José L. Ochoa

Sensations evoked by intraneural microstimulation of C nociceptor fibres in human skin nerves.

1. Seventy‐one C polymodal nociceptors supplying glabrous and hairy skin in limbs of awake human volunteers were identified on the basis of cutaneous stimulus‐response characteristics recorded intraneurally by microneurography (MNG). The large majority of such units were primarily detected during intraneural microstimulation (INMS) on the basis of subjective quality and cutaneous localization of evoked painful sensation. Electrophysiological studies were supplemented with rigorous psychophysical testing during microstimulation delivered at intraneural C recording sites. 2. The conduction velocity of single C nociceptor units could be shown to become transiently slowed following repetitive INMS at threshold intensity for conscious sensation. Such ‘marking’ witnessed that particular C units, identified by recording, had been effectively activated during INMS and psychophysical testing. 3. Cognitive attributes of sensations evoked from C recording sites by INMS at threshold intensity for perception were estimated psychophysically for subjective quality, temporal attributes and localized projection. There was remarkable matching of physiological unit type (C polymodal nociceptor) with subjective quality of evoked sensation (dull or burning pain). Further, there was remarkable spatial matching of receptive field of given C nociceptors with projected field of the pain sensation evoked from the C recording site by INMS delivered at threshold intensity for conscious sensation. 4. Dissociated A nerve fibre blocks caused by compression‐ischaemia did not abolish the sensation of burning pain projected to hairy skin, evoked by INMS delivered at C recording sites. 5. While the double matching of (a) subjective quality and spatial localization with (b) objective physiological unitary type and receptor location, coupled with the results of A blocks, provide evidence that C nociceptor fibres can be fairly selectively activated during INMS, the results also attest that C polymodal nociceptors from human skin evoke delayed dull or burning pain, accurately projected to a defined locus in skin, even after spatial summation is reduced to a minimum.

C-polymodal nociceptors activated by noxious low temperature in human skin.

1. Fifty‐five C‐polymodal nociceptors innervating hairy skin in human volunteers were tested for discrete stimulus‐response properties through microneurography. 2. All fifty‐five units were responsive to mechanical and heat stimuli. Twenty‐two (40%) of these exhibited an additional response to noxious low temperature. The twenty‐two mechano‐heat‐cold nociceptors displayed similar receptor responses to heat and mechanical stimuli, and conduction velocity, as those of the pure mechano‐heat C‐polymodal nociceptors. 3. Low temperature stimuli between 19 and 0 degree C evoked responses at low discharge frequency (0.4 +/‐ 0.22 impulses s‐1, mean +/‐ S.E.M.) in the twenty‐two units sensitive to such energy. These units displayed a tendency to decrease their discharge after a few seconds of steady stimulation. 4. Three units tested with a freezing stimulus responded with relatively vigorous discharge, which never exceeded the maximal discharge frequency elicited by either mechanical or heat stimuli. One of these units became sensitized to heat after the freezing challenge. 5. It is concluded that a subpopulation of C‐polymodal nociceptors is sensitive to noxious low temperature and may thus contribute to the determination of cold pain. The same type of primary afferent is probably one mediator of the symptom cold hyperalgesia in peripheral nerve disease.

Single C nociceptor responses and psychophysical parameters of evoked pain: effect of rate of rise of heat stimuli in humans.

1. Effects of rate of rise of temperature stimuli applied to skin on (i) unitary receptor threshold and frequency response often single C nociceptors, and (ii) on magnitude and reaction times of evoked pain were studied in fifteen healthy human volunteers. 2. Temperature ramps of 32 to 45 or 47 degrees C were applied at three consistent rates of rise to receptive fields of C nociceptors in dorsum of foot (n = 9) or hand (n = 1). For rates of rise of 0.3, 2.0 and 6.0 degrees C/s, mean receptor threshold for heat was remarkably uniform: 41.5 +/‐ 0.57, 41.5 +/‐ 0.61 and 41.9 +/‐ 0.71 degrees C respectively. 3. The mean discharge rate of the ten cutaneous C nociceptors increased with rate of rise of temperature stimuli: 1.22 +/‐ 0.13, 4.57 +/‐ 0.49 and 13.45 +/‐ 0.71 impulses/s, respectively, for stimulus temperature rates of 0.3, 2.0 and 6.0 degrees C/s. 4. Magnitude estimates of pain for thirteen subjects also increased with rate of rise of temperature stimuli. Mean normalized magnitude estimates of heat pain were: 11.8 +/‐ 1.55, 15.1 +/‐ 0.84 and 28.0 +/‐ 1.87 for stimulus rates of rise of 0.3, 2.0 and 6.0 degrees C/s, respectively. 5. Results of simultaneous recordings of reaction time for pain and of C nociceptor responses to heat ramps given at 2.0 degrees C/s, in three subjects, indicate that under those circumstances heat pain messages are exclusively mediated by C nociceptors.

Intraneural microstimulation in humans

Intraneural microstimulation (INMS) was developed independently by Torebjork and Ochoa [20] and by Vallbo [23]. As pioneers, we often wonder whether the awesome yield of the method, as applied to discern subjective attributes of pure evoked sensations in human subjects, has been a mirage. Cultural nihilism resists the proposition that certain single sensory units from skin of the human hand may normally be able to evoke a conscious sensation endowed with specific and consistent subjective quality, measurable magnitude, and chartable location. But, of course, depending on the physical circumstances prevailing in the neighborhood of a given intraneural site, an electrode tip can regularly record anywhere from between zero and multiple nerve fibers, and usually a few. And why not even record one single fiber in focus? The usual situation in which zero to multiple fibers are recordable from the same intra-neural microelectrode site, certainly does not negate that it may be possible also to microstimulate zero, a few, or the whole fiber content of a fascicle at stimulus intensity is gradually increased. And why not even stimulate one single fiber? Indeed, it is more plausible to accept viability of single fiber stimulation than mandatory multi-fiber stimulation at stimulus intensity at threshold for the first detectable sensation. Therefore, after the test of time, we do believe it is possible to excite single sensory nerve fibers through intra-neural microstimulation in humans [10,15,17,18]. Nobody does intraneural microstimulation (INMS) these days. It is extremely demanding.

Genesis of the structural pathology of myelinated fibers in median nerve entrapment

Drs. Gupta et al. have developed a chronic nerve compression (CNC) model by placing silastic tubing around the mouse sciatic nerve. The authors report altered Schwann cell/myelin architecture, illustrated with attractive light micrographs of myelinated fibers, in which they emphasize classic Cajal bands, whose hypothetical pathogenic role is discussed at length by the authors. One thesis the authors propose is that their CNC amounts to a mouse model of chronic nerve entrapment, explicitly carpal tunnel syndrome. This is where the castle of cards collapses. The pathogenesis of focal neuropathy at common sites of entrapment features not just compression, but repetitive to and fro sliding of nerve trunks at those sites. This dynamic is implicated in the cumulative genesis of the characteristic incremental distortion of nodes of Ranvier and paranodes, which are polarized in opposite directions on either side of the compressed area. This could not possibly happen under the silastic tube ‘‘mouse model of carpal tunnel syndrome.’’ That is why the spectacular pathology of myelinated fibers in chronic entrapment, one that tell-tales its mechanical origin, is not identified in the authors’ richly illustrated publication. Be that as it may, the reader anticipated that, among their 36 references, the authors would have cited and discussed classic articles on the matter. (Fig. 1 from References 2 and 3, respectively.)

Mechanisms of neuropathic pain: Nerve, brain, and psyche: Perhaps the dorsal horn but not the sympathetic system

Neuropathic pain was a theme given priority during the World Congress of Neurology recently held in London. Why so much interest in neuropathic pain? Because so many patients are suffering from it, and so many doctors are investigating and treating it. Why so many patients? Because most do not respond to therapies that researchers tell physicians to apply, and the more patients fail to respond, the more doctors puzzle about neuropathic pain. Why dont patients respond? Because, while some patients illnesses are truly incurable, most receive the wrong therapy. Why the wrong therapy? It is because the assumptions about their pathophysiology are often flawed.

Contemporary Techniques in Assessing Peripheral Nervous System Function

ABSTRACT.This article briefly reviews essential aspects of the anatomical and physiological substrates of peripheral nerves and describes diagnostic techniques to evaluate the functional status of various types of nerve fibers. Emphasis is placed on methods for quantifying small caliber sensory fiber function. Nonconventional application of evoked potential technology as well as microneurography research is briefly described.