Masashi Hamada

The Role of Interneuron Networks in Driving Human Motor Cortical Plasticity

The after-effects of repetitive transcranial magnetic stimulation (rTMS) are highly variable between individuals. Because different populations of cortical neurons are stimulated more easily or are more excitable in different people at different times, the variability may not be due to differences between individuals in the plasticity of cortical synapses, but may instead be due to individual differences in the recruitment of cortical neurons. In this study, we examined the effects of rTMS in 56 healthy volunteers. The responses to excitatory and inhibitory theta burst stimulation (TBS) protocols were highly variable between individuals. Surprisingly, the TBS effect was highly correlated with the latency of motor-evoked potentials (MEPs) evoked by TMS pulses that induced an anterior-posterior (AP) directed current across the central sulcus. Finally, we devised a new plasticity protocol using closely timed pairs of oppositely directed TMS current pulses across the central sulcus. Again, the after-effects were related to the latency of MEPs evoked by AP current. Our results are consistent with the idea that variation in response to rTMS plasticity probing protocols is strongly influenced by which interneuron networks are recruited by the TMS pulse.

Cerebellar modulation of human associative plasticity.

Key pointu2002 •u2002 Increases in the strength of synaptic connections in the motor cortex (long term potentiation) can be induced in humans by repetitively pairing peripheral nerve stimuli and motor cortex transcranial magnetic stimuli given 21–25 ms apart – paired associative stimulation (PAS). •u2002 This ‘associative plasticity’ effect has been assumed to relate to synchronicity between sensory input and motor output, with a similar mechanism proposed to underlie effects at all interstimulus intervals. •u2002 Here we show that modulation of cerebellar activity using transcranial direct current stimulation can abolish associative plasticity in the motor cortex, but only for sensory/motor stimuli paired at 25 ms, not at 21.5 ms. •u2002 The results indicate that human associative plasticity can be affected by cerebellar activity and that at least two different mechanisms are involved in the effects previously reported in studies using PAS at different inter‐stimulus intervals.

Direct-current-dependent shift of theta-burst-induced plasticity in the human motor cortex

Animal studies using polarising currents have shown that induction of synaptic long-term potentiation (LTP) and long-term depression (LTD) by bursts of patterned stimulation is affected by the membrane potential of the postsynaptic neurone. The aim of the present experiments was to test whether it is possible to observe similar phenomena in humans with the aim of improving present protocols of inducing synaptic plasticity for therapeutic purposes. We tested whether the LTP/LTD-like after effects of transcranial theta-burst stimulation (TBS) of human motor cortex, an analogue of patterned electrical stimulation in animals, were affected by simultaneous transcranial direct-current stimulation (tDCS), a non-invasive method of polarising cortical neurones in humans. Nine healthy volunteers were investigated in a single-blind, balanced cross-over study; continuous TBS (cTBS) was used to introduce LTD-like after effects, whereas intermittent TBS (iTBS) produced LTP-like effects. Each pattern was coupled with concurrent application of tDCS (<200xa0s, anodal, cathodal, sham). Cathodal tDCS increased the response to iTBS and abolished the effects of cTBS. Anodal tDCS changed the effects of cTBS towards facilitation, but had no impact on iTBS. Cortical motor thresholds and intracortical inhibitory/facilitatory networks were not altered by any of the stimulation protocols. We conclude that the after effects of TBS can be modulated by concurrent tDCS. We hypothesise that tDCS changes the membrane potential of the apical dendrites of cortical pyramidal neurones and that this changes the response to patterned synaptic input evoked by TBS. The data show that it may be possible to enhance LTP-like plasticity after TBS in the human cortex.

Cerebellar stimulation fails to modulate motor cortex plasticity in writing dystonia

Primary dystonia is characterized neurophysiologically by reduced inhibitory mechanisms and abnormal regulation of plasticity responses. The potential of anodal cerebellar transcranial direct current stimulation as a therapeutic tool in writing dystonia was examined, after the observation that cerebellar stimulation reduces responses to an associative plasticity protocol in healthy subjects.

A reflection on plasticity research in writing dystonia

Much attention has focused on the hypothesis that there is enhanced plasticity of sensorimotor circuits in patients with dystonia. A common experimental method to assess plasticity in dystonia research is paired associative stimulation (PAS). Excessive, nonfocal effects of PAS were observed in early studies of dystonia; however, these large effects have not been uniformly replicated. In this viewpoint, data from 15 patients with writing dystonia are presented. We suggest that, as in healthy individuals, the effects of PAS are highly variable. A review of previous studies examining PAS in writing dystonia highlights the range of results that have been observed. We conclude that current experimental evidence cannot be fully explained by the notion that PAS responses in writing dystonia are consistently excessive or nonspecific. The variability of PAS responses is such that enhanced plasticity should not be considered a dystonic fingerprint, because the direction of response can vary, and there is overlap between patient and healthy data. We also discuss evidence questioning the assumption that PAS responses are a clear correlate to levels of synaptic plasticity; we need to define more specifically what PAS responses signify in the dystonic brain. Our conclusions are limited to PAS in writing dystonia; however, much variation exists with other plasticity protocols. Large multicenter studies of both focal and generalized forms of dystonia, probing variability of individual neurophysiological profiles, are encouraged. This will reveal the true role of plasticity in the pathophysiology of dystonia and may expose subject‐specific therapeutic interventions that are currently concealed.

Interaction Between Different Interneuron Networks Involved in Human Associative Plasticity

BACKGROUNDnPaired associative stimulation (PAS) is a widely used method to study spike timing dependent plasticity in motor cortex. Repeated pairing of an electrical stimulus to the median nerve with transcranial magnetic stimulation (TMS) over the contralateral motor cortex at interstimulus intervals (ISIs) of 21.5-25xa0ms leads to a long term potentiation (LTP)-like synaptic plasticity in the corticospinal system. Previously we found that concurrent transcranial direct current stimulation (TDCS) over cerebellum blocked the effect of PAS25 but not PAS21.5, implying that two separate mechanisms were involved.nnnOBJECTIVEnWe hypothesized that if PAS21.5 and PAS25 increased corticospinal excitability by two entirely separate mechanisms then their effects might summate if we intermixed them in the same session.nnnMETHODSnTwenty-four healthy volunteers were studied. Eight subjects were selected who showed the expected facilitation after both standard PAS21.5 and PAS25 with 180 pairs. They participated to two sessions in which PAS consisted of 360 electrical stimuli of the right median nerve paired with a single TMS over the hotspot of right APB at randomly delivered ISIs of 25xa0ms and of 21.5xa0ms (180 pairs for each ISI) (PASvar360p). Either sham or anodal TDCS (2xa0mA, 30xa0min) was applied to the cerebellum simultaneously with PASvar360p. Subsequently, we applied a protocol with 90 pairs for each ISI (PASvar180p). We measured motor evoked potentials (MEPs) before and after each intervention.nnnRESULTSnAlthough PAS21.5 and PAS25 each produce corticospinal facilitation when applied alone, the after-effects disappeared if we randomly intermixed PAS21.5 and PAS25 using either 180 pairs (PASvar360p) or 90 pairs (PASvar180p) for each ISI. Facilitation is restored if anodal but not sham TDCS is applied concurrently over the cerebellum to block the effect of PAS25.nnnCONCLUSIONSnPAS21.5 and PAS25 not only engage two separate mechanisms but also they are mutually inhibitory.

Cortical hemoglobin concentration changes underneath the coil after single-pulse transcranial magnetic stimulation: a near-infrared spectroscopy study

Using near-infrared spectroscopy (NIRS) and multichannel probes, we studied hemoglobin (Hb) concentration changes when single-pulse transcranial magnetic stimulation (TMS) was applied over the left hemisphere primary motor cortex (M1). Seventeen measurement probes were centered over left M1. Subjects were studied in both active and relaxed conditions, with TMS intensity set at 100%, 120%, and 140% of the active motor threshold. The magnetic coils were placed so as to induce anteromedially directed currents in the brain. Hb concentration changes were more prominent at channels over M1 and posterior to it. Importantly, Hb concentration changes at M1 after TMS differed depending on whether the target muscle was in an active or relaxed condition. In the relaxed condition, Hb concentration increased up to 3-6 s after TMS, peaking at ∼6 s, and returned to the baseline. In the active condition, a smaller increase in Hb concentrations continued up to 3-6 s after TMS (early activation), followed by a decrease in Hb concentration from 9 to 12 s after TMS (delayed deactivation). Hb concentration changes in the active condition at higher stimulus intensities were more pronounced at locations posterior to M1 than at M1. We conclude that early activation occurs when M1 is activated transsynaptically. The relatively late deactivation may result from the prolonged inhibition of the cerebral cortex after activation. The posterior-dominant activation at higher intensities in the active condition may result from an additional activation of the sensory cortex due to afferent inputs from muscle contraction evoked by the TMS.

Increased primary motor cortical excitability by a single-pulse transcranial magnetic stimulation over the supplementary motor area

The supplementary motor area (SMA) is a secondary motor area that is involved in various complex hand movements. In animal studies, short latency and probably direct excitatory inputs from SMA to the primary motor cortex (M1) have been established. Although human imaging studies revealed functional connectivity between SMA and M1, its electrophysiological nature has been less studied. This study explored the connection between SMA and M1 in humans using a single-pulse transcranial magnetic stimulation (TMS) over SMA. First, TMS over SMA did not alter the corticospinal tract excitability measured by the size of motor evoked potential elicited by single-pulse TMS over M1. Next, we measured short-interval intracortical facilitation (SICF), which reflects the function of a facilitatory circuit within M1, with or without a single-pulse TMS over SMA. When the intensity of the second pulse in the SICF paradigm (S2) was as weak as 1.0 active motor threshold for a hand muscle, SMA stimulation significantly enhanced the SICF. Furthermore, this enhancement by SMA stimulation was spatially confined and had a limited time window. On the other hand, SMA stimulation did not alter short-interval intracortical inhibition or contralateral silent period duration, which reflects the function of an inhibitory circuit mediated by gamma-aminobutyric acid A (GABAA) or GABAB receptors, respectively. We conclude that a single-pulse TMS over SMA modulates a facilitatory circuit within M1.

P675: Interneuron networks involved in human associative plasticity

s of Poster Presentations / Clinical Neurophysiology 125, Supplement 1 (2014) S1–S339 S235 muscles with 4 and 5 participants exhibiting increased CSE in FDI for the SR curves and map, respectively; and only 2 and 3, respectively, in BB. There were a greater number of participants in whom CSE increased for the distal muscle whilst motor learning performance was not significantly different between muscles. The surprising result that so few participants exhibited increased CSE following motor learning suggests that individual differences should be better reported in studies of motor learning involving TMS. In addition, the inter-individual differences in the changes in CSE should be further examined. P675 Interneuron networks involved in human associative plasticity G. Strigaro1,2, M. Hamada2, R. Cantello1, J. Rothwell2 1University of Piedmont East “A. Avogadro”, Department of Translational Medicine, Section of Neurology, Novara, Italy, Italy; 2University College London Institute of Neurology, Sobell Department of Motor Neuroscience and Movement Disorders, London, United Kingdom, United Kingdom Objective: Paired associative stimulation (PAS) is a method to study motor cortex synaptic plasticity. If a repetitive electrical stimulus to the median nerve is paired with a transcranial magnetic stimulus (TMS) pulse over the controlateral motor cortex at an interstimulus interval (ISI) of 21.5-25 ms, a long-term potentiation (LTP)-like synaptic plasticity is induced in the corticospinal system (Stefan et al., 2000). We investigated the synaptic spatial specificity of PAS25 and PAS21.5, considered to have similar synaptic mechanisms until recently. Materials and methods: Eight subjects (28.6±8.3 years), with the expected facilitation after both standard PAS protocols, participated in two randomized sessions in which PAS consisted of 360 electrical stimuli of the right median nerve at the wrist paired with a single TMS over the hotspot of right APB muscle at randomly delivered ISIs of 25 ms and of 21.5 ms (180 pairs for each ISI) (PASvar). Since cerebellar transcranial direct current stimulation (TDCS) can abolish the plasticity effects of PAS with an interval of 25 ms and not at 21.5 ms (Hamada et al. 2012), either sham or anodal TDCS (2 mA, 30 min) was applied to the cerebellum simultaneously with PASvar (anodal-PASvar and sham-PASvar). We measured MEPs before and after each intervention. Results: Randomly delivered PAS25 and PAS21.5 (sham-PASvar) blocked the induction of PAS plasticity while the concurrent anodal TDCS (anodalPASvar) restored the expected effect. Conclusions: PAS21.5 and PAS25 induce LTP-like changes in different sets of cortical synapses and show mutual inhibition during plasticity induction. Heterosynaptic LTD-like modulation might well explain the loss of effect of combining PAS21.5 and PAS25. References: Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. (2000). Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 123, 572-584. Hamada M, Strigaro G, Murase N, Sadnicka A, Galea JM, Edwards MJ, Rothwell JC. (2012). Cerebellar modulation of human associative plasticity. J Physiol 590, 2365-2374. P677 ADHD awareness, quality of life and treatment acceptance M.V. Santos, M.A. Romano-Silva UFMG, Instituto Nacional de Ciência e Tecnologia Medicina Molecular, BH,

P224: Cauda equina conduction time in GBS, CIDP, and MMN

Introduction: To investigate the conductions of proximal and distal parts of peripheral nerves in Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and multifocal motor neuropathy (MMN), we measured cauda equina conduction time (CECT) and motor conduction velocity (MCV). Methods: Patients were 12 GBS (8 axonal and 4 demyelinating types), 14 CIDP, and 5 MMN patients. Compound muscle action potentials (CMAPs) were recorded from the abductor hallucis muscle. To measure MCV, electrical stimulation was conducted. To obtain CECT, magnetic stimulation was performed using a MATS coil (magnetic augmented translumbosacral stimulation coil). Results: CECT was normal in all axonal GBS patients but prolonged in all demyelinating GBS patients, whereas MCV was normal in all GBS patients. CECT was prolonged in 12 CIDP patients (85.7%), whereas MCV was delayed in 5 CIDP patients (35.7%). Both CECT and MCV were normal in all MMN patients. Conclusions: CECT is frequently prolonged in demyelinating GBS and CIDP, whereas it is usually normal in axonal GBS and MMN. MATS coil stimulation method can detect the conduction delay of cauda equina in some types of demyelinating polyneuropathy.