The effects of music combined to paired associative stimulation on motor-evoked potentials and alertness in spinal cord injury patients and healthy subjects.

Paired associative stimulation (PAS) consisting of high-intensity transcranial magnetic stimulation (TMS) and high-frequency peripheral nerve stimulation (known as high-PAS) induces plastic changes and improves motor performance in patients with incomplete spinal cord injury (SCI). Listening to music during PAS may potentially improve mood and arousal and facilitate PAS-induced neuroplasticity via auditory-motor coupling, but the effects have not been explored. This pilot study aimed to determine if the effect of high-PAS on motor-evoked potentials (MEPs) and subjective alertness can be augmented with music. Ten healthy subjects and nine SCI patients received three high-PAS sessions in randomized order (PAS only, PAS with music synchronized to TMS, PAS with self-selected music). MEPs were measured before (PRE), after (POST), 30 min (POST30), and 60 min (POST60) after stimulation. Alertness was evaluated with a questionnaire. In healthy subjects, MEPs increased at POST in all sessions and remained higher at POST60 in PAS with synchronized music compared with the other sessions. There was no difference in alertness. In SCI patients, MEPs increased at POST and POST30 in PAS only but not in other sessions, whereas alertness was higher in PAS with self-selected music. More research is needed to determine the potential clinical effects of using music during high-PAS.

ICF-linking and psychometric properties of upper extremity mobility outcome measures in spinal cord injury - a scoping review.

OBJECTIVE: The purpose of this study was to explore the outcome measures used in upper extremity rehabilitation and research in spinal cord injury and to investigate their psychometry. DESIGN: Scoping review. DATA SOURCES: PubMed, the Cochrane library, PEDro, Medline (Ovid). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: The search process and study selection was carried out as follows: Firstly, a systematic search was carried out for articles on upper extremity rehabilitation after SCI. Performance or observational outcome measures which were designed for a clinical setting were collected from selected studies. Secondly, eligible outcome measures were linked to the ICF. The ICF-linked outcome measures were further screened for inclusion according to how comprehensively they covered ICF categories. Finally, a search of the selected outcome measures was performed to investigate their psychometry. RESULTS: A total of four outcome measures and nine psychometric studies were selected for the scoping review; six studies addressed GRASSP, one addressed AuSpinal, one addressed SHFT and one addressed TRI-HFT. Of the 13 COSMIN measurement properties, studies of GRASSP covered seven, AuSpinal covered five and both SHFT and TRI-HFT covered three properties. CONCLUSIONS: The psychometric properties of GRASSP were most extensively studied showing eligible reliability and validity. Although there are still some measurement properties to be explored, GRASSP can be recommended for use in the evaluation of upper extremity mobility in the SCI rehabilitation and research. More research is needed on the psychometrics of other outcome measures in people with spinal cord injuries before the outcome measures can be unconditionally recommended.

Repetitive sensorimotor mu-alpha phase-targeted afferent stimulation produces no phase-dependent plasticity related changes in somatosensory evoked potentials or sensory thresholds.

Phase-dependent plasticity has been proposed as a neurobiological mechanism by which oscillatory phase-amplitude cross-frequency coupling mediates memory process in the brain. Mimicking this mechanism, real-time EEG oscillatory phase-triggered transcranial magnetic stimulation (TMS) has successfully induced LTP-like changes in corticospinal excitability in the human motor cortex. Here we asked whether EEG phase-triggered afferent stimulation alone, if repetitively applied to the peaks, troughs, or random phases of the sensorimotor mu-alpha rhythm, would be sufficient to modulate the strength of thalamocortical synapses as assessed by changes in somatosensory evoked potential (SEP) N20 and P25 amplitudes and sensory thresholds (ST). Specifically, we applied 100 Hz triplets of peripheral electrical stimulation (PES) to the thumb, middle, and little finger of the right hand in pseudorandomized trials, with the afferent input from each finger repetitively and consistently arriving either during the cortical mu-alpha trough or peak or at random phases. No significant changes in SEP amplitudes or ST were observed across the phase-dependent PES intervention. We discuss potential limitations of the study and argue that suboptimal stimulation parameter choices rather than a general lack of phase-dependent plasticity in thalamocortical synapses are responsible for this null finding. Future studies should further explore the possibility of phase-dependent sensory stimulation.

Transcranial magnetic stimulation set-up for small animals.

Transcranial magnetic stimulation (TMS) is widely applied on humans for research and clinical purposes. TMS studies on small animals, e.g., rodents, can provide valuable knowledge of the underlying neurophysiological mechanisms. Administering TMS on small animals is, however, prone to technical difficulties, mainly due to their small head size. In this study, we aimed to develop an energy-efficient coil and a compatible experimental set-up for administering TMS on rodents. We applied a convex optimization process to develop a minimum-energy coil for TMS on rats. As the coil windings of the optimized coil extend to a wide region, we designed and manufactured a holder on which the rat lies upside down, with its head supported by the coil. We used the set-up to record TMS-electromyography, with electromyography recorded from limb muscles with intramuscular electrodes. The upside-down placement of the rat allowed the operator to easily navigate the TMS without the coil blocking their field of view. With this paradigm, we obtained consistent motor evoked potentials from all tested animals.

Optimal peripheral nerve stimulation intensity for paired associative stimulation with high-frequency peripheral component in healthy subjects.

Paired associative stimulation (PAS) with high-frequency peripheral nerve stimulation (PNS), called "high-PAS", induces motor-evoked potential (MEP) potentiation in healthy subjects and improves muscle activity and independence in incomplete spinal cord injury patients. Data on optimal PNS intensity in PAS are scarce. In a high-PAS protocol, PNS intensity is defined as "minimal intensity required to produce F-responses". We sought to further refine this definition and to investigate how PNS intensity affects PAS outcome. Two experiments were performed on 10 healthy subjects where MEP amplitude change was measured 0, 30, and 60 min after PAS. In the first experiment, the intensity required to achieve 7/10 persistence of F-responses was used to define PNS intensity level. In the second experiment, we used the intensity required to achieve 1/10 persistence ("baseline"). In addition, we applied this intensity at + 25%, - 25%, and - 50% levels. In the first experiment, PAS did not produce significant MEP potentiation. In the second experiment, PAS produced statistically significant MEP potentiation, with PNS intensity of "baseline" and "baseline - 25%" levels but not at + 25% or - 50% levels. In conclusion, for PAS utilizing high-frequency PNS, the intensity required to achieve 1/10 F-response persistence or the intensity 25% lower produces significant MEP potentiation in healthy subjects.

Effect of long-term paired associative stimulation on the modulation of cortical sensorimotor oscillations after spinal cord injury.

STUDY DESIGN: A prospective interventional case series. OBJECTIVES: To explore changes in the modulation of cortical sensorimotor oscillations after long-term paired associative stimulation (PAS) in participants with spinal cord injury (SCI). SETTING: BioMag Laboratory, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. METHODS: Five patients with chronic incomplete SCI received unilateral spinal PAS to upper limb for 16-22 days. Changes in the modulation of sensorimotor oscillations in response to tactile stimulus and active and imaginary hand movements were assessed with magnetoencephalography recorded before and after the intervention. RESULTS: PAS restored the modulation of sensorimotor oscillations in response to active hand movement in four patients, whereas the modulation following tactile stimulation remained unaltered. The observed change was larger in the hemisphere that received PAS and preceded the clinical effect of the intervention. CONCLUSIONS: Long-term spinal PAS treatment, which enhances the motor functions of SCI patients, also restores the modulation of cortical sensorimotor oscillations.

A New Paired Associative Stimulation Protocol with High-Frequency Peripheral Component and High-Intensity 20 Hz Repetitive Transcranial Magnetic Stimulation-A Pilot Study.

Paired associative stimulation (PAS) is a stimulation technique combining transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) that can induce plastic changes in the human motor system. A PAS protocol consisting of a high-intensity single TMS pulse given at 100% of stimulator output (SO) and high-frequency 100-Hz PNS train, or "the high-PAS" was designed to promote corticomotoneuronal synapses. Such PAS, applied as a long-term intervention, has demonstrated therapeutic efficacy in spinal cord injury (SCI) patients. Adding a second TMS pulse, however, rendered this protocol inhibitory. The current study sought for more effective PAS parameters. Here, we added a third TMS pulse, i.e., a 20-Hz rTMS (three pulses at 96% SO) combined with high-frequency PNS (six pulses at 100 Hz). We examined the ability of the proposed stimulation paradigm to induce the potentiation of motor-evoked potentials (MEPs) in five human subjects and described the safety and tolerability of the new protocol in these subjects. In this study, rTMS alone was used as a control. In addition, we compared the efficacy of the new protocol in five subjects with two PAS protocols consisting of PNS trains of six pulses at 100 Hz combined with (a) single 100% SO TMS pulses (high-PAS) and (b) a 20-Hz rTMS at a lower intensity (three pulses at 120% RMT). The MEPs were measured immediately after, and 30 and 60 min after the stimulation. Although at 0 and 30 min there was no significant difference in the induced MEP potentiation between the new PAS protocol and the rTMS control, the MEP potentiation remained significantly higher at 60 min after the new PAS than after rTMS alone. At 60 min, the new protocol was also more effective than the two other PAS protocols. The new protocol caused strong involuntary twitches in three subjects and, therefore, its further characterization is needed before introducing it for clinical research. Additionally, its mechanism plausibly differs from PAS with high-frequency PNS that has been used in SCI patients.

Analgesic effect of paired associative stimulation in a tetraplegic patient with severe drug-resistant neuropathic pain: a case report.

OBJECTIVES: There is no effective evidence-based non-pharmacological treatment for severe neuropathic pain after spinal cord injury (SCI). Paired associative stimulation (PAS) has been used in motor rehabilitation of patients after SCI. In the SCI-PAS protocol for tetraplegic patients, peripheral and central nerve tracts are activated with subject-specific timing, such that ascending and descending signals appear simultaneously at the cervical level. The effect on motor rehabilitation is thought to arise via strengthening of cervical upper and lower motoneuron synapses. We have observed an analgesic effect of PAS on mild-to-moderate neuropathic pain in tetraplegic patients receiving PAS for motor rehabilitation. Here, we applied PAS to a patient with severe drug-resistant neuropathic pain. METHODS: The patient is a 50-year-old man who had a traumatic cervical SCI three years earlier. He has partial paresis in the upper limbs and completely plegic lower limbs. The most severe pain is located in the right upper limb and shoulder region. The pain has not responded to either pharmacological therapy or repetitive-TMS therapy targeted to either primary motor cortex or secondary somatosensory cortex. PAS was targeted to relieve pain in the right upper arm. Peripheral nerve stimulation targeted the median, ulnar, and radial nerves and was accompanied by TMS pulses to the motor representation area of abductor pollicis brevis, abductor digiti minimi, and extensor digitorum communis muscles, respectively. RESULTS: Hand motor function, especially finger abduction and extension, was already enhanced during the first therapy week. Pain decreased at the end of the second therapy week. Pain was milder especially in the evenings. Numerical rating scale scores (evening) decreased 44% and patient estimation of global impression of change was 1, subjectively indicating great benefit when compared to before therapy. Quality of sleep also improved. CONCLUSIONS: The SCI-PAS protocol reduced neuropathic pain in our subject. The mechanism behind the analgesic effect may involve the modulation of nociceptive and sensory neuronal circuits at the spinal cord level. The possibility to use PAS as an adjunct treatment in drug-resistant post-SCI neuropathic pain warrants further investigation and sham-controlled studies. Patients with neuropathic pain due to SCI may benefit from PAS therapy in addition to PAS therapy-induced improvement in motor function.

Omitting TMS component from paired associative stimulation with high-frequency PNS: A case series of tetraplegic patients.

OBJECTIVES: Earlier studies have shown how chronic spinal cord injury (SCI) patients have benefitted from paired associative stimulation (PAS), consisting of high-frequency peripheral nerve stimulation (PNS) and high-intensity transcranial magnetic stimulation (TMS). Since high-frequency PNS is poorly characterized, its therapeutic effect without TMS should be evaluated. We tested the effect of PNS combined with motor imagery in chronic SCI patients using the same parameters of PNS as in earlier PAS-based studies that also used TMS. METHODS: Five patients with chronic incomplete SCI and tetraplegia received a 6-week treatment of PNS combined with motor imagery to the weaker upper limb. Patients were evaluated with Manual Muscle Testing (MMT), hand function tests (Box and block, grip and pinch strength dynamometry), and spasticity. RESULTS: There was no significant change in hand function tests or spasticity. MMT values improved significantly immediately after the PNS period (0.59 ±â€¯0.17, p = 0.043) and in the 1-month follow-up visit (0.87 ±â€¯0.18, p = 0.043). However, improvement of MMT values was weaker than in chronic tetraplegic patients in a corresponding PAS study that used identical PNS stimulation but also included the TMS component omitted here (Tolmacheva et al., 2019a, Clin Neurophysiol Pract). CONCLUSIONS: The lack of effect on functional hand tests with the protocol presented here suggests that the synergistic effect of PNS and TMS components is essential for the full therapeutic effect previously observed with PAS intervention. The moderate improvement of the MMT score suggests the possible usefulness of PNS and motor imagery for some of those tetraplegic SCI patients who have contraindications to TMS. SIGNIFICANCE: These results add to the understanding of the PAS therapeutic mechanism by highlighting the importance of dual stimulation for achieving the full therapeutic effect of long-term PAS with a high-frequency PNS component.

A novel paired associative stimulation protocol with a high-frequency peripheral component: A review on results in spinal cord injury rehabilitation.

In recent decades, a multitude of therapeutic approaches has been developed for spinal cord injury (SCI), but few have progressed to regular clinical practice. Novel non-invasive, cost-effective, and feasible approaches to treat this challenging condition are needed. A novel variant of paired associative stimulation (PAS), high-PAS, consists of non-invasive high-intensity transcranial magnetic stimulation (TMS) and non-invasive high-frequency electrical peripheral nerve stimulation (PNS). We observed a therapeutic effect of high-PAS in 20 patients with incomplete SCI with wide range of injury severity, age, and time since injury. Tetraplegic and paraplegic, traumatic, and neurological SCI patients benefited from upper- or lower-limb high-PAS. We observed increases in manual motor scores (MMT) of upper and lower limbs, functional hand tests, walking tests, and measures of functional independence. We also optimized PAS settings in several studies in healthy subjects and began elucidating the mechanisms of therapeutic action. The scope of this review is to describe the clinical experience gained with this novel PAS approach. This review is focused on the summary of our results and observations and the methodological considerations for researchers and clinicians interested in adopting and further developing this new method.

Effects of Long-Term Paired Associative Stimulation on Strength of Leg Muscles and Walking in Chronic Tetraplegia: A Proof-of-Concept Pilot Study.

Recovery of lower-limb function after spinal cord injury (SCI) is dependent on the extent of remaining neural transmission in the corticospinal pathway. The aim of this proof-of-concept pilot study was to explore the effects of long-term paired associative stimulation (PAS) on leg muscle strength and walking in people with SCI. Five individuals with traumatic incomplete chronic tetraplegia (>34 months post-injury, motor incomplete, 3 females, mean age 60 years) with no contraindications to transcranial magnetic stimulation (TMS) received PAS to one or both legs for 2 months (28 sessions in total, 5 times a week for the first 2 weeks and 3 times a week thereafter). The participants were evaluated with the Manual Muscle Test (MMT), AIS motor and sensory examination, Modified Asworth Scale (MAS), and the Spinal Cord Independence Measure (SCIM) prior to the intervention, after 1 and 2 months of PAS, and after a 1-month follow-up. The study was registered at clinicaltrials.gov (NCT03459885). During the intervention, MMT scores and AIS motor scores increased significantly (p = 0.014 and p = 0.033, respectively). Improvements were stable in follow-up. AIS sensory scores, MAS, and SCIM were not modified significantly. MMT score prior to intervention was a good predictor of changes in walking speed ( R adj 2 = 0.962). The results of this proof-of-concept pilot study justify a larger trial on the effect of long-term PAS on leg muscle strength and walking in people with chronic incomplete SCI.

The impact of TMS and PNS frequencies on MEP potentiation in PAS with high-frequency peripheral component.

Paired associative stimulation (PAS) combines transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) to induce plastic changes in the corticospinal tract. PAS employing single 0.2-Hz TMS pulses synchronized with the first pulse of 50-100 Hz PNS trains potentiates motor-evoked potentials (MEPs) in a stable manner in healthy participants and enhances voluntary motor output in spinal cord injury (SCI) patients. We further investigated the impact of settings of this PAS variant on MEP potentiation in healthy subjects. In experiment 1, we compared 0.2-Hz vs 0.4-Hz PAS. In experiment 2, PNS frequencies of 100 Hz, 200 Hz, and 400 Hz were compared. In experiment 3, we added a second TMS pulse. When compared with 0.4-Hz PAS, 0.2-Hz PAS was significantly more effective after 30 minutes (p = 0.05) and 60 minutes (p = 0.014). MEP potentiation by PAS with 100-Hz and 200-Hz PNS did not differ. PAS with 400-Hz PNS was less effective than 100-Hz (p = 0.023) and 200-Hz (p = 0.013) PNS. Adding an extra TMS pulse rendered PAS strongly inhibitory. These negative findings demonstrate that the 0.2-Hz PAS with 100-Hz PNS previously used in clinical studies is optimal and the modifications employed here do not enhance its efficacy.

Paired associative stimulation improves hand function after non-traumatic spinal cord injury: A case series.

OBJECTIVES: Long-term paired associative stimulation (PAS) is a non-invasive combination of transcranial magnetic stimulation and peripheral nerve stimulation and leads to improved hand motor function in individuals with incomplete traumatic tetraplegia. Spinal cord injuries (SCIs) can also be induced by neurological diseases. We tested a similar long-term PAS approach in patients with non-traumatic neurological SCI. METHODS: In this case series, five patients with non-traumatic tetraplegia received PAS to the weaker upper limb 3 to 5 times per week for 6 weeks. Patients were evaluated by manual muscle testing (MMT) before and immediately after the therapy and at the 1- and 6-month follow-ups. Patients were also evaluated for spasticity, hand mechanical and digital dynamometry, pinch test and Box and Block test. RESULTS: MMT values of all patients improved at all post-PAS evaluations. The mean ±â€¯standard error MMT increase was 1.44 ±â€¯0.37 points (p = 0.043) immediately after PAS, 1.57 ±â€¯0.4 points (p = 0.043) at the 1-month follow-up and 1.71 ±â€¯0.47 points (p = 0.043) at the 6-month follow-up. The pinch test, digital dynamometry and Box and Block test results also improved in all patients. CONCLUSIONS: Long-term PAS may be a safe and effective treatment for improving hand function in patients with non-traumatic tetraplegia. SIGNIFICANCE: This is the first report demonstrating the therapeutic potential of PAS for neurological SCI.

The use of electronic coil location control for focal magnetic stimulation at the cervical level.

BACKGROUND: Accurate re-positioning of the coil is challenging in magnetic stimulation at the cervical spinal level. The applicability of coil location control for this type of stimulation is unexplored. NEW METHOD: Utilizing a figure-of-eight coil and anatomy-specific models of the magnetic stimulation system, we developed a novel technique that enables probing corticospinal excitability at the cervical spinal level. Magnetic stimulation was performed in 9 healthy subjects at C2-C6 spinal levels using a figure-of-eight coil and a coil tracking system. MEPs were recorded from the abductor digiti minimi muscle. The functioning of the coil tracking system was tested with an estimated electric field maximum (eEFM) above the C1 cervical level (group 1) and below (group 2). Motor-evoked potential (MEP) reproducibility was assessed with intra-class correlation coefficient (ICC). RESULTS: The use of coil location control in cervical level focal magnetic stimulation enabled the recording of highly reproducible MEPs. Within one co-registration, the ICC 95% confidence interval (CI) in group 1 was 0.89-0.99 and in group 2 was 0.24-0.85. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: This method can be used for accurate maintenance and retrieval of the focal coil position at the cervical level with low spatial variability during stimulation. Existing methodologies employ determination of the coil location based on external landmarks, which makes the procedure cumbersome. This technique can optimize existing stimulation protocols and facilitate development of navigated spinal stimulation.

Increasing the frequency of peripheral component in paired associative stimulation strengthens its efficacy.

Paired associative stimulation (PAS), a combination of transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS), is emerging as a promising tool for alleviation of motor deficits in neurological disorders. The effectiveness and feasibility of PAS protocols are essential for their use in clinical practice. Plasticity induction by conventional PAS can be variable and unstable. Protocols effective in challenging clinical conditions are needed. We have shown previously that PAS employing 50 Hz PNS enhances motor performance in chronic spinal cord injury patients and induces robust motor-evoked potential (MEP) potentiation in healthy subjects. Here we investigated whether the effectiveness of PAS can be further enhanced. Potentiation of MEPs up to 60 minutes after PAS with PNS frequencies of 25, 50, and 100 Hz was tested in healthy subjects. PAS with 100 Hz PNS was more effective than 50 (P = 0.009) and 25 Hz (P = 0.016) protocols. Moreover, when administered for 3 days, PAS with 100 Hz led to significant MEP potentiation on the 3rd day (P = 0.043) even when the TMS target was selected suboptimally (modelling cases where finding an optimal site for TMS is problematic due to a neurological disease). PAS with 100 Hz PNS is thus effective and feasible for clinical applications.

Long-Term Paired Associative Stimulation Enhances Motor Output of the Tetraplegic Hand.

A large proportion of spinal cord injuries (SCI) are incomplete. Even in clinically complete injuries, silent non-functional connections can be present. Therapeutic approaches that can strengthen transmission in weak neural connections to improve motor performance are needed. Our aim was to determine whether long-term delivery of paired associative stimulation (PAS, a combination of transcranial magnetic stimulation [TMS] with peripheral nerve stimulation [PNS]) can enhance motor output in the hands of patients with chronic traumatic tetraplegia, and to compare this technique with long-term PNS. Five patients (4 males; age 38-68, mean 48) with no contraindications to TMS received 4 weeks (16 sessions) of stimulation. PAS was given to one hand and PNS combined with sham TMS to the other hand. Patients were blinded to the treatment. Hands were selected randomly. The patients were evaluated by a physiotherapist blinded to the treatment. The follow-up period was 1 month. Patients were evaluated with Daniels and Worthingham's Muscle Testing (0-5 scale) before the first stimulation session, after the last stimulation session, and 1 month after the last stimulation session. One month after the last stimulation session, the improvement in the PAS-treated hand was 1.02 ± 0.17 points (p < 0.0001, n = 100 muscles from 5 patients). The improvement was significantly higher in PAS-treated than in PNS-treated hands (176 ± 29%, p = 0.046, n = 5 patients). Long-term PAS might be an effective tool for improving motor performance in incomplete chronic SCI patients. Further studies on PAS in larger patient cohorts, with longer stimulation duration and at earlier stages after the injury, are warranted.

Paired Associative Stimulation with High-Frequency Peripheral Component Leads to Enhancement of Corticospinal Transmission at Wide Range of Interstimulus Intervals.

Background: In spinal paired associative stimulation (PAS), orthodromic and antidromic volleys elicited by transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) coincide at corticomotoneuronal synapses at the spinal cord. The interstimulus interval (ISI) between TMS and PNS determines whether PAS leads to motor-evoked potential (MEP) potentiation or depression. PAS applied as a long-term treatment for neurological patients might alter conduction of neural fibers over time. Moreover, measurements of motoneuron conductance for determination of ISIs may be challenging in these patients. Results: We sought to design a PAS protocol to induce MEP potentiation at wide range of ISIs. We tested PAS consisting of high-intensity (100% stimulator output, SO) TMS and high-frequency (50 Hz) PNS in five subjects at five different ISIs. Our protocol induced potentiation of MEP amplitudes in all subjects at all tested intervals. TMS and PNS alone did not result in MEP potentiation. The variant of PAS protocol described here does not require exact adjustment of ISIs in order to achieve effective potentiation of MEPs. Conclusions: This variant of PAS might be feasible as a long-term treatment in rehabilitation of neurological patients.

Long-term paired associative stimulation can restore voluntary control over paralyzed muscles in incomplete chronic spinal cord injury patients.

Emerging therapeutic strategies for spinal cord injury aim at sparing or restoring at least part of the corticospinal tract at the acute stage. Hence, approaches that strengthen the weak connections that are spared or restored are crucial. Transient plastic changes in the human corticospinal tract can be induced through paired associative stimulation, a noninvasive technique in which transcranial magnetic brain stimulation is synchronized with electrical peripheral nerve stimulation. A single paired associative stimulation session can induce transient plasticity in spinal cord injury patients. It is not known whether paired associative stimulation can strengthen neuronal connections persistently and have therapeutic effects that are clinically relevant. We recruited two patients with motor-incomplete chronic (one para- and one tetraplegic) spinal cord injuries. The patients received paired associative stimulation for 20-24 weeks. The paraplegic patient, previously paralyzed below the knee level, regained plantarflexion and dorsiflexion of the ankles of both legs. The tetraplegic patient regained grasping ability. The newly acquired voluntary movements could be performed by the patients in the absence of stimulation and for at least 1 month after the last stimulation session. In this unblinded proof-of-principle demonstration in two subjects, long-term paired associative stimulation induced persistent and clinically relevant strengthening of neural connections and restored voluntary movement in previously paralyzed muscles. Further study is needed to confirm whether long-term paired associative stimulation can be used in rehabilitation after spinal cord injury by itself and, possibly, in combination with other therapeutic strategies.

The use of F-response in defining interstimulus intervals appropriate for LTP-like plasticity induction in lower limb spinal paired associative stimulation.

BACKGROUND: In spinal paired associative stimulation (PAS), orthodromic volleys are induced by transcranial magnetic stimulation (TMS) in upper motor neurons, and antidromic volleys by peripheral nerve stimulation (PNS) in lower motor neurons of human corticospinal tract. The volleys arriving synchronously to the corticomotoneuronal synapses induce spike time-dependent plasticity in the spinal cord. For clinical use of spinal PAS, it is important to develop protocols that reliably induce facilitation of corticospinal transmission. Due to variability in conductivity of neuronal tracts in neurological patients, it is beneficial to estimate interstimulus interval (ISI) between TMS and PNS on individual basis. Spinal root magnetic stimulation has previously been used for this purpose in spinal PAS targeting upper limbs. However, at lumbar level this method does not take into account the conduction time of spinal nerves of the cauda equina in the spinal canal. NEW METHOD: For lower limbs spinal PAS, we propose estimating appropriate ISIs on the basis of F-response and motor-evoked potential (MEP) latencies. The use of navigation in TMS and ensuring correct PNS electrode placement with F-response recording enhances the precision of the method. RESULTS: Our protocol induced 186±17% (mean±STE) MEP amplitude facilitation in healthy subjects, being effective in all subjects and nerves tested. COMPARISON WITH EXISTING METHOD: We report for the first time the individual estimation of ISIs in spinal PAS for lower limbs. CONCLUSIONS: Estimation of ISI on the basis of F and MEP latencies is sufficient to effectively enhance corticospinal transmission by lower limb spinal PAS in healthy subjects.

The loop diuretic bumetanide blocks posttraumatic p75NTR upregulation and rescues injured neurons.

Injured neurons become dependent on trophic factors for survival. However, application of trophic factors to the site of injury is technically extremely challenging. Novel approaches are needed to circumvent this problem. Here, we unravel the mechanism of the emergence of dependency of injured neurons on brain-derived neurotrophic factor (BDNF) for survival. Based on this mechanism, we propose the use of the diuretic bumetanide to prevent the requirement for BDNF and consequent neuronal death in the injured areas. Responses to the neurotransmitter GABA change from hyperpolarizing in intact neurons to depolarizing in injured neurons. We show in vivo in rats and ex vivo in mouse organotypic slice cultures that posttraumatic GABA(A)-mediated depolarization is a cause for the well known phenomenon of pathological upregulation of pan-neurotrophin receptor p75(NTR). The increase in intracellular Ca(2+) triggered by GABA-mediated depolarization activates ROCK (Rho kinase), which in turn leads to the upregulation of p75(NTR). We further show that high levels of p75(NTR) and its interaction with sortilin and proNGF set the dependency on BDNF for survival. Thus, application of bumetanide prevents p75(NTR) upregulation and neuronal death in the injured areas with reduced levels of endogenous BDNF.