Angular vestibuloocular reflex responses in Otop1 mice. II. Otolith sensor input improves compensation after unilateral labyrinthectomy.

The role of the otoliths in mammals in the normal angular vestibuloocular reflex (VOR) was characterized in an accompanying study based on the Otopetrin1 (Otop1) mouse, which lacks functioning otoliths because of failure to develop otoconia but seems to have otherwise normal peripheral anatomy and neural circuitry. That study showed that otoliths do not contribute to the normal horizontal (rotation about Earth-vertical axis parallel to dorso-ventral axis) and vertical (rotation about Earth-vertical axis parallel to interaural axis) angular VOR but do affect gravity context-specific VOR adaptation. By using these animals, we sought to determine whether the otoliths play a role in the angular VOR after unilateral labyrinthectomy when the total canal signal is reduced. In five Otop1 mice and five control littermates we measured horizontal and vertical left-ear-down and right-ear-down sinusoidal VOR (0.2-10 Hz, 20-100°/s) during the early (3-5 days) and plateau (28-32 days) phases of compensation after unilateral labyrinthectomy and compared these measurements with baseline preoperative responses from the accompanying study. From similar baselines, acute gain loss was ~25% less in control mice, and chronic gain recovery was ~40% more in control mice. The acute data suggest that the otoliths contribute to the angular VOR when there is a loss of canal function. The chronic data suggest that a unilateral otolith signal can significantly improve angular VOR compensation. These data have implications for vestibular rehabilitation of patients with both canal and otolith loss and the development of vestibular implants, which currently only mimic the canals on one side. NEW & NOTEWORTHY This is the first study examining the role of the otoliths (defined here as the utricle and saccule) on the acute and chronic angular vestibuloocular reflex (VOR) after unilateral labyrinthectomy in an animal model in which the otoliths are reliably inactivated and the semicircular canals preserved. This study shows that the otolith signal is used to augment the acute angular VOR and help boost VOR compensation after peripheral injury.

Angular vestibuloocular reflex responses in Otop1 mice. I. Otolith sensor input is essential for gravity context-specific adaptation.

The role of the otoliths in mammals in the angular vestibuloocular reflex (VOR) has been difficult to determine because there is no surgical technique that can reliably ablate them without damaging the semicircular canals. The Otopetrin1 (Otop1) mouse lacks functioning otoliths because of failure to develop otoconia but seems to have otherwise normal peripheral anatomy and neural circuitry. By using these animals we sought to determine the role of the otoliths in angular VOR baseline function and adaptation. In six Otop1 mice and six control littermates we measured baseline ocular countertilt about the three primary axes in head coordinates; baseline horizontal (rotation about an Earth-vertical axis parallel to the dorsal-ventral axis) and vertical (rotation about an Earth-vertical axis parallel to the interaural axis) sinusoidal (0.2-10 Hz, 20-100°/s) VOR gain (= eye/head velocity); and the horizontal and vertical VOR after gain-increase (1.5×) and gain-decrease (0.5×) adaptation training. Countertilt responses were significantly reduced in Otop1 mice. Baseline horizontal and vertical VOR gains were similar between mouse types, and so was horizontal VOR adaptation. For control mice, vertical VOR adaptation was evident when the testing context, left ear down (LED) or right ear down (RED), was the same as the training context (LED or RED). For Otop1 mice, VOR adaptation was evident regardless of context. Our results suggest that the otolith translational signal does not contribute to the baseline angular VOR, probably because the mouse VOR is highly compensatory, and does not alter the magnitude of adaptation. However, we show that the otoliths are important for gravity context-specific angular VOR adaptation. NEW & NOTEWORTHY This is the first study examining the role of the otoliths (defined here as the utricle and saccule) in adaptation of the angular vestibuloocular reflex (VOR) in an animal model in which the otoliths are reliably inactivated and the semicircular canals preserved. We show that they do not contribute to adaptation of the normal angular VOR. However, the otoliths provide the main cue for gravity context-specific VOR adaptation.

The mammalian efferent vestibular system plays a crucial role in vestibulo-ocular reflex compensation after unilateral labyrinthectomy.

The α9-nicotinic acetylcholine receptor (α9-nAChR) subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic efferent vestibular system (EVS). A recent study has shown that α9-nAChRs play an important role in short-term vestibulo-ocular reflex (VOR) adaptation. We hypothesize that α9-nAChRs could also be important for other forms of vestibular plasticity, such as that needed for VOR recovery after vestibular organ injury. We measured the efficacy of VOR compensation in α9 knockout mice. These mice have deletion of most of the gene (chrna9) encoding the nAChR and thereby lack α9-nAChRs. We measured the VOR gain (eye velocity/head velocity) in 20 α9 knockout mice and 16 cba129 controls. We measured the sinusoidal (0.2-10 Hz, 20-100°/s) and transient (1,500-6,000°/s2) VOR in complete darkness before (baseline) unilateral labyrinthectomy (UL) and then 1, 5, and 28 days after UL. On day 1 after UL, cba129 mice retained ~50% of their initial function for contralesional rotations, whereas α9 knockout mice only retained ~20%. After 28 days, α9 knockout mice had ~50% lower gain for both ipsilesional and contralesional rotations compared with cba129 mice. Cba129 mice regained ~75% of their baseline function for ipsilesional and ~90% for contralesional rotations. In contrast, α9 knockout mice only regained ~30% and ~50% function, respectively, leaving the VOR severely impaired for rotations in both directions. Our results show that loss of α9-nAChRs severely affects VOR compensation, suggesting that complimentary central and peripheral EVS-mediated adaptive mechanisms might be affected by this loss.NEW & NOTEWORTHY Loss of the α9-nicotinic acetylcholine receptor (α9-nAChR) subunit utilized by the efferent vestibular system (EVS) has been shown to significantly affect vestibulo-ocular reflex (VOR) adaptation. In our present study we have shown that loss of α9-nAChRs also affects VOR compensation, suggesting that the mammalian EVS plays an important role in vestibular plasticity, in general, and that VOR compensation is a more distributed process than previously thought, relying on both central and peripheral changes.

Unexpected factors affecting the excitability of human motoneurones in voluntary and stimulated contractions.

KEY POINTS: The output of human motoneurone pools decreases with fatiguing exercise, but the mechanisms involved are uncertain. We explored depression of recurrent motoneurone discharges (F-waves) after sustained maximal voluntary contractions (MVCs). MVC depressed the size and frequency of F-waves in a hand muscle but a submaximal contraction (at 50% MVC) did not. Surprisingly, activation of the motoneurones antidromically by stimulation of the ulnar nerve (at 20 or 40 Hz) did not depress F-wave area or persistence. Furthermore, a sustained (3 min) MVC of a hand muscle depressed F-waves in its antagonist but not in a remote hand muscle. Our findings suggest that depression of F-waves after voluntary contractions is not simply due to repetitive activation of the motoneurones but requires descending voluntary drive.  Furthermore, this effect may depress nearby, but not distant, spinal motoneurone pools. ABSTRACT: There are major spinal changes induced by repetitive activity and fatigue that could contribute to 'central' fatigue but the mechanisms involved are poorly understood in humans. Here we confirmed that the recurrent motoneuronal discharge (F-wave) is reduced during relaxation immediately after a sustained maximal voluntary contraction (MVC) of an intrinsic hand muscle (abductor digiti minimi, ADM) and explored the relationship between motoneurone firing and the depression of F-waves in three ways. First, the depression (in both F-wave area and F-wave persistence) was present after a 10 s MVC (initial decrease 36.4 ± 19.1%; mean ± SD) but not after a submaximal voluntary contraction at 50% maximum. Second, to evoke motoneurone discharge without volitional effort, 10 s tetanic contractions were produced by supramaximal ulnar nerve stimulation at the elbow at physiological frequencies of 25 and 40 Hz. Surprisingly, neither produced depression of F-waves in ADM to test supramaximal stimulation of the ulnar nerve at the wrist. Finally, a sustained MVC (3 min) of the antagonist to ADM (4th palmar interosseous) depressed F-waves in the anatomically close ADM (20 ± 18.2%) but not in the more remote first dorsal interosseous on the radial side of the hand. We argue that depression of F-waves after voluntary contractions may not be due to repetitive activation of the motoneurones but requires descending voluntary drive. Furthermore, this effect may depress nearby, but not distant, spinal motoneurone pools and it reveals potentially novel mechanisms controlling the output of human motoneurones.

The mammalian efferent vestibular system plays a crucial role in the high-frequency response and short-term adaptation of the vestibuloocular reflex.

Although anatomically well described, the functional role of the mammalian efferent vestibular system (EVS) remains unclear. Unlike in fish and reptiles, the mammalian EVS does not seem to play a role in modulation of primary afferent activity in anticipation of active head movements. However, it could play a role in modulating long-term mechanisms requiring plasticity such as vestibular adaptation. We measured the efficacy of vestibuloocular reflex (VOR) adaptation in α9-knockout mice. These mice carry a missense mutation of the gene encoding the α9 nicotinic acetylcholine receptor (nAChR) subunit. The α9 nAChR subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic EVS. We measured the VOR gain (eye velocity/head velocity) in 26 α9-knockout mice and 27 cba129 control mice. Mice were randomly assigned to one of three groups: gain-increase adaptation (1.5×), gain-decrease adaptation (0.5×), or no adaptation (baseline, 1×). After adaptation training (horizontal rotations at 0.5 Hz with peak velocity 20°/s), we measured the sinusoidal (0.2-10 Hz, 20-100°/s) and transient (1,500-6,000°/s(2)) VOR in complete darkness. α9-Knockout mice had significantly lower baseline gains compared with control mice. This difference increased with stimulus frequency (∼ 5% <1 Hz to ∼ 25% >1 Hz). Moreover, vestibular adaptation (difference in VOR gain of gain-increase and gain-decrease adaptation groups as % of gain increase) was significantly reduced in α9-knockout mice (17%) compared with control mice (53%), a reduction of ∼ 70%. Our results show that the loss of α9 nAChRs moderately affects the VOR but severely affects VOR adaptation, suggesting that the EVS plays a crucial role in vestibular plasticity.

Velocity-selective adaptation of the horizontal and cross-axis vestibulo-ocular reflex in the mouse.

One commonly observed phenomenon of vestibulo-ocular reflex (VOR) adaptation is a frequency-selective change in gain (eye velocity/head velocity) and phase (relative timing between the vestibular stimulus and response) based on the frequency content of the adaptation training stimulus. The neural mechanism behind this type of adaptation is not clear. Our aim was to determine whether there were other parameter-selective effects on VOR adaptation, specifically velocity-selective and acceleration-selective changes in the horizontal VOR gain and phase. We also wanted to determine whether parameter selectivity was also in place for cross-axis adaptation training (a visual-vestibular training stimulus that elicits a vestibular-evoked torsional eye movement during horizontal head rotations). We measured VOR gain and phase in 17 C57BL/6 mice during baseline (no adaptation training) and after gain-increase, gain-decrease and cross-axis adaptation training using a sinusoidal visual-vestibular (mismatch) stimulus with whole-body rotations (vestibular stimulus) with peak velocity 20 and 50°/s both with a fixed frequency of 0.5 Hz. Our results show pronounced velocity selectivity of VOR adaptation. The difference in horizontal VOR gain after gain-increase versus gain-decrease adaptation was maximal when the sinusoidal testing stimulus matched the adaptation training stimulus peak velocity. We also observed similar velocity selectivity after cross-axis adaptation training. Our data suggest that frequency selectivity could be a manifestation of both velocity and acceleration selectivity because when one of these is absent, e.g. acceleration selectivity in the mouse, frequency selectivity is also reduced.

Activity-dependent depression of the recurrent discharge of human motoneurones after maximal voluntary contractions.

Despite maximal voluntary effort, the output of human motoneurone pools diminishes during fatigue. To assess motoneurone behaviour, we measured recurrent discharges evoked antidromically by supramaximal nerve stimulation after isometric maximal voluntary contractions (MVCs).They were measured as F-waves in the electromyographic activity (EMG). Supramaximal stimuli to the common peroneal and ulnar nerves evoked F-waves at rest before and after MVCs in tibialis anterior (TA) and abductor digit minimi (ADM), respectively. F-waves were depressed immediately after a sustained MVC. For TA, the size and time course of depression of the F-wave area (26 ± 13%; mean ± SD; P =0.007) and persistence (∼20%) were similar after a 10-s or 1-min MVC. For ADM, the decline in F-wave area (39.8 ± 19.6%; P <0.01) was similar after the two contractions but the decline in persistence (probability of occurrence) of the F-wave differed (14.6 ± 10.5% and 32.5 ± 17.1% after 10-s and 1-min MVCs respectively). Comparison of a very long (2-min) with a very short (2-s)MVC in ADM showed that the depression of F-wave area, as well as persistence, was greater after the longer contraction. This suggests, at least for ADM, that the depression is related to the duration of voluntary activity and that the decrease in F-waves could contribute to central fatigue. To examine whether changes in motor axon excitability caused the depression, we measured compound muscle action potentials (M-waves) to submaximal stimulation of the ulnar nerve after a 2-s and 2-min MVC. Submaximal M-waves were not depressed after a 2-s MVC. They were depressed by a 2-min MVC, but the time course of depression of the F- and M-waves differed. Thus, depression of F-waves does not simply reflect reduced excitability of peripheral motor axons.Hence, we propose that activity-dependent changes at the soma or the initial segment depress the recurrent discharge of human motoneurones and that this may contribute to central fatigue.

A Once-Daily High Dose of Intraperitoneal Ascorbate Improves Vestibulo-ocular Reflex Compensation After Unilateral Labyrinthectomy in the Mouse.

Ascorbate potentiates the response of nicotinic-acetylcholine-receptors containing α9 and α10 subunits found predominantly in the efferent systems of the inner ear, such as the efferent vestibular system (EVS). Prior mouse studies have shown that an attenuated EVS results in reduced vestibulo-ocular reflex (VOR) gain (=eye_velocity/head_velocity) plasticity in intact (VOR adaptation) and surgically-lesioned (VOR compensation) mice. We sought to determine whether ascorbate-treatment could improve VOR recovery after vestibular organ injury, possibly through potentiation of the EVS pathway. We tested 10 cba129 mice, 5 received ascorbate-treatment and 5 did not, but otherwise experienced the same conditions. Ascorbate-treatment comprised a once-daily intraperitoneal injection of L-form reduced ascorbate (4 g/kg) in 0.2 ml saline starting 1 week before, and ending 4 weeks after, unilateral labyrinthectomy surgery. These were deliberately high doses to determine the ascorbate effects on recovery. Baseline, acute, and chronic sinusoidal VOR gains (frequency and velocity ranges: 0.2-10 Hz, 20-100 deg/s) were measured 3-5 days before, 3-5 days after, and 28-31 days after labyrinthectomy. Mice treated with ascorbate had acute ipsilesional VOR gains 12 % higher compared to control mice (+45.2 ± 14.9 % from baseline versus +33.7 ± 15.4 %, P < 0.001). Similarly, chronic ipsilesional and contralesional VOR gains were respectively 16 % (+74.3 ± 16.3 % from baseline versus +58.1 ± 15.8 %, P < 0.001) and 13 % (+78.6 ± 16.0 % versus +65.6 ± 10.9 %, P < 0.001) higher compared to control mice. These data suggest ascorbate-treatment had a prophylactic effect reducing acute loss, and helped recovery during acute to chronic stages of compensation. One possible mechanism is that an ascorbate-enhanced EVS drives an increase in the number and sensitivity of irregular-discharging primary vestibular afferents, important for VOR plasticity.

Vestibulo-Ocular Reflex Short-Term Adaptation Is Halved After Compensation for Unilateral Labyrinthectomy.

Several prior studies, including those from this laboratory, have suggested that vestibulo-ocular reflex (VOR) adaptation and compensation are two neurologically related mechanisms. We therefore hypothesised that adaptation would be affected by compensation, depending on the amount of overlap between these two mechanisms. To better understand this overlap, we examined the effect of gain-increase (gain = eye velocity/head velocity) adaptation training on the VOR in compensated mice since both adaptation and compensation mechanisms are presumably driving the gain to increase. We tested 11 cba129 controls and 6 α9-knockout mice, which have a compromised efferent vestibular system (EVS) known to affect both adaptation and compensation mechanisms. Baseline VOR gains across frequencies (0.2 to 10 Hz) and velocities (20 to 100°/s) were measured on day 28 after unilateral labyrinthectomy (UL) and post-adaptation gains were measured after gain-increase training on day 31 post-UL. Our findings showed that after chronic compensation gain-increase adaptation, as a percentage of baseline, in both strains of mice (~14%), was about half compared to their previously reported healthy, non-operated counterparts (~32%). Surprisingly, there was no difference in gain-increase adaptation between control and α9-knockout mice. These data support the notion that adaptation and compensation are separate but overlapping processes. They also suggest that half of the original adaptation capacity remained in chronically compensated mice, regardless of EVS compromise associated with α9-knockout mice, and strongly suggest VOR adaptation training is a viable treatment strategy for vestibular rehabilitation therapy and, importantly, augments the compensatory process.

The reduction in human motoneurone responsiveness during muscle fatigue is not prevented by increased muscle spindle discharge.

Motoneurone excitability is rapidly and profoundly reduced during a sustained maximal voluntary contraction (MVC) when tested in the transient silent period which follows transcranial magnetic stimulation (TMS) of the motor cortex. One possible cause of this reduction in excitability is a fatigue-induced withdrawal of excitatory input to motoneurones from muscle spindle afferents. We aimed to test if muscle spindle input produced by tendon vibration would ameliorate suppression of the cervicomedullary motor-evoked potential (CMEP) in the silent period during a sustained MVC. Seven subjects performed a 2 min MVC of the elbow flexors. Stimulation of the corticospinal tract at the level of the mastoids was preceded 100 ms earlier by TMS. These stimulus pairs were delivered every 10 s during the 2 min MVC. Stimulus pairs at 30, 50, 70, 90 and 110 s were delivered while vibration (-80 Hz) was applied to the distal tendon of biceps. On a separate day, the protocol was repeated with both stimuli delivered to the motor cortex. The CMEP in the silent period decreased rapidly with fatigue (to -9% of control) and was not affected by tendon vibration (P = 0.766). The motor-evoked potential in the silent period also declined rapidly (to -5% of control) and was similarly unaffected by tendon vibration (P = 0.075). These data suggest motoneurone disfacilitation due to a fatigue-related decrease of muscle spindle discharge does not contribute significantly to the profound suppression of motoneurone excitability during the silent period. Therefore, a change to intrinsic motoneurone properties caused by repetitive discharge is most probably responsible.

Optimal Human Passive Vestibulo-Ocular Reflex Adaptation Does Not Rely on Passive Training.

The vestibulo-ocular reflex (VOR) is the main vision-stabilising system during rapid head movements in humans. A visual-vestibular mismatch stimulus can be used to train or adapt the VOR response because it induces a retinal image slip error signal that drives VOR motor learning. The training context has been shown to affect VOR adaptation. We sought to determine whether active (self-generated) versus passive (externally imposed) head rotation vestibular training would differentially affect adaptation and short-term retention of the active and passive VOR responses. Ten subjects were tested, each over six separate 1.5-h sessions. We compared active versus passive head impulse (transient, rapid head rotations with peak velocity ~ 150 °/s) VOR adaptation training lasting 15 min with the VOR gain challenged to increment, starting at unity, by 0.1 every 90 s towards one side only (this adapting side was randomised to be either left or right). The VOR response was tested/measured in darkness at 10-min intervals, 20-min intervals, and two single 60-min interval sessions for 1 h post-training. The training was active or passive for the 10- and 20-min interval sessions, but only active for the two single 60-min interval sessions. The mean VOR response increase due to training was ~ 10 % towards the adapting side versus ~2 % towards the non-adapting side. There was no difference in VOR adaptation and retention between active and passive VOR training. The only factor to affect retention was exposure to a de-adaptation stimulus. These data suggest that active VOR adaptation training can be used to optimally adapt the passive VOR and that adaptation is completely retained over 1 h as long as there is no visual feedback signal driving de-adaptation.

The Effect of Visual Contrast on Human Vestibulo-Ocular Reflex Adaptation.

The vestibulo-ocular reflex (VOR) is the main retinal image stabilising mechanism during rapid head movement. When the VOR does not stabilise the world or target image on the retina, retinal image slip occurs generating an error signal that drives the VOR response to increase or decrease until image slip is minimised, i.e. VOR adaptation occurs. Visual target contrast affects the human smooth pursuit and optokinetic reflex responses. We sought to determine if contrast also affected VOR adaptation. We tested 12 normal subjects, each over 16 separate sessions. For sessions 1-14, the ambient light level (lx) during adaptation training was as follows: dark, 0.1, 0.2, 0.3, 0.5, 0.7, 1, 2, 8, 16, 32, 64, 128 and 255 lx (light level for a typical room). For sessions 15-16, the laser target power (related to brightness) was halved with ambient light at 0 and 0.1 lx. The adaptation training lasted 15 min and consisted of left/right active head impulses. The VOR gain was challenged to increment, starting at unity, by 0.1 every 90 s for rotations to the designated adapting side and fixed at unity towards the non-adapting side. We measured active and passive VOR gains before and after adaptation training. We found that for both the active and passive VOR, there was a significant increase in gain only towards the adapting side due to training at contrast level 1.5 k and above (2 lx and below). At contrast level 261 and below (16 lx and above), adaptation training resulted in no difference between adapting and non-adapting side gains. Our modelling suggests that a contrast threshold of ~ 1000, which is 60 times higher than that provided by typical room lighting, must be surpassed for robust active and passive VOR adaptation. Our findings suggest contrast is an important factor for adaptation, which has implication for rehabilitation programs.

Core Body Temperature Effects on the Mouse Vestibulo-ocular Reflex.

Core body temperature has been shown to affect vestibular end-organ and nerve afferents so that their resting discharge rate and sensitivity increase with temperature. Our aim was to determine whether these changes observed in extracellular nerve recordings of anaesthetized C57BL/6 mice corresponded to changes in the behavioural vestibulo-ocular reflex (VOR) of alert mice. The VOR drives eye rotations to keep images stable on the retina during head movements. We measured the VOR gain (eye velocity/head velocity) and phase (delay between vestibular stimulus and response) during whole-body sinusoidal rotations ranging 0.5-12 Hz with peak velocity 50 or 100 °/s in nine adult C57BL/6 mice. We also measured the VOR during whole-body transient rotations with acceleration 3000 or 6000 °/s2 reaching a plateau of 150 or 300 °/s. These measures were obtained while the mouse's core body temperature was held at either 32 or 37 °C for at least 35 min before recording. The temperature presentation order and timing were pseudo-randomized. We found that a temperature increase from 32 to 37 °C caused a significant increase in sinusoidal VOR gain of 17 % (P < 0.001). Temperature had no other effects on the behavioural VOR. Our data suggest that temperature effects on regularly firing afferents best correspond to the changes that we observed in the VOR gain.

Aging reduces the high-frequency and short-term adaptation of the vestibulo-ocular reflex in mice.

Prevailing evidence indicates a relatively late life decline in human vestibulo-ocular reflex (VOR) function. Although mice are commonly used in mechanistic studies of vestibular function, it remains unclear whether aging produces a corresponding decline in VOR function in mice. We sought to determine how the baseline VOR and its short-term adaptation were affected by aging. We tested 8 young (3-month old) and 8 aged (30-month old-equivalent to a ∼80-year old human) C57BL/6 mice. We measured their VOR response to whole-body static tilts and during 0.1-10 Hz whole-body sinusoidal and transient rotations before and after VOR adaptation training. Our data revealed minimal differences in static counter-tilt response between young and aged mice, but a significant deficit in baseline VOR gain in aged mice during transient rotations. Moreover, aged mice had a significant decrease in short-term VOR adaptation, particularly for training that sought to decrease the VOR response.

Effect of experimental muscle pain on maximal voluntary activation of human biceps brachii muscle.

Muscle pain has widespread effects on motor performance, but the effect of pain on voluntary activation, which is the level of neural drive to contracting muscle, is not known. To determine whether induced muscle pain reduces voluntary activation during maximal voluntary contractions, voluntary activation of elbow flexors was assessed with both motor-point stimulation and transcranial magnetic stimulation over the motor cortex. In addition, we performed a psychophysical experiment to investigate the effect of induced muscle pain across a wide range of submaximal efforts (5-75% maximum). In all studies, elbow flexion torque was recorded before, during, and after experimental muscle pain by injection of 1 ml of 5% hypertonic saline into biceps. Injection of hypertonic saline evoked deep pain in the muscle (pain rating ∼5 on a scale from 0 to 10). Experimental muscle pain caused a small (∼5%) but significant reduction of maximal voluntary torque in the motor-point and motor cortical studies (P < 0.001 and P = 0.045, respectively; n = 7). By contrast, experimental muscle pain had no significant effect on voluntary activation when assessed with motor-point and motor cortical stimulation although voluntary activation tested with motor-point stimulation was reduced by ∼2% in contractions after pain had resolved (P = 0.003). Furthermore, induced muscle pain had no significant effect on torque output during submaximal efforts (P > 0.05; n = 6), which suggests that muscle pain did not alter the relationship between the sense of effort and production of voluntary torque. Hence, the present study suggests that transient experimental muscle pain in biceps brachii has a limited effect on central motor pathways.

Inhibitory mechanisms following electrical stimulation of tendon and cutaneous afferents in the lower limb.

Electrical stimulation of the Achilles tendon (TES) produced strong reflex depression (duration>250 ms) of a small background contraction in both heads of gastrocnemius (GA) via large diameter electrodes localized to the tendon. The inhibitory responses were produced without electrical (M wave) or mechanical (muscle twitch) signs of direct muscle stimulation. In this study, the contribution of presynaptic and postsynaptic mechanisms to the depression was investigated by studying conditioning effects of tendon afferent stimulation on the mechanical tendon reflex (TR) and magnetic motor evoked potential (MEP). TES completely inhibited the TR over an ISI of 300 ms that commenced before and continued during and after the period of voluntary EMG depression. Tendon afferent conditioning stimuli also partially inhibited the MEP, but over a short time course confined to the period of voluntary EMG depression. The strength and extended time course of tendon afferent conditioning of the TR and its failure to produce a similar depression of the MEP are consistent with a mechanism involving presynaptic inhibition of Ia terminals. Cutaneous (sural nerve) afferent conditioning partially inhibited the TR and MEP over a short time course (ISI <100 ms) resembling the inhibition seen in the voluntary EMG. This was consistent with the postsynaptic origin of cutaneous inhibition of the motoneurons.

Afferents contributing to autogenic inhibition of gastrocnemius following electrical stimulation of its tendon.

Electrical stimulation of the Achilles tendon produced strong reflex inhibition of the ongoing voluntary EMG activity in the two heads of the gastrocnemius (GA) muscle in all tested subjects. The inhibition was seen clearly in both averaged and single sweep surface EMG records. The inhibitory response was produced without electrical (M wave) or mechanical, (muscle twitch) signs of direct muscle stimulation. The onset latency and duration for the first period of inhibition (I(1)) were 47-49 ms and 67 ms, respectively. A second inhibition (I(2)) had an onset latency of 187-193 ms and duration under 40 ms. Non-noxious stimuli in the range of 2.6-7.6 x mean perceptual threshold, when delivered to four locations over the GA tendon, all produced clear inhibition of the voluntary muscle activity. The inhibition was maximal when the cathode was a large metal plate located near the musculotendinous junction and decreased approximately linearly with distances more distal to that site. The effect of passive muscle stretch on the electrically induced tendon reflex inhibition (TRE) was tested at ankle joint angles incremented in steps of 20 degrees. It was found that TRE is strongly dependent on joint angle, being maximal in the fully stretched muscle. TRE was lost completely after partial tibial nerve block. In comparison, GA inhibition produced by cutaneous (sural) nerve stimulation was of a higher threshold, longer latency and persisted after partial tibial nerve block. We thus demonstrated a powerful autogenic inhibition in the lower limb arising from tendon afferents in conscious subjects that is increased by passive muscle stretch and likely to originate from group I tendon afferents.

Reflex inhibition of normal cramp following electrical stimulation of the muscle tendon.

Muscle cramp was induced in one head of the gastrocnemius muscle (GA) in eight of thirteen subjects using maximum voluntary contraction when the muscle was in the shortened position. Cramp in GA was painful, involuntary, and localized. Induction of cramp was indicated by the presence of electromyographic (EMG) activity in one head of GA while the other head remained silent. In all cramping subjects, reflex inhibition of cramp electrical activity was observed following Achilles tendon electrical stimulation and they all reported subjective relief of cramp. Thus muscle cramp can be inhibited by stimulation of tendon afferents in the cramped muscle. When the inhibition of cramp-generated EMG and voluntary EMG was compared at similar mean EMG levels, the area and timing of the two phases of inhibition (I(1), I(2)) did not differ significantly. This strongly suggests that the same reflex pathway was the source of the inhibition in both cases. Thus the cramp-generated EMG is also likely to be driven by spinal synaptic input to the motorneurons. We have found that the muscle conditions that appear necessary to facilitate cramp, a near to maximal contraction of the shortened muscle, are also the conditions that render the inhibition generated by tendon afferents ineffective. When the strength of tendon inhibition in cramping subjects was compared with that in subjects that failed to cramp, it was found to be significantly weaker under the same experimental conditions. It is likely that reduced inhibitory feedback from tendon afferents has an important role in generating cramp.