Advertisement

Region-dependent bidirectional plasticity in M1 following quadripulse transcranial magnetic stimulation in the inferior parietal cortex

  • Fuminari Kaneko
    Correspondence
    Corresponding author. Department of Rehabilitation of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shjinjuku-ku, Tokyo, 160-8582, Japan.
    Affiliations
    First Division of Physical Therapy, School of Health Sciences, Sapporo Medical University, S1 W17, Chuo, Sapporo, Hokkaido, Japan

    Department of Rehabilitation of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shjinjuku-ku, Tokyo, 160-8582, Japan
    Search for articles by this author
  • Eriko Shibata
    Affiliations
    First Division of Physical Therapy, School of Health Sciences, Sapporo Medical University, S1 W17, Chuo, Sapporo, Hokkaido, Japan
    Search for articles by this author
  • Megumi Okawada
    Affiliations
    First Division of Physical Therapy, School of Health Sciences, Sapporo Medical University, S1 W17, Chuo, Sapporo, Hokkaido, Japan

    Department of Rehabilitation of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shjinjuku-ku, Tokyo, 160-8582, Japan
    Search for articles by this author
  • Takashi Nagamine
    Affiliations
    Department of Systems Neuroscience, School of Medicine, Sapporo Medical University, S1 W17, Chuo, Sapporo, Hokkaido, Japan
    Search for articles by this author
Open AccessPublished:October 25, 2019DOI:https://doi.org/10.1016/j.brs.2019.10.016

      Highlights

      • We tested quadripulse transcranial magnetic stimulation (QPS) of cortical sites.
      • We looked at effects on the primary motor cortex (M1) excitability.
      • QPS of the supramarginal gyrus and angular gyrus had different long-lasting effects.
      • The inter-stimulus interval used in QPS also strongly influenced the effects.
      • It was possible to induce long-lasting bidirectional plasticity in M1 noninvasively.

      Abstract

      Background

      The ability to manipulate the excitability of the network between the inferior parietal lobule (IPL) and primary motor cortex (M1) may have clinical value.

      Objective

      To investigate the possibility of inducing long-lasting changes in M1 excitability by applying quadripulse transcranial magnetic stimulation (QPS) to the IPL, and to ascertain stimulus condition- and site-dependent differences in the effects.

      Methods

      QPS was applied to M1, the primary somatosensory cortex (S1), the supramarginal gyrus (SMG) and angular gyrus (AG) IPL areas, with the inter-stimulus interval (ISI) in the train of pulses set to either 5 ms (QPS-5) or 50 ms (QPS-50). QPS was repeated at 0.2 Hz for 30 min, or not presented (sham condition). Excitability changes in the target site were examined by means of single-pulse transcranial magnetic stimulation (TMS).

      Results

      QPS-5 and QPS-50 at M1 increased and decreased M1 excitability, respectively. QPS at S1 induced no obvious change in M1 excitability. However, QPS at the SMG induced mainly suppressive effects in M1 for at least 30 min, regardless of the ISI length. Both QPS ISIs at the AG yielded significantly different MEP compared to those at the SMG. Thus, the direction of the plastic effect of QPS differed depending on the site, even under the same stimulation conditions.

      Conclusions

      QPS at the IPL produced long-lasting changes in M1 excitability, which differed depending on the precise stimulation site within the IPL. These results raise the possibility of noninvasive induction of functional plasticity in M1 via input from the IPL.

      Keywords

      Abbreviations:

      aMT (active motor threshold), AG (angular gyrus), ECR (extensor carpi radialis), FCR (flexor carpi radialis), FDI (first dorsal interosseous), IPL (inferior parietal cortex), M1 (primary motor cortex), MEP (motor evoked potential), MVC (maximum voluntary contraction), QPS (quadripulse transcranial magnetic stimulation), PPC (posterior parietal cortex), S1 (primary sensory cortex), SMG (supramarginal gyrus)

      Introduction

      The parietal lobe is divided into an anterior and a posterior cortex (PPC). The latter is positioned rostral to the primary and secondary visual cortex and caudal to the somatosensory cortex [
      • Mohan H.
      • Haan R.
      • Mansvelder H.D.
      • Kock C.P.J.
      The posterior parietal cortex as integrative hub for whisker sensorimotor information.
      ]. In humans, PPC defects induce misreaching (optic ataxia) and misgrasping not attributable to a basic sensory or motor deficit [
      • Jackson S.R.
      • Newport R.
      • Husain M.
      • Fowlie J.E.
      • O’Donoghue M.
      • Bajaj N.
      There may be more to reaching than meets the eye: Re-thinking optic ataxia.
      ,
      • Wolpert D.M.
      • Kawato M.
      Multiple paired forward and inverse models for motor control.
      ]. Even without direct connections to the spinal cord, the role of the PPC in movement control is suggested by interconnections with premotor areas and coactivation with frontal areas during movement execution and planning [
      • Filimon F.
      Human cortical control of hand movements: parietofrontal networks for reaching, grasping, and pointing.
      ]. The PPC is particularly well-developed in primates, where it includes a superior and an inferior parietal lobule (IPL); the latter is particularly involved in visual spatial processing [
      • Filimon F.
      Human cortical control of hand movements: parietofrontal networks for reaching, grasping, and pointing.
      ,
      • Berlucchi G.
      • Vallar G.
      The history of the neurophysiology and neurology of the parietal lobe.
      ].
      The IPL is the ventral part of the parietal lobe, located below the intraparietal sulcus. The supramarginal gyrus (SMG), situated in the IPL, anterior to the angular gyrus (AG), arching upward at the end of the lateral fissure, participates in reaching toward both visible and nonvisible targets [
      • Filimon F.
      Human cortical control of hand movements: parietofrontal networks for reaching, grasping, and pointing.
      ]. The AG arches over the posterior end of the superior temporal sulcus in the posterior IPL, and is consistently activated in various motor tasks [
      • Seghier M.L.
      The angular gyrus. Multiple functions and multiple subdivisions.
      ]. Furthermore, the IPL is involved in action observation, especially during object-related action [
      • Buccino G.
      • Binkofski F.
      • Fink G.R.
      • Fadiga L.
      • Fogassi L.
      • Gallese V.
      • et al.
      Action observation activates premotor and parietal areas in a somatotopic manner.
      ]. The SMG is activated during mouth and hand movements, and the AG during foot as well as mouth and hand actions [
      • Buccino G.
      • Binkofski F.
      • Fink G.R.
      • Fadiga L.
      • Fogassi L.
      • Gallese V.
      • et al.
      Action observation activates premotor and parietal areas in a somatotopic manner.
      ]. The SMG and AG areas are considered part of the human mirror neuron system [
      • Rizzolatti G.
      • Fogassi L.
      • Gallese V.
      Neurophysiological mechanisms underlying the understanding and imitation of action.
      ]. Electrical stimulation of the IPL in humans induces the intention to move the contralateral limb [
      • Desmurget M.
      • Reilly K.T.
      • Richard N.
      • Szathmari A.
      • Mottolese C.
      • Sirigu A.
      Movement intention after parietal cortex stimulation in humans.
      ]. Thus, functional interaction between motor-associated areas and parietal cortex is of interest.
      The direct excitatory or inhibitory effects of input from the IPL to the ipsilateral primary motor cortex (M1) have been demonstrated using dual-coil transcranial magnetic stimulation (TMS) [
      • Koch G.
      • Fernandez Del Olmo M.
      • Cheeran B.
      • Ruge D.
      • Schippling S.
      • Caltagirone C.
      • et al.
      Focal stimulation of the posterior parietal cortex increases the excitability of the ipsilateral motor cortex.
      ,
      • Koch G.
      • Cercignani M.
      • Pecchioli C.
      • Versace V.
      • Oliveri M.
      • Caltagirone C.
      • et al.
      In vivo definition of parieto-motor connections involved in planning of grasping movements.
      ,
      • Koch G.
      • Ponzo V.
      • Di Lorenzo F.
      • Caltagirone C.
      • Veniero D.
      Hebbian and anti-Hebbian spike-timing-dependent plasticity of human cortico-cortical connections.
      ,
      • Karabanov A.N.
      • Chao C.C.
      • Paine R.
      • Hallett M.
      Mapping different intra-hemispheric parietal-motor networks using twin coil TMS.
      ], and indicated that input from the IPL influences at least short-term M1 excitability. In addition to those functional associations, anatomical connections between motor-associated areas and the IPL has been reported in humans [
      • Tomassini V.
      • Jbabdi S.
      • Klein J.C.
      • Behrens T.E.
      • Pozzilli C.
      • Matthews P.M.
      • et al.
      Diffusion-weighted imaging tractography-based parcellation of the human lateral premotor cortex identifies dorsal and ventral subregions with anatomical and functional specializations.
      ]. If a physiological intervention that modulates excitability in M1 by input from the IPL for a certain period could be established, the functional role of the network between the motor areas and the IPL (for sensory and motor functions) could be investigated more easily, which may facilitate development of therapeutic interventions. The report of predominant inhibitory/excitatory pathways to M1 [
      • Koch G.
      • Fernandez Del Olmo M.
      • Cheeran B.
      • Ruge D.
      • Schippling S.
      • Caltagirone C.
      • et al.
      Focal stimulation of the posterior parietal cortex increases the excitability of the ipsilateral motor cortex.
      ,
      • Koch G.
      • Cercignani M.
      • Pecchioli C.
      • Versace V.
      • Oliveri M.
      • Caltagirone C.
      • et al.
      In vivo definition of parieto-motor connections involved in planning of grasping movements.
      ,
      • Koch G.
      • Ponzo V.
      • Di Lorenzo F.
      • Caltagirone C.
      • Veniero D.
      Hebbian and anti-Hebbian spike-timing-dependent plasticity of human cortico-cortical connections.
      ,
      • Karabanov A.N.
      • Chao C.C.
      • Paine R.
      • Hallett M.
      Mapping different intra-hemispheric parietal-motor networks using twin coil TMS.
      ] prompted us to hypothesize that long-lasting bidirectional excitability changes in M1 could be induced by IPL stimulation.
      Quadripulse transcranial magnetic stimulation (QPS) is a form of repetitive TMS (rTMS), which affects cortical excitability when applied to M1 [
      • Hamada M.
      • Hanajima R.
      • Terao Y.
      • Arai N.
      • Furubayashi T.
      • Inomata-Terada S.
      • et al.
      Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex.
      ]. Originally, this technique was derived from I-wave TMS (monophasic paired-pulse rTMS), under the hypothesis that greater motor cortical excitability enhancement could be provoked by increasing the number of pulses. QPS can increase or decrease excitability, depending on the inter-stimulus interval (ISI) in the train of pulses [
      • Hamada M.
      • Terao Y.
      • Hanajima R.
      • Shirota Y.
      • Nakatani-Enomoto S.
      • Furubayashi T.
      • et al.
      Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.
      ]. QPS effects reportedly last longer and are greater than those of other rTMS approaches [
      • Pascual-Leone A.
      • Valls-Sole J.
      • Wassermann E.M.
      • Hallett M.
      Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex.
      ,
      • Maeda F.
      • Keenan J.P.
      • Tormos J.M.
      • Topka H.
      • Pascual-Leone A.
      Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability.
      ,
      • Muellbacher W.
      • Ziemann U.
      • Boroojerdi B.
      • Hallett M.
      Effects of low-frequency transcranial magnetic stimulation on motor excitability and basic motor behavior.
      ,
      • Agostino R.
      • Iezzi E.
      • Dinapoli L.
      • Gilio F.
      • Conte A.
      • Mari F.
      • et al.
      Effects of 5 Hz subthreshold magnetic stimulation of primary motor cortex on fast finger movements in normal subjects.
      ].
      The present study explored whether physiological intervention at the IPL by means of noninvasive QPS could induce long-term effects on M1 excitability. We also investigated whether these influences were bidirectional (facilitatory and inhibitory) or unidirectional, and whether the effects were ISI- and/or stimulation site-dependent.

      Materials and methods

      Participants

      The 28 healthy volunteers (18 men, 10 women, age [mean ± SD] 21.8 ± 2.0 years [range 19–26]; height 168.8 ± 7.6 cm; weight 60.9 ± 8.3 kg) were right-handed according to the Oldfield handedness inventory [
      • Oldfield R.C.
      The assessment and analysis of handedness: the Edinburgh inventory.
      ] and were blinded to the experimental hypothesis throughout the experiment. Subjects provided written informed consent and the study conformed to the tenets of the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Sapporo Medical University.

      Electromyogram measurement

      Surface electromyograms (EMGs) were recorded from the first dorsal interosseus (FDI) of the right hand with 8-mm-diameter Ag/AgCl-plated surface electrodes, using a belly-tendon montage. The absence of background EMG signals from the flexor carpi radialis and the extensor carpi radialis of the right forearm was monitored using bipolar electrodes. Prior to placement of the electrodes, the skin was cleaned with alcohol and abraded with skin-prepping gel. EMG signals were amplified (Neuropack MEB2200, Nihonko-den Co. Ltd., Tokyo, Japan) to an appropriate level and band-pass filtered at 5–1000 Hz. Signals were sampled at 20 kHz, beginning 500 ms before and ending 500 ms after the delivery of the stimulus, using an A/D converter (Power 1401 with Signal 2.14 software, Cambridge Electronic Design, Cambridge, UK), and stored on a computer.
      To avoid head movement, the chin was supported by a horizontally fixed bar and the right temporal portion was supported by a cushion.

      Selecting the M1 hotspot

      Subjects wore a custom-made head cap, on which a 10-mm grid was drawn to facilitate TMS mapping. The TMS procedure was performed as per standard guidelines [
      • Rossi S.
      • Hallett M.
      • Rossini P.M.
      • Pascual-Leone A.
      Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research.
      ,
      • Matsumoto H.
      • Ugawa Y.
      Safety guidelines for the use of magnetic stimulation.
      ]. A TMS-mapping session was performed to define the right FDI hotspot functionally (i.e., the point over the left M1 where stimulation generated the largest magnitude of motor evoked potential [MEP] of the FDI), using a single-pulse monophasic stimulator with a figure 8-shaped magnetic coil (9-cm diameter for each loop; Magstim 2002, The Magstim Company Limited, Whitland, UK). The direction of the induced current in the brain was adjusted posterolateral to anteromedial at a 45° angle.

      Quadripulse transcranial magnetic stimulation

      Overall procedure. Prior to the first baseline test (Fig. 1), the isometric maximum voluntary contraction (MVC) force was first measured for index finger abduction using a force transducer (LMR-S-SA2, Kyowa Electronic Instruments Co., LTD, Tokyo, Japan). The active motor threshold (aMT) was measured by single-pulse TMS during 5% MVC of the FDI. aMT was defined as the minimum strength of the TMS device that produced more than 200 μV in active muscles in at least five of 10 trials [
      • Chen R.
      • Cros D.
      • Curra A.
      • Di Lazzaro V.
      • Lefaucheur J.P.
      • Magistris M.R.
      • et al.
      The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee.
      ]. QPS was delivered using a single-pulse monophasic stimulator with the same coil as used for TMS examination for both selecting the hotspot and determining the aMT. The QPS coil was connected to four magnetic stimulators through a 4-into-1 combining module (The Magstim Company Limited, Whitland, UK). The intensity of QPS was set to 90% of aMT.
      Fig. 1
      Fig. 1Outline of the experiment plan. Each quadripulse transcranial magnetic stimulation (QPS) session was conducted for 30 min. Excitability of the primary motor cortex (M1) and kinesthetic perception were measured prior to QPS to establish control conditions (Baseline = pre-QPS, PRE = 15 min after baseline) and at 0-, 30-, and 60-min after QPS (Post-0 = 0 min post-QPS, Post-30 = 30 min, and Post-60 = 60 min). We calculated the ratio of motor-evoked potential (MEP) amplitudes at each post-QPS time-point relative to baseline [(MEP amplitude at each stage – baseline MEP amplitude)/baseline MEP amplitude × 100].
      QPS was performed as previously reported [
      • Hamada M.
      • Hanajima R.
      • Terao Y.
      • Arai N.
      • Furubayashi T.
      • Inomata-Terada S.
      • et al.
      Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex.
      ,
      • Hamada M.
      • Terao Y.
      • Hanajima R.
      • Shirota Y.
      • Nakatani-Enomoto S.
      • Furubayashi T.
      • et al.
      Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.
      ]. Each train of QPS consisted of four pulses separated by 5 ms (QPS-5), 50 ms (QPS-50), or no pulses (sham condition), and was repeated at 0.2 Hz for 30 min (Fig. 1). For sham stimulation, the edge of the coil was attached vertically to the stimulus point used for the QPS-5 condition. This procedure generated stimulation noise mimicking the sound of genuine QPS. Participants were blinded to the conditions, including the sham condition (single-blind), and no participant enquired about the stimulation; hence, we deduced that participants remained unaware of sham stimulation. We conducted stimulation using these three conditions for each subject on different days, spaced by at least 6 days, and the order of conditions was counterbalanced across subjects.

      QPS for each site

      We assigned one of the four sites to each subject. The four sites were the left SMG, the left AG, the hotspot for the right FDI in the left M1 (6.0 ± 1.3 cm left and 2.1 ± 1.1 cm rostral from Cz; Fig. 2A) and 2 cm behind C3 (7.2 ± 0.3 cm left from Cz; Fig. 2A) on the International 10–20 system for EEG (S1, as a control cerebral site) (Fig. 2). The distance between M1 and S1 coordinates was 4.2 cm. QPS was applied for 30 min; thus, 360 QPS stimuli (30 × 60 × 0.2) were delivered to one site on an experimental day.
      Fig. 2
      Fig. 2Locations of the primary motor cortex (M1), the primary somatosensory cortex (S1), the supramarginal gyrus (SMG), and the angular gyrus (AG) sites (A: M1 and S1, B: SMG and AG). For quadripulse transcranial magnetic stimulation (QPS) of M1, the coil position was the hotspot for the right FDI in left M1 (6.0 ± 1.3 cm left and 2.1 ± 1.1 cm rostral from Cz of the International 10–20 system for electroencephalograms). For QPS of S1, the coil position was 2 cm behind C3 of the International 10–20 system (7.2 ± 0.3 cm left from Cz). The distance between M1 and S1 coordinates was 4.2 cm. For QPS of the SMG and the AG, the coil position was monitored online with a transcranial magnetic stimulation (TMS) neuronavigation system and adjusted to the target location based on reconstructions of individual brain anatomy by using the Talairach coordinates template. White circles of the SMG and AG show the coordinates [SMG (x, y, z: −51.9 ± 0.8, −43.0 ± 6.2, 45.2 ± 3.5), AG (x, y, z: −35.2 ± 5.1, −78.7 ± 6.2, 26.5 ± 5.1)]. The distance between the SMG and AG coordinates was 5.3 cm.
      For QPS at the SMG and AG, the stimulation site was located using a TMS neuronavigation system (Visor2, ANT Neuro, Enschede, Netherlands). Prior to the experiment, high-resolution structural T1-weighted magnetic resonance images (slice thickness: 1 mm, pixel size: 0.488 mm) were acquired from all subjects for anatomical localization. Individual brain images were transformed into a common standard space by using the Talairach coordinate template in the Visor2 function. For SMG QPS, we focused stimulation on the dorsal apex of the Sylvian fissure (x, y, z: −51.9 ± 0.8, −43.0 ± 6.2, 45.2 ± 3.5; Fig. 2B). The AG was identified by its horseshoe-shaped appearance, near the dorsal-posterior segment of the superior temporal sulcus on a sagittal view (x, y, z: −35.2 ± 5.1, −78.7 ± 6.2, 26.5 ± 5.1; Fig. 2B) [
      • Seghier M.L.
      The angular gyrus. Multiple functions and multiple subdivisions.
      ]. The distance between SMG and AG coordinates was 5.3 cm. The coil position was monitored online using the neuronavigation system and adjusted to the target location.
      Each stimulus site was targeted in 10 subjects, with some subjects participating in stimulation at more than one site; QPS was delivered at two (M1 and S1, three subjects; S1 and SMG, one subject), and three sites (M1, S1, and SMG in four subjects) in some subjects, also at intervals of at least 6 days.

      Examination of M1 excitability

      To explore temporal changes in M1 excitability, serial MEP tests of the hotspot were recorded following the baseline test, which consisted of 10 pulses at intervals of 6–8-s, with a pulse intensity that produced a 1-mV MEP in the baseline test. Fifteen minutes thereafter, the same MEP test was conducted as prestimulation test (PRE), followed by QPS conditioning. Then, MEP tests were repeated immediately after, and 30 and 60 min after the intervention (Post-0, Post-30, Post-60). EMG signals were observed on a 19-inch computer display in real-time to identify any minute muscular contractions. An individual stimulus attempt was rejected if background EMG greater than 20 μV was observed during TMS or during off-line checking immediately post-TMS. If individual stimulus attempts were rejected, TMS was added until 10 acceptable trials were completed. Consequently, the MEP amplitude recorded from the FDI was determined by averaging the peak-to-peak amplitude of the 10 trials. The ratio of the MEP amplitude at the PRE time-point and that at each post-intervention time-point was calculated relative to the baseline MEP (MEP amplitude at each time-point/baseline MEP amplitude).

      Statistical analysis

      We used SPSS (IBM SPSS Statistics V23, IBM, NY, USA) for statistical analysis. Three-way repeated-measures analysis of variance (ANOVA) was used to test the main effects of stimulation site (M1, S1, SMG, and AG), time (PRE, Post-0, Post-30, and Post-60), and condition (QPS-5, QPS-50, and sham) using the calculated test-to-baseline MEP ratio as the dependent variable (between-subject factors: stimulation site factor, within-subject factors: time and conditions). To investigate the effects of the experimental time-point further, we used Dunnett’s test, as appropriate for examination of data with respect to a single set of reference data. Multiple t-tests with Bonferroni correction were used to investigate the effect of condition further. The significance level was set at p < 0.05.

      Results

      No subject reported any adverse experiences during or after QPS for any brain sites. The mean aMT, measured on each experimental day, was 44.9% ± 6.1% of the maximum stimulation output.
      Fig. 3A, E, I, and M show the time-series of the raw MEP data recorded from a single subject’s FDI before and after QPS at the M1, S1, SMG, and AG. Fig. 3B–D, F–H, J–L, and F–H show the average (±SD) MEP ratio induced by each QPS condition. Three-way ANOVA revealed main effects of condition, time, and stimulation site, and interactions of condition × time × stimulation site, condition × time, and condition × stimulation site (Table 1). Given the significant second-order interaction, the simple interaction effect of condition and time for each stimulus site was examined.
      Fig. 3
      Fig. 3Motor-evoked potential (MEP) data. Superimposed raw electromyogram (EMG) of MEPs recorded from a single subject’s first dorsal interosseus (FDI) at each time-point (A: primary motor cortex [M1], E: primary somatosensory cortex [S1], I: supramarginal gyrus [SMG], M: angular gyrus [AG]) and results of the average MEP ratio from the FDI are shown for each time-point (B–D: M1, F–H: S1, J–L: SMG, N–P: AG). Error bars indicate the standard deviation. Thick black lines indicate averaged values and gray lines indicate individual data. Those with significant differences compared to other conditions or other site at the same time-point are listed in the table. *: p < 0.05 vs. PRE, **: p < 0.01 vs. PRE (Dunnett’s post-hoc test).
      Fig. 3
      Fig. 3Motor-evoked potential (MEP) data. Superimposed raw electromyogram (EMG) of MEPs recorded from a single subject’s first dorsal interosseus (FDI) at each time-point (A: primary motor cortex [M1], E: primary somatosensory cortex [S1], I: supramarginal gyrus [SMG], M: angular gyrus [AG]) and results of the average MEP ratio from the FDI are shown for each time-point (B–D: M1, F–H: S1, J–L: SMG, N–P: AG). Error bars indicate the standard deviation. Thick black lines indicate averaged values and gray lines indicate individual data. Those with significant differences compared to other conditions or other site at the same time-point are listed in the table. *: p < 0.05 vs. PRE, **: p < 0.01 vs. PRE (Dunnett’s post-hoc test).
      Table 1Results of three-way ANOVA, revealing significant main effects of condition, time, stimulation site, and condition × time × stimulation site, condition × time, condition × stimulation site, time × stimulation site interactions.
      FactordfErrorFP
      condition27214.113<0.001
      time31083.1100.029
      stimulation site3364.6460.008
      condition × site4.118150.7655.1400.001
      condition × stimulation site6726.721<0.001
      time × stimulation site91082.4490.014
      condition × time × stimulation site12.564150.7653.114<0.001
      For M1, two-way repeated-measures ANOVA revealed a significant main effect of condition and an interaction between time and condition [condition: F (2, 18) = 33.592, p < 0.001; time: F (3, 27) = 1.159, p = 0.334; time × condition interaction: F (1.911, 17.198) = 6.645, p = 0.008] (Fig. 3B–D). There were significant differences between conditions [QPS-5 vs. QPS-50: p < 0.001, vs. Sham: p = 0.007; QPS-50 vs. Sham: p = 0.002]. Application of QPS at M1 increased the MEP ratio for QPS-5 and decreased the ratio for QPS-50, as compared to PRE. For QPS-5, the MEP ratio was significantly larger at all time-points than at the PRE time-point (Post-0: p = 0.018, Post-30: p = 0.003, Post-60: p = 0.014). The MEP ratio after QPS-50 stimulation was significantly decreased at all time-points compared to the PRE value (Post-0: p < 0.001, Post-30: p < 0.001, Post-60: p < 0.001). Comparisons of the MEP ratio against the sham condition also indicated significant differences for QPS-5 and QPS-50 at Post-0 (vs. QPS-5: p = 0.013, vs. QPS-50: p = 0.005) and Post-30 (vs. QPS-5: p < 0.001, vs. QPS-50: p < 0.001). Furthermore, the MEP ratio of QPS-5 was significantly increased at Post-0, Post-30, and Post-60 (Post-0: p = 0.002; Post-30: p < 0.001; Post-60: p = 0.003). Thus, statistical analysis for each type of QPS at M1 revealed robust changes. For the sham condition, there was no significant difference in the MEP ratio at any time-point (PRE vs. Post-0: p = 0.938, vs. Post-30: p = 0.997, vs. Post-60: p = 0.540).
      For S1, there were no significant main effects or interactions for QPS [condition: F (2, 18) = 0.279, p = 0.760; time: F (1.443, 12.987) = 1.425, p = 0.268; time × condition interaction: F (2.662, 23.962) = 2.240, p = 0.115] (Fig. 3F–H).
      For SMG QPS, there were significant main effects of time and condition on the MEP ratio [time: F (1.592, 14.330) = 7.131, p = 0.010; condition: F (2,18) = 4.018, p = 0.036] (Fig. 3J–L). The interaction between time and condition was also significant [F (6,54) = 2.408, p = 0.039]. There were no significant differences between conditions [QPS-5 vs. QPS-50: p = 1.000, vs. Sham: p = 0.101; QPS-50 vs. Sham: p = 0.142]. At the Post-30 time-point, the MEP ratio under the QPS-5 condition was significantly suppressed compared to the sham condition (p = 0.025). Under the QPS-50 condition, the MEP ratio was significantly decreased at Post-0, Post-30, and Post-60 compared to PRE (Post-0: p = 0.004, Post-30: p = 0.004, Post-60: p = 0.048). There was no significant difference among the MEP ratio at each time-point for the sham condition (PRE vs. Post-0: p = 0.922, vs. Post-30: p = 0.345, vs. Post-60: p = 0.936).
      Two-way repeated-measures ANOVA disclosed no significant main effect of time or interaction between time and condition [time: F (3,27) = 1.453, p = 0.249; time × condition interaction: F (6,54) = 1.088, p = 0.382] on the MEP ratio after AG QPS. There was a significant main effect of condition on the MEP ratio [F (2,18) = 3.631, p = 0.047] (Fig. 3N–P). Although the MEP ratio revealed decreasing tendencies for QPS-5, there were no statistically significant differences between the QPS conditions (QPS-5 vs QPS-50: p = 0.207, QPS-5 vs Sham: p = 0.154, QPS-50 vs Sham: p = 1.000).
      Furthermore, we compared changes in the MEP ratio after QPS at the SMG and the AG for each condition, to reveal differences within the IPL. The MEP ratio after QPS-5 at the AG increased and decreased after that at the SMG; two-way factorial ANOVA indicated a significant interaction of time and stimulation site [F (3,54) = 5.598, p = 0.002] for QPS-5. Post-hoc tests showed a significant difference in the MEP ratio between the SMG and AG at Post-0 and Post-30 (p < 0.001). The MEP ratio after QPS-50 at the SMG decreased, whereas it remained essentially unchanged after that at the AG. The interaction between time and stimulation site was significant [F (3,54) = 3.422, p = 0.024]. Post-hoc tests showed significant differences in the MEP ratio between the SMG and AG at Post-0 and Post-30 (Post-0: p = 0.017, Post-30: p = 0.026).

      Discussion

      We investigated the effect of QPS at sites that provide ipsilateral afferent input to M1, and the effect of modulating M1 excitability by stimulation of the IPL in the left hemisphere. Partly consistent with our expectations, SMG QPS produced long-lasting changes in M1 excitability, depending on the stimulation conditions; moreover, the effect of QPS on M1 excitability had different directions for the SMG and the AG. Thus, we demonstrated sustained, bidirectional M1 excitability change after IPL QPS. For some conditions, there were differences relative to the sham condition (QPS-5 and 50 in M1; QPS-5 at SMG), while for others, significant differences relative to baseline were observed (QPS-50 at SMG). For the AG, but not the SMG, Bonferroni-corrected comparisons are reported for comparison across all conditions. Our findings did not contradict evidence of the instantaneous opposite effects on M1 excitability after AG and SMG stimulation by a dual-coil paradigm [
      • Koch G.
      • Fernandez Del Olmo M.
      • Cheeran B.
      • Ruge D.
      • Schippling S.
      • Caltagirone C.
      • et al.
      Focal stimulation of the posterior parietal cortex increases the excitability of the ipsilateral motor cortex.
      ].

      Different effects of QPS on M1 excitability, depending on the stimulation site

      We found that MEP at M1 increased after QPS-5 and decreased after QPS-50, in line with previous studies [
      • Hamada M.
      • Hanajima R.
      • Terao Y.
      • Arai N.
      • Furubayashi T.
      • Inomata-Terada S.
      • et al.
      Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex.
      ,
      • Hamada M.
      • Terao Y.
      • Hanajima R.
      • Shirota Y.
      • Nakatani-Enomoto S.
      • Furubayashi T.
      • et al.
      Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.
      ,
      • Hamada M.
      • Ugawa Y.
      Quadripulse stimulation--a new patterned rTMS.
      ]. However, long-lasting changes in M1 excitability after QPS at the SMG and AG have not previously been examined. We found that changes in MEP at M1 after SMG QPS were unidirectional for 5-ms and 50-ms ISIs: both suppressed the MEP at M1 for 30 min and 60 min after stimulation. Notably, the suppressive effect was roughly the same as the effect of QPS applied at M1 with a 50-ms ISI. We applied QPS to S1 as a control, to confirm the site-dependence of the QPS effect, to investigate whether the effect of QPS on M1 excitability would be produced by local connections. S1 QPS did not significantly change the MEP. However, since functional connectivity (inhibitory and facilitatory effect from S1) was previously indicated in a rTMS study and a study of the intracortical circuit [
      • Tsang P.
      • Jacobs M.F.
      • Lee K.G.H.
      • Asmussen M.J.
      • Zapallow C.M.
      • Nelson A.J.
      Continuous theta-burst stimulation over primary somatosensory cortex modulates short-latency afferent inhibition.
      ,
      • Chah R.F.
      • Isayama R.
      • Gunraj C.A.
      • Ni Z.
      • Chen R.
      The influence of sensory afferent input on local motor cortical excitatory circuitry in humans.
      ], S1 is probably tightly linked to M1. Our S1 QPS findings were not stable across subjects. The absence of MEP changes may not suggest an absence of functional and structural changes in the S1–M1 network. The significance of finding no changes in M1 excitability changes after S1 QPS is that S1 is located between M1 and the parietal sites. Since the S1 stimulus site is located between M1 and the SMG, if QPS at the SMG had affected M1 directly; QPS at S1 would be expected to affect it at least as strongly. However, the effects of QPS at M1, S1, and SMG were clearly distinct in this study. Hence, the present results probably suggest that the effect of QPS at the three different sites were independent, and thus we focused on each site individually.
      The finding that suppression of M1 excitability by ISIs of both 5 ms and 50 ms applied at the SMG was sustained for a certain period is entirely novel. The opposite effects of those ISI protocols on M1 excitability have been reported. The effects of input from the IPL after single-pulse TMS to the ipsilateral M1 have already been reported in previous studies. Thus, in a dual-coil experiment, enhancement of M1 excitability depended on stimulus intensity and timing of the conditioning stimulus [
      • Koch G.
      • Fernandez Del Olmo M.
      • Cheeran B.
      • Ruge D.
      • Schippling S.
      • Caltagirone C.
      • et al.
      Focal stimulation of the posterior parietal cortex increases the excitability of the ipsilateral motor cortex.
      ]; conditioning TMS of the IPL suppressed M1 excitability in a stimulus site-dependent and condition-dependent way (anterior IPL stimulation suppressed it, but stimulation at another site did not) [
      • Karabanov A.N.
      • Chao C.C.
      • Paine R.
      • Hallett M.
      Mapping different intra-hemispheric parietal-motor networks using twin coil TMS.
      ], and finally, M1 excitability was enhanced in a task-dependent way by a conditioning stimulus delivered to the SMG or PPC [
      • Koch G.
      • Cercignani M.
      • Pecchioli C.
      • Versace V.
      • Oliveri M.
      • Caltagirone C.
      • et al.
      In vivo definition of parieto-motor connections involved in planning of grasping movements.
      ,
      • Vesia M.
      • Bolton D.A.
      • Mochizuki G.
      • Staines W.R.
      Human parietal and primary motor cortical interactions are selectively modulated during the transport and grip formation of goal-directed hand actions.
      ]. Karabanov et al. suggested that a method similar to “hotspot” determination over M1 might be more suitable for stimulation at the most effective site in the parietal cortex [
      • Karabanov A.N.
      • Chao C.C.
      • Paine R.
      • Hallett M.
      Mapping different intra-hemispheric parietal-motor networks using twin coil TMS.
      ]. If this is correct, it means that the effect of a conditioning stimulus of the IPL on M1 excitability is not uniform and depends on the precise stimulus site. A key difference between the previous dual-coil experiments and the present study is that we found a long-lasting change in the neural network associated with the IPL, which had both inhibitory and facilitatory effects on M1 excitability. Furthermore, the fact that changes in M1 excitability after SMG or AG stimulation were sustained for at least half an hour implies that the input from the IPL–motor area network can produce long-lasting effects on M1, and that the effects for a given condition differ from those that occur when the same QPS is directly applied to M1 [
      • Hamada M.
      • Hanajima R.
      • Terao Y.
      • Arai N.
      • Furubayashi T.
      • Inomata-Terada S.
      • et al.
      Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex.
      ,
      • Hamada M.
      • Terao Y.
      • Hanajima R.
      • Shirota Y.
      • Nakatani-Enomoto S.
      • Furubayashi T.
      • et al.
      Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.
      ,
      • Hamada M.
      • Ugawa Y.
      Quadripulse stimulation--a new patterned rTMS.
      ].
      Changes in MEP after AG QPS were opposite to those after SMG QPS, but the former changes only caused MEP enhancement. For AG stimulation, only QPS-5 produced long-lasting MEP enhancement. Comparison of the effects of QPS at the SMG and AG indicated different directions of M1 excitability changes between the two areas. This difference was common to both ISIs (5 ms and 50 ms). This suggests that different anterior (SMG) and posterior (AG) parts of the IPL have different, and possibly opposite, effects on M1. There was a long-lasting excitability change after AG QPS, which was in an opposing directional change to those obtained at the SMG.

      Why did opposite effects occur depending on the portion of the IPL stimulated?

      IPL QPS may affect the superior longitudinal fasciculus, since its fibers connect the IPL (BA 39, 40) to the premotor and motor cortices in the same hemisphere [
      • Okabe S.
      • Hanajima R.
      • Ohnishi T.
      • Nishikawa M.
      • Imabayashi E.
      • Takano H.
      • et al.
      Functional connectivity revealed by single-photon emission computed tomography (SPECT) during repetitive transcranial magnetic stimulation (rTMS) of the motor cortex.
      ,
      • Koch G.
      • Ruge D.
      • Cheeran B.
      • Fernandez Del Olmo M.
      • Pecchioli C.
      • Marconi B.
      • et al.
      TMS activation of interhemispheric pathways between the posterior parietal cortex and the contralateral motor cortex.
      ,
      • Catani M.
      • Schotten M.
      Atlas of human brain connections.
      ]. Studies in non-human primates have demonstrated a rich pattern of connectivity between the dorsal premotor cortex and M1 [
      • Parmigiani S.
      • Barchiesi G.
      • Cattaneo L.
      The dorsal premotor cortex exerts a powerful and specific inhibitory effect on the ipsilateral corticofacial system: a dual-coil transcranial magnetic stimulation study.
      ]. The forelimb area of M1 receives topographically organized inputs from the dorsal and ventral premotor areas [
      • Tokuno H.
      • Tanji J.
      Input organization of distal and proximal forelimb areas in the monkey primary motor cortex: a retrograde double labeling study.
      ,
      • Hatanaka N.
      • Nambu A.
      • Yamashita A.
      • Takada M.
      • Tokuno H.
      Somatotopic arrangement and corticocortical inputs of the hindlimb region of the primary motor cortex in the macaque monkey.
      ]. Connections of the SMG and AG to the ventral subregion of the premotor cortex were shown by diffusion-tensor imaging (DTI) tractography, although many connections, including those from the SMG, were with its more anterior parts [
      • Tomassini V.
      • Jbabdi S.
      • Klein J.C.
      • Behrens T.E.
      • Pozzilli C.
      • Matthews P.M.
      • et al.
      Diffusion-weighted imaging tractography-based parcellation of the human lateral premotor cortex identifies dorsal and ventral subregions with anatomical and functional specializations.
      ]. Koch et al. [
      • Koch G.
      • Cercignani M.
      • Pecchioli C.
      • Versace V.
      • Oliveri M.
      • Caltagirone C.
      • et al.
      In vivo definition of parieto-motor connections involved in planning of grasping movements.
      ] showed that distinct functional and anatomical pathways link different regions of the IPL with the ipsilateral motor cortex; this is important during planning of grasping movements, such as grasping a small object precisely with the index finger and thumb or grasping an object positioned in the contralateral space with the whole hand. Furthermore, DTI tractography showed that the AG and SMG are connected with PMv by distinct fiber bundles of the SLF, likely corresponding to the SLF II (fiber from the AG) and SLF III (fiber from the SMG) subdivisions. The conditioning site-dependent differences in M1 excitability changes may be due to anatomical differences in the networks connecting the IPL to M1, local effects within the IPL, or the pathway to the premotor cortex that was activated. Alternatively, if there were two types of networks from the premotor cortex, and those affected M1 excitability oppositely, the SMG and AG would connect to those two networks differently. The precise mechanism of the site-dependent effects of QPS of the IPL should be investigated in future. However, the functional differences between the SMG and AG in terms of their effects on M1 excitability, which were in line with previous findings [
      • Koch G.
      • Fernandez Del Olmo M.
      • Cheeran B.
      • Ruge D.
      • Schippling S.
      • Caltagirone C.
      • et al.
      Focal stimulation of the posterior parietal cortex increases the excitability of the ipsilateral motor cortex.
      ], was shown here to have a long-lasting effect.
      As study limitations, the sample size was relatively small, and the study contained no behavioral/functional tasks or dual-site connectivity probes, which might have been at least as informative as MEP recordings. Furthermore, the peculiar effects induced by AG and SMG QPS on M1 excitability were not elucidated here. Given the intracortical activity demonstrated by Koch et al. [
      • Koch G.
      • Ruge D.
      • Cheeran B.
      • Fernandez Del Olmo M.
      • Pecchioli C.
      • Marconi B.
      • et al.
      TMS activation of interhemispheric pathways between the posterior parietal cortex and the contralateral motor cortex.
      ], it should be investigated whether the same effects can be replicated at other ISIs between 5 and 50 ms. How intracortical circuits in M1 mediate the effect of AG or SMG QPS should be tested by using paired-pulse protocols in future.

      Conclusions

      The present study demonstrated that QPS applied to the IPL produced long-lasting changes in M1 excitability, the direction of which depended on the stimulus site within the IPL, even under the same stimulation conditions. QPS (both QPS-5 and QPS-50) at the SMG inhibited M1 excitability, while QPS at the AG enhanced M1 excitability only for QPS-5. Thus, there are functionally distinguishable networks connecting the IPL to M1 that can be modified long-term and it should be possible to induce functional plasticity in M1 noninvasively via connectivity with the IPL.

      Declaration of competing interest

      None.

      Acknowledgements

      I would like to thank Dr. Yoshikazu Ugawa (Department of Neurology, School of Medicine, Fukushima Medical University) for his useful comments.
      This work was supported by Grants-in-Aid for Scientific Research (B) (grant number 26282157, 23300202) from JSPS.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Mohan H.
        • Haan R.
        • Mansvelder H.D.
        • Kock C.P.J.
        The posterior parietal cortex as integrative hub for whisker sensorimotor information.
        Neuroscience. 2018; 368: 240-245https://doi.org/10.1016/j.neuroscience.2017.06.020
        • Jackson S.R.
        • Newport R.
        • Husain M.
        • Fowlie J.E.
        • O’Donoghue M.
        • Bajaj N.
        There may be more to reaching than meets the eye: Re-thinking optic ataxia.
        Neuropsychologia. 2009; 47: 1397-1408https://doi.org/10.1016/j.neuropsychologia.2009.01.035
        • Wolpert D.M.
        • Kawato M.
        Multiple paired forward and inverse models for motor control.
        Neural Netw. 1998; 11: 1317-1329
        • Filimon F.
        Human cortical control of hand movements: parietofrontal networks for reaching, grasping, and pointing.
        The Neuroscientist. 2010; 16: 388-407https://doi.org/10.1177/1073858410375468
        • Berlucchi G.
        • Vallar G.
        The history of the neurophysiology and neurology of the parietal lobe.
        Handb Clin Neurol. 2018; 151: 3-30https://doi.org/10.1016/B978-0-444-63622-5.00001-2
        • Seghier M.L.
        The angular gyrus. Multiple functions and multiple subdivisions.
        The Neuroscientist. 2013; 19: 43-61https://doi.org/10.1177/1073858412440596
        • Buccino G.
        • Binkofski F.
        • Fink G.R.
        • Fadiga L.
        • Fogassi L.
        • Gallese V.
        • et al.
        Action observation activates premotor and parietal areas in a somatotopic manner.
        Eur J Neurosci. 2001; 13: 400-404
        • Rizzolatti G.
        • Fogassi L.
        • Gallese V.
        Neurophysiological mechanisms underlying the understanding and imitation of action.
        Nat Rev. 2001; 2: 661-670
        • Desmurget M.
        • Reilly K.T.
        • Richard N.
        • Szathmari A.
        • Mottolese C.
        • Sirigu A.
        Movement intention after parietal cortex stimulation in humans.
        Science. 2009; 324: 811-813https://doi.org/10.1126/science.1169896
        • Koch G.
        • Fernandez Del Olmo M.
        • Cheeran B.
        • Ruge D.
        • Schippling S.
        • Caltagirone C.
        • et al.
        Focal stimulation of the posterior parietal cortex increases the excitability of the ipsilateral motor cortex.
        J Neurosci. 2007; 27: 6815-6822
        • Koch G.
        • Cercignani M.
        • Pecchioli C.
        • Versace V.
        • Oliveri M.
        • Caltagirone C.
        • et al.
        In vivo definition of parieto-motor connections involved in planning of grasping movements.
        Neuroimage. 2010; 51: 300-312https://doi.org/10.1016/j.neuroimage.2010.02.022
        • Koch G.
        • Ponzo V.
        • Di Lorenzo F.
        • Caltagirone C.
        • Veniero D.
        Hebbian and anti-Hebbian spike-timing-dependent plasticity of human cortico-cortical connections.
        J Neurosci. 2013; 33: 9725-9733https://doi.org/10.1523/jneurosci.4988-12.2013
        • Karabanov A.N.
        • Chao C.C.
        • Paine R.
        • Hallett M.
        Mapping different intra-hemispheric parietal-motor networks using twin coil TMS.
        Brain Stimul. 2013; 6: 384-389https://doi.org/10.1016/j.brs.2012.08.002
        • Tomassini V.
        • Jbabdi S.
        • Klein J.C.
        • Behrens T.E.
        • Pozzilli C.
        • Matthews P.M.
        • et al.
        Diffusion-weighted imaging tractography-based parcellation of the human lateral premotor cortex identifies dorsal and ventral subregions with anatomical and functional specializations.
        J Neurosci. 2007; 27: 10259-10269
        • Hamada M.
        • Hanajima R.
        • Terao Y.
        • Arai N.
        • Furubayashi T.
        • Inomata-Terada S.
        • et al.
        Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex.
        Clin Neurophysiol. 2007; 118: 2672-2682
        • Hamada M.
        • Terao Y.
        • Hanajima R.
        • Shirota Y.
        • Nakatani-Enomoto S.
        • Furubayashi T.
        • et al.
        Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.
        J Physiol. 2008; 586: 3927-3947https://doi.org/10.1113/jphysiol.2008.152793
        • Pascual-Leone A.
        • Valls-Sole J.
        • Wassermann E.M.
        • Hallett M.
        Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex.
        Brain. 1994; 117: 847-858
        • Maeda F.
        • Keenan J.P.
        • Tormos J.M.
        • Topka H.
        • Pascual-Leone A.
        Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability.
        Exp Brain Res. 2000; 133: 425-430
        • Muellbacher W.
        • Ziemann U.
        • Boroojerdi B.
        • Hallett M.
        Effects of low-frequency transcranial magnetic stimulation on motor excitability and basic motor behavior.
        Clin Neurophysiol. 2000; 111: 1002-1007
        • Agostino R.
        • Iezzi E.
        • Dinapoli L.
        • Gilio F.
        • Conte A.
        • Mari F.
        • et al.
        Effects of 5 Hz subthreshold magnetic stimulation of primary motor cortex on fast finger movements in normal subjects.
        Exp Brain Res. 2007; 180: 105-111
        • Oldfield R.C.
        The assessment and analysis of handedness: the Edinburgh inventory.
        Neuropsychologia. 1971; 9: 97-113
        • Rossi S.
        • Hallett M.
        • Rossini P.M.
        • Pascual-Leone A.
        Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research.
        Clin Neurophysiol. 2009; 120: 2008-2039https://doi.org/10.1016/j.clinph.2009.08.016
        • Matsumoto H.
        • Ugawa Y.
        Safety guidelines for the use of magnetic stimulation.
        Jpn J Clin Neurophysiol. 2011; 39 ([in Japanese)]): 34-45
        • Chen R.
        • Cros D.
        • Curra A.
        • Di Lazzaro V.
        • Lefaucheur J.P.
        • Magistris M.R.
        • et al.
        The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee.
        Clin Neurophysiol. 2008; 119: 504-532https://doi.org/10.1016/j.clinph.2007.10.014
        • Hamada M.
        • Ugawa Y.
        Quadripulse stimulation--a new patterned rTMS.
        Restor Neurol Neurosci. 2010; 28: 419-424https://doi.org/10.3233/RNN-2010-0564
        • Tsang P.
        • Jacobs M.F.
        • Lee K.G.H.
        • Asmussen M.J.
        • Zapallow C.M.
        • Nelson A.J.
        Continuous theta-burst stimulation over primary somatosensory cortex modulates short-latency afferent inhibition.
        Clin Neurophysiol. 2014; 125: 2253-2259https://doi.org/10.1016/j.clinph.2014.02.026
        • Chah R.F.
        • Isayama R.
        • Gunraj C.A.
        • Ni Z.
        • Chen R.
        The influence of sensory afferent input on local motor cortical excitatory circuitry in humans.
        J Physiol. 2015; 593: 1667-1684https://doi.org/10.1113/jphysiol.2014.286245
        • Vesia M.
        • Bolton D.A.
        • Mochizuki G.
        • Staines W.R.
        Human parietal and primary motor cortical interactions are selectively modulated during the transport and grip formation of goal-directed hand actions.
        Neuropsychologia. 2013; 51: 410-417https://doi.org/10.1016/j.neuropsychologia.2012.11.022
        • Okabe S.
        • Hanajima R.
        • Ohnishi T.
        • Nishikawa M.
        • Imabayashi E.
        • Takano H.
        • et al.
        Functional connectivity revealed by single-photon emission computed tomography (SPECT) during repetitive transcranial magnetic stimulation (rTMS) of the motor cortex.
        Clin Neurophysiol. 2003; 114: 450-457
        • Koch G.
        • Ruge D.
        • Cheeran B.
        • Fernandez Del Olmo M.
        • Pecchioli C.
        • Marconi B.
        • et al.
        TMS activation of interhemispheric pathways between the posterior parietal cortex and the contralateral motor cortex.
        J Physiol. 2009; 587: 4281-4292https://doi.org/10.1113/jphysiol.2009.174086
        • Catani M.
        • Schotten M.
        Atlas of human brain connections.
        Oxford University Press, the UK2012
        • Parmigiani S.
        • Barchiesi G.
        • Cattaneo L.
        The dorsal premotor cortex exerts a powerful and specific inhibitory effect on the ipsilateral corticofacial system: a dual-coil transcranial magnetic stimulation study.
        Exp Brain Res. 2015; 233: 3253-3260https://doi.org/10.1007/s00221-015-4393-7
        • Tokuno H.
        • Tanji J.
        Input organization of distal and proximal forelimb areas in the monkey primary motor cortex: a retrograde double labeling study.
        J Comp Neurol. 1993; 333: 199-209
        • Hatanaka N.
        • Nambu A.
        • Yamashita A.
        • Takada M.
        • Tokuno H.
        Somatotopic arrangement and corticocortical inputs of the hindlimb region of the primary motor cortex in the macaque monkey.
        Neurosci Res. 2001; 40: 9-22