Yasuto Inukai

Comparison of Three Non-Invasive Transcranial Electrical Stimulation Methods for Increasing Cortical Excitability

Transcranial direct current stimulation (tDCS) is a representative non-invasive brain stimulation method (NIBS). tDCS increases cortical excitability not only in healthy individuals, but also in stroke patients where it contributes to motor function improvement. Recently, two additional types of transcranial electrical stimulation (tES) methods have been introduced that may also prove beneficial for stimulating cortical excitability; these are transcranial random noise stimulation (tRNS) and transcranial alternating current stimulation (tACS). However, comparison of tDCS with tRNS and tACS, in terms of efficacy in cortical excitability alteration, has not been reported thus far. We compared the efficacy of the three different tES methods for increasing cortical excitability using the same subject population and same current intensity. Fifteen healthy subjects participated in this study. Similar stimulation patterns (1.0 mA and 10 min) were used for the three conditions of stimulation (tDCS, tRNS, and tACS). Cortical excitability was explored via single-pulse TMS elicited motor evoked potentials (MEPs). Compared with pre-measurements, MEPs significantly increased with tDCS, tACS, and tRNS (p < 0.05). Compared with sham measurements, significant increases in MEPs were also observed with tRNS and tACS (p < 0.05), but not with tDCS. In addition, a significant correlation of the mean stimulation effect was observed between tRNS and tACS (p = 0.019, r = 0.598). tRNS induced a significant increase in MEP compared with the Pre or Sham at all time points. tRNS resulted in the largest significant increase in MEPs. These findings suggest that tRNS is the most effective tES method and should be considered as part of a treatment plan for improving motor function in stroke patients.

Influence of Transcranial Direct Current Stimulation to the Cerebellum on Standing Posture Control.

Damage to the vestibular cerebellum results in dysfunctional standing posture control. Patients with cerebellum dysfunction have a larger sway in the center of gravity while standing compared with healthy subjects. Transcranial direct current stimulation (tDCS) is a noninvasive technique for selectively exciting or inhibiting specific neural structures with potential applications in functional assessment and treatment of neural disorders. However, the specific stimulation parameters for influencing postural control have not been assessed. In this study, we investigated the influence of tDCS when applied over the cerebellum on standing posture control. Sixteen healthy subjects received tDCS (20 min, 2 mA) over the scalp 2 cm below the inion. In Experiment 1, all 16 subjects received tDCS under three stimulus conditions, Sham, Cathodal, and Anodal, in a random order with the second electrode placed on the forehead. In Experiment 2, five subjects received cathodal stimulation only with the second electrode placed over the right buccinator muscle. Center of gravity sway was measured twice for 60 s before and after tDCS in a standing posture with eyes open and legs closed, and average total locus length, locus length per second, rectangular area, and enveloped area were calculated. In Experiment 1, total locus length and locus length per second decreased significantly after cathodal stimulation but not after anodal or sham stimulation, while no tDCS condition influenced rectangular or enveloped areas. In Experiment 2, cathodal tDCS again significantly reduced total locus length and locus length per second but not rectangular and enveloped areas. The effects of tDCS on postural control are polarity-dependent, likely reflecting the selective excitation or inhibition of cerebellar Purkinje cells. Cathodal tDCS to the cerebellum of healthy subjects can alter body sway (velocity).

Regulation of primary motor cortex excitability by repetitive passive finger movement frequency

Somatosensory input induced by passive movement activates primary motor cortex (M1). We applied repetitive passive movement (RPM) of different frequencies to test if modulation of M1 excitability depends on RPM frequency. Twenty-seven healthy subjects participated in this study. Motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) to left M1 were recorded from the right first dorsal interosseous muscle (FDI) to assess corticospinal excitability (experiment 1: n=15), and F-waves were measured from the right FDI as an index of spinal motoneuron excitability (experiment 2: n=15). Passive abduction/adduction of the right index finger was applied for 10min at 0.5, 1.0, 3.0, and 5.0Hz. Both 0.5Hz-RPM and 1.0Hz-RPM decreased MEPs for 2min (p<0.05), and 5.0Hz-RPM decreased MEPs for 15min compared with baseline (p<0.05); however, there was no difference in MEPs after 3.0Hz-RPM. No F-wave changes were observed following any RPM intervention. Based on the results of experiments 1 and 2, we investigated whether RPM modulates cortical inhibitory circuit using the paired-pulse TMS technique (experiment 3: n=12). Short-interval intracortical inhibition (SICI) was measured using paired-pulse TMS (inter-stimulus interval of 3ms) before and after 1.0, 3.0, and 5.0Hz-RPM. Both 1.0 and 5.0Hz-RPM increased SICI compared with baseline (p<0.05). These experiments suggest that M1 excitability decreases after RPM depending on movement frequency, possibly through frequency-dependent enhancement of cortical inhibitory circuit in M1.

Effects of Passive Finger Movement on Cortical Excitability

This study examined the effects of joint angle and passive movement direction on corticospinal excitability. The subjects were 14 healthy adults from whom consent could be obtained. We performed two experiments. In Experiment 1, we measured motor evoked potential (MEP) amplitude, F-wave and M-wave at 0° and 20° adduction during adduction or abduction movement, in the range of movement from 10° abduction to 30° adduction. In Experiment 2, MEPs were measured at static 0° and 20° adduction during passive adduction from 10° adduction to 30° adduction and static 20° adduction. MEP, F-waves and M-waves were recorded from the right first dorsal interosseous (FDI) muscle. Experiment 1 revealed significantly increased MEP amplitude at 0° during passive adduction compared to static 0° (p < 0.01). No other significant differences in MEP, M-wave and F-wave parameters were observed. In Experiment 2, MEP amplitude was significantly higher at 20° adduction during passive adduction compared with static 0° (p < 0.01). Based on these findings, it appears that fluctuations in MEP amplitude values during passive movement are not influenced by joint angle, but rather it is possible that it is due to intracortical afferent facilitation (AF) dependent on afferent input due to the start of movement and interstimulus interval (ISI) of transcranial magnetic stimulation (TMS).

Presence and Absence of Muscle Contraction Elicited by Peripheral Nerve Electrical Stimulation Differentially Modulate Primary Motor Cortex Excitability

Modulation of cortical excitability by sensory inputs is a critical component of sensorimotor integration. Sensory afferents, including muscle and joint afferents, to somatosensory cortex (S1) modulate primary motor cortex (M1) excitability, but the effects of muscle and joint afferents specifically activated by muscle contraction are unknown. We compared motor evoked potentials (MEPs) following median nerve stimulation (MNS) above and below the contraction threshold based on the persistence of M-waves. Peripheral nerve electrical stimulation (PES) conditions, including right MNS at the wrist at 110% motor threshold (MT; 110% MNS condition), right MNS at the index finger (sensory digit nerve stimulation [DNS]) with stimulus intensity approximately 110% MNS (DNS condition), and right MNS at the wrist at 90% MT (90% MNS condition) were applied. PES was administered in a 4 s ON and 6 s OFF cycle for 20 min at 30 Hz. In Experiment 1 (n = 15), MEPs were recorded from the right abductor pollicis brevis (APB) before (baseline) and after PES. In Experiment 2 (n = 15), M- and F-waves were recorded from the right APB. Stimulation at 110% MNS at the wrist evoking muscle contraction increased MEP amplitudes after PES compared with those at baseline, whereas DNS at the index finger and 90% MNS at the wrist not evoking muscle contraction decreased MEP amplitudes after PES. M- and F-waves, which reflect spinal cord or muscular and neuromuscular junctions, did not change following PES. These results suggest that muscle contraction and concomitant muscle/joint afferent inputs specifically enhance M1 excitability.

Variability and Reliability of Paired-Pulse Depression and Cortical Oscillation Induced by Median Nerve Stimulation

Paired-pulse depression (PPD) has been widely used to investigate the functional profiles of somatosensory cortical inhibition. However, PPD induced by somatosensory stimulation is variable, and the reasons for between- and within-subject PPD variability remains unclear. Therefore, the purpose of this study was to clarify the factors influencing PPD variability induced by somatosensory stimulation. The study participants were 19 healthy volunteers. First, we investigated the relationship between the PPD ratio of each component (N20m, P35m, and P60m) of the somatosensory magnetic field, and the alpha, beta, and gamma band changes in power [event-related desynchronization (ERD) and event-related synchronization (ERS)] induced by median nerve stimulation. Second, because brain-derived neurotrophic factor (BDNF) gene polymorphisms reportedly influence the PPD ratio, we assessed whether BDNF genotype influences PPD ratio variability. Finally, we evaluated the test–retest reliability of PPD and the alpha, beta, and gamma ERD/ERS induced by somatosensory stimulation. Significant positive correlations were observed between the P60m_PPD ratio and beta power change, and the P60m_PPD ratio was significantly smaller for the beta ERD group than for the beta ERS group. P35m_PPD was found to be robust and highly reproducible; however, P60m_PPD reproducibility was poor. In addition, the ICC values for alpha, beta, and gamma ERD/ERS were 0.680, 0.760, and 0.552 respectively. These results suggest that the variability of PPD for the P60m deflection may be influenced by the ERD/ERS magnitude, which is induced by median nerve stimulation.

Somatosensory Inputs Induced by Passive Movement Facilitate Primary Motor Cortex Excitability Depending on the Interstimulus Interval, Movement Velocity, and Joint Angle

Somatosensory inputs affect primary motor cortex (M1) excitability; however, the effect of movement-induced somatosensory inputs on M1 excitability is unknown. This study examined whether M1 excitability is modulated by somatosensory inputs with passive movement in 29 healthy subjects. Motor-evoked potentials (MEPs), elicited by transcranial magnetic stimulation (TMS) were recorded from the first dorsal interosseous (FDI) muscle (Experiment 1). M- and F-waves were measured from the FDI muscle (Experiment 2). Passive movements of the index finger were performed in the adduction direction. TMS pulses were preceded by starting passive movements with interstimulus intervals (ISIs) of 30, 60, 90, 120, 150, 180, and 210 ms. TMS or electrical stimulation was performed in the midrange of the metacarpophalangeal joint during passive movements. MEPs were significantly facilitated at 90, 120, and 150 ms (p < 0.05). No M- or F-wave changes were observed for any ISI. In addition, we investigated whether MEP changes were dependent on passive movement velocity and joint angle. Passive movement was performed at two movement velocities (Experiment 3) or joint angles (Experiment 4). MEP facilitation was observed depending on the movement velocities or joint angles. These experiments demonstrated that somatosensory inputs induced by passive movements facilitated M1 excitability depending on the ISIs, passive movement velocity, and joint angle.

Inhibitory Mechanisms in Primary Somatosensory Cortex Mediate the Effects of Peripheral Electrical Stimulation on Tactile Spatial Discrimination

Selective afferent activation can be used to improve somatosensory function, possibly by altering cortical inhibitory circuit activity. Peripheral electrical stimulation (PES) is widely used to induce selective afferent activation, and its effect may depend on PES intensity. Therefore, we investigated the effects of high- and low-intensity PES applied to the right index finger on tactile discrimination performance and cortical somatosensory-evoked potential paired-pulse depression (SEP-PPD) in 25 neurologically healthy subjects. In Experiment 1, a grating orientation task (GOT) was performed before and immediately after local high- and low-intensity PES (both delivered as 1-s, 20-Hz trains of 0.2-ms electrical pulses at 5-s intervals). In Experiment 2, PPD of SEP components N20/P25_SEP-PPD, N20_SEP-PPD and P25_SEP-PPD, respectively, were assessed before and immediately after high- and low-intensity PES. Improved GOT discrimination performance after high-intensity PES (reduced discrimination threshold) was associated with lower baseline performance (higher baseline discrimination threshold). Subjects were classified into low and high (baseline) GOT performance groups. Improved GOT discrimination performance in the low GOT performance group was significantly associated with a greater N20_SEP-PPD decrease (weaker PPD). Subjects were also classified into GOT improvement and GOT decrement groups. High-intensity PES decreased N20_SEP-PPD in the GOT improvement group but increased N20_SEP-PPD in the GOT decrement group. Furthermore, a greater decrease in GOT discrimination threshold was significantly associated with a greater N20_SEP-PPD decrease in the GOT improvement group. These results suggest that high-intensity PES can improve somatosensory perception in subjects with low baseline function by modulating cortical inhibitory circuits in primary somatosensory cortex.

Repetitive Passive Finger Movement Modulates Primary Somatosensory Cortex Excitability

Somatosensory inputs induced by repetitive passive movement (RPM) modulate primary motor cortex (M1) excitability; however, it is unclear whether RPM affects primary somatosensory cortex (S1) excitability. In this study, we investigated whether RPM affects somatosensory evoked potentials (SEPs) and resting state brain oscillation, including alpha and beta bands, depend on RPM frequency. Nineteen healthy subjects participated in this study, and SEPs elicited by peripheral nerve electrical stimulation were recorded from the C3’ area in order to assess S1 excitability (Exp. 1: n = 15). We focused on prominent SEP components such as N20, P25 and P45-reflecting S1 activities. In addition, resting electroencephalograms (EEGs) were recorded from C3’ area to assess the internal state of the brain network at rest (Exp. 2: n = 15). Passive abduction/adduction of the right index finger was applied for 10 min at frequencies of 0.5, 1.0, 3.0, and 5.0 Hz in Exp. 1, and 1.0, 3.0, and 5.0 Hz in Exp. 2. No changes in N20 or P25 components were observed following RPM. The 3.0 Hz-RPM decreased the P45 component for 20 min (p < 0.05), but otherwise did not affect the P45 component. There was no difference in the alpha and beta bands before and after any RPM; however, a negative correlation was observed between the rate of change of beta power and P45 component at 3.0 Hz-RPM. Our findings indicated that the P45 component changes depending on the RPM frequency, suggesting that somatosensory inputs induced by RPM influences S1 excitability. Additionally, beta power enhancement appears to contribute to the P45 component depression in 3.0 Hz-RPM.

Transcranial Alternating Current Stimulation With Gamma Oscillations Over the Primary Motor Cortex and Cerebellar Hemisphere Improved Visuomotor Performance

Transcranial alternating current stimulation (tACS) can be used to modulate oscillatory brain activity. In this study, we investigated whether tACS applied over the primary motor cortex (M1) and cerebellar cortex region improved motor performance. We applied tACS (1.0 mA) to 20 healthy adults while they performed an isometric force task with some visuomotor control using their right index finger. Gamma (70 Hz) oscillations in the Experiment 1 or beta (20 Hz) oscillations in the Experiment 2 were applied for 30 s over the left M1, right cerebellar hemisphere or both regions (“M1-Cerebellum”), and errors performing the task were compared. Beta-oscillation tACS did not affect motor performance. With the gamma-oscillation tACS, a negative correlation was found between the difference of error in the M1-Cerebellum condition and the number of errors in the sham condition (P = 0.005, Pearson’s r = −0.597), indicating that motor performance improved with M1-Cerebellum tACS for subjects with low motor performance in the sham condition. Those who performed poorly in the sham condition made significantly fewer errors with M1-Cerebellum tACS (P = 0.004). Thus, for subjects with poorer motor performance, tACS with gamma oscillations applied over the M1 and contralateral cerebellar hemisphere improved their performance.