Clinical Neurophysiology xxx (2014) xxx–xxx

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Movement observation-induced modulation of pain perception and motor cortex excitability Magdalena Sarah Volz a,b, Vanessa Suarez-Contreras a, Andrea L. Santos Portilla a, Ben Illigens c, Felix Bermpohl b, Felipe Fregni a,c,d,⇑ a Spaulding Neuromodulation Center, Department of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA b Charité – Universitätsmedizin Berlin, Germany c Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA d NEC, Psychology Institute, University of Sao Paulo, Sao Paulo, Brazil

a r t i c l e

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Article history: Accepted 16 September 2014 Available online xxxx Keywords: Motor cortex M1 Movement observation Pain Corticospinal excitability

h i g h l i g h t s  The observation of movements significantly reduces the perception of pain.  This effect was associated with decreased intracortical inhibition in the primary motor cortex.  These findings support the association between motor control and pain processing and should be used

to guide the development of novel targeted therapies for pain control.

a b s t r a c t Objective: The observation of movements increases primary motor cortex (M1) excitability. This exploratory study examined the effects of movement observation on pressure pain threshold (PPT) and transcranial magnetic stimulation (TMS)-indexed corticospinal excitability bilaterally. Methods: Thirty healthy right-handed subjects were randomized to a left hand-movement observation task or a control task. Statistical analyses were performed using ANOVA models and t-tests. Results were not corrected for multiple comparisons. Quantitative sensory assessments were measured in both hands, while M1 excitability has only been tested for the right (non-dominant) M1 corresponding to the observed left hand movements. Results: Analysis of pain and cortical silent period (CSP) outcomes demonstrated a significant interaction between task (hand-movement group) versus control group and time (pre-/postintervention). PPT increased in the left hand (moving hand in the task) and declined significantly in the contralateral hand (still hand) in the movement-observation-task-group, whereas PTT in the control group remained unchanged. CSP was significantly shorter in the movement-observation group indicating decreased intracortical inhibition (results uncorrected for multiple comparisons). Conclusions: The observation of hand-movements led to a side-specific reduction in pain perception and a decrease in intracortical inhibition. Significance: These exploratory findings support the notion that M1 is a robust modulator of pain-related neural networks. This effect might be mediated through modulation of the GABAergic system and appears to differ from what is observed in chronic pain. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction ⇑ Corresponding author at: Laboratory of Neuromodulation, Spaulding Rehabilitation Hospital, Harvard Medical School, 79/96 13th Street, Charlestown, MA 02129, USA. Tel.: +1 617 952 6156. E-mail address: [email protected] (F. Fregni).

Recent neurophysiological and treatment studies have demonstrated a significant relationship between the motor system and pain control (Hodges and Smeets, 2014; Misra and Coombes,

http://dx.doi.org/10.1016/j.clinph.2014.09.022 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Volz MS et al. Movement observation-induced modulation of pain perception and motor cortex excitability. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.09.022

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2014; Ribaud et al., 2013). This evidence comes from neurophysiological and therapeutic human studies as well as animal studies. Motor neural networks are extensively connected to pain related neural circuits (Bolognini et al., 2013; Dube and Mercier, 2011; Reyns et al., 2012). One of the main areas that may mediate this relationship is the thalamus (Tsubokawa et al., 1985, 1991). Although connectivity between thalamus and motor cortex has been well established (Ansari et al., 2012), only recently it has been demonstrated that motor cortex activity may induce a strong modulation in thalamic nuclei including those associated with pain processing. Such notion has been supported by the initial animal and preliminary surgical studies showing that epidural motor cortex stimulation leads to a decrease of thalamic overactivation and also pain decrease, respectively (Fregni et al., 2007; Tsubokawa et al., 1984). Further therapeutic trials with transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) have confirmed that stimulation of the primary motor cortex reduces pain in several neuropathic syndromes (Fregni et al., 2006a, 2006b; Kwon et al., 2008; Lefaucheur et al., 2008; Pell et al., 2011). Notably, this effect is specific for motor cortex stimulation (Fregni et al., 2007; Zaghi et al., 2011). Interestingly, not only electrical stimulation of the motor cortex leads to pain reduction, but also other modalities of behavioral therapies that involve the motor system, such as aerobic exercise and mental imagery, are associated with pain control (Desy and Theoret, 2007; Longo et al., 2012; Maeda et al., 2002; Theoret et al., 2005), as also reported in neurophysiological studies. In fact, mental imagery seems to be a potent modulator of thalamic activity. For instance, a recent neuroimaging study confirmed that the strongest activation signature associated with mental imagery was in the thalamus (Muller et al., 2012). In addition, direct thalamic recording has shown that phantom and imagined movements elicit responses in the following thalamic nuclei (somatic sensory nucleus (ventral caudal – Vc), motor nuclei (ventral intermediate (Vim) and ventral oral posterior (Vop))) (Anderson et al., 2010). A useful neural signature associated with modulation of the primary motor cortex and pain control is the TMS-indexed intracortical inhibition (Lefaucheur et al., 2006; Wagle-Shukla et al., 2009). Studies have shown an increase in motor cortex ICI associated with pain reduction. Similar findings have been generated in EEG studies (Di Lazzaro et al., 2005; Mhalla et al., 2011). Based on its significance, we examined this association further by studying the effects of movement observation on pain threshold and corticospinal excitability. Movement observation correlates with changes in corticospinal excitability (Battaglia et al., 2011; Borroni and Baldissera, 2008; Decety et al., 1997; Fadiga et al., 1995; Fecteau et al., 2005; Funase et al., 2007; Gangitano et al., 2001; Rizzolatti et al., 1996; Roosink and Zijdewind, 2010; Strafella and Paus, 2000; Theoret et al., 2005), but there is limited evidence of its effects on pain control, which must be determined to understand the function of the motor cortex in pain control on a behavioral task that has a robust effect on the motor system. It is thought that movement observation may influence the perception of pain through shifting cortical activity. Increased motor cortical activity can modulate pain-related networks and decrease neuronal activity in thalamic nuclei. Thus, nociceptive input may be reduced. There is evidence that observations of movements are able to alter excitability in the motor cortex. This alteration in excitability may also alter the activity in pain-related networks. Moreover, movement observation distracts attention away from painful stimulus. We hypothesized that hand movement observations would alter pain perception and that this effect would be linked to changes in corticospinal excitability or intracortical inhibition, whereas a control group (observation of geometric shapes) would

not experience such effects. Motor cortex excitability was assessed by transcranial magnetic stimulation (TMS) using such parameters as CSP (cortical silent period) and SICI (short intracortical inhibition). Given the number of outcomes in this study, we aimed to test this hypothesis in an exploratory study. 2. Methods 2.1. Subjects Thirty healthy right-handed male subjects (mean age: 30.07 ± 10.91 years, range: 18–49 years) were recruited through postings in public areas and on the internet. Participants who fulfilled the following criteria were eligible for participation: (1) male; (2) between ages 18 and 49 years; (3) right-handed, as indexed by the Edinburgh Handedness Inventory (Oldfield, 1971); (4) no neurological or psychiatric disorders [as assessed by the Beck Depression Inventory (Beck and Steer, 1984) (mean score: 1.33 ± 2.41)]; (5) no rheumatological disease; (6) no history of alcohol or substance abuse within the last 6 months; (7) no use of central nervous system-effective medications; and (8) no contraindications to TMS (Rossi et al., 2009). All subjects provided written informed consent. To form a homogeneous study population, we enrolled only right-handed male participants aged up to 49 years, because hormonal changes significantly alter cortical excitability throughout the menstrual cycle (Smith et al., 1999). 2.2. Experimental design Thirty right-handed healthy male subjects were enrolled in this double-blinded, randomized, controlled, parallel designed trial. The experimenter was blinded, and the subjects were not informed on the purpose of the study. Participants were randomized into 1 of 2 groups (15 volunteers each)—observation of left hand movement and observation of geometric shapes (control)—by a randomization method that chose random blocks of 6. Both groups underwent the same procedures, comprising pre- and postintervention pressure pain threshold and cortical excitability measurements. We sequentially assessed the secondary outcomes, TMS of corticospinal excitability, and the primary outcome, pressure pain threshold. Then, the task order was reversed: pressure pain threshold was measured first, after which TMS measures and secondary outcomes were recorded. We also administered the visual analog scale for anxiety, the affective go– no go task (Bermpohl et al., 2006; Gopin et al., 2011) and the Purdue pegboard test (Tiffin and Asher, 1948) to determine whether motor function, processing of emotional stimuli, and anxiety changed over time between groups. The study was approved by the institutional review board of Spaulding Rehabilitation Hospital (Harvard Medical School, Boston, USA) and was conducted per the ethical principles of the World Medical Association. 2.3. Interventions: observation of hand movements and geometric shapes Both interventions comprised a 20-min movie, differing in content between groups. The subjects in the test group were asked to observe movements passively. Moreover, they were told to imagine that the hands in the film were theirs and that the movements were performed as if with their left hands. Thus, the participants focused on a moving left hand. The movement observation group watched a movie of various finger movements of the left hand, similar to what has been described (Feurra et al., 2011; Maeda et al., 2002; Strafella and Paus, 2000; Theoret et al., 2005). The

Please cite this article in press as: Volz MS et al. Movement observation-induced modulation of pain perception and motor cortex excitability. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.09.022

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movie showed the left and right hands of a male. The left hand performed such movements as finger abduction and adduction, index finger extension and flexion (Maeda et al., 2002; Theoret et al., 2005), and thumb and finger pinch grip movements (Feurra et al., 2011), and the right hand remained immobile (Fig. 1A). Thus, the intervention targeted several muscles and movements of the left hand. The movie for the control group presented various geometric shapes that also moved (Fig. 1B), mimicking the experimental setting of the active group and keeping participants alert. The control movie had similar visual stimulation load (size and color of geometric shapes such as the human hand pictures). All subjects were seated comfortably in a chair with arms and were instructed to keep their fingers, hands, and arms still during the movie to remove artifacts from the subjects’ movements. During the movie, subjects were monitored by an experimenter to maintain adherence to the protocol (keeping their hands still and their focus on the screen). 2.4. Pain assessment: pressure pain threshold The primary outcome was pressure pain threshold. All subjects were seated in a comfortable chair with arms. Pressure pain threshold was measured in both hands with a Commander algometer (JTech Medical Industries, Salt Lake City, UT, USA) by 1 experimenter to control for interindividual variability. The algometer had a 1-cm2 rubber probe that was pressed against the thenar eminence bilaterally. Pressure pain threshold was measured at 3 locations on the thenar to avoid inducing sensitization of the underlying tissue on repeat testing. The slope of the applied fore was 30 lb = 13.6 kg. Subjects indicated when the pressure became painful. Outcome measures were reported in kg (Chesterton et al., 2002). The investigator was blinded to the subject’s intervention and was unable to view the pressure intensities. Three repetitions were performed, across which the thresholds averaged.

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of 20–2000 kHz. Offline analyses were performed using LabChart (ADinstruments, Colorado Springs, CO, USA). Subjects were seated in a comfortable chair with armrests and backrest to ensure comfortable and relaxed position. TMS was assessed over the right hemisphere and on the contralateral left FDI. Resting motor threshold (MT) was determined by eliciting 3 of 5 MEPs with a minimal peak-to-peak amplitude of 100 lV. MEPs were excited with 130% of the individual MT, which produced an amplitude of at least 1 mV peak to peak. Ten MEP were collected and mean was calculated for further analyses. Moreover, cortical silent periods (CSPs) were administered at 110% of the individual MT (Kallioniemi et al., 2014; Samargia et al., 2013). During the CSP recordings (Stetkarova et al., 1994), subjects were instructed to perform isometric voluntary contractions at 10% to 20% of maximal contraction, controlled by a mechanical pinch gauge (BaselineÒ Evaluation Instruments, Chattanooga, TN, USA). This assessment was conducted approximately 20 min before and 20 min after the intervention task. Ten CSP were collected and mean was calculated for further analyses. The TMS measurements also included short intracortical inhibition (SICI) with an interstimulus interval (ISI) of 3 ms and intracortical facilitation (ICF) with an ISI of 10 ms (Heide et al., 2006). For both measurements, the conditioning stimulus (first pulse of the paired pulse measurement) was set to 70% of the individual MT and the test stimulus (second pulse of the paired pulse measurement) was set to individual MEP intensity (Kobayashi and PascualLeone, 2003; Wagle-Shukla et al., 2009). In total, 15 recordings of each measure (ICF, SICI, and MEP) were elicited randomly to avoid habituation. All recordings were collected to calculate mean for further statistical analyses. Analyses comprised measurements of peak-to-peak amplitude, the areaunder-the-curve of all MEPs, and the relative duration of the CSP (duration from the beginning of the last MEP, including the absolute cortical silent period, to the beginning of the next MEP). 2.6. Additional secondary outcomes

2.5. Assessment of cortical excitability: transcranial magnetic stimulation (TMS) A Bistim2 stimulator and a figure-of-eight coil (Magstim Company LTDA, UK) were used to assess TMS. To record motor-evoked potentials (MEPs), Ag/AgCl electrodes (ADinstruments, Colorado Springs, CO, USA) were placed over the first dorsal interosseus muscle (FDI), and a reference electrode was placed over the subject’s forearm. Recordings were processed through a Powerlab 4/ 30 (ADinstruments, Colorado Springs, CO, USA) with a band pass

The Purdue pegboard test (Tiffin and Asher, 1948) was administered to measure motor function changes. To monitor mood changes, the visual analog scale (VAS) for anxiety and go–no go test were performed. The VAS comprises an 11-point rating system (0 indicates no anxiety, 10 indicates worst possible anxiety). The go–no go test uses a pass/fail test principle with 2 boundary conditions. Participants were shown words that had a positive, neutral, or negative connotation. Three blocks were presented, each of which comprised 30 words including 10 correct answers of either

Fig. 1. Observational tasks. (A) Hand movement movie: male left hand performed finger abduction and adduction, index finger extension and flexion, finger-thumb pinch grip movements. Note: right hand remained completely unmoved. (B) Control movie: presentation of different geometric shapes.

Please cite this article in press as: Volz MS et al. Movement observation-induced modulation of pain perception and motor cortex excitability. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.09.022

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meaning (positive, neutral, or negative connotation). Subjects were instructed to press a button whenever the word had a valence meaning (e.g., ‘‘angry’’ for negative, ‘‘nice’’ for positive, and ‘‘adult’’ for neutral). The test measured reaction time and ability with regard to affective processing and identified changes in mood and affective/cognitive abilities (Bermpohl et al., 2006; Gopin et al., 2011). 2.7. Statistical analyses Data were analyzed using STATA (version 11.0, College Station, Texas, US), and figures were created with GraphPad Prism (version 4.00 for Windows, GraphPad Software, La Jolla, CA, USA). Data were tested for normal distribution by skewness and kurtosis tests for normality. For pain outcome (pressure pain threshold), mixed ANOVA models were used to analyze the interaction between time (preand postintervention) and hand (left hand = moving hand; right hand = stationary hand) and between interaction task (movement observation versus control) and time for each hand. In addition, post hoc paired t-tests were used to compare each group with the preintervention values. TMS data were analyzed using a mixed ANOVA model with measures of cortical excitability and intracortical inhibition (MEP, CSP, SICI, ICF) to examine the interaction between time (pre vs post) and task (movement observation versus control). Paired ttests were performed to analyze the differences within and between groups. Changes were defined as differences between pre-intervention and post-intervention measurements of TMS and pain outcomes. SICI and ICF were determined as ratio of SICI or ICF/MEP test to reveal true changes. Significance was considered at a 2-sided p-value 0.05, indicating no differences in baseline cortical excitability. We determined whether there was a change in cortical excitability and/or cortical inhibition measurements (time: pre vs postintervention) between groups by ANOVA and observed a significant interaction between time and task for CSP (ANOVA: F(1,28) = 4.66, p = 0.0396) and near-significance for SICI (amplitude: F(1,25) = 4.08, p = 0.0543), indicating that the groups differed significantly in CSP TMS values. Post hoc t-test results for each group are shown in Table 1. We then compared TMS measurements within groups. Analyzing preintervention and postintervention values, intracortical inhibition decreased significantly in the observational group, as evidenced by a shorter CSP (preintervention 0.088 s ± 0.0223, postintervention: 0.076 s ± 0.0164; p = 0.0399). There was no significant changes in SICI in the hand movement observation group, but in the control group, SICI decreased significantly (p = 0.024). MEP, test pulse MEP of SICI and ICF, and ICF (ratio) (amplitude and integral) did not change in either group (p > 0.5 for all analyses). 3.3. Secondary outcomes Anxiety and emotional stimulus processing did not change over time, based on the results of the visual analog scale for anxiety

Fig. 3. Behavioral results with post hoc analyses. Ordinate: pressure pain threshold level (kg). Abscissa: left and right hand pre- and post-intervention (pre/post). ⁄⁄ p < 0.01 and ns = not significant as shown with paired two-tailed t-test. (Error bars = standard error of the mean.)

(preintervention mean: 0.95 ± 1.33; post-intervention mean 0.98 ± 1.45; p = 0.75 compared with pre-intervention) and the affective go–no go task (preintervention: mean: 26.3 ± 3.56; postintervention: mean: 26.3 ± 4.48; ANOVA of interaction time vs task: F(1,28) = 0.00, p = 1.0). Moreover, motor function was unaltered, based on the Purdue pegboard test. There was no significant interaction between task (movement observation versus control) and time for either hand (ANOVA: left: F(1,28) = 0.09, p = 0.77; right: F(1,28) = 0.00, p = 0.95).

4. Discussion This exploratory study has demonstrated that in male healthy subjects, pressure pain thresholds of the left hand increase following movement observation of the left hand, thus, reducing the perception of pain. Concurrently, there was an opposite effect in the right hand, which was not involved in the movement observation, in which pain thresholds decreased, indicating a rise in pain perception. In the control group, the perception of pain was unchanged in both hands. Additionally, changes in TMS assessments of the right motor cortex (corresponding to the left hand) differed significantly between intervention groups. Overall, in the movement observation group, the CSP of the hemisphere that was contralateral to the left hand was significantly shorter, indicating less intracortical inhibition. In this study, pressure pain thresholds were altered due to observation of hand movements, which is consistent with previous findings, in which seeing the body or parts of the body can reduce pain perception. It is believed that this visually induced analgesic effect is a component of multisensory analgesia that results from changing activity in the ‘‘pain matrix,’’ which includes several brain regions, such as the brainstem, thalamic nuclei, and somatosensory areas (Longo et al., 2012). Our experiments targeted the left hand, in which a movie only showed movements of the left hand, with the right hand stationary. On observation of movements, pressure pain thresholds increased in the left hand, indicating lower pain perception. In the contralateral hand, pain threshold levels decreased as pressure threshold declined. The first major finding of our study is that unilateral hand movements (i.e., extensive movement of one hand while the other hand remains practically unmoved) have bilateral but side-specific effects on pressure pain threshold, suggesting that movement observations modulate specific pain-related networks. This novel finding contrasts to findings from brain stimulation studies when assessing unilateral modulation of the primary motor cortex, as it

Table 1 Transcranial magnetic stimulation measurements. Transcranial magnetic stimulation measurements

MEP amplitude MEP integral CSP SICI amplitude SICI integral ICF amplitude ICF integral

Group Hand movement observation (n = 15)

Control (n = 15)

Pre: 1.9320 mV ± 0.7511 Post: 1.8910 mV ± 0.7402 (p = 0.375) Pre: 0.0321 mV s ± 0.0164 Post: 0.0306 mV s ± 0.0142 (p = 0.422) Pre: 88.000 ms ± 22.314 Post: 76.146 ms ± 16.416 (p = 0.039) Pre: 0.1482 mV ± 0.1187 Post: 0.1372 mV ± 0.1327 (p = 0.617) Pre: 0.0847 mV s ± 0.0856 Post: 0.0857 mV s ± 0.0981 (p = 0.949) Pre: 0.4567 mV ± 0.3475 Post: 0.4497 mV ± 0.3688 (p = 0.939) Pre: 0.3122 mV s ± 0.3300 Post: 0.3728 mV s ± 0.4093 (p = 0.434)

Pre: 1.7992 mV ± 0.7808 Post: 1.6550 mV ± 0.7549 (p = 0.472) Pre: 0.0292 mV s ± 0.0170 Post: 0.0273 mV s ± 0.0149 (p = 0.129) Pre: 96.250 ms ± 32.760 Post: 101.064 ms ± 32.787 (p = 0.411) Pre: 0.1029 mV ± 0.1198 Post: 0.1674 mV ± 0.1633 (p = 0.050) Pre: 0.0667 mV s ± 0.0847 Post: 0.1154 mV s ± 0.1204 (p = 0.024) Pre: 0.3989 mV ± 0.2285 Post: 0.4997 mV ± 0.2289 (p = 0.092) Pre: 0.2655 mV s ± 0.1961 Post: 0.3817 mV s ± 0.2279 (p = 0.053)

Paired two-tailed t-tests comparing to baseline: p-value (mean ± standard deviation, pre- and post-intervention). Significance indicated in bold. MEP: motor evoked potential (amplitude in mV; integral in mV s). ICF: intracortical facilitation. SICI: short intracortical inhibition (given as their ratio relative to test stimuli). CSP: cortical silent period (in s).

Please cite this article in press as: Volz MS et al. Movement observation-induced modulation of pain perception and motor cortex excitability. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.09.022

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decreases bilateral (rather than unilateral) pain reduction (see review (Zaghi et al., 2011)). As expected, movement observation had primary effects on the contralateral motor cortex. A PET study found that movement observation is associated with asymmetrical activation of the left and right hemispheres, which can explain our hand-specific outcomes (Decety et al., 1997). Further, other studies suggest that the contralateral motor cortex is especially activated on unilateral movement observation (Biagi et al., 2010; Borroni and Baldissera, 2008; Matthys et al., 2009). We propose 3 explanations for this discrepancy: (i) keeping the contralateral hand (almost) still has detrimental effects on pain threshold (increasing pain), as we reported recently (Volz et al., 2013); and (ii) given the hand-specific presentation of our task, it is possible that this more focal activation of neural networks would trigger inter-hemispheric competition mechanisms (that would not be observed with a more diffuse approach such as with brain stimulation) and thus lead to side-specific effects in pain perception; and (iii) movement observation activates a more extensive neural network than the motor cortex mainly as observed with, for instance, brain stimulation techniques. Further studies should test the observation of bimanual movements. Moreover, mental imagery of hand movements should be examined with regard to pain and laterality effects. Movement observation and mental imagery have been linked hypothetically, because both target the same neuronal structures (Fourkas et al., 2006; Izumi et al., 1995; Kasai et al., 1997; Ossipov et al., 2010; Woolf, 2010). The effects on pain threshold can be explained through activation of the motor cortex and the resulting increase in excitability or decrease in inhibition, which has been proposed to modulate pain perception. This is based on the belief that it mediates pain modulatory effects through corticothalamic networks of the motor cortex and changes in neuronal plasticity (Lefaucheur et al., 2008; Xie et al., 2009; Zaghi et al., 2011). Our findings support data that have suggested that the primary motor cortex is a robust modulator of pain networks. One implication of these results concerns the combination of movement observation with other neuromodulation techniques, such as noninvasive brain stimulation. The combination of motor cortex stimulation and other techniques, such as visual illusion (Matthys et al., 2009; Ramachandran and Altschuler, 2009; Soler et al., 2010), and methods that modulate pain-related neural systems, such as TENS (Chesterton et al., 2002; Hurlow et al., 2012) and DNIC (Peters et al., 1992; Villanueva, 2009), increases pain reduction compared with stimulation of motor cortex alone. Our neurophysiological data showed that hand movement observation decreased intracortical inhibition in the targeted motor cortex (based on the shortened CSP) consistent with other motor observation studies that used intracortical excitability/inhibition measurements (Desy and Theoret, 2007; Fadiga et al., 1995; Funase et al., 2007; Gangitano et al., 2004, 2001; Maeda et al., 2002; Murakami et al., 2011; Roosink and Zijdewind, 2010; Strafella and Paus, 2000; Theoret et al., 2005). However, we could not confirm an increase in MEP revealed in other studies. This may be attributed to differences in the experimental design. For instance Gangitano et al. (2001), Maeda et al. (2002), and Roosink and Zijdewind (2010) used the observation of an actual person, grasping movements or assessed TMS with short latency after the end of the intervention. Finally, we can summarize the following: it has been previously proven that movement observation leads to an increase in cortical excitability at the motor cortex. It is also known that motor cortex stimulation (via non-invasive brain stimulation, physical therapy and other methods) induces an increase in neuronal activity that results in pain alleviation. In our present study we applied the method of movement observation to activate the motor cortex. We determined pain pressure threshold, which increased

(increased pain threshold as an indicator for pain alleviation, because threshold is reached later) in the corresponding contralateral hand of M1 activation. We now take this data as supporting evidence to the hypothesis that movement observation may reduce pain perception. In fact maladaptive plasticity of M1 is commonly shown in patients with chronic pain as indexed by TMS measures and also these markers of maladaptive plasticity in M1 seem to normalize after a successful treatment for chronic pain. Therefore there seems to be a strong link between M1 plasticity and pain modulation as discussed elsewhere (Castillo Saavedra et al., 2014) that was also evidenced in this study. One limitation of our study is that we only assessed TMS measurements in 1 hemisphere. Moreover, the opposite (i.e., targeted hand), such as right hand movements, and the analgesic effects on both hands and the effects on both hemispheres should be examined. CSP measures intracortical inhibition and our findings support the hypothesis that the primary motor cortex mediates the effects in this study what supports the strength of the relationship between pain and motor control processing. Another important limitation that also applies more to the TMS results is that this study was set out as an exploratory study given the number of outcomes and lack of correction for multiple comparisons. We chose not to correct as to avoid inflating type II error given these outcomes are somewhat related (TMS outcomes); thus results of our study need to be viewed as exploratory, hypothesis generating. Given that most of TMS results are close to the significance threshold and given the number of testing performed, it is likely that at least one of these results are due to chance. Although our study included only healthy male subjects, our results should be compared with studies that examined changes in intracortical inhibition and cortical excitability that are associated with interventions that are directed against the motor cortex. Our findings, at some extent, contrast with other studies in chronic pain subjects that showed that a reduction in pain perception increases intracortical inhibition (Fregni et al., 2007; Lefaucheur et al., 2006; Passard et al., 2007). We showed no difference in SICI in the group that received the active intervention and had increased pain threshold; and, in addition, we showed decreased (rather than increased) intracortical inhibition as indexed by CSP shortening in this active intervention group. This difference is likely related to the decreased intracortical inhibition in chronic patients at baseline and to endogenous analgesic and homeostatic mechanisms, as shown in a study of epilepsy patients (Fregni et al., 2006c). In fact, one explanation to understand the different signature of intracortical inhibition in healthy subjects vs pain patients may be on the role of motor cortex as a strong modulator of pain-related neural areas such as thalamic nuclei (see review Castillo Saavedra et al., 2014). In this context, in a patient with chronic pain, motor cortex activity is disinhibited as an attempt to compensate for increased pain; therefore interventions that can lead to further increase in motor cortex excitability (such as motor cortex stimulation or movement observation) can then reach a threshold in which pain is successfully modulated and therefore intracortical inhibition is restored (or decreased). In healthy subjects on the other hand that has a relative normal intracortical inhibition, a stimulation of the motor cortex (such as with movement observation) leads to decreased intracortical inhibiton and pain reduction. Finally, interestingly, the control group showed reduced SICI. This result may indicate decreased attention and alertness during the 20-min movie.

5. Conclusions The observation of movements of the left hand significantly reduces the perception of pain in this hand, an effect that was

Please cite this article in press as: Volz MS et al. Movement observation-induced modulation of pain perception and motor cortex excitability. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.09.022

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