., cold detection threshold, warm detection threshold, heat pain, cold pain, etc.). Other electrophysiological techniques such as laser evoked potentials (LEP) and contact heat evoked potentials (CHEPS) may be an option, though sometimes these methods are challenging because patients with certain pathologies sometimes evoke responses
that are difficult to assess. The problem, again, is that you cannot assess positive phenomena. Most of the available tests are actually assessing only the deficit, the negative sensory phenomena. Microneurography is a simple technique that can be used to quantify spontaneous activity in nociceptor fibers and measure both positive and negative phenomena. A microelectrode is placed inside the nerve; the cutaneous receptive field of the nerve is stimulated with another set of electrodes. The recorded signal is not a compound nerve action potential, but a series of action potentials from individual peripheral axons. There are different techniques to visualize these evoked action potentials, but raster plots have proved to be extremely useful. Because we can easily measure the conduction distance between stimulating and recording electrodes, one can calculate the conduction velocity and discern between myelinated and unmyelinated fibers, due to their extremely different conduction velocities. Also, by changing the stimulation rate one can follow the changes in latency that appear because of the phenomenon of activity-dependent slowing of conduction velocity, a property of unmyelinated fibers. If you stimulate the C-fibers, at very low frequencies, conduction velocity settles at a fixed stable latency. By changing the frequency of the stimulating electrode from, for instance, a baseline of 0.25 Hz (one impulse every 4 s), to something like 2 Hz, C-fibers cannot cope and there is a slowing of conduction velocity. By repeating these stimulations with different fibers, different profiles of activity-dependent slowing can be seen. These different profiles correspond to a specific subpopulation of dorsal root ganglion neurons (DRG) and sympathetic neurons (Serra et al., 1999). Identifying different subpopulations of the DRG neurons is important and a very useful method to study unmyelinated fibers in humans and animals. Not only can microneurography identify nociceptors from the rest of the sensory afferents, it can also distinguish between the two big classes of nociceptors that are present in the periphery: the mechano-sensitive and the mechano-insensitive C-nociceptor. The mechano-insensitive nociceptor is probably the nerve growth factor (NGF)-dependent nociceptor which is increasingly being associated with the experience of neuropathic burning or deep-aching pain that we see in our patients. Microneurography has changed a lot over the years. The technique itself is the same as it was in the early 1970s, however, improved software permits us to better analyze the responses. The analysis is quite reliable now. It is fast, standardized, and produces results that can be compared across different trials and across different experiments. Researchers can extract units of interest and analyze different properties such S23
Wallace
Journal of the Peripheral Nervous System 19(Supplement):S15–S27 (2014)
fibromyalgia patients abnormal peripheral C-nociceptor ongoing activity and increased mechanical sensitivity could contribute to the pain (Serra et al., 2014). Spontaneous activity in peripheral nociceptors is a key phenomenon in patients with spontaneous pain. To be clear, pain is not the action potential; but there is a correlation between the presence of action potentials and the occurrence of pain. If we are able to devise machines or devices that can record these correlations in a very systematic way, then we will have a very powerful tool to aid us in research and patient care.
as the conduction velocity, excitability, or presence of pathological behaviors. Comparison of healthy human controls to patients with different pathologies shows pathological findings. One pathological finding in C-nociceptors which is relevant to pain is the occurrence of spontaneous ongoing discharges. Microneurographic raster plots nociceptors which are not discharging spontaneously show latencies that are “flat”. In contrast, spontaneously discharging C-nociceptors produce baselines that are jittering and jumping up and down, in a characteristic “saw-tooth” profile. There are an increasing number of microneurographic studies showing abnormalities in the neuropathic pain patient, from extreme cold sensitivity in patients with cold allodynia, to abnormal discharges in painful small fiber neuropathies (Serra et al., 2009). More strikingly, a study has compared fibromyalgia and small fiber neuropathy patients and shown that in fibromyalgia, the mechano-sensitive nociceptors behave normally, but in 76.6% of the patients the silent, mechano-insensitive ones exhibit abnormalities. Specifically, many silent nociceptors exhibited hyperexcitability resembling that seen in small-fiber neuropathy. These data suggest that in the majority of
References Serra J, Campero M, Ochoa J, Bostock H (1999). Activity-dependent slowing of conduction differentiates functional subtypes of C fibres innervating human skin. J Physiol 515:799–811. Serra J, Solà R, Quiles C, Casanova-Molla J, Pascual V, Bostock H, Valls-Sole J (2009). C-nociceptors sensitized to cold in a patient with small-fiber neuropathy and cold allodynia. Pain 147:46–53. Serra J, Collado A, Solà R, Antonelli F, Torres X, Salgueiro M, Quiles C, Bostock H (2014). Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 75:196–208.
S24
