Effects of water immersion on short- and long-latency afferent inhibition, short-interval intracortical inhibition, and intracortical facilitation

Clinical Neurophysiology 124 (2013) 1846–1852

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Effects of water immersion on short- and long-latency afferent inhibition, short-interval intracortical inhibition, and intracortical facilitation Daisuke Sato a,b,⇑, Koya Yamashiro a,b, Takuya Yoshida b, Hideaki Onishi a,c, Yoshimitsu Shimoyama b, Atsuo Maruyama a,b a b c

Institute for Human Movement and Medical Sciences, Niigata University of Health and Welfare, Japan Department of Health and Sports, Niigata University of Health and Welfare, Japan Department of Physical Therapy, Niigata University of Health and Welfare, Japan

a r t i c l e

i n f o

Article history: Accepted 10 April 2013 Available online 18 May 2013 Keywords: Water immersion SAI LAI Sensorimotor integration

h i g h l i g h t s  We demonstrate that water immersion (WI) modulates sensorimotor integration as indicated by

decreased short- and long-latency afferent inhibition.  WI did not change corticospinal excitability, short-interval intracortical inhibition, or intracortical

facilitation.  A greater understanding of the neurophysiological effects of WI could lead to more efficacious use of

aquatic therapy in rehabilitation regimens.

a b s t r a c t Objective: The aim of the present study was to investigate the effect of water immersion (WI) on shortand long-latency afferent inhibition (SAI and LAI), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Methods: Motor evoked potentials (MEPs) were measured from the first dorsal interosseous (FDI) muscle of fifteen healthy males before, during, and after a 15-min WI at 30 °C up to the axilla. Both SAI and LAI were evaluated by measuring MEPs in response to transcranial magnetic stimulation (TMS) of the left motor cortex following electrical stimulation of the right median nerve (fixed at about three times the sensory threshold) at interstimulus intervals (ISIs) of 20 ms to assess SAI and 200 ms to assess LAI. The paired-pulse TMS paradigm was used to measure SICI and ICF. Results: Both SAI and LAI were reduced during WI, while SICI and ICF were not significantly different before, during, and after WI. Conclusions: WI decreased SAI and LAI by modulating the processing of afferent inputs. Significance: Changes in somatosensory processing and sensorimotor integration may contribute to the therapeutic benefits of WI for chronic pain or movement disorders. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Water immersion (WI) activates several distinct somatosensory modalities, including tactile, pressure, and thermal sensations. Somatosensory inputs received during WI can induce a variety of cardiovascular and respiratory responses, including decreased heart rate (Marabotti et al., 2009), increased stroke volume caused by increasing venous return (Christie et al., 1990), and reduced ⇑ Corresponding author. Address: Institute for Human Movement and Medical Sciences, Niigata University of Health and Welfare, Shimami-cho 1398, kita-ku, Niigata City 950-3198, Japan. Tel./fax: +81 25 257 4624. E-mail address: [email protected] (D. Sato).

functional residual capacity (Farhi and Linnarsson, 1977; Leddy et al., 2001). These physiological responses can have therapeutic benefits; indeed, WI is part of rehabilitation regimes for orthopedic, cardiovascular, and respiratory disorders. WI once a week also improves the activities of daily living (ADL) in frail elderly and hemiplegic patients after stroke (Sato et al., 2007). Benefits to neurological patients suggest that WI may influence cerebrocortical processing; however, this remains to be determined. Elucidating the cortical sensorimotor processes induced or modulated by WI and the effects of WI on the excitability of the motor cortex will help delineate the mechanisms of sensorimotor integration and could facilitate the development of improved aquatic therapies for neurological patients.

1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.04.008

D. Sato et al. / Clinical Neurophysiology 124 (2013) 1846–1852

Transcranial magnetic stimulation (TMS) is a noninvasive technique useful for the functional evaluation of the circuits of the human cerebral cortex (Hallett, 2000). Paired-pulse TMS of the motor cortex and pairing of single TMS pulses with peripheral electrical nerve stimuli at specific interstimulus intervals (ISIs) can recruit distinct inhibitory circuits in the motor cortex (Di Lazzaro et al., 2004) and thereby modulate sensorimotor integration and motor output. Two TMS responses indicative of the activation of inhibitory circuits in the motor cortex are short- and long-latency afferent inhibition (SAI and LAI). Motor evoked potentials (MEPs) in hand muscles elicited by TMS of the motor cortex can be attenuated by conditioning electrical stimuli (ES) of the contralateral median nerve evoked about 20 ms (for SAI) or 200 ms (for LAI) before TMS (Chen et al., 1999; Tokimura et al., 2000). Both SAI and LAI result from corticocortical inhibitory transmission originating in the somatosensory cortex (Chen et al., 1999; Tokimura et al., 2000). Several studies have shown that SAI is pathway specific in that local sensory inputs induce greater MEP decreases in nearby muscles (Classen et al., 2000; Tamburin et al., 2001). However, Tamburin et al. (2005) also demonstrated weaker SAI for more widespread sensory inputs, possibly due to afferent convergence. Paired-pulse TMS can measure short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) (Kujirai et al., 1993; Ziemann et al., 1996) depending on ISI. There is strong evidence that SICI and ICF originate in the motor cortex (Di Lazzaro et al., 1998, 2000, 2006). Several studies have found that a focused afferent input can influence SICI and ICF only in local muscles (Rosenkranz et al., 2003; Rosenkranz and Rothwell, 2003, 2004). Sensorimotor integration is the process by which the motor system continuously processes sensory information to prepare for motor tasks and to improve the execution of fine motor activities (Evarts and Fromm, 1977; Rosen and Asanuma, 1972). Sensorimotor integration has been studied in animal models using microstimulation (Cheney and Fetz, 1984; Rosen and Asanuma, 1972) and in the intact human cortex using TMS. In a previous study, we found that water immersion attenuated the amplitude of somatosensory evoked potentials (SEPs) induced by median nerve stimuli (Sato et al., 2012b). These results suggested that WI influences the somatosensory processing of other sensory inputs. In addition, our previous study using functional near infrared spectroscopy (fNIRS) found that WI influenced activity throughout the sensorimotor cortex, including the primary somatosensory area (SI), posterior parietal cortex (PPC), primary motor area (MI), and supplementary motor area (SMA) (Sato et al., 2012a). In light of these results, we suggest that WI may also influence sensorimotor integration; however, there is no direct experimental evidence for this. In the present study, we examined sensorimotor integration and modulation of intracortical neuronal circuits in the hand area of the motor cortex during WI. Based on our previous results that WI enhanced SEP gating (Sato et al., 2012b) and increased the activities of the sensorimotor region (Sato et al., 2012a), we hypothesized that WI of most of the body would substantially change SAI and LAI. Additionally, sensory inputs changed SICI and ICF (Golaszewski et al., 2012; Rosenkranz and Rothwell, 2004), suggesting that WI may also modulate intracortical circuits. However, since SICI and ICF show great topographic specificity for the afferent input (Rosenkranz and Rothwell, 2003), we speculated that they would not be changed by WI when the hand was not actually in the water.

2. Methods 2.1. Subjects We examined 15 healthy male volunteers between 19 and 26 years of age (mean age, 21.7 ± 0.4 years) after obtained their in-

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formed consent. All subjects were right-handed, none had a history of neurological or psychiatric disease, and none were taking any medications. The present study was conducted in accordance with the Declaration of Helsinki and approved by the local ethical committee. 2.2. Electromyography (EMG) recording EMG recordings were obtained using surface electrodes placed over the right first dorsal interosseous (FDI) muscle using 9-mmdiameter disposable adhesive silver/silver-chloride surface electrodes. The active electrode was placed over the muscle belly and the reference over the interphalangeal joint of the index finger. Signals were amplified and filtered (gain  1000, 5 Hz–1 kHz; AB601G Nihon Kohden, Japan) and then transferred via a micro 1401 laboratory interface (CED Cambridge, UK) to a personal computer for further analysis. 2.3. Transcranial magnetic stimulation (TMS) TMS was performed using two MAGSTIM 200 stimulators connected by a Y-cable to a figure 8 coil with an external wing diameter of 9 cm (Magstim, Dyfed, UK). The coil was held with the handle pointing backwards and laterally at approximately 45° to the sagittal plane and was optimally positioned to obtain MEPs in the target muscle. The coil position was marked on the skull to allow the experimenter to reposition the coil in the same spot before each measurement and consistency of the coil position was continuously monitored during the experiment. With this coil orientation, the induced current in the brain would flow in a posterior to anterior direction. Resting motor threshold (RMT) was defined as TMS intensity needed to elicit MEPs of at least 50 lV or more in at least 3 of 6 successive trials in the relaxed target muscle (Maruyama et al., 2006). For the active motor threshold (AMT), a minimum MEP of 200 lV was necessary in 50% of all trials in activated (5% of maximum voluntary contraction) muscle (Ridding et al., 1995). The subjects viewed the EMG activity as visual feedback to assist in complete relaxation or to maintain a constant level of background activity. 2.4. SAI and LAI SAI was studied by pairing TMS (Test Stimulation, TS) and median nerve (afferent) stimulation (Conditioning Stimulation, CS) with a 20-ms ISI (Chen et al., 1999; Di Lazzaro et al., 2005, 2007; Tokimura et al., 2000). LAI was examined using the same method (Chen et al., 1999) but with a 200-ms ISI. Conditioning stimuli were single electrical pulses (200 ls) applied through bipolar electrodes to the right median nerve at the wrist (cathode proximal) before TS. The intensity of CS was set at about three times the sensory threshold. The intensity of TS was adjusted to evoke an EMG response in the relaxed FDI muscle of approximately 1 mV peak-topeak. 2.5. SICI and ICF SICI and ICF were studied using the technique of Kujirai et al. (1993) and Ziemann et al. (1996). Two TMS pulses were administered through the same stimulating coil over the left motor cortex and the effect of the first (conditioning) stimulation on the second (test) stimulation was measured. CS was set at an intensity of 80% AMT. The intensity of TS was adjusted to elicit an unconditioned test MEP in the relaxed right FDI muscle of approximately 1 mV peak-to-peak amplitude. The following ISIs were selected: 3 and 10 ms.

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Fig. 1. Experimental protocol in the present study. Trials were performed before, during and after 15 min water immersion. Coupling peripheral electrical median nerve stimulus with single pulse TMS and paired-pulse TMS were stimulated at rest in each trial.

2.6. Skin temperature The effects of body temperature on corticospinal excitability, sensorimotor integration, and intracortical circuit responses were tested by skin temperature in five subjects. A temperature logger (LT-8; Gram Corporation) was used to measure skin temperatures from the right femoral surface (immersion area) and the right hand surface (a nonimmersed area) during the experiment.

2.7. Experimental design Measurements were performed before, during, and after 15 min of WI under the environmental setting described previously (Sato et al., 2012b). Fig. 1 illustrates the experimental protocol. The subjects wore only swimwear and were seated on a comfortable reclining armchair with a mounted headrest. They were instructed to relax during the measurements. For the measurements before and after WI, the ambient temperature was 30 °C, the same as the water temperature during immersion. Water was poured up to the axilla of each subject, and the right hand was placed on the arm rest above the water level for MEP recording (Fig. 1). Each trial consisted of test TMS pulses alone (TS) and four paired stimuli with different ISIs: a TMS pulse 20 and 200 ms after a right median nerve stimulus to measure SAI and LAI, respectively, and a test TMS pulse following a conditioning TMS pulse by 3 and 10 ms to measure SICI and ICF. The four paired stimulus trials were randomly intermixed with TS-alone trials at an intertrial interval of 4 s. Twelve trials for each ISI were collected and compared with the TS alone. The intensity of TS was constant throughout the experiment.

2.8. Data analysis All MEPs were expressed as peak-to-peak amplitudes. The peakto-peak amplitude of the test MEP evoked by a single (unpaired) TMS stimulus is termed MEPTEST. The four experimental MEP values are MEP20 ms (the MEP amplitude when evoked by a TMS pulse occurring 20 ms after the median nerve stimulus), MEP200 ms (the MEP amplitude evoked by a TMS pulse occurring 200 ms after the median nerve stimulus), MEP3 ms (the amplitude of the second of two TMS-evoked MEPs with an ISI of 3 ms), and MEP10 ms (the amplitude of the second of two TMS-evoked MEPs with an ISI of 10 ms). In turn, MEP20 ms/MEPTEST is a measure of SAI, MEP200 ms/ MEPTEST is a measure of LAI, MEP3 ms/MEPTEST is a measure of SICI, and MEP10 ms/MEPTEST is a measure of ICF.

All values in figures are expressed as mean ± standard error (SE) over the entire experiment or within the three experimental phases (before, during, and after WI). The effect of the experimental phase on MEPTEST, MEP20 ms, MEP200 ms, MEP3 ms, and MEP10 ms was evaluated using two-way repeated measures analysis of variance (ANOVA) with ISI and phase as within-subject factors. Changes in SAI, LAI, SICI, and ICF were similarly analyzed with two-way repeated measures ANOVA. Further analysis was performed with one-way repeated measures ANOVA on each parameter alone, using phase as the main factor. The skin temperature was subjected to the one-factor repeated measures ANOVA for time (before, during, and after WI). If the assumption of sphericity was violated in Mauchly’s sphericity test, the degree of freedom was corrected using Greenhouse-Geisser’s correction coefficient epsilon, and F- and P-values were recalculated. Post hoc tests (Bonferroni–Dunn) were performed for pair-wise comparisons, and the significance level was set at 5%. 3. Results The mean RMT (in mean ± SE) was 42.5 ± 1.3% of the maximum TMS output and the mean AMT (mean ± SE) was 31.4 ± 1.2% of the maximum TMS output. The mean stimulus intensities used in the paired-pulse TMS paradigms used to measure SICI and ICF were 52.8 ± 1.8% for TS, which initially evoked an MEP of about 1.0 mV peak-to-peak at the start of the experiments, and 27.0 ± 0.6% for CS. CS was set to 80% AMT. The mean current intensity of median nerve stimulation was 9.4 ± 0.6 mA. Fig. 2 presents the averaged MEPs of a representative subject before, during, and after WI. Results of two-way repeated measures ANOVA revealed a significant interaction between the experimental phase (before, during, and after WI) and ISI (TS alone, TS at 20 or 200 ms after a median nerve stimulus, and paired TMS pulses at 3 and 10 ms ISI) (phase  ISI: F(8, 112) = 13.214, P < 0.01), and significant effects of ISI (F(4, 56) = 31.665, P < 0.01) and time (F(2, 28) = 24.479, P < 0.01). Fig. 3 plots the mean MEP amplitudes for TS alone, MEP20 ms, MEP200m s, MEP3 ms, and MEP10 ms before, during, and after WI. One-way repeated measures ANOVA showed no significant effect of phase on the MEPTEST (F(2, 28) = 2.53, P = 0.12), MEP3 ms (F(2, 28) = 0.789, P = 0.46), or MEP10 ms (F(2, 28) = 0.639, P = 0.54). One-way repeated measures ANOVA revealed a significant effect of the experimental phase on MEP20 ms (F(2, 28) = 38.57, P < 0.01) and MEP200 ms (F(2, 28) = 50.14, P < 0.01), and Bonferroni–Dunn’s post hoc tests revealed that WI significantly increased the amplitudes of MEP20 ms and MEP200 ms.

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Fig. 2. A raw data traces from a representative subject before, during and after water immersion. Averaged MEPs for the test stimulus (TS) alone, after conditioning stimulus (CS) by TMS at ISIs of 3 ms and 10 ms, and after median nerve stimulus at ISIs of 20 ms and 200 ms (A) before, (B) during and (C) after water immersion. The TS was set to produce MEPs of approximately 1 mV. MEPTEST, MEP3 ms and MEP10 ms did not change among three trials. On the other hand, MEP20 ms and MEP200 ms increased during water immersion compared to before and after water immersion.

Fig. 3. Motor evoked potentials (MEPs) in test stimulus (TS) alone and TS after four different CS of ISIs before, during and after water immersion. Mean values (±SE) are shown. White, grey and black bar represent mean data before, during and after water immersion from 15 subjects.

Fig. 4 plots the mean percentages of SICI, ICF, SAI and LAI (conditioned MEP/unconditioned MEP  100) before, during, and after WI. Results of two-way repeated measures ANOVA revealed a significant interaction between the experimental phase (before, during, and after WI) and the four indices of cortical excitability, SAI, LAI, SICI, and ICF (F(6, 84) = 12.472, P < 0.01). There were also significant effects of excitability index (F(3, 42) = 33.288, P < 0.01) and phase (F(2, 28) = 25.569, P < 0.01). One-way repeated measures ANOVA showed no significant effect of phase on SICI (F(2, 28) = 0.25, P = 0.78) or ICF (F(2, 28) = 0.29, P = 0.75), but one-way repeated measures ANOVA showed a significant effect of phase on SAI (F(2, 28) = 41.025, P < 0.01) and LAI (F(2, 28) = 49.99, P < 0.01). Bonferroni–Dunn’s post hoc tests revealed significant effects of WI on SAI and LAI. Relative MEP amplitudes were significantly larger after median nerve stimulation during WI compared with that before and after WI, indicating that WI decreases SAI and LAI.

Fig. 4. Short interval intracortical inhibition (SICI), intracortical facilitation (ICF), short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI) before, during and after water immersion. Mean values (±SE) are shown. The values of vertical axis indicate the persentage of SICI, ICF, SAI and LAI (conditioned MEP/ unconditioned MEP  100). White, grey and black bar represent mean data before, during and after water immersion from 15 subjects.

Changes in body temperature can significantly alter neuronal excitability though effects on voltage-gated and ligand-gate ionic channel kinetics. While both water and ambient temperature were controlled, we measured the mean skin temperatures before, during, and after WI (Fig. 5). One-way repeated measures ANOVA showed no significant effect of phase on the skin temperatures of the immersed femoral area (F(2, 8) = 1.00, P = 0.41) or the nonimmersed hand area (F(2, 8) = 0.023, P = 0.977).

4. Discussion The present study examined sensorimotor integration and modulation of intracortical neuronal circuits in the hand area of the hu-

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Fig. 5. Skin temperature before, during, and after water immersion. Mean values (±SE) are shown. White, grey and black bar represent mean data before, during and after water immersion from five subjects.

man motor cortex during WI. While WI did not affect corticospinal excitability, SAI and LAI were significantly decreased by WI. These results suggest that WI up to the axilla can modulate sensorimotor integration of other afferent inputs in humans. Additionally, we controlled the water and ambient temperatures (both 30 °C) and found no change in measured skin temperatures during the experiment, strongly suggesting that the decreases in SAI and LAI were unlikely influenced by changes in body temperature. WI can alter numerous physiological parameters depending on physical characteristics such as buoyancy, hydrostatic pressure, and temperature. Several studies have revealed that WI can provide relief from edema and improve blood flow (Bressel et al., 2011; IO et al., 2003; Wilcock et al., 2006) and that these effects are beneficial for the rehabilitation of patients with orthopedic (Suomi and Collier, 2003), cardiovascular (Mourot et al., 2010), or respiratory disorders (Cider et al., 2005). On the other hand, the effects of WI on sensorimotor integration and intracortical excitability in MI have never been examined, despite the fact that deep WI would activate a large area of the somatosensory cortex and is known to influence multimodal sensory processing (Sato et al., 2012b). The present study is the first to investigate modulation of sensorimotor integration induced by WI, and the results illuminate many of the neurophysiological changes that occur in the sensorimotor cortex during WI. A greater understanding of these changes may allow for more effective use of aquatic therapy for neurorehabilitation. 4.1. Effect of WI on MEPTEST Many previous reports have shown that afferent inputs from proximal skin and muscle spindles increase the evoked MEPs in relaxed hand muscles (Rosenkranz et al., 2003; Rosenkranz and Rothwell, 2003; Terao et al., 1995, 1999). This response has been explained by increased excitability of corticospinal neurons (Datta et al., 1989), spinal motor neurons (Brouwer et al., 1989), or both in response to afferent input. In the present study, however, the MEPTEST amplitude was not affected by WI, suggesting no significant changes in motor pathway excitability. Alternatively, the stability of MEPTEST during WI could result from the distal stimulus site (WI up to the axilla but not of the right hand, the target of TMS), the nature of the afferent input (water versus other stimuli) or the sensory stimulus intensity. Previous studies reported increased MEPTEST amplitudes in hand muscles when paired with afferent inputs from the hand, such as air-puffs (Terao et al., 1995), electrical stimulation (Golaszewski et al., 2012), and muscle vibration (Rosenkranz and Rothwell, 2003). However, the hand from which we measured MEPTEST was not actually in the water, and thus, changes in MEPTEST may require afferent input from the same region receiving the motor output. Rosenkranz et al. (2003) investigated whether a local afferent input can induce focal alter-

ation of intracortical excitability and found that muscle vibration led to a decrease in the motor threshold and facilitation of MEPTEST only in the vibrated muscle. Thus, modulation of MEPTEST may require hydrostatic pressure to the hand itself. An alternative explanation for the lack of effect on MEPTEST is the stimulus intensity. Golaszewski et al. (2012) examined the effect of different wholehand electrical mesh-glove (MG) stimulation intensities: subthreshold for sensory and motor responses at 50 Hz, sensory theshold at 50 Hz and 2 Hz, and motor threshold at 2 Hz. The authors found that 50 Hz MG stimulation at the sensory threshold or 2 Hz at the motor threshold, but not subthreshold stimuli, increased MEPTEST amplitude. In the present study, the subjects were only sitting in static water, and thus the pressure on the body surface would be minimal. We suggests that the afferent input from static WI may have been insufficient to influence motor pathway excitability and hence the MEPTEST amplitude in the hand. Further studies are required to determine the effects of proximity and pressure (intensity) on the MEPTEST amplitude during WI. 4.2. Effect of WI on SAI SAI decreased significantly during WI and returned to baseline rapidly thereafter. SAI occurs at the cortical level rather than at the local spinal level because the corticospinal waves (I-waves) induced by TMS are decreased by median nerve stimulation (Tokimura et al., 2000). An afferent volley takes 18–20 ms to reach the cortex, which is about the minimum ISI for afferent inhibition. Thus, inhibitory signals from the somatosensory cortex (activated by afferent input) must be transmitted to the motor cortex with few intervening processing steps. Given these time constraints, reduction in SAI by WI indicates that this widespread somatosensory input must directly interfere with inhibitory signals from the somatosensory cortex to the motor cortex. We can only speculate on the mechanisms that led to decreased SAI during WI. Tambrurin et al. (2005) examined the effect of receptive field size on SAI mediated by cutaneous afferent inputs to sensorimotor areas in humans and found that larger receptive fields induced a decreased SAI. Previous studies using microelectrode recordings in monkeys (Gardner and Kandel, 2000) and functional MRI in humans (Krause et al., 2001; Kurth et al., 2000) documented receptive fields of different sizes across the various divisions of the somatosensory cortex. In particular, neurons that participate in later stages of cortical processing (Brodmann’s area 1 and 2) appeared to have larger receptive fields and more specialized inputs than the neurons in area 3b (Gardner and Kandel, 2000). Our previous study showed that WI reduced short-latency SEP components known to originate in several somatosensory cortical areas and suggested that WI influences the cortical processing of somatosensory inputs (Sato et al., 2012b). In the present study, the subjects received afferent inputs from almost the entire body surface, which would result in afferent inputs to almost all subdivisions of the somatosensory cortex. 4.3. Effect of WI on LAI LAI was also significantly decreased during WI. There are few direct sensory projections to the motor cortex (Friedman and Jones, 1981; Jones, 1983), and thus, changes in motor cortex excitability during median nerve stimulation must be due to activation of corticocortical connections originating in sensory cortices. In particular, since SI, SII, and PPC all have direct projections to the motor cortex, these pathways may be involved in inhibition of the motor cortex during afferent sensory input. That is, LAI may result from activation of SI, SII, and the posterior parietal cortex (PPC) (Chen et al., 1999). In our previous study, we found that WI increased S1 and PPC activity as measured by fNIRS (Sato et al.,

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2012a), while a second study suggests that somatosensory input induced by WI may modulate hierarchical somatosensory processing from area SI to PPC (Sato et al., 2012b). Therefore, we speculate that somatosensory processing from area SI to PPC induced by WI decreased LAI. Another possible explanation for the decrease in LAI during WI assumes involvement of the basal ganglia-thalamocortical loop. Animal studies and intraoperative recordings in humans have shown that neurons in the basal ganglia respond to cutaneous and proprioceptive stimuli (Aosaki et al., 1994; Levy et al., 2001; Rothblat and Schneider, 1993). Sailer et al. (2003) showed that LAI is reduced or absent in Parkinson’s disease and speculated that the basal ganglia function as a sensory analyzer and abnormal afferent processing in the basal ganglia might contribute to motor manifestations in Parkinson’s disease (Brown et al., 1997). In the present study, since we did not investigate the basal ganglia response to the somatosensory input during WI, we cannot exclude a contribution from these circuits.

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Financial interests None. Conflict of interest The authors have no conflicts of interest to declare. Acknowledgments This study was supported by a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. It was also supported by a Grant-inAid for Advanced Research from the Niigata University of Health and Welfare. We appreciate the specialized advice of Prof. J.C. Rothwell. The authors would like to thank Enago (http:// www.enago.jp) for the English language review. References

4.4. Effect of WI on SICI and ICF We measured SICI and ICF using the paired-pulse design first described by Kujirai et al. (1993) in which a subthreshold CS altered a subsequent short latency response to a suprathreshold TS. There is good evidence that this interaction relies on activation of GABAA circuits in the motor cortex (Hanajima et al., 1998; Ilic et al., 2002). WI did not alter SICI or ICF, at least as reflected by MEPs in a hand muscle. Again, this negative result may be because of the motor target not actually being submerged. Many previous experiments have demonstrated that afferent inputs modulate intracortical circuits (Ridding et al., 2005; Ridding and Rothwell, 1999; Rosenkranz et al., 2003). Ridding and Rothwell (1999) examined whether intracortical inhibition is influenced by ES to the digits and suggested that this afferent input had a direct effect on the excitability of circuits involved in intracortical inhibition. They speculated that the afferent inputs reduced the excitability of feedforward inhibitory circuits projecting onto the motor circuits activated by the magnetic conditioning stimulus. Subsequently, Ridding et al. (2005) demonstrated that electrical cutaneous stimuli are capable of modulating SICI in a topographically specific manner. In the present study, a portion of the hand innervated by the median nerve was out of the water during WI, which may explain why we observed no change in SICI and ICF during WI in the present study. An alternative explanation is that changes in SICI or ICF require more than cutaneous stimulation from the skin. Rosenkranz and Rothwell (2003) compared the effects of muscle vibration and cutaneous digit nerve stimulation on MEPTEST, SICI, and ICF and found that low amplitude vibration of a muscle decreased SICI in motor inputs to that muscle, while specific digit nerve stimulation has no effect on SICI in the digit muscle. From these results, the authors concluded that the effects of SICI depend on the modality of the afferent sensory stimulus. In particular, the muscle spindle input activated by vibration has a greater effect on the cortical circuits controlling SICI than cutaneous inputs from digit nerve stimulation. Similarly, the afferent input from water was insufficient to alter SICI and ICF in the hand muscle.

5. Conclusions We demonstrated that WI decreases afferent inhibition (SAI and LAI) but does not change corticospinal excitability, SICI, and ICF. These results suggest that WI influences the sensorimotor integration.

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