Effect of Motor State on Postactivation Depression of the Soleus H-Reflex in Parkinson's Disease During Deep Brain Stimulation and Dopaminergic Medication Treatment: A Pilot Study.

PURPOSE: Postactivation depression of the Hoffmann reflex is reduced in Parkinson's disease (PD), but how the recovery is influenced by the state of the muscle is unknown. The present pilot study examined postactivation depression in PD at rest and during a voluntary contraction while patients were off treatment and while receiving medications and/or deep brain stimulation. METHODS: The authors recruited nine patients with PD treated with implanted deep brain stimulation and examined postactivation depression under four treatment conditions. Paired pulses were delivered 25 to 300 ms apart, and soleus Hoffmann reflex recovery was tested at rest and during voluntary plantar flexion. Trials were matched for background muscle activity and compared with 10 age-matched controls. RESULTS: Patients with Parkinson disease who were OFF medications (OFF meds) and OFF stimulation (OFF stim) at rest showed less postactivation depression at the 300 ms interpulse interval (86.1% ± 21.0%) relative to control subjects (36.4% ± 6.1%; P < 0.05). Postactivation depression was restored when dopaminergic medication and/or deep brain stimulation was applied. Comparisons between resting and active motor states revealed that the recovery curves were similar OFF meds/OFF stim owing to faster recovery in PD seen at rest. In contrast, the effect of the motor state was different ON meds/OFF stim and ON meds/ON stim (both P < 0.05), with a nonsignificant trend OFF meds/ON stim ( P > 0.08). During a contraction, recovery curves were similar between all treatment conditions in PD and control. CONCLUSIONS: Disrupted Hoffmann reflex recovery is restored to control levels in PD patients at rest when receiving medications and/or deep brain stimulation or when engaged in voluntary contraction.

Effects of Deep Brain Stimulation and Dopaminergic Medication on Excitatory and Inhibitory Spinal Pathways in Parkinson Disease.

PURPOSE: Abnormal activity within the corticospinal system is believed to contribute to the motor dysfunction associated with Parkinson disease. However, the effect of treatment for parkinsonian motor symptoms on dysfunctional descending input to the motor neuron pool remains unclear. METHODS: We recruited nine patients with PD treated with deep brain stimulation and examined the time course of interaction between a conditioning pulse from transcranial magnetic stimulation and the soleus H-reflex. Patients with Parkinson disease were examined under four treatment conditions and compared with 10 age-matched control subjects. RESULTS: In healthy controls, transcranial magnetic stimulation conditioning led to early inhibition of the H-reflex (76.2% ± 6.3%) at a condition-test interval of -2 ms. This early inhibition was absent when patients were OFF medication/OFF stimulation (132.5% ± 20.4%; P > 0.05) but was maximally restored toward control levels ON medication/ON stimulation (80.3% ± 7.0%). Of note, early inhibition ON medication/ON stimulation tended to be stronger than when medication (85.4% ± 5.9%) or deep brain stimulation (95.7% ± 9.4%) were applied separately. Late facilitation was observed in controls at condition-test intervals ≥5 ms but was significantly reduced (by 50% to 80% of controls) in Parkinson disease OFF stimulation at condition-test intervals ≥15 ms. The late facilitation was akin to control subjects when patients were ON stimulation. CONCLUSIONS: The present pilot study demonstrates that the recruitment of early inhibition and late facilitation is disrupted in untreated Parkinson disease and that medication and deep brain stimulation may act together to normalize supraspinal drive to the motor neuron pool.

Characterizing the effect of low intensity transcranial magnetic stimulation on the soleus H-reflex at rest.

Modulation of a Hoffmann (H)-reflex following transcranial magnetic stimulation (TMS) has been used to assess the nature of signals transmitted from cortical centers to lower motor neurons. Further characterizing the recruitment and time-course of the TMS-induced effect onto the soleus H-reflex adds to the discussion of these pathways and may improve its utility in clinical studies. In 10 healthy controls, TMS was used to condition the soleus H-reflex using TMS intensities from 65 to 110% of the resting motor threshold (RMT). Early facilitation [- 5 to - 3 ms condition-test (C-T) interval] was evident when TMS was 110% of RMT (P < 0.05). By comparison, late facilitation (+ 10 to + 20 ms C-T interval) was several times larger and observed over a wider range of TMS intensities, including 65-110% of RMT. The early inhibition (- 3 to - 1 ms C-T interval) had a low TMS threshold and was elicited over a wide range of intensity from 65% to 95% of RMT (all P < 0.05). A second inhibitory phase was seen ~ 4 ms later (+ 1 to + 4 ms C-T intervals) and was only observed for a TMS intensity of 95% of RMT (P < 0.05). The present findings reaffirm that subthreshold TMS strongly modulates soleus motor neurons and demonstrates that distinct pathways can be selectively probed at discrete C-T intervals when using specific TMS intensities.

Intraoperative spinal cord monitoring using low intensity transcranial stimulation to remove post-activation depression of the H-reflex.

OBJECTIVE: To investigate whether low intensity transcranial electrical stimulation (TES) can be used to condition post-activation depression of the H-reflex and simultaneously monitor the integrity of spinal motor pathways during spinal deformity correction surgery. METHODS: In 20 pediatric patients undergoing corrective surgery for spinal deformity, post-activation depression of the medial gastrocnemius H-reflex was initiated by delivering two pulses 50-125ms apart, and the second H-reflex was conditioned by TES. RESULTS: Low intensity TES caused no visible shoulder or trunk movements during 19/20 procedures and the stimulation reduced post-activation depression of the H-reflex. The interaction was present in 20/20 patients and did not diminish throughout the surgical period. In one case, the conditioning effect was lost within minutes of the disappearance of the lower extremity motor evoked potentials. CONCLUSION: Post-activation depression was used to detect the arrival of a subthreshold motor evoked potential at the lower motor neuron. The interaction produced minimal movement within the surgical field and remained stable throughout the surgical period. SIGNIFICANCE: This is the first use of post-activation depression during intraoperative neurophysiological monitoring to directly assess the integrity of descending spinal motor pathways.

Reduced postactivation depression of soleus H reflex and root evoked potential after transcranial magnetic stimulation.

Postactivation depression of the Hoffmann (H) reflex is associated with a transient period of suppression following activation of the reflex pathway. In soleus, the depression lasts for 100-200 ms during voluntary contraction and up to 10 s at rest. A reflex root evoked potential (REP), elicited after a single pulse of transcutaneous stimulation to the thoracolumbar spine, has been shown to exhibit similar suppression. The present study systematically characterized the effect of transcranial magnetic stimulation (TMS) on postactivation depression using double-pulse H reflexes and REPs. A TMS pulse reduced the period of depression to 10-15 ms for both reflexes. TMS could even produce postactivation facilitation of the H reflex, as the second reflex response was increased to 243 ± 51% of control values at the 75-ms interval. The time course was qualitatively similar for the REP, yet the overall increase was less. While recovery of the H reflex was slower in the relaxed muscle, the profile exhibited a distinct bimodal shape characterized by an early peak at the 25-ms interval, reaching 72 ± 23% of control values, followed by a trough at 50 ms, and then a gradual recovery at intervals > 50 ms. The rapid recovery of two successively depressed H reflexes, ∼ 25 ms apart, was also possible with double-pulse TMS. The effect of the TMS-induced corticospinal excitation on postactivation depression may be explained by a combination of pre- and postsynaptic mechanisms, although further investigation is required to distinguish between them.

Safety and Feasibility of Intermittent Electrical Stimulation for the Prevention of Deep Tissue Injury.

Objective: To investigate the safety, feasibility, and acceptability of a novel treatment, intermittent electrical stimulation (IES), for preventing deep tissue injury (DTI) in different healthcare settings. Approach: Testing was conducted in an acute rehabilitation unit of a general hospital, a tertiary rehabilitation hospital, a long-term care facility, and homecare (HC). IES was delivered through surface electrodes placed either directly on the gluteal muscles or through mesh panels inside a specialized garment. Study participants at risk for DTI used the system for an average of 4 weeks. Outcome measures included skin reaction to long-term stimulation, demands on the caregiver, stability of induced muscle contraction, and acceptability as part of the users' daily routine. Results: A total of 48 study participants used the IES system. The system proved to be safe and feasible in all four clinical settings. No pressure ulcers were observed in any of the participants. There was no difference between the clinical settings in patient positioning, ease of finding optimal stimulation site, and patient acceptance. Although donning and doffing time was longer in the long-term care and HC settings than the acute rehabilitation unit and tertiary rehabilitation facility, time required to apply the IES system was <18 min (including data collection). The patients and caregivers did not find the application disruptive and indicated that the stimulation was acceptable as part of their daily routine in over 97% of the time. Innovation and Conclusion: We demonstrated the safety, feasibility, and acceptability of a novel method of IES to prevent DTI in a continuum of healthcare settings.

Post-activation depression in the human soleus muscle using peripheral nerve and transcutaneous spinal stimulation.

Transcutaneous stimulation of the human lumbar spine can be used to elicit root-evoked potentials (REPs). These sensory-motor responses display notable similarities to the monosynaptic H-reflex. The purpose of this study was to compare post-activation depression of the soleus REP to that of the H-reflex, when conditioned by either an H-reflex or an REP. Paired pulses were delivered 25-200ms apart and the recovery was characterized using three levels of stimulation. In all conditions, post-activation depression was reduced during contraction as compared to rest (P<0.001). REP doublets, delivered using an inter-pulse interval of 150ms, recovered to 68±8% of control during plantarflexion and 20±6% of control at rest. During contraction, recovery of a second REP was 65% of the corresponding recovery for a second H-reflex. The recovery of an H-reflex was equivalent, when conditioned by either an H-reflex or an REP, even though the spinal stimulus activated and/or engaged more afferent and efferent fibers. Our results suggest that the additional elements activated by the spinal stimulus did not affect the recovery of the H-reflex. However, the transcutaneous spinal stimulus produced more inhibition when it was assessed using two low-intensity REPs (P<0.05) suggesting that the pathway mediating the spinally-evoked response was more susceptible to being inhibited.

Interaction of transcutaneous spinal stimulation and transcranial magnetic stimulation in human leg muscles.

Transcutaneous spinal stimulation is a noninvasive method that can activate dorsal and/or ventral roots depending on the location and intensity of stimulation. Reflex root-evoked potentials (REPs) were studied in muscles that traditionally evoke large (soleus) and small H-reflexes (tibialis anterior), as well as muscles where H-reflexes are difficult to study (hamstrings). This study characterizes the interaction of the REP and the motor-evoked potential (MEP). Transcranial magnetic stimulation (TMS) delivered 11-25 ms before spinal stimulation resulted in more than linear summation of the two responses. Because of overlap, the modulation was quantified after subtracting the contribution of the conditioning MEP or REP. At rest, the mean-rectified soleus response was facilitated by up to ~250 µV (21-times the MEP or 161% of the REP). The increases were more reliable during a voluntary contraction (up to ~300 µV, 517% of the MEP or 181% of the REP). At the 13-ms interval, the mean-rectified response in the pre-contracted hamstrings was increased by 227% of the MEP or 300% of the REP. In some subjects, TMS could also eliminate the post-activation depression produced using two spinal stimuli, confirming that the interaction can extend to presynaptic spinal neurons. The spatiotemporal facilitation in tibialis anterior was not significant. However, the large MEP was facilitated when the spinal stimulus preceded TMS by 100-150 ms, presumably because of rebound excitation. These strong interactions may be important for inducing motor plasticity and improved training procedures for recovery after neurological damage.

Effect of a foot-drop stimulator and ankle-foot orthosis on walking performance after stroke: a multicenter randomized controlled trial.

BACKGROUND: Studies have demonstrated the efficacy of functional electrical stimulation in the management of foot drop after stroke. OBJECTIVE: To compare changes in walking performance with the WalkAide (WA) foot-drop stimulator and a conventional ankle-foot orthosis (AFO). METHODS: Individuals with stroke within the previous 12 months and residual foot drop were enrolled in a multicenter, randomized controlled, crossover trial. Subjects were assigned to 1 of 3 parallel arms for 12 weeks (6 weeks/device): arm 1 (WA-AFO), n = 38; arm 2 (AFO-WA), n = 31; arm 3 (AFO-AFO), n = 24. Primary outcomes were walking speed and Physiological Cost Index for the Figure-of-8 walking test. Secondary measures included 10-m walking speed and perceived safety during this test, general mobility, and device preference for arms 1 and 2 for continued use. Walking tests were performed with (On) and without a device (Off) at 0, 3, 6, 9, and 12 weeks. RESULTS: Both WA and AFO had significant orthotic (On-Off difference), therapeutic (change over time when Off), and combined (change over time On vs baseline Off) effects on walking speed. An AFO also had a significant orthotic effect on Physiological Cost Index. The WA had a higher, but not significantly different therapeutic effect on speed than an AFO, whereas an AFO had a greater orthotic effect than the WA (significant at 12 weeks). Combined effects on speed after 6 weeks did not differ between devices. Users felt as safe with the WA as with an AFO, but significantly more users preferred the WA. CONCLUSIONS: Both devices produce equivalent functional gains.

Facilitation of corticospinal connections in able-bodied people and people with central nervous system disorders using eight interventions.

BACKGROUND: Voluntary contractions (VOL), functional electrical stimulation (FES), and transcranial magnetic stimulation (TMS) can facilitate corticospinal connections. OBJECTIVE: To find the best methods for increasing corticospinal excitability by testing eight combinations: (1) VOL, (2) FES, (3) FES + VOL, (4) TMS, (5) TMS + VOL, (6) paired associative stimulation (PAS) consisting of FES + TMS, (7) PAS + VOL, and (8) double-pulse TMS + VOL. METHODS: Interventions were applied for 3 × 10 minutes in 15 able-bodied subjects, 14 subjects with stable central nervous system lesions (e.g., chronic stroke, and incomplete spinal cord injury) and 16 subjects with progressive central nervous system conditions (e.g., secondary progressive multiple sclerosis). Motor-evoked potentials (MEP), M-waves, and H-reflexes were monitored over a 1-hour period. RESULTS: Three interventions (PAS, PAS + VOL, and double-pulse TMS + VOL) caused 15% to 20% increases (P < 0.05) in the MEP at a stimulus level that initially produced a half-maximal response (MEP(half)) during a contraction. Interventions were less effective in both clinical groups than in the able-bodied group. Interventions with VOL were more effective in increasing the MEP(half) than those without (P = 0.022). When more modalities were combined, the MEP increases were larger (P = 0.022). CONCLUSIONS: (1) Short-term application of FES, TMS, and VOL can facilitate corticospinal pathways, particularly when methods are combined. (2) The effects may depend on the total activation of neural pathways, which is reduced in central nervous system disorders.

Effect of percutaneous stimulation at different spinal levels on the activation of sensory and motor roots.

Percutaneous spinal stimulation is a promising new technique for understanding human spinal reflexes and for evaluating the pathophysiology of motor roots. Previous studies have generally stimulated the T11/T12 or T12/L1 vertebral junctions, sites that overlie the lumbosacral enlargement. The present study sought to determine the best location for targeting sensory and motor roots during sitting. We used paired stimuli, 50 ms apart, to distinguish the contribution of the reflex and motor components which make up the root evoked potential. This assumed that post-stimulation attenuation, primarily through homosynaptic depression, would abolish the second potential if it was trans-synaptic in origin. Conversely, successive responses would be unchanged if motor roots were being stimulated. Here, we show that sensory root reflexes were optimally elicited with percutaneous stimulation over the L1-L3 vertebrae. However, the optimal position varied between subjects and depended on the target muscle being studied. A collision test showed that the reflex recorded in pre-tibial flexors was low in amplitude and was prone to crosstalk from neighbouring muscles. In contrast to the reflex response, direct motor root activation was optimal with stimulation over the more caudal L5-S1 vertebrae. The present results support the utility of paired stimulation for evaluating the topographical recruitment of sensory and motor roots to human leg muscles.

External sensors for detecting the activation and deactivation times of the major muscles used in walking.

Functional electrical stimulation (FES) can improve walking in individuals with mobility impairments. We evaluated accelerometers, force sensitive resistors, segment angles, and segment angular velocities to identify which sensor best determines the activation and deactivation times of the main muscles used during walking. This sensor(s) can be used in the future in conjunction with FES systems to improve walking. Able-bodied subjects walked at various speeds. Threshold levels were set for each sensor that minimized the difference between the times of activating and deactivating the electromyogram (EMG) of six muscles and the times of sensor threshold crossings as a percent of the step cycle. Mobility-impaired subjects walked at their preferred speed with and without FES to correct foot drop. Thresholds were set for these subjects so that sensor signals would cross at times that matched those of able-bodied subjects. Segment angles were generally the most effective sensor signals. Using segment angles of the thigh, shank, and foot, activation and deactivation times of the six muscles could be determined to within 6% of the step cycle. The shank segment angle produced the lowest overall error and was among the top three sensors for 10 of the 12 events (activation and deactivation of six muscle groups). A segment angle sensor was implemented using a complementary filter (accelerometer/gyroscope combination). Using this sensor improved rule-based timing of FES in subjects with foot drop as compared to accelerometers alone.

An implantable neural stimulator for intraspinal microstimulation.

This paper reports on a wireless stimulator device for use in animal experiments as part of an ongoing investigation into intraspinal stimulation (ISMS) for restoration of walking in humans with spinal cord injury. The principle behind using ISMS is the activation of residual motor-control neural networks within the spinal cord ventral horn below the level of lesion following a spinal cord injury. The attractiveness to this technique is that a small number of electrodes can be used to induce bilateral walking patterns in the lower limbs. In combination with advanced feedback algorithms, ISMS has the potential to restore walking for distances that exceed that produced by other types of functional electrical stimulation. Recent acute animal experiments have demonstrated the feasibility of using ISMS to produce the coordinated walking patterns. Here we described a wireless implantable stimulation system to be used in chronic animal experiments and for providing the basis for a system suitable for use in humans. Electrical operation of the wireless system is described, including a demonstration of reverse telemetry for monitoring the stimulating electrode voltages.

Restoring stepping after spinal cord injury using intraspinal microstimulation and novel control strategies.

The overall objective of this project is to develop a feedback-driven intraspinal microstimulation (ISMS) system. We hypothesize that ISMS will enhance the functionality of stepping by reducing muscle fatigue and producing synergistic movements by activating neural networks in the spinal cord. In the present pilot study, the controller was tested with ISMS and external sensors (force plates, gyroscopes, and accelerometers). Cats were partially supported in a sling and bi-laterally stepped overground on a 4-m instrumented walkway. The walkway had variable friction. Limb angle was controlled to within 10° even in the presence of variable friction. Peak ground reaction forces in each limb were approximately 12% of body weight (12.5% was full load bearing in this experimental setup); rarely, the total supportive force briefly decreased to as low as 4.1%. Magnetic resonance images were acquired of the excised spinal cord and the implanted array. The majority of electrodes (75%) were implanted successfully into their target regions. This represents the first successful application of ISMS for overground walking.

Long-term therapeutic and orthotic effects of a foot drop stimulator on walking performance in progressive and nonprogressive neurological disorders.

BACKGROUND: Stimulators applying functional electrical stimulation (FES) to the common peroneal nerve improve walking with a foot drop, which occurs in several disorders. OBJECTIVE: To compare the orthotic and therapeutic effects of a foot drop stimulator on walking performance of subjects with chronic nonprogressive (eg, stroke) and progressive (eg, multiple sclerosis) disorders. METHODS: Subjects with nonprogressive (41) and progressive (32) conditions used a foot drop stimulator for 3 to 12 months while walking in the community. Walking speed was measured with a 10-m test and a 4-minute figure-8 test; physiological cost index (PCI) and device usage were also measured. The subjects were tested with FES on and off (orthotic effect) before and after (therapeutic effect) stimulator use. RESULTS: After 3 months of FES use, the nonprogressive and progressive groups had a similar, significant orthotic effect (5.0% and 5.7%, respectively, P < .003; percentage change in mean values) and therapeutic effect with FES off (17.8% and 9.1%, respectively, P < .005) on figure-8 walking speed. Overall, PCI showed a decreasing trend (P = .031). The therapeutic effect on figure-8 speed diverged later between both groups to 28.0% (P < .001) and 7.9% at 11 months. The combined therapeutic plus orthotic effect on figure-8 speed at 11 months was, respectively, 37.8% (P < .001) and 13.1% (P = .012); PCI decreased 18.2% (P = .038) and 6.5%, respectively. CONCLUSIONS: Subjects with progressive and nonprogressive disorders had an orthotic benefit from FES up to 11 months. The therapeutic effect increased for 11 months in nonprogressive disorders but only for 3 months in progressive disorders. The combined effect remained significant and clinically relevant.

Does functional electrical stimulation for foot drop strengthen corticospinal connections?

BACKGROUND: Long-term use of a foot-drop stimulator applying functional electrical stimulation (FES) to the common peroneal nerve improves walking performance even when the stimulator is off. This "therapeutic" effect might result from neuroplastic changes. OBJECTIVE: To determine the effect of long-term use of a foot-drop stimulator on residual corticospinal connections in people with central nervous system disorders. METHODS: Ten people with nonprogressive disorders (eg, stroke) and 26 with progressive disorders (eg, multiple sclerosis) used a foot-drop stimulator for 3 to 12 months while walking in the community. Walking performance and electrophysiological variables were measured before and after FES use. From the surface electromyogram of the tibialis anterior muscle, we measured the following: (1) motor-evoked potential (MEP) from transcranial magnetic stimulation over the motor cortex, (2) maximum voluntary contraction (MVC), and (3) maximum motor wave (M(max)) from stimulating the common peroneal nerve. RESULTS: After using FES, MEP and MVC increased significantly by comparable amounts, 50% and 48%, respectively, in the nonprogressive group and 27% and 17% in the progressive group; the changes were positively correlated (R(2) = .35; P < .001). Walking speed increased with the stimulator off (therapeutic effect) by 24% (P = .008) and 7% (P = .014) in the nonprogressive and progressive groups, respectively. The changes in M(max) were small and not correlated with changes in MEP. CONCLUSIONS: The large increases in MVC and MEP suggest that regular use of a foot-drop stimulator strengthens activation of motor cortical areas and their residual descending connections, which may explain the therapeutic effect on walking speed.

Spinal reflexes in ankle flexor and extensor muscles after chronic central nervous system lesions and functional electrical stimulation.

OBJECTIVE: Spinal reciprocal inhibitory and excitatory reflexes of ankle extensor and flexor muscles were investigated in ambulatory participants with chronic central nervous system (CNS) lesions causing foot drop as a function of time after lesion and stimulator use. METHODS: Thirty-nine participants with progressive (eg, secondary progressive MS) and 36 with generally nonprogressive (eg, stroke) conditions were studied. The tibialis anterior (TA) and soleus maximum H-reflex/M-wave (Hmax/Mmax) ratios and maximum voluntary contractions (MVC) were measured and compared with those in age-matched control participants. Reciprocal inhibition was measured as a depression of the ongoing electromyographic (EMG) activity produced by antagonist muscle-nerve stimulation. RESULTS: Participants with CNS lesions had significantly higher soleus Hmax/Mmax ratios than control participants, and reduced voluntary modulation of the reflexes occurred in both muscles. Reciprocal inhibition of soleus from common peroneal (CP) nerve stimulation was not significantly different from controls in either group. Inhibition of the TA by tibial nerve stimulation decreased and was eventually replaced by excitation in participants with nonprogressive disorders. No significant change occurred in progressive disorders. Use of a foot drop stimulator increased the TA, but not the soleus MVC overall. H-reflexes only showed small changes. Reciprocal inhibition of the TA increased considerably, while that of the soleus muscle decreased toward control values. CONCLUSIONS: Disorders that produce foot drop also produce reflex changes, some of which only develop over a period of years or even decades. Regular use of a foot drop stimulator strengthens voluntary pathways and changes some reflexes toward control values. Thus, stimulators may provide multiple benefits to people with foot drop.

Interaction of paired cortical and peripheral nerve stimulation on human motor neurons.

This paper contrasts responses in the soleus muscle of normal human subjects to two major inputs: the tibial nerve (TN) and the corticospinal tract. Paired transcranial magnetic stimulation (TMS) of the motor cortex at intervals of 10-25 ms strongly facilitated the motor evoked potential (MEP) produced by the second stimulus. In contrast, paired TN stimulation produced a depression of the reflex response to the second stimulus. Direct activation of the pyramidal tract did not facilitate a second response, suggesting that the MEP facilitation observed using paired TMS occurred in the cortex. A TN stimulus also depressed a subsequent MEP. Since the TN stimulus depressed both inputs, the mechanism is probably post-synaptic, such as afterhyperpolarization of motor neurons. Presynaptic mechanisms, such as homosynaptic depression, would only affect the pathway used as a conditioning stimulus. When TN and TMS pulses were paired, the largest facilitation occurred when TMS preceded TN by about 5 ms, which is optimal for summation of the two pathways at the level of the spinal motor neurons. A later, smaller facilitation occurred when a single TN stimulus preceded TMS by 50-60 ms, an interval that allows enough time for the sensory afferent input to reach the sensory cortex and be relayed to the motor cortex. Other work indicates that repetitively pairing nerve stimuli and TMS at these intervals, known as paired associative stimulation, produces long-term increases in the MEP and may be useful in strengthening residual pathways after damage to the central nervous system.