Segmental effects of epidural spinal cord stimulation in humans

Transcription

1 A18S 225, pp Journal of Physiology (1994), Segmental effects of epidural spinal cord stimulation in humans J. P. Hunter and P. Ashby* Department of Anatomy, University of Toronto and *Playfair Neuroscience Unit, University of Toronto, Toronto Western Hospital, Toronto, Canada 1. The segmental effects of spinal cord stimulation (SCS) were studied in twenty-four human subjects who had spinal cord stimulators implanted for the treatment of pain. The cathode was in the epidural space over the dorsum of the thoracic cord. 2. SCS generated action potentials in sensory, motor and mixed nerves which could be recorded with near-nerve electrodes. These action potentials could follow high frequencies of stimulation and appeared to be due to the antidromic activation of primary afferents in the dorsal columns. 3. Synaptic actions on single lumbosacral motoneurons were derived from peristimulus time histograms (PSTHs) of single motor units. SCS produced a brief short-latency period of increased firing probability (PIF) in motoneurons of all of the muscles examined, probably representing monosynaptic activation. It is argued that the facilitation arises from the antidromic activation of Ia afferents in the dorsal columns. This is the probable explanation for the muscle contractions that can be induced by SCS. 4. SCS inhibited short-latency group I homonymous facilitation and reciprocal inhibition. The mechanism appears to be presynaptic to the motoneurons and may represent collision in I a afferents, presynaptic inhibition or homosynaptic depression. 5. It was difficult to demonstrate consistent effects of SCS on reflex pathways from cutaneous afferents to flexor motoneurons because the effects of stimulation of cutaneous nerves on these motoneurons were themselves variable. 6. It is concluded that SCS applied with epidural electrodes over the dorsal cord activates primary afferents in the dorsal columns. Antidromic activation of these afferents results in strong monosynaptic facilitation of motoneurons as well as reduction in transmission in some reflex pathways to motoneurons. Epidural spinal cord stimulation has been used in an attempt to control pain (for review see Gybels & Kuypers, 1987), to modify muscle tone (for review see Gybels & Van Roost, 1987) and to improve peripheral circulation in peripheral vascular disease (Roldan, Santamaria, Barcia- Salorio, Casans, Carbonell & Tejerina, 1987). However, little is known of the fibre systems that are activated by (spinal cord stimulation (SCS) in humans or of the physiological consequences of such activation at the spinal or supraspinal levels. The present study was undertaken to examine the spinal effects of SCS delivered through epidural electrodes over the dorsum of the spinal cord (as currently placed for the control of pain or spasticity). The study was restricted to the immediate, short-latency segmental effects of SCS on the assumption that it is necessary to understand these segmental effects before exploring actions at other levels of the central nervous system. METHODS Selection of subjects and documentation of clinical findings Subjects who used SCS for the control of musculoskeletal pain were studied. The study was approved by the local Human Ethics Review Committee. All subjects gave informed consent. Each subject had a full clinical neurological examination, sensory and motor nerve conduction studies and EMG studies of selected muscles to document any neurological deficits (for example nerve root lesions) which could affect the interpretation of the subsequent findings. In general, subjects were excluded if there were neurological deficits involving either primary afferents or lower motoneurons (e.g. peripheral neuropathy). Certain subjects with focal deficits (e.g. L5 root lesion) were included and these deficits were taken into account when the data were interpreted. Sixty-seven different studies were carried out on twenty-four subjects. There were thirty electrode configurations as six subjects were retested after the electrodes had been moved to a different position. Seven additional subjects passed the selection criteria but satisfactory data could not be

2 48 J. P. Hunter and P. Ashby J. Physiol. 474 obtained because of technical failure of the stimulator or the inability of the subject to complete a study. Stimulating techniques Stimulation of the spinal cord. Subjects had a period of trial stimulation (stage 1) before final implantation of the stimulator (stage 2). In stage 1 a fine wire cathode was threaded percutaneously into the extradural space to the mid-thoracic region. The anode was placed on the skin over the paraspinal muscles. The cathode and anode were connected directly to a battery-operated Medtronic (Minneapolis, MN, USA) model 753 screening stimulator. Ten subjects (1 studies) were examined with this system. In stage 2 the fine wires from the cathode were tunnelled subcutaneously to an implanted stimulator and radio frequency receiving coil embedded in the abdominal wall. Fourteen subjects (2 studies) were examined after stage II of the SCS implantation procedure. Medtronic stimulators were used in twenty-three subjects and a Neuromod stimulator in one subject. The position of the anode and the cathode were established from anterior-posterior and lateral radiographs of the entire spine including the iliac crests (see Fig. 1). The subject was 2 m from the X-ray source to minimize magnification. The cathode was in the epidural space over the dorsum of the spinal cord, usually at the level of the T9-1 vertebral interspace but ranging from levels as rostral as the T7 interspace to as caudal as the superior border of the LI vertebra. The anode was internalized in one of four locations: (1) For ten studies the anode was a disc (19-5 mm diameter, Medtronic model 3462) at the receiver site in the anterior abdominal wall. (2) For five studies the anode was. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....,. ~O Figure 1. Radiograph of a subject with spinal cord stimulator in place The cathode is in the epidural space opposite the vertebral body of T1O. The anode is a disc at the receiver site in the lateral abdominal wall at the level of the iliac crest.

3 J. Physiol. 474 Segmental effects of spinal cord stimulation 49 a 'dental mirror' circular disc electrode (25-4 mm diameter, Miedtronics model 3492) embedded in the paraspinal muscles. (3) For four studies one of two types of four-electrode systems was implanted in the epidural space (a quadripolar system or a 'resume' system). In these subjects the most rostral electrode was the cathode and the most caudal electrode was the anode (separation 3 mm). (4) In one study the anode was a second electrode inserted in the epidural space at the level of the T11-12 vertebrae. To activate the implanted receiver, a flat coil antenna was taped on the skin over the implanted receiver. A Medtronic stimulator (SE4 model 3424) with radio frequency transmitter was used to trigger the implanted subcutaneous receiver which delivered electrical stimuli to the spinal cord. The transmitter had an intensity control with a ten-unit scale. The implanted receiver had an output range of -1 V. The actual current depended on a number of factors, including the state of the charge of the batteries, the distance of the receiver from the transmitter and the impedance at the cathode. The delivered current could not be measured in vivo. For most observations the stimulus intensity was set by the subject to that intensity which produced paraesthesias in the lower limbs. The transmitter was modified for use in these studies so that it could be triggered to deliver a single stimulus or multiple stimuli at chosen intervals. To ensure that the stimulators were capable of delivering stimuli at short interstimulus intervals without decrement, both a nonimplanted stimulator and an implantable stimulator were triggered at various intervals and the output monitored directly on an oscilloscope. This showed that the stimulators could deliver stimuli at intervals as short as 1 ms without decrement. Stimulation of peripheral nerves. The tibial nerve was stimulated in the popliteal fossa and the peroneal nerve was stimulated at the head of the fibula through bipolar surface electrodes placed 3 cm apart. In order to deliver group I volleys the tibial nerve or the common peroneal nerve was stimulated at intensities just below that required to excite the lowest threshold a-motoneuron axons in the homonymous nerve. This 'motor threshold' (MT) was repeatedly checked throughout the experiment. The stimulus intensity used during a recording was expressed as a percentage of MT. Cutaneous afferents were stimulated with ring electrodes on the second (cathode) and fifth (anode) toes at an intensity of times the sensory perception threshold. Vibratory stimuli. Vibration was applied to the lower limb with a vibrator (Wahl 563G) which has an unloaded amplitude of 1P5 mm and a rate of 6 Hz. Recording techniques All recordings were made while the subject was reclining comfortably on a stretcher. The limbs were kept warm with blankets if necessary. The single motor unit recordings required that the subject watch an oscilloscope and make a gentle muscle contraction of the muscle under investigation. All other recording situations allowed the subject to relax completely. Peripheral nerve recordings. Nerve action potentials were recorded from the common peroneal nerve at the head of the fibula, the medial gastrocnemius nerve just below the popliteal fossa, or the sural nerve at the ankle (and 1 cm proximal to the lateral malleolus in one study). Two Teflon-coated needle electrodes bared at the tip (Dantec 13L64 or Dantec 13L62) were placed 3 cm apart, close to the nerve. For the motor nerves the electrodes were positioned close enough to the nerve that an evoked muscle response could be elicited by a stimulus ( 5 ms duration) of less than 1 ma. For the sural nerve the proximity of the electrodes to the nerve was checked by averaging the nerve action potentials to stimulation of the nerve at a more distal site. The signals were filtered between 1 Hz and 3 khz and amplified 2 times. Up to 256 sweeps were averaged. The conduction velocity of the fibres in the sural nerve that were excited by SCS was calculated in one subject by simultaneously recording from two locations (8 cm apart) along the course of the sural nerve in the distal leg. Skin temperature was measured in this subject by a thermistor (resolution -1 C, accuracy ± 3 C, model 811-2, Cole Palmer Instrument Co., Chicago, IL, USA). Single motor unit recordings. Single motor units were recorded with concentric needle electrodes (Dantec 13L49, crosssectional area -45 mm2, central recording surface area 7 mm2) in one of three muscles: soleus (SOL), tibialis anterior (TA), or vastus medialis (VM). The needle electrode was positioned close to a motor unit activated by a gentle voluntary contraction. The EMIG signal was amplified up to 1 times. The bandpass was 1 Hz to 3 khz. The action potentials of the motor unit were selected by a window discriminator and displayed on a second storage oscilloscope with a delay line. The subject w!as provided with visual and auditory feedback of the unit's discharges and was instructed to maintain steady firing of the motor unit and to avoid activating other motor units in the vicinity of the recording electrode. Each occurrence of the motor unit action potential was carefully monitored on the storage oscilloscope to ensure that the entire spike train of the motor unit was recorded neither contaminated nor occluded by other units or artifact. A 'satisfactory recording' was defined as a run in which a single motor unit's spike train was recorded without contamination during more than 5 (usually 2) stimuli. Peristimulus time histograms (PSTHs) with bin widths of 2 or 4 #us were generated by a lab computer. Most histograms were recorded with a 3 ms prestimulus time period. The computer displayed a frequency histogram of the bin contents of the prestimulus portion and calculated the mean and the standard deviation. A period of increased firing probability (PIF) in the PSTH was accepted if there was a coherent cluster of three or more bins with contents greater than the mean plus two standard deviations. A running average of two bins was used to define the beginning and the end of the change in firing probabilit) and thus its duration. A period of decreased firing probability (PDF) was established by comparing the contents of a running series of five bin segments to the 15 bin prestimulus portion by using a series of Student's t tests. The rise time of the motor unit action potential was subtracted from all latencies. For details of the collection and interpretation of the PSTH see AMao, Ashby, Wang & McCrea (1984). Calculation of central conduction velocity WVhen SCS produced a short-latency PIF in a TA or SOL motor unit and the latency of the Ia monosynaptic facilition for that unit could also be established, the central conduction velocity was calculated as follows. The location of the spinal cord stimulator was determined from the 2 m standing radiograph of the spine. It was assumed that the fibre system responsible for the PIF was activated opposite the cathode. TA motoneurons were assumed to lie opposite the lower level of the T12 vertebra and SOL motoneurons were assumed to lie opposite the upper level of the first lumbar vertebra. The central distance (DI) from the cathode to the estimated level of the motoneuron was

4 J. P. Hunter and P. Ashby 41 J. Physgiol. 474 measured from the radiograph. Based on the assumption that the SCS-induced facilitation of motor units was monosynaptic (see Discussion), the latency of the facilitation included a central conduction delay (tl), a synaptic delay and a peripheral efferent delay ( ). The latency of the (presumed monosynaptic) facilitation from homonymous group I afferents elicited by peripheral nerve stimulation was also recorded for the same motor unit. This latency included an afferent delay, a synaptic delay and the same efferent delay ( ). The efferent delay was estimated (after subtracting 1 ms for the synaptic delay) based on the assumption that the ratio of the conduction velocities of the fastest sensory and motor fibres in the peripheral loop was 1P17 (Gandevia, Burke & McKeon, 1982) and the ratio of the fastest to the slowest motor fibres was 1P7 (Arasaki, lijima & Nakanishi, 1991). The central conduction delay was estimated by subtracting t2 (and lo ms for the synaptic delay) from the latency of the SCS-induced facilitation. The minimum conduction velocity of the spinal cord pathway(s) responsible for the short-latency, SCS-induced motor unit facilitation was calculated as DI/t1. Statistical analysis Statistical tests included Student's t test and the Wilcoxon rank sum test for paired differences. Probabilities of less than 5, two-tailed, were considered statistically significant, and results are expressed as means + S.D. unless otherwise specified. RESULTS Clinical effects of SOS As the intensity of the SCS (3 Hz) was slowly increased, subjects first reported local paraesthesia in a band-like distribution around the trunk at the level of the cathode and then paraesthesias referred to one or both legs. As the stimulus intensity was further increased, the paraesthesias increased in intensity and eventually became intense and disturbing. No subjects reported pain. At slow rates of stimulation (e.g. 3 Hz), the same sensations were felt as individual pulses in the same distribution. A _ 5 ms AAov" 4 _-3 * J 2-6 V 5 ms B C Jl y ~~~~5 ms JJ11 4~~~~ 3 j ra 2 Figure 2. Nerve action potentials averaged from the sural nerve in the distal leg (A), the nerve to medial gastrocnemius (B), and the common peroneal nerve (C) following epidural spinal cord stimulation at 3 Hz at the T9-1 vertebral level The traces show responses to twin stimuli with different interstimulus intervals. The large dots (S) indicate the onset of the response to the first stimulus. The small dots (e) indicate the expected onset of the response to the second stimulus. In each case the absolute refractory period was less than 3 ms.

5 J. Physiol. 474 Segmental effects of spinal cord stimulation 411 A x T- Figure 3. A, change in the size of the second of two nerve compound action potentials recorded from the common peroneal nerve after twin spinal cord stimuli with different interstimulus intervals. B, change in the size of the second of two compound nerve action potentials recorded from the sural nerve after twin spinal cord stimuli with different intervals. The size of the second response is expressed as a ratio of the first response. Different symbols represent different subjects. U) a U) csj a) CO a). U) U1) 1) -o E 1 1 Interstimulus interval (ms) 1 At slow rates of stimulation (e.g. 3 Hz), muscle contractions were elicited in response to each stimulus. These were first noticed in muscles innervated at the segmental level of the stimulator (e.g. abdominal muscles), but as the stimulus intensity was increased, contractions could be detected in many muscles of both lower limbs. At higher stimulus frequencies (e.g. 3 Hz), these muscle contractions became tetanic and were thus difficult to detect. In some subjects, in whom the cathode was placed asymmetrically, the observed effects were largely unilateral, at least at lower stimulus intensities. Movements of the spinal cord or the cathode within the spinal canal (for example by flexion and extension of the spine) altered the intensity of the effects at any one stimulus setting in some subjects. There were no clinical effects above the level of the cathode. A Left Right Iu &maalhi Vastus medialis * anterior L MW W11dkahd * 1 counts Soleus S Figure 4. Peristimulus time histograms showing the changes in firing probability of single voluntarily activated motor units produced by continuous 2 Hz epidural spinal cord stimulation at the T9-1 vertebral level Peaks represent periods of increased firing probability following the stimulus () at times and 5 ms. These recordings are from three different muscles from both lower extremities in one subject. This subject was one in whom the stimulator could not be programmed to deliver single stimuli. Abscissa: time in ms.

6 412 J. P. Hunter and P. Ashby J. Physiol. 474 Interstimulus interval (ms) ILL-, - I- I- 1 1 counts.mu.lt. I LJ ljlju LU -1 - Figure 5. Peristimulus time histograms of a single, voluntarily activated VM motor unit in response to paired stimulation of the 5 spinal cord at T9 vertebral level with interstimulus intervals of 1, 25, 5 and 1 ms The facilitation produced by the second of the paired stimuli was less when the interstimulus interval was 25 and 5 ms Activation of peripheral nerves by SCS To determine whether impulses were generated in peripheral nerve axons by SCS, recordings were made from sensory, motor and mixed nerves during SCS at 3 Hz. Recordings from a pure sensory nerve (the sural nerve) in response to SCS at the T9-1 vertebral level are shown in Fig. 2A. The nerve action potentials indicate that cutaneous afferents in this nerve were activated by SCS. The peripheral conduction velocity of the excited fibres (estimated in one subject) was 35 m s' (local skin temperature was 29f9 C), which is similar to that of the fastest afferents in this nerve in humans. When paired stimuli were used (Figs 2A and 3) it was clear that the refractory period was less that 3 ms. Nerve action potentials could also be averaged from a motor nerve (the MG nerve; Fig. 2B). These could have arisen from antidromic activation of primary muscle afferents or from trans-synaptic activation of a-motoneurons. The latter was easily excluded. Activation of motoneurons could be readily detected by the occurrence of motor unit action potentials which had very large amplitudes at the levels of amplification used. The refractory period was less than 3 ms. The most detailed studies of refractoriness were carried out on the common peroneal nerve (n = 6). The results of paired stimulation at various intervals are shown in Figs 2C and 3. There was a period of refractoriness lasting approximately 2 ms. The second of the two compound nerve action potentials was larger at interstimulus intervals between 5 and 1 ms. When continuous trains of stimuli, rather than paired stimuli, were delivered at the same interstimulus intervals, the depression was more profound at any given interstimulus interval. x 14 D 12 c a a) a) - 4 a) 2 Figure 6. Recovery of the short-latency period of facilitation in lower extremity motoneurons following twin pulse spinal cord stimulation Abscissa: interstimulus interval (ms). Ordinate: number of extra counts in PSTH peak, test/control x 1. Different symbols represent different subjects. E Interstimulus interval (ms)

7 Segmental effects of spinal cord stimulation J. Physiol Effects of SCS on motoneurons The effects of SCS on spinal motoneurons at segmental levels well below the site of the cathode were studied in thirteen subjects using PSTHs of individual motor units to derive synaptic actions. The predominant effect was a shortlatency PIF of all motoneuron species studied. Examples of this are shown in Fig. 4. The mean latencies from spinal cord stimulation to the beginning of the PIF were ms (n = 17) for VM, ms (n = 26) for TA and ms (n = 19) for SOL motoneurons. The durations of the PIFs were short: VM, ms; TA, ms; and SOL, 1P9 + '34 ms. As the stimulus intensity was increased, the size of the PIF increased until the motor unit was brought to threshold with every stimulus and a visible muscle contraction occurred. At the stimulus levels commonly used by the subjects (and used for these recordings) the mean peak areas (extra counts in the peak per 1 sweeps) were large: VM, ; TA, ; SOL, The conduction velocity of the pathway(s) in the spinal cord responsible for the initial PIF was calculated in three subjects (see Methods). The values were 23, 43 and 68 m s-' (mean, 45 m s-'). When twin SCS pulses were given, a smaller PIF was produced by the second stimulus when the interstimulus interval was 25 or 5 ms. An example is shown in Fig. 5 and the data from seven studies are shown in Fig. 6. Similar recovery curves were obtained for VM, TA and SOL. This reduction could occur without evidence of postsynaptic inhibition, i.e. without reduction in the mean background firing probability in the control PSTH at a time when the PIF was reduced. In addition to the prominent short-latency PIF, certain later effects were observed. Some examples are shown in Fig. 7. In TA motoneurons a PDF was seen with a latency of about 5-55 ms, (25 ms later than the short-latency PIF, n = 4). TA motoneurons also demonstrated a later, more diffuse PIF about 4 ms after the early PIF (n = 3). The fibre system responsible for this effect sometimes had a lower threshold than the fibre system responsible for the short-latency PIF. Effects of SCS on spinal reflex pathways Effect of continuous SCS on group I facilitation of motoneurons Stimulation of the common peroneal nerve below the threshold of the a-motoneuron axons results in a shortlatency PIF in TA motoneurons, which represents homonymous monosynaptic facilitation (Mao et al. 1984). During continuous 3 Hz SCS the size of the PIF produced by homonymous group I input was slightly reduced. An example is shown in Fig. 8A. A similar effect was seen on the short-latency PIF produced by homonymous group I input to SOL motoneurons. The results of thirty-one alternating A C i"ijkill., Awwk.w I.diLu m _LLi..-AAp kllak kj.. J" ILL I...L i".a" B 1-ki I L, i. di lllih Ld-.1 "Li., -M QL- IAWtAW ilm.lj 1-2do I1 counts Figure 7. Examples of late effects observed in three different subjects A, an example of later inhibition (arrow) of a TA motoneuron produced by SCS. The threshold for this effect was lower than that of the early facilitation seen in the lower trace. Stimulator settings were: 7 for the upper trace and 7-5 for the lower trace. B, example of a second period of facilitation (arrow) of a SOL motoneuron by SCS occurring at 4 ms. The threshold for this effect was lower than that for the early facilitation. Stimulator settings were: 7.5 for the upper trace and 8 for the lower trace. C, an example of the later facilitation (arrow) of a TA motoneuron by SCS at the T9 vertebral level. The threshold for this effect was lower than for the early facilitation seen on the bottom tracing. Stimulator settings were: 8 for the upper trace, 8f2 for the middle trace and 8-4 for the lower trace.

8 J. P. Hunter and P. Ashby 414 J. Physiol. 474 runs in seven subjects are shown in Fig. 8B. The number of extra counts in the PIF was significantly less during SCS (mean difference, 16-5 counts; P < 25). Effects of continuous SCS on reciprocal inhibition Stimulation of the posterior tibial nerve below the threshold of the a-motoneuron axons results in a shortlatency PDF of TA motoneurons which represents disynaptic reciprocal inhibition (Ashby & Wiens, 1989). In five studies (18 runs) carried out on four subjects, the inhibition of TA motoneurons produced by tibial nerve stimulation was less during continuous 3 Hz SCS stimulation (Fig. 9A and B) than during control runs (mean difference, 7415 counts). Effects of vibration on facilitation of motoneurons by SCS In four studies on three subjects the SCS-induced shortlatency PIF in single motor units of VM, TA and SOL was recorded with and without continuous vibration applied over TA (or over its tendon). The PIF was reduced by vibration. The mean difference between successive runs (n = 13) was '8 counts (P < 5). Effects of continuous SCS on pathways from cutaneous afferents to flexor motoneurons High-intensity (3 times the threshold of perception) stimulation of the second and the fifth toes produced, in the TA motoneurons of some subjects, a PIF with a latency of 8-9 ms, sometimes preceded by a PDF. The effect of continuous (3 Hz) SCS on the size of the PIF was studied in eight subjects (6 runs). In one subject the PDF was reduced by SCS in four runs with SCS compared to five runs without SCS (P < 25). A second patient demonstrated a different pattern of cutaneous facilitation and inhibition of the TA motoneuron, but the PDF was again reduced with SOS. In a third subject the PIF (with a latency of 84 ms) was less during SCS. In the other five subjects no consistent changes were seen. Thus SCS may alter transmission in the pathways from cutaneous afferents to motoneurons, but the effects are too variable to be succinctly described. DISCUSSION Predicting the fibre systems activated by SCS Swiontek et al. (1976) used a current probe to record the currents induced by subdural SCS (with various electrode A I. I..L. i..1 Control A. 1.1._ B 15 l ~~~scs a 1 Control. scs 8 L.&~~~~~~~oto Li,..I A A.'I A, 5 w 1 counts 2 o l Control scs Figure 8. A, peristimulus time histograms of a single, voluntarily activated SOL motor unit during lowintensity stimulation of the tibial nerve at time zero. Peaks represent periods of increased firing probability following stimulation of group I afferents. Control runs were alternated with runs during continuous 3 Hz epidural SCS at the T7-8 vertebral level. The size of the group I facilitation was consistently decreased during SCS. (Top 2 traces have 6 sweeps, bottom 3 traces have 1 sweeps.) B, magnitude of the periods of increased firing probability produced in single TA motoneurons by lowintensity stimulation of the common peroneal nerve. The peaks are significantly smaller during spinal cord stimulation.

9 Segmental effects of spinal cord stimulation J. Physiol configurations) in the cords of anaesthetized monkeys (in situ) and in isolated human cadaver spinal cords. The current densities were maximum in the dorsum of the spinal cord and less anteriorly. Coburn & Sin (1985), taking into account the anisotropic nature of the spinal cord and the vertebral canal, modelled in three dimensions the electric fields and current densities generated in the spinal cord by a 1 ma current delivered through a pair of epidural electrodes 2 cm apart. The electric field was focused in the dorsal columns at the level of the electrodes falling from a maximum of 4-15 V cm' dorsally to 34 V cm' ventrally. Coburn (1985) tried to predict which fibres would be activated by a monopolar epidural stimulating electrode situated over the mid-line of the dorsal columns and concluded that currents through such an electrode would excite: (i) axons rather than cell bodies; (ii) large myelinated fibres at a lower intensity than small ones; (iii) axons running transversely (e.g. in dorsal roots) at a lower intensity than those running longitudinally (e.g. in the spinal cord funiculi); and (iv) axons of a given diameter in the superficial dorsal columns at a lower intensity than axons in the lateral columns, and these before axons in the ventral columns. The largest longitudinally running fibres in the human spinal cord are in the superficial dorsolateral columns in the dorsal spinocerebellar tract (Hiiggvist, 1936). The remaining fibres in the dorsolateral column and the fibres in the dorsal columns have rather similar spectra. From these spectra one might expect that stimuli applied over the dorsal columns would excite fibres in the dorsal columns first and that, at higher intensities, fibres in the superficial dorsolateral columns might be recruited. This seems to be the case. Tsuyama, Tsuzuki, Kurokawa & Imai (1978) recorded the spinal cord potentials in humans evoked by stimulation over the dorsal columns. At low stimulus intensities, pathways with a conduction velocity of about 47 m s-' were activated. Higher stimulus intensities recruited fibres with a faster conduction velocity (73 m s-). When the stimuli were applied over the dorsolateral cord the rapidly conducting fibre system was recruited first. Stimulation over the spinal cord in cats also resulted in two negative waves, the Ni travelling at 6-8 m s', which could be abolished by lesions of the dorsolateral columns, and the N2 travelling at 3-4 m s-1, which could be abolished by lesions of the dorsal columns (Tsuyama et al. 1978). From the above, epidural SCS in humans might be expected to excite spinal cord neural elements in this order: first, the transversely running large myelinated fibres entering through the dorsal roots, then, the longitudinally running large myelinated fibres in the superficial part of the B A Control a) a) CL SCS 3._e. U) counts Control Li I6-AlihhW".m6.i 7 Control SCS Figure 9. A, peristimulus time histograms of a single voluntarily activated TA motor unit during stimulation of the low-threshold afferents in the tibial nerve at time zero. The inhibition about 4 ms represents disynaptic reciprocal inhibition. Control runs (top and bottom) are alternated with a run (middle) during continuous (3 Hz) SCS at the T1 vertebral level. The inhibition was less during SCS. B, magnitude of the periods of decreased firing probability produced in single TA motoneurons by lowintensity stimulation of the ipsilateral tibial nerve. The inhibition is significantly less during spinal cord stimulation.

10 J. P. Hunter and P. Ashby 416 J. Phy8iol. 474 dorsal columns, and then, the large myelinated fibres ascending or descending in the dorsolateral columns. Deductions from clinical observations When the stimulator was set at a slow rate (3 Hz) and the intensity gradually increased, the subjects first noted paraesthesias in a girdle distribution at the level of the cathode. This suggests that transversely oriented fibres in the dorsal roots were the first to be activated by the epidural electrodes as predicted. As the stimulus intensity was further increased, subjects noted paraesthesias in the lower limbs. This was never described in a manner (such as painful or burning) to suggest excitation of the spinothalamic pathways in the anterior cord. The sensory symptoms were always reported at or below the level of the stimulator, so it is unlikely that there was activation of descending collaterals of primary afferents from more rostral segments. At an intensity which produced mild paraesthesias, contractions of muscles of the trunk at the level of the cathode occurred with each stimulus, presumably due to activation of dorsal or ventral roots. At higher stimulus intensities contractions also occurred in lower limb muscles. Since these contractions occurred only in muscles whose segmental representation was below the level of the SCS cathode there was no evidence that pathways with collateral projections to trunk or upper limb motoneurons (e.g. propriospinal or corticospinal pathways) were responsible. As the frequency of the stimulation was increased to 5 Hz, the paraesthesias became continuous and the muscle contractions became tetanic and were easily overlooked. It is likely that, at the intensities and frequencies commonly chosen by subjects, muscle contractions usually occur. Action potentials generated in peripheral nerve axons by SCS Action potentials could be recorded from the sural nerve, the nerve to MG and the common peroneal in response to epidural SCS. The sural nerve action potentials must have arisen from cutaneous afferents. The MG nerve action potentials must have arisen from muscle afferents, not efferents, since they had a short refractory period and could be recorded without concomitant motor unit activation. The common peroneal nerve action potentials could have arisen from cutaneous and/or muscle afferents. The action potentials appear to be generated in large myelinated axons. The distal conduction velocity of the axons activated by SCS in the sural nerve was close to that of the fastest afferents in distal sensory nerves in humans of comparable age. The refractory period and subsequent supranormal and subnormal periods in nerve axons activated by SCS are similar to those observed after submaximal stimulation of populations of sensory fibres in peripheral nerves (e.g. Stys & Ashby, 199). During continuous rapid stimulation the nerve action potentials were depressed, presumably due to the summation of refractory and subnormal periods. These action potentials probably arose from the antidromic activation of the central processes of primary cutaneous and muscle afferents. The action potentials could also have been generated by a trans-synaptic mechanism (e.g. primary afferent depolarization) but the nerve action potentials would have had a longer latency, would not have been so precisely time locked to the stimulus, and would not have followed rapid repetition rates. Nerve action potentials have been recorded from dorsal roots and the sciatic nerve in cats following SCS at the T7 level (Niznik, 1988). These responses could also follow 2 Hz and were abolished when the dorsal columns were sectioned. In humans, Machida, Weinstein, Yamada & Kimura (1985) recorded SCS-evoked action potentials from the tibial nerve. These were thought to have arisen from the activation of dorsal column fibres because they corresponded in latency to the N2 wave (Tsuyama et al. 1978) which was recorded from the SCS electrode when the tibial nerve was stimulated. The paraesthesias reported by the subjects arose at the same stimulus intensity as the recordable nerve action potentials. Thus it is likely that the centrally perceived sensations and the nerve action potentials resulted from the simultaneous orthodromic and antidromic activation of the central projections of primary afferents. Effects of SCS on motoneurons The short-latency PIF SCS produced a prominent short-latency facilitation of motoneurons. This was not due to direct activation of motoneurons or motor roots (which lay well below the level of the cathode) since the latencies were too long, and there was some variability in the latency (indicating presence of a synapse). The PIF, however, was very brief (mean duration 1-8 ms, range ms) suggesting that the facilitation was monosynaptic (Mao et al. 1984). The PIF occurred with low-intensity stimulation similar to that resulting in paraesthesias. Thus the fibre system responsible for motoneuron PIF was either the same as that which produced the paraesthesias or was located near to it and had fibres of similar diameter. The latency of the apparently monosynaptic facilitation of motoneurons indicated a central conduction velocity of 45 m s'. This was similar to measurements of the conduction velocity of the central projections of group I afferents in the cat spinal cord of m s' (Lloyd & McIntyre, 195) and to estimates of conduction velocity of dorsal column fibres in the cat of 35 m s' (Niznik, 1988) and in humans of 3-5 m s' (Machida et al. 1985). The magnitude of the composite EPSPs generated in motoneurons by SCS can be obtained from the number of displaced counts in a PSTH. If the maximum excursion of the motoneuron membrane potential from threshold is assumed to be 15 mv, a 1-5 mv EPSP would produce a PSTH peak of 1 displaced counts per 1 stimuli. According to these criteria, the EPSPs generated in spinal neurons by SCS (at intensities commonly used in subjects) had mean amplitudes of -75-1P5 mv. The amplitude, of course, depended on the stimulus intensity. At higher stimulus intensities the EPSPs were sufficient to bring many Cquieseent' motoneurons to threshold and cause visible

11 Segmental effects of spinal cord stimulation J. Physi'ol muscle contractions. At a given stimulus intensity the relative size of the SCS-induced PIF in each of the muscles examined in a given individual was similar (Fig. 4) indicating that the responsible fibre systems project in a rather non-selective manner to each of the motoneuron pools. Several fibre systems in the spinal cord have monosynaptic projections onto motoneurons and could contribute to this short-latency facilitation. Dorsal roots. Dorsal roots near the cathode (T9 or TIO vertebral level in most cases) were readily activated by SCS judging from the radicular sensory symptoms. Orthodromic activation of descending projections of Ia afferents to motoneurons could, theoretically, account for the monosynaptic facilitation within approximately six segments, but this is unlikely for the following reasons: (1) heteronymous facilitation even between synergists is weak in the human (Bayoumi & Ashby, 1989) making it unlikely that Ia afferents at the T9 vertebral level (Til segmental level) would have strong projections to motoneurons at the L5/S1 segmental level; (2) in some subjects twitches of trunk muscles (indicating strong activation of roots) were observed following SCS without facilitation of motoneurons at lower segmental levels; (3) in normal subjects, percutaneous stimulation of the lower thoracic radicular nerves, sufficient to produce strong intercostal and abdominal muscle activation, had no short-latency effects on the firing probability of motoneurons in VM and TA muscles. Dorsal columns. The excitation of motoneurons could certainly be related to the activation of longitudinally oriented fibre systems in the dorsal columns. The effects in motoneurons are observed at about the same stimulus intensity as the paraesthesias. In cats, Niznik (1988) showed that responses in the L7 ventral nerve root, sciatic nerve and lower extremity muscles were produced by epidural SCS at T7 and were abolished by dorsal column lesions caudal to the stimulator, but unchanged by a lesion that left only the dorsal columns intact. Of the fibres in the dorsal column that would be activated by SCS, the largest proportion transmit cutaneous information (Vierck, 1978). While these afferents have segmental collaterals projecting to laminae III-VI, the minimum linkage between cutaneous afferents and motoneurons is bi- or trisynaptic. Thus the antidromic activation of these afferents cannot account for the short-latency, presumed monosynaptic, period of facilitation. Antidromic activation of Ia afferents in the dorsal columns is the most likely explanation for the following reasons: (1) in the cat, primary Ia afferents from the lower extremity ascend four to twelve segments before synapsing in Clarke's column (Lloyd & McIntyre, 195) so the primary afferents would be present at the level of the cathode; (2) there are strong homonymous I a projections to all motoneurons of lower limb muscles in humans (Bayoumi & Ashby, 1989) which would account for the non-specific facilitation of lower extremity motoneurons; (3) the way in which the facilitation produced by the second of a pair of SCS volleys varied with the interstimulus interval (Figs 5 and 6) was very similar to that reported following paired group I volleys to peripheral nerves (Mailis & Ashby, 199) as would be expected if the same axons and synapses were involved; (4) vibration of the limb reduced the facilitation of motoneurons produced by SCS in the same manner that it reduces the facilitation of motoneurons produced by group I volleys in the peripheral nerves (Ashby, Stalberg, Winkler & Hunter, 1987). The dorsal columns also contain the axons of second-order neurons with cell bodies in laminae III and IV (the postsynaptic dorsal column pathway). These axons give off one to three collaterals at the segmental level, but these dendritic trees probably influence neurons only within a few millimetres of the cell body (Brown, 1981), and there are no known monosynaptic connections to motoneurons. A fibre system descending from the dorsal column nuclei to the spinal cord has been described in the cat, rat and monkey (Burton & Loewy, 1977). It is not known whether such a system exists in the human. Dorsolateral columns. Corticospinal axons make monosynaptic connections with lower extremity motoneurons in primates (Bernhard, Bohm & Peterson, 1953) and in humans (Day et al. 1989; Brouwer & Ashby, 1992), but it is unlikely that these fibres contribute to the short-latency facilitation observed in this study for the following reasons. First, these axons are located in the dorsal and ventral parts of the lateral column (Nathan, Smith & Deacon, 199) and would require more current than the smaller but more superficial dorsal column fibres (Coburn & Sin, 1985). Second, the conduction velocity of corticomotoneuronal axons in the spinal cord has been estimated at 65-7 m s-' in the monkey (Bernhard & Bohm, 1954) and 65 m s-' in the human (Rothwell et al. 1987), which is faster than the estimated conduction velocity of the axons responsible for the short-latency PIF recorded in this study. Third, the projections of corticomotoneuronal axons to lower limb motoneurons in the human are rather specific. For example, the TA motoneurons are strongly facilitated whereas SOL motoneurons are inhibited or show only a longer-latency (most probably polysynaptic) facilitation (Cowan, Day, Marsden & Rothwell, 1986; Brouwer & Ashby, 1992). Small monosynaptic rubrospinal EPSPs have been described in distal hindlimb motoneurons of the rhesus monkey (Shapovalov, Karamjan, Kurchavyi & Repina, 1971), but no rubrospinal projections have been demonstrated below the thoracic level in humans (Nathan & Smith, 1982). Thus it seems unlikely that activation of rubrospinal axons accounts for the short-latency facilitation of motoneurons. Propriospinal axons terminate in laminae VII and VIII. The long propriospinal axons ascend and descend mainly through the ventral funiculus and so can be excluded. The dorsal half of the lateral funiculus contains only the short propriospinal neurons, which travel up to six segments to motoneurons of distal extremity muscles (Kuypers, 1982). It is unlikely that these fibres are responsible for the observed activation of motoneurons, since the SOL motoneurons are at least 6 segments away from the T9-1

12 418 J. P. Hunter and P. Ashby J. Physiol. 474 cathode. There was no evidence of facilitation of motoneurons above the level of the SCS cathode to suggest activation of propriospinal axons. In summary, while a number of pathways could contribute to the short-latency, presumed monosynaptic, facilitation of motoneurons produced by SCS, antidromic activation of Ia afferents in the dorsal columns seems the most likely. The muscle contractions which occur in almost all subjects using SCS (Machida et al. 1985; Guru, Mailis, Ashby & Vanderlinden, 1987) probably result from this strong Ia synaptic input. Longer-latency effects A number of later effects were observed, but not studied in detail. In TA motoneurons a PDF 25 ms after the early PIF sometimes had a lower threshold than the short-latency PIF (Fig. 7). A later, more diffuse PIF (about 4 ms after the early PIF) in TA appeared to have a threshold similar to the early PIF. This was not observed in SOL motoneurons. Effects of continuous SCS on spinal reflex pathways The short-latency facilitation of TA motoneurons produced by stimulation of low-threshold afferents in the peroneal nerve has been attributed to the homonymous composite Ia EPSP (Mao et al. 1984). Continuous SCS reduced this facilitation without a reduction in the mean firing rate of the motoneuron, suggesting that the depression was not postsynaptic but was occurring in the peripheral nerve or at the synapse. If SCS activated Ia afferents antidromically, there would be several possible explanations for the reduction of I a facilitation. Collision in the peripheral segment of Ia afferents would be the simplest. It is curious, however, that the effects were not more profound. Since the SCS-initiated common peroneal nerve action potentials had a latency of 18 ms, of which 15-8 ms represents conduction time in peripheral nerve segments, one would expect that SCS at 3 Hz (33 ms intervals) would have resulted in complete collision in the Ia fibres. This was not observed. However, it is possible that only a proportion of the Ia afferents from TA muscle were antidromically activated by the SCS, either because some had already synapsed in Clarke's column or because different populations of Ia fibres were excited by SCS and by the peripheral nerve electrodes. Both presynaptic inhibition of Ia afferents produced by axoaxonic synapses (Baldissera, Hultborn & Illert, 1981) and homosynaptic depression at the Ia-motoneuron synapse resulting from the passage of a previous impulse in the same fibre (Katz, Morin, Pierrot-Deseilligny & Hibino, 1977), could also have contributed to the reduction in the Ia EPSP. The short-latency inhibition of TA motoneurons produced by stimulation of low-threshold afferents in the tibial nerve has been attributed to the Ia IPSP (Ashby & Wiens, 1989). Continuous SCS consistently reduced but did not abolish this inhibition. The reduction of Ia inhibition occurred without a reduction in mean firing rate of the motoneuron and thus it also is not a postsynaptic effect. All of the factors mentioned above could have reduced the excitation of Ia inhibitory interneurons, but in addition, the Ia inhibitory interneurons could have been inhibited by the Ia inhibitory interneurons of the antagonist. REFERENCES ARASAKI, K., IIJIMA, M. & NAKANISHI, T. (1991). Normal maximal and minimal motor nerve conduction velocities in adults determined by a collision method. Muscle and Nerve 14, ASHBY, P., STALBERG, E., WINKLER, T. & HUNTER, J. P. (1987). Further observations on the depression of group Ia facilitation of motoneurons by vibration in man. 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