Smad2 and Smad3 expressed in skeletal muscle promote immobilization-induced bone atrophy in mice.

Skeletal muscle is known to regulate bone homeostasis through muscle-bone interaction, although factors that control this activity remain unclear. Here, we newly established Smad3-flox mice, and then generated skeletal muscle-specific Smad2/Smad3 double conditional knockout mice (DcKO) by crossing Smad3-flox with skeletal muscle-specific Ckmm Cre and Smad2-flox mice. We show that immobilization-induced gastrocnemius muscle atrophy occurring due to sciatic nerve denervation was partially but significantly inhibited in DcKO mice, suggesting that skeletal muscle cell-intrinsic Smad2/3 is required for immobilization-induced muscle atrophy. Also, tibial bone atrophy seen after sciatic nerve denervation was partially but significantly inhibited in DcKO mice. Bone formation rate in wild-type mouse tibia was significantly inhibited by immobilization, but inhibition was abrogated in DcKO mice. We propose that skeletal muscle regulates immobilization-induced bone atrophy via Smad2/3, and Smad2/3 represent potential therapeutic targets to prevent both immobilization-induced bone and muscle atrophy.

Sensory nerves protect from the progression of early stage osteoarthritis in mice.

PURPOSE: Osteoarthritis (OA) is a chronic degenerative joint disease. Sensory nerves play an important role in bone metabolism and in the progression of inflammation. This study explored the effects of sensory nerve on OA progression at early stage in mice. MATERIALS AND METHODS: OA was induced via destabilization of the medial meniscus (DMM) in C57BL/6 mice. Sensory denervation was induced by subcutaneous injection of capsaicin (90 mg/kg) one week prior to DMM. One week after capsaicin injection, sensory denervation in the tibia was confirmed by immunofluorescent staining. Four weeks after DMM, micro-CT scans, histological analysis, and RT-PCR tests were performed to evaluate OA progression. RESULTS: Subcutaneous injection of capsaicin successfully induced sensory denervation in tibia. The Osteoarthritis Research Society International (OARSI) score and synovitis score of the capsaicin+DMM group were significantly higher than the score of the vehicle+DMM group. The BV/TV of the tibial subchondral bone in the capsaicin+DMM group was significantly lower than in the vehicle+DMM group. In addition, the level of expression of inflammatory factors in the capsaicin+DMM group was significantly higher than in the vehicle+DMM group. CONCLUSIONS: Capsaicin-induced sensory denervation accelerated OA progression at early stage in mice. To put it another way, sensory nerve protects from OA progression at early stage in mice.

Sciatic Nerve Variants in Patients Diagnosed With Sciatica: Is There a Correlation?

PURPOSE: Compression of the sciatic nerve in its path along the piriformis muscle can produce sciatica-like symptoms. There are 6 predominant types of sciatic nerve variations with type 1 being the most common (84.2%), followed by type 2 (13.9%). However, there is scarce literature on the prevalence of sciatic nerve variation in those diagnosed with sciatica. MATERIALS AND METHODS: The charts of 95 patients clinically diagnosed with sciatica who had a magnetic resonance imaging of the pelvis/hip were retrospectively studied. All patients had T1-weighted axial, coronal, and sagittal images. Magnetic resonance imagings were interpreted separately by 2 board-certified fellowship-trained musculoskeletal radiologists to identify the sciatic nerve variant. RESULTS: Seven cases were excluded because of inadequate imaging. Of the remaining 88 patients, 5 had bilateral sciatica resulting in a sample size of 93 limbs. Fifty-two (55.9%) had type 1 sciatic nerve anatomy, 39 (41.9%) had type 2, and 2 (2.2%) had type 3. The proportions of type 1 and 2 variations were significantly different from the normal distribution (P < 0.001), whereas type 3, 4, 5, and 6 variants were not (P = 1.00). CONCLUSIONS: There is strong statistical significance regarding the relationship between sciatic nerve variation and the clinical diagnosis of sciatica. Preoperative magnetic resonance imaging can be considered in sciatica patients to prevent iatrogenic injury in pelvic surgery.

Posterior tibial perforators relationship with superficial nerves and veins: A cadaver study.

BACKGROUND: Most authors have evaluated the location of lower leg arterial perforators, but little is still known about the relationship between the arterial network and great saphenous vein (GSV) and saphenous nerve (SN). The aim of this study is to evaluate the relationship between the arterial network of the posterior tibial artery perforators, the cutaneous nerves, and the superficial venous system in the lower one third of the leg. METHODS: Eighteen lower limbs from cadavers were used for this study. The arterial and venous compartment were selectively injected with a mixture of barium sulfate and epoxy. The specimen were CT scanned and the superficial veins, nerves, and the arterial perforators were dissected. RESULTS: A large perforator of the posterior tibial artery was found at a mean distance of 6.23 cm ± 0.88, with a 95% CI: 5.79-6.67, from the medial malleolus. The average diameter was 0.9 mm ± 0.17, with a 95% CI: 0.81-0.99. In 67% the connection of the venae comitantes to the superficial venous system was established with the GSV, in the other cases, with Leonardo's vein. Both dissection and imaging studies showed perineural interperforator connections along the branches of SN in all the specimens examined. CONCLUSIONS: The distribution pattern of posterior tibial artery perforators followed the superficial nerves in this region. There is an interperforator anastomotic network along the SN. The various patterns of the venous drainage system, in relationship to the distribution of the branches of posterior tibial artery perforators, have been clarified.

Two accessory muscles of leg: potential source of entrapment of posterior tibial vessels.

Accessory muscles can be found in any part of the body. In most of the regions, they go unnoticed. However, in some cases, they become symptomatic or of cosmetic concern. In this particular case, the presence of two accessory muscle slips was observed in the flexor compartment of the leg. Among the two, the first accessory muscle belly connected the lower part of flexor hallucis longus to the tibialis posterior. The muscle crossed superficial to the posterior tibial vessels. The second accessory muscle took origin from the connective tissue around the lower part of the posterior tibial vessels and was inserted to the upper part of the lateral border of tibia near the attachment of the interosseous membrane. One of the accessory muscles crossed the posterior tibial vessels, while the other surrounded them. The above accessory muscles were supplied by the branches of tibial nerve.

Anatomical feasibility study of flexor hallucis longus transfer in treatment of Achilles tendon and posteromedial portal of ankle arthroscopy.

PURPOSE: The aim of this study was to evaluate the occurrence of anatomical variations of the musculotendinous junction of the flexor hallucis longus (FHL) muscle, the relationship between FHL tendon or muscle and the tibial neurovascular bundle at the level of the posterior ankle joint in human cadavers. METHODS: Seventy embalmed feet from 20 male and 15 female cadavers, the cadavers' mean age was 65.4 (range from 14 to 82) years, were dissected and anatomically classified to observe FHL muscle morphology define the relationship between FHL tendon or muscle and the tibial neurovascular bundle. The distance between the musculotendinous junction and the relationship between FHL tendon or muscle and the tibial neurovascular bundle was determined. RESULTS: Three morphology types of FHL muscle were identified: a long lateral and shorter medial muscle belly, which was observed in 63 specimens (90%); equal length medial and lateral muscle bellies, this variant was only observed in five specimens (7.1%); one lateral and no medial muscle belly, which was observed in two specimens (2.9%). No statistically significant difference was observed according to gender or side (p > 0.05). Two patterns were identified and described between FHL tendon or muscle and the tibial neurovascular bundle. Pattern 1, the distance between the neurovascular bundle and FHL tendon was 3.46 mm (range 2.34-8.84, SD = 2.12) which was observed in 66 specimens (94.3%); Pattern 2, there was no distance which was observed in four specimens (5.7%). CONCLUSION: Knowing FHL muscle morphology, variations provide new important insights into secure planning and execution of a FHL transfer for Achilles tendon defect as well as for the interpretation of ultrasound and magnetic resonance images. With posterior arthroscopic for the treatment of various ankle pathologies, posteromedial portal may be introduced into the posterior aspect of the ankle without gross injury to the tibial neurovascular structures because of the gap between the neurovascular bundle and FHL tendon.

[Automated two-point discrimination (TPD) for phantom pain : Effect of a 3­week automated therapy based on TPD for a transtibial amputee with phantom pain]. / Automatisierte Zweipunktdiskrimination bei Phantomschmerzen : Effekt einer 3­wöchigen automatisierten Therapie auf der Basis der Zweipunktdiskrimination (ZPD) bei einem unterschenkelamputierten Patienten mit Phantomschmerzen.

There is preliminary evidence that phantom pain is associated with disturbed organization of the sensory cortex and that this organization can be normalized with two-point discrimination (TPD) training. In this case study, a reduction in phantom pain and painful phantom sensation during a test period of 19 days, was achieved using an automated TPD procedure. In a patient with a transtibial amputation, pain levels decreased from a mean of 2.3/10 on the visual analog scale (VAS) to 1.3/10 (VAS) and the painful phantom sensation level decreased from a mean 3.7/10 (VAS) to 2.0/10 (VAS). These results show a positive trend, but are (except of the nocturnal pain attacks) rather of limited clinical relevance.

Approach for needle insertion into the tibialis posterior: An ultrasonography study.

INTRODUCTION: To avoid neurovascular damage by needle electrode insertion into the tibialis posterior, we used ultrasonography to determine the proper insertion point based on anatomic landmarks. METHODS: Using ultrasonography, the safety window, the corrected safety window, and the depth of the tibialis posterior were measured at 4 points (the upper third and midpoint of the tibia using anterior and posterior approaches) in healthy volunteers. RESULTS: The safety window at the midpoint for the posterior approach was significantly larger than at the other points. The corrected safety window could be defined only at the upper third for the anterior approach and at the midpoint for the posterior approach. CONCLUSIONS: Among the 4 points used for needle insertion into the tibialis posterior, the midpoint by the posterior approach may be the most favorable insertion point. The upper third may be better for the anterior approach.

Sacral nerve stimulation versus percutaneous posterior tibial nerve stimulation in the treatment of severe fecal incontinence in men.

BACKGROUND: Sacral nerve stimulation and percutaneous posterior tibial nerve stimulation have been described previously as effective treatments for fecal incontinence. Nevertheless, there does not exist any study that compares the efficiency of both. The aim of this study was to compare the use of SNS and PPTNS in males with FI. METHODS: We conducted a prospective cohort study on men with FI treated with SNS or PTNS in the Coloproctology Unit of the University General Hospital of Elche and Reina Sofia of Murcia between January 2010 and December 2011. Preoperative assessment included physical examination, anorectal manometry, and anal endosonography. Anal continence was evaluated using the Wexner continence grading system. Quality of life was evaluated using the Fecal Incontinence Quality of life Scale. RESULTS: Nineteen patients were included (ten patients SNS and nine PPTNS). SNS improved FI in nine of the ten patients. The mean Wexner score decreased significantly from a median of 14 (12-16) (preoperative) to 4 (1-8) (6-month revision) (p = 0.007). PTNS improved FI in seven of the nine patients. The mean Wexner score decreased significantly from a median of 12 (11-19) (preoperative) to 5 (4-7) (6-month revision) (p = 0.018). Both treatments produced symptomatic improvement without statistical differences between them. CONCLUSIONS: Our study was nonrandomized with a relatively small number of patients. PPTNS had similar efficiency to the SNS in our men population. However, more studies are necessary to exclude selection bias and analyze long-term results.

Long Term Outcome of Conservative Management or Surgical Treatment of Bovine Spastic Paresis: 79 Cases.

OBJECTIVE: To report the long term clinical outcome of calves treated surgically or managed conservatively for bovine spastic paresis of the gastrocnemius (BSP-G), quadriceps femoris muscle (BSP-Q), or mixed muscle involvement (BSP-M). STUDY DESIGN: Retrospective case study. ANIMALS: Calves (n = 79) with bovine spastic paresis. METHODS: Medical records of calves treated by partial tibial neurectomy or managed conservatively for bovine spastic paresis were analyzed for sex, breed, lineage history, and the onset, duration, and severity of clinical signs. Cases were classified as unilateral or bilateral BSP-G, BSP-Q, or BSP-M. Long term follow-up information was obtained by telephone questionnaire. RESULTS: The study group included 26 BSP-G (33%), 16 BSP-Q (20%), and 37 BSP-M (47%) calves. BSP-M and BSP-Q calves were significantly more bilaterally affected compared to BSP-G calves. Twenty-five of 26 BSP-G calves were treated surgically; 86% had complete resolution of clinical signs. Twenty-nine of 37 BSP-M calves were treated surgically; 81.5% improved, but none completely recovered. In all of the conservatively managed BSP-M calves, clinical signs gradually worsened. None of the BSP-Q calves were treated surgically; in 66.7%, clinical signs gradually worsened and 33.3% of calves spontaneously improved. CONCLUSION: Partial tibial neurectomy is advocated for the treatment of BSP-G and in selected cases of BSP-M. However, only partial resolution of clinical signs should be expected for BSP-M. No surgical treatment exists for BSP-Q calves, although spontaneous improvement is possible.

Morphofunctional Changes in the Tibial and Peroneal Nerves in Shin Lengthening Using High Speed Daily Distraction Technique.

A sustained decrease in the M-response amplitudes of m. gastrocnemius and m. tibialis anterior was revealed during experimental orthopedic shin lengthening in dogs using Ilizarov external fixator with an automated drive (distraction 3 mm/day in 120 steps). Transverse contraction of intrafascicular content (by 13.2%), endoneural hypervascularization (by 28-95%), axonal degeneration and myelin decompactization, and destructive changes of no more than 5% fibers were detected in the tibial nerve. In the peroneal nerve, the contraction reached 17.3%. Endoneurium hypovascularization (by 12%), axonal degeneration and demyelinization, and destructive changes of more than 20% fibers were detected in 6 of 9 experiments.

Paradoxical response to mechanical unloading in bone loss, microarchitecture, and bone turnover markers.

BACKGROUND: Sclerostin, encoded by the SOST gene, has been implicated in the response to mechanical loading in bone. Some studies demonstrated that unloading leads to up-regulated SOST expression, which may induce bone loss. PURPOSE: Most reported studies regarding the changes caused by mechanical unloading were only based on a single site. Considering that the longitudinal bone growth leads to cells of different age with different sensitivity to unloading, we hypothesized that bone turnover in response to unloading is site specific. METHODS: We established a disuse rat model by sciatic neurectomy in tibia. In various regions at two time-points, we evaluated the bone mass and microarchitecture in surgically-operated rats and control rats by micro-Computed Tomography (micro-CT) and histology, sclerostin/SOST by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (qPCR), tartrate resistant acid phosphatase 5b (TRAP 5b) by ELISA and TRAP staining, and other bone markers by ELISA. RESULTS: Micro-CT and histological analysis confirmed bone volume in the disuse rats was significantly decreased compared with those in the time-matched control rats, and microarchitecture also changed 2 and 8 weeks after surgery. Compared with the control groups, SOST mRNA expression in the diaphysis was down-regulated at both week 2 and 8. On the contrary, the percentage of sclerostin-positive osteocytes showed an up-regulated response in the 5 - 6 mm region away from the growth plate, while in the 2.5 - 3.5 mm region, the percentage was no significant difference. Nevertheless, in 0.5 - 1.5 mm region, the percentage of sclerostin-positive osteocytes decreased after 8 weeks, consistent with serum SOST level. Besides, the results of TRAP also suggested that the expression in response to unloading may be opposite in different sites or system. CONCLUSION: Our data indicated that unloading-induced changes in bone turnover are probably site specific. This implies a more complex response pattern to unloading and unpredictable therapeutics which target SOST or TRAP 5b.

Anatomical relationship between the deep peroneal nerve and the anterolateral surface of the tibia in Thai cadavers.

BACKGROUND: The deep peroneal nerve innervates muscles of the anterior leg compartment and the dorsum of the foot, and also receives sensation from the first interdigital cleft of the foot. Along its course in lower part of the leg, this nerve is very close to the anterolateral surface of the tibia and might be vulnerable to injury in fractures of the tibia or during surgery. OBJECTIVE: The objective of this study is to clarify the relationship between the deep peroneal nerve and anterolateral surface of tibia. MATERIAL AND METHOD: Variations in the course of the deep peroneal nerve related to the anterolateral surface of tibia were investigated by dissection of 82 legs from 45 fresh cadavers. The distance by which the deep peroneal nerve was directly contacted to the tibia was measured and compared to the length from the tibial tuberosity to the medial malleolus. The length of that association, as a percentage ofthe distance from the tibial tuberosity to the medial malleolus, was calculated. RESULTS: The fraction of the distance along which the deep peroneal nerve was in direct contact with the anterolateral surface of the tibia as a percentage of the distance between the tibial tuberosity and the medial malleolus ranged from 40.38% to 84.11%, with an average of 64.87% (95% confidence interval: 63.23-66.52%). In the majority of the legs studied (52.44%), the percentage range between 60-70%. CONCLUSION: An majority of the deep peroneal nerve was directly in contact with the anterolateral surface of tibia and ranged from 60-70% of the distance between tibia tuberosity and medial malleolus. Surgical incision along this area should be carefully performed.

[CHANGES OF THE SUPERFICIAL PERONEAL NERVE IN RELATION TO THE FREQUENCY OF HIGH-FRACTIONAL AUTODISTRACTION IN ORTHOPEDIC LENGTHENING OF THE TIBIA IN DOGS WITH A DAILY RATE OF 3 mm].

The experiments on the elongation of the tibia in 18 dogs were performed for 10 days using the Ilizarov apparatus with an automatic drive providing the pace of 3 mm/day for 120 moves (group 1) and 180 moves (group 2). The impact of fractionation of distraction on the structure of the peroneal nerve was estimated. In group 1, perineurium micro-injuries and endoneural blood vessel destruction were detected. In group 2, perineurium preserved its integrity and fine-lamellar structure, endoneural blood vessels were also preserved, however, the decrease in the total area of nerve fiber bundles was more pronounced. Morphometric analysis of the preserved myelinated nerve fibers 60 days after the cessation of distraction indicated less marked axonal atrophy and better myelination in group 2.

Ipsilateral corticomotor excitability is associated with increased gait variability in unilateral transtibial amputees.

Ipsilateral primary motor cortex (M1) reorganisation after unilateral lower-limb amputation may degrade function of the amputated limb. We hypothesised unilateral lower-limb amputees would have a bilateral increase in corticomotor excitability, and increased excitability of ipsilateral M1 would be associated with increased step-time variability during gait. Twenty transtibial amputees (16 male) aged 60.1 years (range 45-80 years), and 20 age- and gender-matched healthy adult controls were recruited. Single-pulse transcranial magnetic stimulation assessed corticomotor excitability. Two indices of corticomotor excitability were calculated. An index of corticospinal excitability (ICE) determined relative excitability of ipsilateral and contralateral corticomotor projections to alpha-motoneurons innervating the quadriceps muscle (QM) of the amputated limb. A laterality index (LI) assessed relative excitability of contralateral projections from each hemisphere. Spatial-temporal gait analysis was performed to calculate step-time variability. Amputees had lower ICE values, indicating relatively greater excitability of ipsilateral corticomotor projections than controls (P = 0.04). A lower ICE value was associated with increased step-time variability for amputated (P = 0.04) and non-amputated limbs (P = 0.02). This association suggests corticomotor projections from ipsilateral M1 to alpha-motoneurons innervating the amputated limb QM may interfere with gait. Cortical excitability in amputees was not increased bilaterally, contrary to our hypothesis. There was no difference in excitability of contralateral M1 between amputees and controls (P = 0.10), and no difference in LI (P = 0.71). It appears both hemispheres control one QM, with predominance of contralateral corticomotor excitability in healthy adults. Following lower-limb amputation, putative ipsilateral corticomotor excitability is relatively increased in some amputees and may negatively impact on function.

The pulse duration of electrical stimulation influences H-reflexes but not corticospinal excitability for tibialis anterior.

The afferent volley generated by neuromuscular electrical stimulation (NMES) influences corticospinal (CS) excitability and frequent NMES sessions can strengthen CS pathways, resulting in long-term improvements in function. This afferent volley can be altered by manipulating NMES parameters. Presently, we manipulated one such parameter, pulse duration, during NMES over the common peroneal nerve and assessed the influence on H-reflexes and CS excitability. We hypothesized that compared with shorter pulse durations, longer pulses would (i) shift the H-reflex recruitment curve to the left, relative to the M-wave curve; and (ii) increase CS excitability more. Using 3 pulse durations (50, 200, 1000 µs), M-wave and H-reflex recruitment curves were collected and, in separate experiments, CS excitability was assessed by comparing motor evoked potentials elicited before and after 30 min of NMES. Despite finding a leftward shift in the H-reflex recruitment curve when using the 1000 µs pulse duration, consistent with a larger afferent volley for a given efferent volley, the increases in CS excitability were not influenced by pulse duration. Hence, although manipulating pulse duration can alter the relative recruitment of afferents and efferents in the common peroneal nerve, under the present experimental conditions it is ineffective for maximizing CS excitability for rehabilitation.

Treatment of medial tibial stress syndrome according to the fascial distortion model: a prospective case control study.

Medial tibial stress syndrome (MTSS) is a common problem among athletes and soldiers. There is no proven theory that could explain the pathophysiology of shin splints. The therapies described so far are time-consuming and involve a high risk of relapse. The method according to the fascial distortion model (FDM) addresses local changes in the area of the lower leg fascia. It is suited to reduce pain and functional impairments associated with this symptom complex by applying targeted manual techniques. 32 patients (male: 30; female: 2) participated in this study. Visual analogue scale (VAS) was used for the quantification of pain. Scores were also given to rate the maximum painless exercise tolerance of the patients. Subsequently treatment of the crural fascia was performed. Patients retested ability of running and jumping. Therapy was continued until full exercise tolerance or painlessness was reached. A significant reduction of the VAS pain score from 5.2 to 1.1 could be achieved (P < 0.001). The impairment of exercise tolerance could be reduced from 7 to 2 points (P < 0.001). The duration of treatment was 6.3 (SD: 4.3) days on average. The FDM therapy is a potential effective method for acute treatment of MTSS.

Changes over time in structural plasticity of trabecular bone in rat tibiae immobilized by reversible sciatic denervation.

OBJECTIVE: The present study aimed to clarify the structural recovery, and to compare the time course of morphological changes in trabeculae and the process of bone mass change in rat tibiae following temporary immobilization of hind limb by sciatic neurectomy or nerve freezing. METHODS: In 11-week-old male Fischer 344 rats, 4-5 mm of the sciatic nerve was removed (neurectomy group) or frozen by 5-second application of a stainless steel rod immersed in liquid nitrogen (nerve-freezing group). Quantitative changes in cancellous bone were assessed by histomorphometry. RESULTS: The results clarified that: trabecular bone volume (BV/TV) decreases until 3 weeks after denervation, and in the nerve-freezing group, it then increases from week 4, recovering to pre-surgery levels by week 10 (no recovery was seen in the neurectomy group); in the initial phase of bone atrophy, the decrease in BV/TV is more gradual in the nerve-freezing group than in the neurectomy group; and changes in trabecular architecture in the bone atrophy-recovery process are strongly associated with changes in trabecular thickness. CONCLUSION: The findings suggested that after transient injury by nerve freezing and subsequent recovery of neuromuscular function, bone tissue undergoes recovery from bone loss, but that trabeculae may not show complete structural recovery.

Time course of the soleus M response and H reflex after lidocaine tibial nerve block in the rat.

AIMS: In spastic subjects, lidocaine is often used to induce a block predictive of the result provided by subsequent surgery. Lidocaine has been demonstrated to inhibit the Hoffmann (H) reflex to a greater extent than the direct motor (M) response induced by electrical stimulation, but the timecourse of these responses has not been investigated. METHODS: An animal (rat) model of the effects of lidocaine on M and H responses was therefore developed to assess this time course. M and H responses were recorded in 18 adult rats before and after application of lidocaine to the sciatic nerve. RESULTS: Two to five minutes after lidocaine injection, M responses were markedly reduced (mean reduction of 44%) and H reflexes were completely abolished. Changes were observed more rapidly for the H reflex. The effects of lidocaine then persisted for 100 minutes. The effect of lidocaine was therefore more prolonged on the H reflex than on the M response. CONCLUSION: This study confirms that lidocaine blocks not only alpha motoneurons but also Ia afferent fibres responsible for the H reflex. The authors describe, for the first time, the detailed time course of the effect of lidocaine on direct or reflex activation of motoneurons in the rat.

Precise temporal association between cortical potentials evoked by motor imagination and afference induces cortical plasticity.

In monkeys, the repeated activation of somatosensory afferents projecting onto the motor cortex (M1) has a pivotal role in motor skill learning. Here we investigate if sensory feedback that is artificially generated at specific times during imagination of a dorsiflexion task leads to reorganization of the human M1. The common peroneal nerve was stimulated to generate an afferent volley timed to arrive during specific phases of the cortical potential generated when a movement was imagined (50 repetitions). The change in the output of M1 was quantified by applying single transcranial magnetic stimuli to the area of M1 controlling the tibialis anterior muscle. The results demonstrated that the concomitance between the cognitive process of movement (motor imagination) and the ascending volley due to the peripheral nerve stimulation can lead to significant increases in cortical excitability. These increases were critically dependent on the timing between the peripherally generated afferent volley and the cortical potential generated during the imagined movement. Only if the afferent volley arrived during the peak negative deflection of the potential, were significant alterations in motor cortical output attained. These results demonstrate that an artificially generated signal (the peripheral afferent volley) can interact with a physiologically generated signal in humans leading to plastic changes within the M1, the final output stage for movement generation within the human brain. The results presented may have implications in systems for artificially inducing cortical plasticity in patients with motor impairments (neuromodulation).