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Objective Sub-motor threshold 5 Hz repetitive paired associative stimulation (5 Hz-rPAS25ms) produces a long-lasting increase in corticospinal excitability. Assuming a spike-timing dependent plasticity-like (STDP-like) mechanism, we hypothesized that 5 Hz-rPAS at a shorter inter-stimulus interval (ISI) of 15 ms (5 Hz-rPAS15ms) would exert a lasting inhibitory effect on corticospinal excitability. Methods 20 healthy volunteers received two minutes of 5 Hz-rPAS15ms. Transcranial magnetic stimulation (TMS) was applied over the motor hotspot of the right abductor pollicis brevis muscle at 90% active motor threshold. Sub-motor threshold peripheral electrical stimulation was given to the left median nerve 15 ms before each TMS pulse. We assessed changes in mean amplitude of the unconditioned motor evoked potential (MEP), short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition (LAI), and cortical silent period (CSP) before and for 60 minutes after 5-Hz rPAS15ms. Results Subthreshold 5-Hz rPAS15ms produced a 20–40% decrease in mean MEP amplitude along with an attenuation in SAI, lasting at least 60 minutes. A follow-up experiment revealed that MEP facilitation was spatially restricted to the target muscle. Conclusions Subthreshold 5-Hz rPAS15ms effectively suppresses corticospinal excitability. Together with the facilitatory effects of subthreshold 5-Hz rPAS25ms (Quartarone et al., J Physiol 2006;575:657–670), the results show that sub-motor threshold 5-Hz rPAS induces STDP-like bidirectional plasticity in the motor cortex. Significance The results of the present study provide a new short-time paradigm of long term depression (LTD) induction in human sensory-motor cortex.

Objective: To investigate the mechanism subtending the analgesic effect of high frequency non-painful somatosensory stimulation. Methods: Laser evoked potentials (LEPs) and laser-pain rating were obtained from healthy subjects to stimulation of different parts of the body. LEPs were recorded at baseline and during non-painful electrical stimulation of the superficial branch of the right radial nerve (RRES). Results: RRES reduced N2/P2 LEP amplitude to right radial (F(8,10) = 82.4, p < 0.001), left radial (F(8,10) = 22.2, p < 0.001), and right ulnar (F(8,10) = 7.2, p = 0.008) stimulation, while the N2/P2 amplitude to left ulnar territory stimulation remained unchanged (F(8,10) = 3.6, p = 0.07). The laser-pain rating was reduced by RRES to bilateral radial territory stimulation (p < 0.05). In a control experiment, laser-pain rating and LEPs to left foot stimulation were not modified by RRES (p > 0.05). Conclusions: Our study confirms that the non-nociceptive afferents dampen the nociceptive input. The spatial pattern of this interaction suggests that, when conditioning higher frequency non-painful stimulation is used, the inhibition takes place at the spinal cord. Significance: Our experimental design reproduces what happens when non-painful somatosensory stimuli are used to reduce pain, such as rubbing a wound or during transcutaneous electrical nerve stimulation. Therefore, in these situations the analgesia is likely to occur at the spinal cord level.

Levodopa-induced dyskinesias are motor complications following long term dopaminergic therapy in Parkinson's disease (PD). Impaired brain plasticity resulting in the creation of aberrant motor maps intended to encode normal voluntary movement is proposed to result in the development of dyskinesias. Traditionally, the various nodes in the motor network like the striato-cortical and the cerebello-thalamic loops were thought to function independent of each other with little communication among them. Anatomical evidence from primates revealed the existence of reciprocal loops between the basal ganglia and the cerebellum providing an anatomical basis for communication between the motor network loops. Dyskinetic PD patients reveal impaired brain plasticity within the motor cortex which may be modulated by cortico-cortical, cerebello-cortical or striato-cortical connections. In this article, we review the evidence for altered plasticity in the multicomponent motor network in the context of levodopa induced dyskinesias in PD. Current evidence suggests a pivotal role for the cerebellum in the larger motor network with the ability to integrate sensorimotor information and independently influence multiple nodes in this network. Targeting the cerebellum seems to be a justified approach for future interventions aimed at attenuating levodopa-induced dyskinesias.

Objectives The inhibition of single nociceptive inputs by single non-painful stimuli was shown to occur at supraspinal level (Testani et al., 2015). However, the neurophysiological mechanism subserving the analgesia induced by rubbing the painful part of the body or during TENS is still unknown. Our aim was to investigate the site of this inhibition. Methods We studied 10 healthy volunteers. LEPs were recorded after stimulation of the radial and ulnar territories of both the right and left hand dorsum in 2 conditions: (1) no conditioning stimulation (baseline condition), and (2) high-frequency (5 Hz) non-painful electrical stimulation of the right radial nerve (gating condition). Results As compared to the baseline, in the gating condition the N2/P2 amplitude was reduced in amplitude after stimulation of the radial territory of both hands ( p 0.001 and p 0.001 for right and left hand, respectively) and of the right ulnar region (p = 0.008), while no inhibition was found to left ulnar region stimulation (p = 0.06). Discussion Our results show that high-frequency non-painful stimulation of the right radial nerve inhibits the nociceptive input coming from both the ispilateral and contralateral homotopic regions, and from a close ispilateral heterotopic territory. On the contrary, it does not have any effect on the nociceptive input due to stimulation of a contralateral heterotopic area. Conclusion Spinal segmental mechanisms are mainly involved in the nociceptive input inhibition by high-frequency non-noxious somatosensory stimulation. Significance Pain inhibition induced by high-frequency somatosensory stimulation, such as TENS, is likely to occur at the spinal cord level.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain-stimulation procedure noted for its effects on emotional, cognitive, sensory, and motor functions in patients with neuropsychiatric diseases. Despite the large use of rTMS in different neuroscience fields the precise mechanism of this technique remain poorly understood. It is likely that rTMS induces long-term potentiation (LTP) or depression, which, in turn, produce lasting changes on neocortical excitability and synaptic connections. In recent years, brain-derived neurotrophic factor (BDNF) and its cognate receptor tyrosine receptor kinase B (TrkB), a member of the neurotrophin receptor tyrosine kinase family, have emerged as important upstream regulators of LTP in brain regions, including hippocampus and neocortex (Minichiello, 2009; Fritsch et al., 2010). In keeping with these findings we have recently reported that daily 5 Hz rTMS for 5 d improves BDNF–TrkB signaling in rats by increasing the affinity of BDNF for TrkB, which results in higher tyrosine-phosphorylated TrkB, increased recruitment of PLC- γ 1 and shc/N-shc to TrkB, and heightened downstream ERK2 and PI-3K activities in prefrontal cortex and in lymphocytes. The elevated BDNF–TrkB signaling is accompanied by an increased association between the activated TrkB and NMDA receptor (NMDAR). In normal human subjects, 5 d rTMS to motor cortex decreased resting motor threshold, which correlates with heightened BDNF-TrkB signaling and intensified TrkB–NMDAR association in lymphocytes. These findings suggest that rTMS to cortex facilitates BDNF–TrkB–NMDAR functioning in both cortex and lymphocytes. We propose TMS as a non invasive tool to test the NMDA receptor machinery at a molecular level.

Objective To explore if sensory information is processed and integrated during sensory-motor plasticity phenomena by using lateral inhibition mechanisms in normal humans and in patients with dystonia. Background Several evidence suggest that lateral inhibition is a system within sensory-motor cortex operating during the acquisition of new motor tasks in order to select the appropriate muscle sequence to be stored within the final motor engram. This mechanism is thought to be lost in dystonia and this should explain the development of redundant motor memories which could culminate in overflow phenomena and overt dystonia. Methods We have used transcranial magnetic stimulation to explore lateral inhibition during sensory-motor plasticity in 12 dystonic patients (7 focal hand dystonia, 5 cranial dystonia) and in 8 healthy subjects. In particular we looked at motor evoked potential (MEP) facilitation, in the abductor pollicis brevis (APB) and abductor digiti minimi (ADM), obtained after 5 Hz repetitive paired associative stimulation after median (PAS M), ulnar nerve stimulation (PAS U) and median + ulnar nerve (PAS MU) stimulation. In this way we evaluated the ratio MU/M + Ux100 (lateral inhibition index). Moreover, we evaluated the lateral inhibition index (Li index). This parameter is easily obtained by using the following formula: ratio MU/(M + U) x 100. MU is the MEP facilitation measured after PAS with simultaneous stimulation of median and ulnar and M + U is the amount of MEP facilitation, after PAS, induced from stimulation of the individual nerves. Results Our data confirmed that patients with dystonia had two main abnormalities: first the amount of facilitation was larger than normal subjects; second and more important the spatial specificity was lost. A three-factorial ANOVA demonstrated a significant time × group × conditioning interaction ( F = 7.9; p = 0.005). Lateral inhibition index was similar (about 50%) in healthy subjects and dystonic patients. Conclusions These data suggest that lateral inhibition is normal in dystonia during sensory-motor plasticity. Another mechanism could contribute to the formation of motor memories with redundant information, which could culminate in overt dystonia.

Introduction In a previous paper we showed that sub-motor threshold 5 Hz rENS of the right median nerve when synchronized with sub-motor threshold 5 Hz rTMS of the left M1 at a constant interval of 25 ms for 2 min caused a somatotopically specific increase in cortical excitability (5 Hz PAS LTP ). Objective In this study we used a similar protocol with a different interstimulus interval (ISI) to evaluate if an asynchronous paired stimulation could cause a somatotopically specific reduction of motor cortical excitability (5 Hz PAS LTD ). We also study the effect of 5 Hz PAS LTD on intracortical paired-pulse excitability and sensorimotor intracortical inhibition. Material and methods 5 Hz rPAS consisted of 600 pairs of stimuli which were continuously delivered to the left M1 at a rate of 5 Hz for 2 min in 20 healthy volunteers. Each pair of stimuli consisted of an electrical conditioning stimulus given to the right median nerve followed by a biphasic transcranial magnetic stimulus given to the left M1 controlling APB at 15 ms interval. Before and after rPAS (T0–T30–T60), we measured the amplitude of MEP, intracortical inhibition (ICI) and facilitation (ICF), short (SAI 20) and long latency (LAI 200 ms) afferent inhibition. We also recorded the MEP amplitudes at rest from first dorsal interosseus (FDI) and extensor carpi radialis (ECR) muscle at baseline and up to 1 h after 5 Hz rPAS 15 ms conditioning. Results The 5 Hz PAS LTD protocol caused a significant and somatotopically specific decrease in mean MEP amplitudes in the APB muscle that lasted for at least 1 h which was paralleled by a reduction of SAI. Conclusions These findings show that 2 min of 5 Hz rPAS at 15 ms can induce a long-lasting and somatotopically specific reduction in the excitability of the corticospinal output from the stimulated M1 for 60 min.