NeuroMeasure: A Software Package for Quantification of Cortical Motor Maps Using Frameless Stereotaxic Transcranial Magnetic Stimulation.

The recent enhanced sophistication of non-invasive mapping of the human motor cortex using MRI-guided Transcranial Magnetic Stimulation (TMS) techniques, has not been matched by refinement of methods for generating maps from motor evoked potential (MEP) data, or in quantifying map features. This is despite continued interest in understanding cortical reorganization for natural adaptive processes such as skill learning, or in the case of motor recovery, such as after lesion affecting the corticospinal system. With the observation that TMS-MEP map calculation and quantification methods vary, and that no readily available commercial or free software exists, we sought to establish and make freely available a comprehensive software package that advances existing methods, and could be helpful to scientists and clinician-researchers. Therefore, we developed NeuroMeasure, an open source interactive software application for the analysis of TMS motor cortex mapping data collected from Nexstim® and BrainSight®, two commonly used neuronavigation platforms. NeuroMeasure features four key innovations designed to improve motor mapping analysis: de-dimensionalization of the mapping data, fitting a predictive model, reporting measurements to characterize the motor map, and comparing those measurements between datasets. This software provides a powerful and easy to use workflow for characterizing and comparing motor maps generated with neuronavigated TMS. The software can be downloaded on our github page: https://github.com/EdwardsLabNeuroSci/NeuroMeasure. AIM: This paper aims to describe a software platform for quantifying and comparing maps of the human primary motor cortex, using neuronavigated transcranial magnetic stimulation, for the purpose of studying brain plasticity in health and disease.

Robotic Arm Rehabilitation in Chronic Stroke Patients With Aphasia May Promote Speech and Language Recovery (but Effect Is Not Enhanced by Supplementary tDCS).

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia. Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol. Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS. Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS.

Augmenting Plasticity Induction in Human Motor Cortex by Disinhibition Stimulation.

Cellular studies showed that disinhibition, evoked pharmacologically or by a suitably timed priming stimulus, can augment long-term plasticity (LTP) induction. We demonstrated previously that transcranial magnetic stimulation evokes a period of presumably GABA(B)ergic late cortical disinhibition (LCD) in human primary motor cortex (M1). Here, we hypothesized that, in keeping with cellular studies, LCD can augment LTP-like plasticity in humans. In Experiment 1, patterned repetitive TMS was applied to left M1, consisting of 6 trains (intertrain interval, 8 s) of 4 doublets (interpulse interval equal to individual peak I-wave facilitation, 1.3-1.5 ms) spaced by the individual peak LCD (interdoublet interval (IDI), 200-250 ms). This intervention (total of 48 pulses applied over ∼45 s) increased motor-evoked potential amplitude, a marker of corticospinal excitability, in a right hand muscle by 147% ± 4%. Control experiments showed that IDIs shorter or longer than LCD did not result in LTP-like plasticity. Experiment 2 indicated topographic specificity to the M1 hand region stimulated by TMS and duration of the LTP-like plasticity of 60 min. In conclusion, GABA(B)ergic LCD offers a powerful new approach for augmenting LTP-like plasticity induction in human cortex. We refer to this protocol as disinhibition stimulation (DIS).

Stroke subtype and motor impairment influence contralesional excitability.

OBJECTIVE: The nonlesioned motor cortex (M1NL) is thought to be hyperexcitable in patients with subacute or chronic stroke and offers a promising therapeutic target. However, whether M1NL excitability behaves the same for subcortical and cortical strokes is unknown. The aim of the present study was to determine whether cortical, or purely subcortical, strokes have a different effect on M1NL excitability. METHODS: We looked for correlations between the Fugl-Meyer (FM) score and M1NL resting motor threshold (RMTNL) in 34 stroke survivors classified according to lesion location (cortico-subcortical or purely subcortical). In addition to the FM, the Wolf Motor Score and motor power were measured. RESULTS: FM correlated with RMTNL for subcortical (r = 0.82; p = 0.001) but not for cortical strokes (r = 0.11; p = 0.62). Likewise, Wolf Motor Score (r = -0.62; p = 0.03) and motor power (r = 0.64; p = 0.023) were correlated with RMTNL for the subcortical group, but not for the cortical group. CONCLUSION: We show that the impact on M1NL depends on lesion location and conclude that protocols aimed at reducing M1NL cortical excitability may be worth exploring for subcortical but not for cortical stroke.

Evidence for an excitatory GABAA response in human motor cortex in idiopathic generalised epilepsy.

PURPOSE: Impaired GABAergic inhibition has been implicated in the pathophysiology of epilepsy. The possibility of a paradoxical excitatory effect of GABA in epilepsy has been suggested, but has not been investigated in vivo. We investigated pre- and post-synaptic GABAergic mechanisms in patients with idiopathic generalised epilepsy (IGE). METHOD: In 10 patients and 12 control subjects we explored short- and long-interval intracortical inhibition (SICI, LICI; post-synaptic GABAA and GABAB-mediated respectively) and long-interval intracortical facilitation (LICF; pre-synaptic disinhibition) using transcranial magnetic stimulation. RESULTS: While post-synaptic GABAB-mediated inhibition was unchanged in IGE (p=0.09), LICF was reduced compared to controls (controls: 141±17% of baseline; untreated patients: 107±12%, p=0.2; treated patients: 79±10%, p=0.003). GABAA-mediated inhibition was reduced in untreated patients (response amplitude 56±4% of baseline vs. 26±6% in controls, p=0.004) and normalised with treatment (37±12%, p=0.5 vs. controls). When measured during LICI, GABAA-mediated inhibition became excitatory in untreated IGE (response amplitude 120±10% of baseline, p=0.017), but not in treated patients. CONCLUSION: Pre- and post-synaptic GABA-mediated inhibitory mechanisms are altered in IGE. The findings lend in vivo support to evidence from experimental models and in vitro studies of human epileptic brain tissue that GABA may have a paradoxical excitatory role in ictogenesis.

Movement-generated afference paired with transcranial magnetic stimulation: an associative stimulation paradigm.

BACKGROUND: A peripheral nerve stimulus can enhance or suppress the evoked response to transcranial magnetic stimulation (TMS) depending on the latency of the preceding peripheral nerve stimulation (PNS) pulse. Similarly, somatosensory afference from the passively moving limb can transiently alter corticomotor excitability, in a phase-dependent manner. The repeated association of PNS with TMS is known to modulate corticomotor excitability; however, it is unknown whether repeated passive-movement associative stimulation (MAS) has similar effects. METHODS: In a proof-of-principal study, using a cross-over design, seven healthy subjects received in separate sessions: (1) TMS (120% of the resting motor threshold-RMT, optimal site for Flexor Carpi Radialis) with muscle at rest; (2) TMS paired with cyclic passive movement during extension cyclic passive movement (400 pairs, 1 Hz), with the intervention order randomly assigned. Normality was tested using the Kolmogorov-Smirnov test, then compared to pre-intervention baseline using repeated measures ANOVA with a Dunnet multiple comparisons test. RESULTS: MAS led to a progressive and significant decrease in the motor evoked potential (MEP) amplitude over the intervention (R(2) = 0.6665, P < 0.0001), which was not evident with TMS alone (R(2) = 0.0068, P = 0.641). Post-intervention excitability reduction, only present with MAS intervention, remained for 20 min (0-10 min = 68.2 ± 4.9%, P < 0.05; 10-20 min = 73.3 ± 9.7%, P < 0.05). CONCLUSION: The association of somatosensory afference from the moving limb with TMS over primary motor cortex in healthy subjects can be used to modulate corticomotor excitability, and may have therapeutic implications.

Modulation of corticomotor excitability after maximal or sustainable-rate repetitive finger movement is impaired in Parkinson's disease and is reversed by levodopa.

OBJECTIVES: In healthy subjects, fatiguing exercises induce a period of post-exercise corticomotor depression (PECD) that is absent in Parkinson's disease (PD). Our objective is to determine the time-course of corticomotor excitability changes following a 10-s repetitive index finger flexion-extension task performed at maximal voluntary rate (MVR) and a slower sustainable rate (MSR) in PD patients OFF and ON levodopa. METHODS: In 11 PD patients and 10 healthy age-matched controls, motor evoked potentials (MEPs) were recorded from the extensor indicis proprius (EIP) and first dorsal interosseous (FDI) muscles of the dominant arm immediately after the two tasks and at 2-min intervals for 10 min. RESULTS: In the OFF condition the PECD was absent in the two test muscles after both the MVR and MSR tasks. In the ON condition finger movement kinematics improved and a period of PECD comparable to that in controls was present after both tasks. CONCLUSION: The absence of PECD in PD subjects off medication indicates a persisting increase in corticomotor excitability after non-fatiguing repetitive finger movement that is reversed by levodopa. SIGNIFICANCE: Dopamine depletion is associated with impaired modulation of corticomotor excitability after non-fatiguing repetitive finger movement.

Improved motor performance in chronic spinal cord injury following upper-limb robotic training.

BACKGROUND: Recovering upper-limb motor function has important implications for improving independence of patients with tetraplegia after traumatic spinal cord injury (SCI). OBJECTIVE: To evaluate the feasibility, safety and effectiveness of robotic-assisted training of upper limb in a chronic SCI population. METHODS: A total of 10 chronic tetraplegic SCI patients (C4 to C6 level of injury, American Spinal Injury Association Impairment Scale, A to D) participated in a 6-week wrist-robot training protocol (1 hour/day 3 times/week). The following outcome measures were recorded at baseline and after the robotic training: a) motor performance, assessed by robot-measured kinematics, b) corticospinal excitability measured by transcranial magnetic stimulation (TMS), and c) changes in clinical scales: motor strength (Upper extremity motor score), pain level (Visual Analog Scale) and spasticity (Modified Ashworth scale). RESULTS: No adverse effects were observed during or after the robotic training. Statistically significant improvements were found in motor performance kinematics: aim (pre 1.17 ± 0.11 raduans, post 1.03 ± 0.08 raduans, p = 0.03) and smoothness of movement (pre 0.26 ± 0.03, post 0.31 ± 0.02, p = 0.03). These changes were not accompanied by changes in upper-extremity muscle strength or corticospinal excitability. No changes in pain or spasticity were found. CONCLUSIONS: Robotic-assisted training of the upper limb over six weeks is a feasible and safe intervention that can enhance movement kinematics without negatively affecting pain or spasticity in chronic SCI. In addition, robot-assisted devices are an excellent tool to quantify motor performance (kinematics) and can be used to sensitively measure changes after a given rehabilitative intervention.

Inverse correlation between resting motor threshold and corticomotor excitability after static magnetic stimulation of human motor cortex.

BACKGROUND: High-strength static magnetic field stimulation (SMS) results in a period of reduced corticomotor excitability that may be mediated through a decrease in membrane excitability. OBJECTIVE: As resting motor threshold (RMT) is thought to reflect membrane excitability, we hypothesized that SMS may increase RMT and that there would be an inverse relationship between RMT and motor-evoked potential (MEP) amplitude. METHODS: Ten healthy subjects (aged 20-29; 4 females) participated in a double-blinded crossover design comparing MEP amplitude and RMT before and after a 15-min period of SMS or sham stimulation over primary motor cortex (M1). RESULTS: MEP amplitude was initially significantly reduced post-SMS (∼20%), and returned to baseline by 6 min post-intervention. MEP amplitude and RMT were inversely correlated (r(2) = 0.924; P = 0.001). Sham stimulation had no effect on MEP amplitude (P = 0.969) or RMT (P = 0.549). CONCLUSION: After SMS, corticomotor excitability is transiently reduced in association with a correlated modulation of RMT. SMS after effects may be mediated in part by a reduction in membrane excitability, suggesting a possible role for non-synaptic (intrinsic) plasticity mechanisms.

Conditioning the cortical silent period with paired transcranial magnetic stimulation.

BACKGROUND: A single supra-threshold pulse of transcranial magnetic stimulation (TMS) over human motor cortex elicits multiple descending volleys (I-waves) that generate a motor evoked potential (MEP) followed by a period of electromyographic silence in the tonically contracted target muscle (silent period; SP). A sub-threshold conditioning stimulus (CS) delivered at inter-pulse intervals (IPIs) of 1-5 ms after a supra-threshold test stimulus (TS) conditions I-waves elicited by TS and can increase MEP amplitude (short-interval intracortical facilitation; SICF), however its effect on the SP remains unknown. OBJECTIVE: We investigated whether it is possible to modulate the SP resulting from a TS by delivering a sub-threshold CS 1-5 ms later. METHODS: Paired-pulse TMS was delivered while subjects performed slight contraction of the first dorsal interosseous muscle. SICF and SP duration were measured at each IPI and compared to amplitude-matched MEPs evoked by single-pulse TMS. RESULTS: Paired stimulation at IPI 2-5 ms prolonged the SP by 21 ± 3% (P < 0.001) but had no effect on MEP amplitude. At shorter IPIs the CS increased MEP amplitude (by 170 ± 31%), but the SP was not prolonged when compared to an amplitude-matched single-pulse stimulus. CONCLUSION: The SP can be modified by a CS applied during the early phase of its genesis. We suggest that this is in keeping with an early GABAA contribution to the SP, and it is possible that this new conditioning paradigm may offer another means for probing the excitability of cortical inhibitory networks in human motor cortex.

Interaction between simultaneously applied neuromodulatory interventions in humans.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique with the potential to enhance the efficacy of traditional therapies such as neuromuscular electrical stimulation (NMES). Yet, concurrent application of tDCS/NMES may also activate homeostatic mechanisms that block or reverse effects on corticomotor excitability. It is unknown how tDCS and NMES interact in the human primary motor cortex (M1) and whether effects are summative (increase corticomotor excitability beyond that of tDCS or NMES applied alone) or competitive (block or reduce corticomotor excitability effects of tDCS or NMES applied alone). OBJECTIVE: To investigate corticomotor excitability in response to NMES after concurrent application of tDCS protocols that enhance (anodal tDCS) or suppress (cathodal tDCS) excitability of M1. METHODS: We used transcranial magnetic stimulation (TMS) to examine corticomotor excitability before and after the concurrent application of: i) NMES with anodal tDCS; and ii) NMES with cathodal tDCS. Effects were contrasted to four control conditions: i) NMES alone, ii) anodal tDCS alone, iii) cathodal tDCS alone, and iv) sham stimulation. RESULTS: Concurrent application of two protocols that enhance excitability when applied alone (NMES and anodal tDCS) failed to induce summative effects on corticomotor excitability, as predicted by homeostatic plasticity mechanisms. Combined cathodal tDCS and NMES suppressed the enhanced excitation induced by NMES, an effect that might be explained by calcium dependent anti-gating models. CONCLUSIONS: These novel findings highlight the complex mechanisms involved when two neuromodulatory techniques are combined and suggest that careful testing of combined interventions is necessary before application in clinical contexts.

Interventional repetitive I-wave transcranial magnetic stimulation (TMS): the dimension of stimulation duration.

BACKGROUND: A range of transcranial magnetic stimulation (TMS) techniques are now available to modulate human corticomotor excitability and plasticity. One presumably critical aspect of these interventions is their duration of application. OBJECTIVE: In the current study, we investigated whether doubling the duration of an intervention would offer any additional benefit, or invoke self-limiting mechanisms controlling corticomotor excitability or synaptic plasticity. METHODS: We compared (in a cross-over design) corticomotor excitability (to the first dorsal interosseous muscle) during and after a 15-minute (I15) and 30-minute (I30) TMS intervention targeting indirect (I-) wave interaction (iTMS). The interventions consisted of equi-intensity paired stimuli with an interpulse interval (IPI) of 1.5 milliseconds, corresponding to I-wave periodicity, delivered at a frequency of 0.2 Hz. RESULTS: During both the I15 and I30 interventions, paired-pulse (I-wave) motor evoked potential (iMEP) amplitude significantly increased (by 98.3% and 120.6%, respectively, last versus first minute, P = .001). The increase for I30 occurred in the first 15 minutes, and there was no further change during the remainder of the intervention. Both interventions were equally effective overall. Postintervention, single-pulse MEP amplitude increased by a mean of 91% and 106% (I15 and I30, respectively, P < .01) with no significant difference between interventions. CONCLUSIONS: We conclude that repetitive iTMS can increase corticomotor excitability after a relatively short intervention period of stimulation, and that a longer stimulation period has no additional benefit or detriment, perhaps as a result of the action of regulatory mechanisms.

Reversal of TMS-induced motor twitch by training is associated with a reduction in excitability of the antagonist muscle.

BACKGROUND: A single session of isolated repetitive movements of the thumb can alter the response to transcranial magnetic stimulation (TMS), such that the related muscle twitch measured post-training occurs in the trained direction. This response is attributed to transient excitability changes in primary motor cortex (M1) that form the early part of learning. We investigated; (1) whether this phenomenon might occur for movements at the wrist, and (2) how specific TMS activation patterns of opposing muscles underlie the practice-induced change in direction. METHODS: We used single-pulse suprathreshold TMS over the M1 forearm area, to evoke wrist movements in 20 healthy subjects. We measured the preferential direction of the TMS-induced twitch in both the sagittal and coronal plane using an optical goniometer fixed to the dorsum of the wrist, and recorded electromyographic (EMG) activity from the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles. Subjects performed gentle voluntary movements, in the direction opposite to the initial twitch for 5 minutes at 0.2 Hz. We collected motor evoked potentials (MEPs) elicited by TMS at baseline and for 10 minutes after training. RESULTS: Repetitive motor training was sufficient for TMS to evoke movements in the practiced direction opposite to the original twitch. For most subjects the effect of the newly-acquired direction was retained for at least 10 minutes before reverting to the original. Importantly, the direction change of the movement was associated with a significant decrease in MEP amplitude of the antagonist to the trained muscle, rather than an increase in MEP amplitude of the trained muscle. CONCLUSIONS: These results demonstrate for the first time that a TMS-twitch direction change following a simple practice paradigm may result from reduced corticospinal drive to muscles antagonizing the trained direction. Such findings may have implications for training paradigms in neurorehabilitation.

Spinal associative stimulation: a non-invasive stimulation paradigm to modulate spinal excitability.

OBJECTIVE: Repetitive, paired peripheral and transcranial stimulation targeting the cerebral cortex can increase cortical excitability, outlasting the stimulation period. It is unknown whether paired stimulation specifically targeting the spinal cord can modulate spinal excitability. We tested whether the H-reflex facilitation from a sub-threshold conditioning TMS pulse could modulate spinal excitability if delivered repetitively. METHOD: In 13 healthy subjects, we delivered single-pulse TMS (80% RMT) for the right soleus muscle, 20 ms prior to an electrical peripheral nerve stimulus delivered over the posterior tibial nerve on the same side at 0.1 Hz during 15 min. RESULTS: PNS alone evoked an H-reflex of 0.25 mV ± 0.06 SEM, while pairing of TMS and PNS facilitated the H-reflex to 0.7 ± 0.11 mV. TMS-PNS pairs delivered at 0.1 Hz for 15 min progressively increased in the evoked response to ∼130% (r(2) = 0.97) of the starting amplitude (normalized to 1st min). Post-intervention, H-reflex threshold decreased (pre = 12.9 ± 1.7 mA; post =11.6 ± 1.6 mA; p = 0.04), as did the stimulus intensity at maximum H-reflex amplitude (pre = 23.5 ± 02.8 mA; post = 21.6 ± 2.6 mA; p = 0.03), and recruitment curve width (pre = 11.6 ± 1.5 mA; post = 10.93 ± 1.4 mA; p = 0.03). No such changes were observed with intervention of PNS or TMS alone. CONCLUSION: Paired stimulation targeting spinal facilitatory interactions, when applied repetitively, can increase spinal excitability during and after the intervention. SIGNIFICANCE: Spinal associative stimulation may have potential for neuromodulation in spinal cord injury patients.

A model of the contribution of late I-waves to α-motoneuronal activation: implications for paired-pulse TMS.

BACKGROUND: In paired-pulse (conditioned-test) transcranial magnetic stimulation (TMS) protocols, the effect of the conditioning pulse on the test response can be substantial. Epidural recordings indicate that this is mediated through modulation of late indirect (I-) wave volleys. It is not well understood how strong effect sizes could arise from the later, and usually weaker, I-wave volleys. OBJECTIVE: To formulate a model of I-wave summation at the spinal level to explore the contribution of late I-waves to the activation of the α-motoneuronal pool and to paired-pulse TMS measures of intracortical inhibition and facilitation. METHODS: I-wave recruitment curves were modeled for the first three I-waves. A series of steps converted I-wave inputs to α-motoneuronal activation. The role of I3 in activating the α-motoneuronal pool was investigated by manipulating the amplitude of the I3 volley. RESULTS: For all TMS intensities, I3 made a contribution to the firing of the α-motoneuronal pool that was disproportional to its contribution to the descending volley. At its most influential, I3 increased the descending volley by 23.5% but increased the proportion of motoneurons that fired by 567%. There was a U-like relationship to stimulus intensity with inhibition of I3, and an inverted-U relationship for facilitation of I3, in keeping with empirical observation. Changes in spinal excitability disproportionally influenced α-motoneuronal recruitment. CONCLUSIONS: Late I-waves have a pivotal role in determining the response to paired-pulse TMS. The spinal transfer function that converts I-wave input to α-motoneuron activation can amplify the role of late I-waves and potentially influence paired-pulse TMS measures of intracortical inhibition and facilitation.

Improvement in aerobic capacity after an exercise program in sporadic inclusion body myositis.

OBJECTIVES: The study aimed to investigate the effects of a combined functional and aerobic exercise program on aerobic capacity, muscle strength, and functional mobility in a group of patients with sporadic inclusion body myositis (IBM). METHODS: Aerobic capacity, muscle strength, and functional capacity assessments were conducted on 7 participants with sporadic IBM before and after a 12-week exercise program, which included resistance exercises and aerobic stationary cycling 3 times per week on alternative days. RESULTS: Aerobic capacity of the group increased significantly by 38%, and significant strength improvements were observed in 4 of the muscle groups tested (P < 0.05). The exercise program was well tolerated, and there was no significant change in the serum creatine kinase level after the exercise period. CONCLUSIONS: An aerobic exercise program can be safely tolerated by patients with sporadic IBM and can improve aerobic capacity and muscle strength when combined with resistance training. These findings indicate that aerobic and functional muscle strengthening exercise should be considered in the management of patients with IBM.

Rapid slowing of maximal finger movement rate: fatigue of central motor control?

Exploring the limits of the motor system can provide insights into the mechanisms underlying performance deterioration, such as force loss during fatiguing isometric muscle contraction, which has been shown to be due to both peripheral and central factors. However, the role of central factors in performance deterioration during dynamic tasks has received little attention. We studied index finger flexion/extension movement performed at maximum voluntary rate (MVR) in ten healthy subjects, measuring movement rate and amplitude over time, and performed measures of peripheral fatigue. During 20 s finger movements at MVR, there was a decline in movement rate beginning at 7-9 s and continuing until the end of the task, reaching 73% of baseline (P < 0.001), while amplitude remained unchanged. Isometric maximum voluntary contraction force and speed of single ballistic flexion and extension finger movements remained unchanged after the task, indicating a lack of peripheral fatigue. The timing of finger flexor and extensor EMG burst activity changed during the task from an alternating flexion/extension pattern to a less effective co-contraction pattern. Overall, these findings suggest a breakdown of motor control rather than failure of muscle force generation during an MVR task, and therefore that the mechanisms underlying the early decline in movement rate are central in origin.

Plasticity in neurological disorders and challenges for noninvasive brain stimulation (NBS).

There has been considerable interest in trialing NBS in a range of neurological conditions, and in parallel the range of NBS techniques available continues to expand. Underpinning this is the idea that NBS modulates neuroplasticity and that plasticity is an important contributor to functional recovery after brain injury and to the pathophysiology of neurological disorders. However while the evidence for neuroplasticity and its varied mechanisms is strong, the relationship to functional outcome is less clear and the clinical indications remain to be determined. To be maximally effective, the application of NBS techniques will need to be refined to take into account the diversity of neurological symptoms, the fundamental differences between acute, longstanding and chronic progressive disease processes, and the differential part played by functional and dysfunctional plasticity in diseases of the brain and spinal cord.

Spike-timing-related plasticity is preserved in Parkinson's disease and is enhanced by dopamine: evidence from transcranial magnetic stimulation.

We sought to investigate the effects of dopamine on motor cortical plasticity in Parkinson's disease (PD) using a novel interventional transcranial magnetic stimulation protocol that targets spike-timing-dependent plasticity (iTMS). Six patients (3F, mean age 62 years) with mild-moderate PD (mean disease duration 6 years, UPDRS-off 13, UPDRS-on 3, H&Y stage 2, daily levodopa dosage 450 mg) were studied off and on levodopa on separate days. Paired TMS pulses at resting motor threshold with an inter-stimulus interval of 1.5 ms were given over the hand area of the motor cortex for 20 min at 0.2 Hz. Single-pulse motor evoked potential (MEP) amplitude and visually cued simple reaction time (SRT) were measured before and after iTMS. When on levodopa, MEP amplitude increased to 278+/-36% of baseline (p<0.01), and when off levodopa to 157+/-13% of baseline (p=0.02). All patients showed a significantly greater increase in MEP amplitude when on levodopa than off levodopa (p=0.01). SRT was reduced to 95% baseline after iTMS off levodopa (p=0.02), but did not change on levodopa. These findings indicate that motor cortex plasticity to iTMS is preserved in mild-moderate PD. The effects of this spike-timing-related TMS protocol on cortical excitability were consistent and were enhanced by levodopa. The results support the important role of dopamine in regulating synaptic plasticity and justify a larger crossover study to assess the therapeutic effects of iTMS in PD.