Medullary Thyroid Carcinoma: Survival Analysis and Evaluation of Mutation-Specific Immunohistochemistry in Detection of Sporadic Disease.

INTRODUCTION: Medullary thyroid cancer (MTC) is a rare tumour of neuroendocrine origin with a more aggressive profile than differentiated thyroid cancer. Familial cases of MTC are associated with RET mutations whilst RAS mutations appear to be a frequent finding in RET negative tumours. The aims of this study were to analyse survival outcomes in MTC and to evaluate the role of RAS immunohistochemistry in the identification of sporadic disease. MATERIALS AND METHODS: A retrospective cohort study of consecutive patients with MTC was undertaken. The primary outcome measures were overall survival and disease-free survival. Survival analysis was performed on the basis of sporadic and familial disease. Patients had routine RET testing using the capillary (Sanger) sequencing method. Histopathological MTC slides from 100 patients were tested for HRASQ61R, a common somatic RAS mutation in MTC, with mutation-specific immunohistochemistry (IHC). RESULTS: A total of 195 patients had surgical treatment of MTC in the period 1980 to 2016. There were 83 males and 112 females with a mean age of 53.0 years. A total of 39 (20%) patients had familial disease. Sporadic cases had a higher median pre-op calcitonin (969.5 vs. 257.5 pg/ml), greater mean primary tumour size (23.5 vs. 12.5 mm) and more distant metastases (12.8 vs. 10.3%). Multivariate analysis showed age (p = 0.005), Multiple Endocrine Neoplasia Type 2 (MEN2) status (p = 0.021) and distant metastasis (p = 0.002) to be significant independent predictors of survival. Significant independent predictors for disease-free survival were age (p = 0.015), MEN2 (p = 0.002), pre-op calcitonin (p = 0.033) and venous invasion (p = 0.001). The overall 5-year survival was 100% for familial MTC and 78% for sporadic MTC. The 10-year disease-free survival was 94% for familial MTC and 61% for sporadic cases. A total of 100 cases of MTC underwent mutation-specific IHC for HRASQ61R. Of these, 18 had confirmed MEN2. IHC had 100% specificity in excluding MEN2. Twelve (12%) of 100 patients stained positive for HRASQ61R mutation. CONCLUSION: In the era of genetic testing, RET status significantly influences disease-specific survival in MTC. Mutation-specific IHC for HRASQ61R may have a role in the identification of patients presenting with sporadic disease.

BRAF(V600E) Mutation is Associated with Decreased Disease-Free Survival in Papillary Thyroid Cancer.

BACKGROUND: The BRAF (V600E) mutation is a recognised molecular marker in papillary thyroid cancer (PTC), reported incidence from 30 to 80 %. BRAF(V600E) aberrantly activates the MAPK pathway, a central regulator of cell growth and proliferation. Previous studies have reported conflicting data regarding the impact of BRAF(V600E) on clinicopathological features of PTC. The study aims to determine whether BRAF(V600E) is useful as a prognostic biomarker in PTC. METHODS: A cohort study of patients undergoing surgery for PTC was undertaken. The primary outcome measure was disease-free survival. Secondary outcome measures were tumour size, nodal positivity and radioactive iodine ablation rate. All cases were re-examined to confirm PTC. Immunohistochemistry for BRAF(V600E) was performed on tissue microarrays. A single endocrine pathologist, blinded to clinicopathological data, interpreted staining. RESULTS: 496 patients with PTC were included, and 309 (62 %) were BRAF(V600E) positive. Tumour size was similar for BRAF(V600E)-positive and -negative tumours (21.3 vs. 23.2 mm, p = 0.23). BRAF(V600E)-positive patients were significantly older at first operation (mean age 45 versus 49 years, p = 0.003). BRAF(V600E)-positive PTCs had a higher rate of disease recurrence (12.9 vs. 5.6 %, p = 0.004), lymph node metastasis (44 vs. 29.4 %, p = 0.004) and extra-thyroidal extension (44 vs. 22 %, p < 0.001). Five-year disease-free survival was 89.6 % for BRAF(V600E) positive and 96.3 % for negative tumours, p < 0.001. There was no difference between groups for vascular invasion or multifocality. The mean follow-up was 57 months for both groups. CONCLUSION: BRAF(V600E) in PTC predicts an increased risk of lymph node metastasis, extra-thyroidal extension and reduced disease-free survival. It is an additional useful prognostic biomarker.

Risk of needing completion thyroidectomy for low-risk papillary thyroid cancers treated by lobectomy.

Background: Low-risk differentiated thyroid cancers may, according to the American Thyroid Association (ATA) 2015 guidelines, be managed initially with lobectomy. However, definitive risk categorization requires pathological assessment of the specimen, resulting in completion thyroidectomy being recommended when discordance between preoperative and postoperative staging occurs. This study sought to establish the expected rate of completion thyroidectomy in patients with papillary thyroid cancer (PTC) treated by lobectomy. Methods: Patients with PTC treated over 5 years (2013-2017 inclusive) and meeting the ATA criteria for lobectomy were identified from the prospectively developed database of a high-volume, university department of endocrine surgery. Concordance between the ATA initial and final recommendation, and the putative rate of completion thyroidectomy were calculated. Multivariable analysis was used to assess preoperative factors as predictors of the need for total thyroidectomy. Results: Of 275 patients with PTC who met ATA preoperative criteria for lobectomy there was concordance between this and the final recommendation in 158 (57·5 per cent) and discordance in 117 (43·5 per cent). Most common reasons for discordance were: angioinvasion (30·8 per cent), local invasion (23·9 per cent) or both (20·5 per cent). Four patients (1·5 per cent) had permanent hypoparathyroidism. On multivariable analysis, age, sex, tumour size and family history did not independently predict the final treatment required. Conclusion: Although many patients may be treated adequately with lobectomy, just under half would require completion thyroidectomy. Further work is needed on preoperative risk stratification but, before this, total thyroidectomy remains the treatment of choice for low-risk 1-4-cm PTC in the hands of high-volume thyroid surgeons who can demonstrate low complication rates.

Slowness of movement in melancholic depression.

We studied 10 subjects each with melancholic depression evidencing significant motor retardation (RM), Parkinson's disease (PD) with bradykinesia, and normal healthy controls (NC), matched closely for age and gender, on measurements of motor function and depression, and their performance of simple and complex ballistic movements. The simple movements involved the execution of 10 degrees, 20 degrees, and 40 degrees angular movements using a methodology adapted from Hallett and Khoshbin (1980). The complex movements involved the performance by the right arm and hand of a squeeze and a flexion movement, both sequentially and simultaneously, using a methodology adopted from Benecke et al (1986, 1987). The RM and PD groups demonstrated a smaller increase in the angular velocity as the angle of the movement increased from 10 degrees to 40 degrees than did the NC group. Many PD and RM subjects showed multiple electromyographic (EMG) bursts during the ballistic movements. The RM and PD subjects tended take longer to perform the simultaneous and sequential movements, but nonsignificantly so. The RM group performed the squeeze movement slower when executed as part of the simultaneous movement than when performed as a simple movement. The pause time between the movements when performed sequentially was longer (nonsignificantly) for the RM subjects. Our study demonstrated a disturbance in the execution of simple and complex movements by RM subjects that resembled the disturbance seen in PD. This argues for a common pathophysiological basis for at least some aspects of motor retardation in the two disorders. Reduced dopamine function is one common abnormality that may partially account for these findings.

The audiogenic startle reflex in Tourette's syndrome.

The motor response pattern of the audiogenic startle reflex was studied in 15 Tourette's syndrome (TS) patients and 15 normal, age-matched control subjects, using auditory stimuli at 88 and 114 dB. The louder stimuli readily elicited responses in the orbicularis oculi (in all subjects), masseter, sternomastoid, trapezius, deltoid, and biceps (in most subjects) muscles, with a few subjects having responses in the forearm flexors and quadriceps. The TS subjects did not differ from controls in the onset latency, amplitude, and first peak latency of the reflex response in any of the muscles. Rates of habituation in the orbicularis oculi muscle were widely variable across the subjects, and the two groups did not differ overall in the habituation rates. Our study does not support the reports of an abnormal audiogenic startle reflex in TS.

Human rectosigmoid electromyography: a new approach and some pitfalls.

A method has been developed to record directly myoelectrical activity from the smooth muscle of the colon of intact subjects using pairs of intramuscular wires. Discrete bursts of myoelectrical activity occurred at 4-20 per min. A small interelectrode distance in this method allows contamination of colonic myoelectrical activity by the electromyogram of skeletal muscle to be excluded. This artefact has not been considered in previous recordings of 'colonic' activity.

Concordance between surface and intra-muscular recordings of facial emg during emotional expression.

Needle and surface EMG recordings were made from the left corrugator supercilii and zygomaticus major muscles, and the skin overlying them, in 12 right-handed normal subjects during imagined and posed sad, happy and angry states. The surface and needle EMG recordings showed good correspondence for the corrugator and zygomaticus major muscles within each individual subject. Considerable inter-subject and inter-emotion variability was, however, observed. The surface to needle concordance was poor when the EMG activity itself was low. While this study does not suggest that specific surface EMG recordings from the face are inappropriate, it provides a note of caution when the activity is low.

Effect of voluntary muscle contraction on the startle response to auditory stimuli.

Startle reflex responses were studied in 15 normal human subjects using weak (88 dB) and strong (114 dB) auditory stimuli in the orbicularis oculi, masseter, sternocleidomastoid, trapezius, deltoid, biceps, forearm flexors and quadriceps muscles. With the subjects in the relaxed state, no consistent responses were seen with the weak stimuli, and with the strong stimuli responses were only present in orbicularis oculi muscles. When the above muscles were in a state of voluntary contraction, the strong stimuli produced complex responses which were not always excitatory in nature, with muscle relaxation being noted in a number of stimulation sequences. Repetitive weak and strong stimuli were used to study habituation effects in the orbicularis oculi muscles. The repetitive strong stimuli produced a wide range of response patterns, indicating a high inter-individual variability in habituation. In two subjects, no habituation effects were present. Our study supports the high intra-individual variability of the startle response, and suggests that this response is affected by the state of muscle contraction at the time of stimulation. Startle response is more easily elicited in a state of muscular contraction. Future studies of startle reflex should take this into consideration.

The Australian experience with the Bethesda classification system for thyroid fine needle aspiration biopsies.

Fine needle aspiration biopsy (FNAB) is the initial investigation of choice for thyroid nodules. The Bethesda system, which classifies thyroid FNABs into different categories each linked to a risk of malignancy, has been widely adopted. However, the risk of malignancy implied by each Bethesda category is likely to vary due to population characteristics and inconsistency in the application of diagnostic criteria.We present our experience of the Bethesda system in 2076 thyroid nodules from 1410 patients. Categories were as follows: 266 (12.8%) were category 1 (B1) non-diagnostic, 1551 (74.7%) category 2 (B2) benign, 97 (4.7%) category 3 (B3) atypia of uncertain significance, 98 (4.7%) category 4 (B4) suspicious for follicular neoplasm, 16 (0.8%) category 5 (B5) suspicious for malignancy and 48 (2.3%) category 6 (B6) malignant.Surgery was performed on 425 nodules from 315 patients. Malignancy rates in the target nodules were B1 4.2%, B2 0.26%, B3 9.3%, B4 15.3%, B5 79% and B6 100%. Twelve patients with B3 nodules underwent repeat FNAB, with eight reclassified as B2, one as B3, one as B1 and two as B4. An incidental microcarcinoma separate to the target nodule was identified in 11.1%.As applied in our institution, and despite very sparing use of B3 and B5 categories, our audit has demonstrated risks of malignancy broadly in keeping with that predicted. Of note, the risk of malignancy in the clinically indeterminate categories of B1, B3 and B4 were all at the lower ranges of those predicted in the Bethesda atlas and mostly lower than those reported by other studies.

Reflex changes in muscle spindle discharge during a voluntary contraction.

1. This study was undertaken to determine whether low-threshold cutaneous and muscle afferents from mechanoreceptors in the foot reflexly affect fusimotor neurons innervating the plantar and dorsiflexors of the ankle during voluntary contractions. 2. Recordings were made from 29 identified muscle spindle afferents innervating triceps surae and the pretibial flexors. Trains of electrical stimuli (5 stimuli, 300 impulses per second) were delivered to the sural nerve at the ankle (intensity: 2-4 times sensory threshold) and to the posterior tibial nerve at the ankle (intensity: 1.5-3 times motor threshold for the small muscles of the foot). The stimuli were delivered while the subject maintained an isometric voluntary contraction of the receptor-bearing muscle, sufficient to accelerate the discharge of each spindle ending. This ensured that the fusimotor neurons directed to the ending were active and influencing the spindle discharge. The effects of these stimuli on muscle spindle discharge were assessed using raster displays, frequencygrams, poststimulus time histograms (PSTHs) and cumulative sums ("CUSUMs") of the PSTHs. Reflex effects onto alpha-motoneurons were determined from poststimulus changes in the averaged rectified electromyogram (EMG). Reflex effects of these stimuli onto single-motor units were assessed in separate experiments using PSTHs and CUSUMs. 3. Electrical stimulation of the sural or posterior tibial nerves at nonnoxious levels had no significant effect on the discharge of the 14 spindle endings in the pretibial flexor muscles. The electrical stimuli also produced no significant change in discharge of 11 of 15 spindle endings in triceps surae. With the remaining four endings in triceps surae, the overall change in discharge appeared to be an increase for two endings (at latencies of 60 and 68 ms) and a decrease for two endings (at latencies of 110 and 150 ms). The difference in the incidence of the responses of spindle endings in tibialis anterior and in triceps surae was significant (P less than 0.05, chi 2 test). 4. For both triceps surae and pretibial flexor muscles the electrical stimuli to sural or posterior tibial nerves had clear effects on the alpha-motoneuron pool, whether assessed using surface EMG or the discharge of single-motor units. Based on EMG recordings using intramuscular wire electrodes, the reflex effects differed for the gastrocnemii and soleus. 5. In this study, reflex changes in the discharge of human spindle endings were more difficult to demonstrate than comparable changes in the discharge of alpha-motoneurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in perceived heaviness and motor commands produced by cutaneous reflexes in man.

1. This study examined the relationship between the perceived heaviness of a weight and reflexes acting on the motoneurones required for the contraction. The perceived heaviness of low (100 g) and high (500 g) reference weights lifted by the first dorsal interosseous muscle was estimated using a matching task. Weights were also lifted during stimulation of the digital nerves of the index finger at two times and four times sensory threshold (T). Averages of force and EMG were also made when isometric forces of 100 and 500 g were maintained. 2. Stimuli at 4T produced a significant increase in perceived heaviness in each subject for both reference weights. Averages of EMG made under isometric conditions showed a short-latency inhibition with a reflex reduction in force following single stimuli. This inhibition was also observed during weight lifting when trains of stimuli were given. 3. Stimuli at 2T produced less-marked changes in EMG, averaged force, and perceived heaviness for individual subjects. However, for the group of subjects, perceived heaviness declined significantly with 2T stimuli for the 500 g but not the 100 g weight. This decrease in perceived heaviness was associated with evidence of short-latency facilitation within the motoneurone pool. 4. Inhibition of the motoneurone pool was associated with an increase and facilitation with a decrease in perceived heaviness. These observations favour a role for a signal of centrally generated motor command in the sensation of heaviness and provide insight as to how this signal must change when reflex inputs change and when high-threshold motoneurones are recruited.

Concordance between colonic myoelectrical signals recorded with intramuscular electrodes in the human rectosigmoid in vivo.

The myoelectrical activity of the human rectosigmoid colon was studied simultaneously in six subjects at two sites using two pairs of fine wire bipolar electrodes. The electrodes were spaced 2-5 cm apart in the rectosigmoid after insertion into the smooth muscle layers under direct vision at sigmoidoscopy. The electrodes were implanted at positions between 8 and 25 cm from the anal verge in different subjects. The frequency of myoelectrical burst activity together with the burst duration recorded by each electrode pair was examined. The relation of burst frequency and burst duration in the higher and lower placed electrodes was also assessed. In none of the subjects was three evidence of synchrony between the electrode pairs. In addition, there was no relation between the relative position of the electrodes and the intrinsic frequency of duration of myoelectrical bursts. It is concluded that regions of smooth muscle in the unstimulated human colon in vivo act independently and that there is no effective common neuromuscular drive under these conditions.

Reflex responses in active muscles elicited by stimulation of low-threshold afferents from the human foot.

1. Reflex responses were elicited in muscles that act at the ankle by electrical stimulation of low-threshold afferents from the foot in human subjects who were reclining supine. During steady voluntary contractions, stimulus trains (5 pulses at 300 Hz) were delivered at two intensities to the sural nerve (1.2-4.0 times sensory threshold) or to the posterior tibial nerve (1.1-3.0 times motor threshold for the intrinsic muscles of the foot). Electromyographic (EMG) recordings were made from tibialis anterior (TA), peroneus longus (PL), soleus (SOL), medial gastrocnemius (MG), and lateral gastrocnemius (LG) muscles by the use of intramuscular wire electrodes. 2. As assessed by averages of rectified EMG, stimulation of the sural or posterior tibial nerves at nonpainful levels evoked a complex oscillation with onset latencies as early as 40 ms and lasting up to 200 ms in each muscle. The most common initial responses in TA were a decrease in EMG activity at an onset latency of 54 ms for sural stimuli, and an increase at an onset latency of 49 ms for posterior tibial stimuli. The response of PL to stimulation of the two nerves began with a strong facilitation of 44 ms (sural) and 49 ms (posterior tibial). With SOL, stimulation of both nerves produced early inhibition beginning at 45 and 50 ms, respectively. With both LG and MG, sural stimuli produced an early facilitation at 52-53 ms. However, posterior tibial stimuli produced different initial responses in these two muscles: facilitation in LG at 50 ms and inhibition in MG at 51 ms. 3. Perstimulus time histograms of the discharge of 61 single motor units revealed generally similar reflex responses as in multiunit EMG. However, different reflex components were not equally apparent in the responses of different single motor units: an individual motor unit could respond slightly differently with a change in stimulus intensity or background contraction level. The multiunit EMG record represents a global average that does not necessarily depict the precise pattern of all motor units contributing to the average. 4. When subjects stood erect without support and with eyes closed, reflex patterns were seen only in active muscles, and the patterns were similar to those in the reclining posture. 5. It is concluded that afferents from mechanoreceptors in the sole of the foot have multisynaptic reflex connections with the motoneuron pools innervating the muscles that act at the ankle. When the muscles are active in standing or walking, cutaneous feedback may play a role in modulating motoneuron output and thereby contribute to stabilization of stance and gait.

In-parallel and in-series behavior of human muscle spindle endings.

1. The responses of 62 putative muscle spindle afferents innervating the pretibial flexor muscles of normal human subjects were studied during graded twitch contractions of the receptor-bearing muscle to search for possible in-series coupling between spindle endings and motor units. 2. The majority of afferents (n = 57) responded unequivocally in an in-parallel manner to the twitch contractions, regardless of contraction strength. There were two patterns of in-parallel response: afferents without background activity discharged during the relaxation phase of the twitch; afferents with a background discharge were transiently silenced during the contraction phase and resumed their discharge on the relaxation phase. 3. Evidence of in-series coupling was found for five afferents during submaximal twitch contractions, to which each afferent responded in a mixed "biphasic" manner, with increases in discharge during both the contraction and relaxation phases of the twitch. Background discharge, response to stretch, and response during isometric voluntary contractions suggested that four of the afferents innervated primary spindle endings and the fifth a secondary spindle ending. 4. It is argued that the five atypical spindle endings responded in an ambiguous manner during twitch contractions of the receptor-bearing muscle because there was an in-series mechanical coupling between motor units and the spindle. The incidence of demonstrable in-series responses has serious implications for the mechanisms of spindle activation during normal motor behavior, but has only minor implications for the use of the twitch test to identify muscle spindle endings.

Reduction in perceived intensity of cutaneous stimuli during movement: a quantitative study.

The effect of movement of the index finger on the perceived intensity of trains of electrical stimuli to the digital nerves of the same finger was studied quantitatively using a novel intramodality stimulus-matching task. Subjects consistently were able to match reliably the perceived intensity of stimuli delivered on the 'reference' side with that of stimuli delivered simultaneously to the digital nerves of the index finger on the other ('matching') side. Both active and passive movement of the index finger (on the reference side) in the palmar plane reduced the matched stimulus voltage by about 10% of its control value for stimuli at twice the sensory threshold. This reduction in perceived intensity did not persist beyond the period of stimulation. An isometric contraction of first dorsal interosseous muscle produced a smaller, but statistically significant, reduction in perceived intensity. Non-noxious electrical stimulation of the digital nerves of the ipsilateral thumb or little finger also reduced the perceived intensity of stimuli to the index finger. Perceived intensity of stimuli during movement was also reduced, but to a lesser extent, when the index finger was stimulated at painful levels. Psychophysical studies using open magnitude scaling indicated that the relationship between stimulus intensity and perceived magnitude of electrical stimuli could be described by a power law with an exponent close to 1.0. Therefore, the percentage reduction in matching voltage accurately represents the percentage decline in perceived intensity. These results suggest that the perceived intensity of cutaneous stimuli to the index finger over a range of intensities can be reduced by afferent activity from the hand. The motor command appears to play a relatively minor role in modulating the perceived intensity.

Behavior of human muscle receptors when reliant on proprioceptive feedback during standing.

1. This study investigated the muscle-spindle discharge from the pretibial flexor muscles of standing human subjects while they performed maneuvers that altered their reliance on proprioceptive feedback to control balance. Single-unit recordings were made from 100 identified muscle afferents, 81 from muscle-spindle endings and 19 from Golgi tendon organs. 2. With 49 spindle endings the subjects stood on a horizontal platform and with 32, on a platform tilted in dorsiflexion (4 degrees) to ensure that the pretibial muscles were active to maintain balance. When standing freely on a horizontal platform without support or vision, there was little or no electromyographic (EMG) activity in the pretibial muscles, and spindle discharge rates were low (55% active; mean rate for all 49 endings, 4.1 Hz). When standing similarly on the tilted platform, 69% of the spindle afferents were active, and the mean discharge rate was 5.4 Hz. The greater number of actively discharging spindle afferents and the preservation of mean discharge rate despite muscle shortening indicates that the pretibial muscles are subjected to increased fusimotor drive when they are tonically active to maintain balance. 3. The effects of small degrees of body sway induced voluntarily or by an external stimulus were studied with 41 afferents (29 spindles; 12 tendon organs). Activation of the pretibial muscles to compensate for backward sway was accompanied by a spindle discharge that usually exceeded the discharge produced by comparable passive movement. This indicates that the pretibial muscles are subjected to increased fusimotor drive when they are phasically active to maintain balance. 4. To vary the reliance placed on the feedback from proprioceptive inputs, the subjects abruptly opened and shut their eyes, took and released support, or tilted their heads. There were no detectable changes in afferent activity unless the maneuver produced a change in EMG activity in the pretibial muscles and/or body sway. Thirty afferents (26 of 46 spindles; 4 of 7 tendon organs) underwent a change in discharge rate associated with a transient change in posture, as recorded by the force platform, or a change in EMG activity in the receptor-bearing muscle. The discharge pattern of 23 afferents did not show any clear change with these maneuvers. 5. It is concluded that maneuvers that increase the reliance on proprioceptive feedback when subjects are standing quietly do not significantly alter the fusimotor drive to the pretibial muscles in the absence of muscle contraction.(ABSTRACT TRUNCATED AT 400 WORDS)

Reflex activation of muscle spindles in human pretibial muscles during standing.

1. Experiments were performed in standing subjects to determine whether low-threshold cutaneous and muscle afferents from mechanoreceptors in the human foot reflexly influence fusimotor neurons innervating pretibial flexor muscles. Recordings were made from 30 identified muscle-spindle afferents, four tendon-organ afferents, and one alpha-motor axon innervating the pretibial flexor muscles. The subjects stood without support or vision on a force platform while trains of electrical stimuli (5 stimuli, 300 Hz) were delivered at nonpainful intensities to the sural nerve or to the posterior tibial nerve at the ankle. 2. Seventeen of the 30 spindle endings had no background discharge, and none was activated by the sural or posterior tibial stimuli. Five silent afferents were given a background discharge by sustained pressure on the relevant tendon, but with two the discharge was dominated by a tremor rhythm obscuring any reflex response to the stimuli. Based on peristimulus time histograms (PSTHs), the sural stimuli then produced increases in discharge of two of the remaining three endings at latencies of 84 and 90 ms. These effects could not be explained by muscle stretch and are presumed to have been fusimotor mediated. 3. When the subjects stood freely without support or vision, 13 muscle-spindle endings had a background discharge, but with three endings tremor developed at the ankle and dominated the spindle discharge. Sural stimuli affected the discharge of five of nine endings unaffected by tremor. With three of these endings, there were changes in discharge that could be explained by muscle stretch.(ABSTRACT TRUNCATED AT 250 WORDS)

Reflex influences on muscle spindle activity in relaxed human leg muscles.

The study was designed to determine whether low-threshold cutaneous and muscle afferents from the foot reflexly activate gamma-motoneurons innervating relaxed muscles of the leg. In 15 experiments multiunit recordings were made from 21 nerve fascicles innervating triceps surae or tibialis anterior. In a further nine experiments the activity of 19 identified single muscle spindle afferents was recorded, 13 from triceps surae, 5 from tibialis anterior, and 1 from extensor digitorum longus. Trains of electrical stimuli (5 stimuli, 300 Hz) were delivered to the sural nerve at the ankle (intensity, twice sensory threshold) and the posterior tibial nerve at the ankle (intensity, 1.1 times motor threshold for the small muscles of the foot). In addition, a tap on the appropriate tendon at varying times after the stimuli was used to assess the dynamic responsiveness of the afferents under study. The conditioning electrical stimuli did not change the discharge of single spindle afferents. Recordings of rectified and averaged multiunit activity also revealed no change in the overall level of background neural activity following the electrical stimuli. The afferent responses to tendon taps did not differ significantly whether or not they were preceded by stimulation of the sural or posterior tibial nerves. These results suggest that low-threshold afferents from the foot do not produce significant activation of fusimotor neurons in relaxed leg muscles, at least as judged by their ability to alter the discharge of muscle spindle afferents. As there may be no effective background activity in fusimotor neurons innervating relaxed human muscles, it is possible that these inputs from the foot could influence the fusimotor system during voluntary contractions when the fusimotor neurons have been brought to firing threshold. In one subject trains of stimuli were delivered to the posterior tibial nerve at painful levels (30 times motor threshold). They produced an acceleration of the discharge of a spindle in soleus at a latency of approximately 125 ms, in advance of detectable activity in skeletomotor neurons and before an increase in muscle length was noted. It presumably resulted from activation of gamma-motoneurons innervating soleus by small myelinated afferents (A-delta range).