Jens Ellrich

C- and Aδ-fiber components of heat-evoked cerebral potentials in healthy human subjects

Abstract Feedback-controlled laser heat was used to stimulate the hairy skin of the hand dorsum and forearm, and heat-evoked cerebral potentials were recorded at midline (Fz, Cz, Pz) and temporal (T3, T4) scalp positions. Based on data from primary afferent electrophysiology a stimulus level (40°C) was chosen, which is above C-fiber heat threshold, but clearly below Aδ-nociceptor heat threshold in order to excite selectively C-fibers without concomitant excitation of Aδ-fibers. Feedback-controlled stepped heat stimuli to 40°C elicited ultralate laser evoked potentials (LEPs) at the vertex in a high proportion of experiments (90%). Estimates of conduction velocity calculated from latency shifts between the hand and forearm sites of ultralate LEPs (2.4 m/s) and of reaction times (2.8 m/s) confirmed mediation of ultralate potentials by unmyelinated nerve fibers (nociceptors and/or warm fibers). The ultralate LEP could be differentiated from resolution of contingent negative variation (CNV), an endogenous potential related to expectation and response preparation, by its scalp topography. Strong heat stimuli of 48°C, which is suprathreshold for most Aδ- and C-fiber nociceptors, elicited the well-known late LEPs mediated by nociceptive Aδ-fibers confirming previous studies. The LEP waveform to strong heat stimuli also contained an ultralate component reminiscent of an ultralate LEP following the late LEP. Ultralate and late LEP had identical scalp topography. In conclusion, the method of temperature-controlled laser heat stimuli allows the selective and reliable examination of Aδ- and C-fiber-mediated afferent pathways and the related cortical processing without the complication of dissociating A-fiber nerve blocks.

Characterization of blink reflex interneurons by activation of diffuse noxious inhibitory controls in man.

The blink reflex consists of an early, pontine R1-component and a late, medullary R2-component. R1 and R2 can be evoked by innocuous stimuli, but only the R2 also by painful heat, suggesting that the R2 is mediated by wide dynamic range neurons (WDR) of the spinal trigeminal nucleus. Remote noxious stimuli suppress the activity in WDR neurons via activation of diffuse noxious inhibitory controls (DNIC), whereas low-threshold mechanoreceptive neurons (LTM) are unaffected. In order to characterize the trigeminal interneurons of R1 and R2 we investigated the modulation of the blink reflex by remote painful heat. The blink reflex was elicited in 11 healthy subjects by innocuous electrical pulses applied to the left supraorbital nerve. The remote, painful heat stimuli were applied by a Peltier type thermode to the left volar forearm. Remote painful heat of 44 to 46 degreesC significantly suppressed the R2 by 15% (p<0.01), while the R1 remained unchanged. These results provide further evidence that the R2 is mediated by medullary WDR neurons and the R1 by pontine LTM neurons.

Pain-evoked blink reflex.

The electrically evoked blink reflex (BR) consists of an ipsilateral R1 component (R1) at 11 ms and two bilateral components R2 at 33 ms and R3 at 83 ms. It is still unclear whether the R2 is mediated by activation of tactile or nociceptive afferents. For testing the nociceptive hypothesis, nociceptors of the supraorbital nerve were selectively activated by infrared laser stimuli in 10 subjects. Only painful laser stimuli evoked a bilateral early polyphasic BR response (LR2) at 71 ms. Stimulation of infraorbital and mental nerve dermatomes was equally effective. A late bilateral reflex response at 130 ms was occasionally observed. Regarding the nociceptor activation time of about 40 ms, onset latencies were within the range of the electrically evoked R2 and R3, respectively. The good accordance of R2 and LR2 may be due to activation of identical nociceptive fibers or to convergence of electrically evoked tactile and laser‐elicited nociceptive input onto common multireceptive neurons.

The R3 component of the blink reflex : normative data and application in spinal lesions

The clinical value of the R3 component (R3) of the blink reflex (BR) for differentiating between lesions at the medulla oblongata and cervical spinal cord level is still unclear. In 50 healthy volunteers (25 women, 25 men, aged 20-75 years) reproducible ipsi- and contralateral R3 responses could be evoked showing a mean onset latency of 84 ms, a duration of 32 ms and a side-to-side difference of almost 3 ms. The latency increased with age. Eleven patients with lesions of the cervical spinal cord (segments C1-C6) showed normal R3 latencies. In 4 patients with pathology of the brain-stem, however, R3 was abnormal, showing identical changes as observed with the R2 component. Our results suggest that the reflex arc of R3 does not descend to the cervical spinal cord but within the brain-stem possibly takes the same connections as the R2 component.

Nociceptive masseter inhibitory reflexes evoked by laser radiant heat and electrical stimuli

Electrical stimulation of the mental nerve evokes two suppression periods SP1 and SP2 in masseter muscle activity bilaterally. In order to investigate a possible nociceptive origin of the suppression periods, we compared the reflex responses evoked by electrical stimulation and by selective activation of nociceptors in hairy skin using painful infrared laser stimuli. The SP was elicited during more than 90% maximal voluntary contraction. Thresholds for detection, pain, and SP in the mental nerve area were determined by the method of limits. A suppression period was evoked by laser stimuli in nine of ten subjects bilaterally. The mean onset latency was 46.9 ms, the mean duration 58.9 ms. The electrical threshold of SP1 (9 mA) was 7.7 x I(0), about 20% smaller than I(P), and significantly higher than I(SP2) (4.7 mA). The onset latencies and durations were 11.7 ms and 21 ms for SP1, and 45 ms and 42.7 ms for SP2 (stimulus intensity 2 x I(P)). The mean difference in onset latencies between laser SP and electrically evoked SP1 was 35.1 +/- 6.2 ms, which closely matches the nociceptor response latency to a laser heat pulse. Based on the threshold and the onset latency we conclude that at least SP1 and laser SP are nociceptive in origin and mediated by group III fibers.

Brain electrical source analysis of primary cortical components of the tibial nerve somatosensory evoked potential using regional sources

Tibial nerve somatosensory evoked potentials (SEPs) show higher amplitudes ipsilateral to the side of stimulation, whereas subdural recordings revealed a source in the foot area of the contralateral hemisphere. We now investigated this paradoxical lateralization by performing a brain electrical source analysis in the P40 time window (34-46 ms). The tibial nerve was stimulated behind the ankle (8 subjects). On each side, 2048 stimuli were applied twice. SEPs were recorded using 32 magnetic resonance imaging (MRI)-verified electrode positions (bandpass 0.5-500 Hz). In each case, the P40 amplitude was higher ipsilaterally (0.45 +/- 0.14 microV) than contralaterally (-0.49 +/- 0.16 microV). The best fitting regional source, however, was always located in the contralateral hemisphere with a mean distance of 8.2 +/- 4.3 mm from the midline. The positivity pointed ipsilaterally shifting from a frontal orientation (P37) to a parietal direction (P40). The P40 dipole moment was 2.5 times stronger than the dipole moment of P37, which makes P40 most prominent in EEG recordings. However, with its oblique dipole orientation compared to the tangential P37 dipole, it is systematically underestimated in MEG. Dipole orientations explained interindividual variability of scalp potential distribution. SEP amplitudes were smaller when generated in the dominant (left) hemisphere. This is explained by deeper located sources (5.4 +/- 1.6 mm) with a more tangential orientation (delta theta = 17.5 +/- 2.3 degrees) in the left hemisphere.

Convergence of nociceptive and non-nociceptive input onto the medullary dorsal horn in man

REFERRED pain arising in orofacial pain states is probably due to convergence of different somatosensory input onto the medullary dorsal horn (MDH). To examine convergence between nociceptive and nonnociceptive input onto the MDH, the blink reflex (BR) was applied. R1-and R2-components can be evoked by innocuous stimuli, but only the R2 is elicited by painful heat. The BR was elicited by innocuous electrical stimuli applied to the supraorbital nerve. A conditioning painful heat pulse which did not evoke any BR was homotopically applied to the left forehead preceding the electrical stimulus by 75 ms. While R1 remained unchanged, the R2 was facilitated by about 30%. This study demonstrates a convergence of low-threshold mechanoreceptive and nociceptive inputs onto interneurons of the MDH in man.

Conditioning of the masseter inhibitory reflex by homotopically applied painful heat in humans

During contraction of the jaw-closing muscles, afferent input from the intraoral and perioral region can elicit two bilateral suppression periods (SP1 and SP2, respectively) in the masseter electromyogram (EMG). Non-painful electrical stimulation 2 cm from the left labial commissure was used in the present study to evoke these trigeminal inhibitory reflexes. The subjects maintained a level of 50% of their maximum masseter EMG. The degree of suppression was quantified as the percentage suppression of the mean EMG activity in a fixed post-stimulus interval (SP2, 40-90 ms). Further, brief (200 ms) painful radiant heat conditioning stimuli were delivered to the ipsilateral cheek, in order to investigate the influence of nociceptive input on the (non-nociceptive) trigeminal masseter inhibitory reflex. Nine different conditions combining radiant heat and electrical stimuli were used. Twelve stimuli were presented for each condition. The radiant heat preceded the electrical test stimuli by fixed inter-stimulus intervals (ISI), ranging from 100 ms to 500 ms. At 250-350 ms ISIs, the bilateral SP2 suppression was significantly reduced to less than 10%, in comparison to an average suppression degree of 32.5% without conditioning stimuli. The subjects perceived the heat stimulus before the electrical stimulus for a majority of the 12 pairs of stimuli at these ISIs. No differences were found in the VAS ratings for the different conditions. For the contralateral SP1, larger suppression was seen for the 300 ms ISI compared with stimulation without conditioning heat stimuli. Onset and offset for the SP1 was, however, only detected in three subjects using a criteria of 20% suppression of the pre-stimulus activity. A pre-pulse inhibitory effect onto inter-neurons in the SP2 pathways or habituation of the same inter-neurons by the heat stimuli are suggested as possible explanations for the interaction between the non-nociceptive and nociceptive input in the present study.

The Hoffmann reflex of human plantar foot muscles

Electrical stimulation of the tibial nerve in the popliteal fossa evoked an M wave (10.9 ms) and a late reflex response (38.1 ms) in the plantar foot muscles of all 10 volunteers. The late response had a somewhat lower electrical threshold than the corresponding M wave (8.5 versus 9 mA), and reached a maximum of amplitude when the stimulus intensity was increased, but was strongly suppressed by further increased intensity. A more distal stimulation of the tibial nerve at the ankle shortened the onset latency of the M wave and lengthened that of the late response. The reflex was facilitated by activation of synergists and inhibited by activation of antagonists. We showed that the late response was contaminated neither by volume conducted activity from the soleus muscle, as shown by intramuscular recordings from the abductor hallucis muscle, nor by a F wave, as shown by double stimulation. In summary, we conclude that this late response in human plantar foot muscles corresponded to an H reflex, which may be used to assess alterations of distal motoneuronal excitability.