ORIGINAL ARTICLE
‘Virtual lesion’ in pain research; a study on magnetic stimulation of the primary motor cortex Y. Granovsky1,2, K.S. Liem3, I. Weissman-Fogel4, D. Yarnitsky1,2, A. Chistyakov5, A. Sinai1,5 1 2 3 4 5
Department of Neurology, Rambam Medical Center, Haifa, Israel Clinical Neurophysiology Laboratory, Technion Faculty of Medicine, Haifa, Israel Faculty of Medicine, University Utrecht, The Netherlands Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel Neurosurgery Laboratory, Rambam Medical Center, Haifa, Israel
Correspondence Dr. Yelena Granovsky E-mail: [email protected] Funding sources This study was sponsored by the Israel Science Foundation, Grant no. 518/2012. Conflicts of interest No authors declare any conflict of interests.
Accepted for publication 16 March 2015 doi:10.1002/ejp.715
Abstract Background: ‘Virtual lesion’ (‘VL’) is a transient disruption of cortical activity during task performance. It can be induced by single pulses or short trains of transcranial magnetic stimulation (TMS) directed to functionally relevant brain areas. We applied ‘VL’ methodology of a short train of TMS given on top of experimental tonic pain, expecting to see changes in pain scores. Methods: Thirty young healthy subjects (15 women) were assessed with active (‘VL’) or ‘sham’ TMS in different sessions, randomly. In each session, 30 sec-long contact heat (47.5 °C, right forearm) was applied stand-alone (‘baseline’) and with 5 sec-long 10 Hz-TMS over left primary motor cortex (M1) starting at 17 sec of the heat stimulation. Results: Pain scores decreased after ‘VL’ or ‘sham’ (p < 0.001). Independently of the type of TMS, pain reduction was stronger in women (p = 0.012). A triple Sex x Stimulation type (‘VL’ or ‘sham’) x Condition (‘baseline’ heat pain vs. heat pain with TMS) interaction (p = 0.027) indicated stronger pain reduction by ‘VL’ in women (p = 0.008) and not in men (p = 0.78) as compared to ‘baseline’. Pain catastrophizing and perceived stress ratings affected the model (p = 0.010 and p < 0.001, respectively), but without sex differences. Conclusions: This study indicates that interactions between cortical excitability of the motor cortex and nociceptive processing may be gender-related.
1. Introduction One of the methodological approaches to study the involvement of specific brain regions in the neural activity related to various high functions is the induction of a ‘virtual lesion’ (‘VL’) via application of brief transcranial magnetic stimulation (TMS) during task performance (Ziemann, 2010). The effect of ‘VL’ induced by TMS is a transient and reversible interference with cortical processing during the task (Pascual-Leone et al., 2000; Ziemann, 2010). ‘VL’
© 2015 European Pain Federation - EFICâ
can be achieved either by a single TMS pulse timelocked to the stimulus (Amassian et al., 1989) or by using a short high-frequency (>10 Hz) rTMS train (Epstein et al., 1999; Siebner et al., 2009), with both resulting in behavioural changes. Two main mechanisms have been suggested to underlie ‘VL’: (1) silencing of pyramidal neurons probably through activation of GABAergic interneurons (Haug et al., 1992), and (2) disruption of neural processing due to the addition of noise to the ongoing activity (Siebner et al., 2001; Di Lazzaro et al., 2004). The balance between these two mechanisms depends mainly on
Eur J Pain 20 (2016) 241--249
241
TMS-induced ‘virtual lesion’ attenuates heat pain
What is already known about this topic? • Transcranial magnetic stimulation (TMS) can be used to modify the activity in the motor cortex and to induce changes in pain perception. • When used in ‘virtual lesion’ mode (i.e. single pulse or short train of stimuli during the stimulus processing), TMS can interrupt activity in the stimulated motor cortex as well as in distant connected brain areas that are involved in stimulus processing. What does this study add?
• TMS-induced ‘virtual lesion’ directed to the motor cortex changes the experimental pain perception, i.e. reducing the perceived pain intensity. • TMS-induced pain reduction is sex dependent, i.e. more efficient in women.
the stimulus intensity (Di Lazzaro et al., 2004) and on the intrinsic excitability of the neurons. Imaging studies demonstrated pain-related activation of the primary motor cortex (M1), when applying the contact tonic heat paradigms (Casey et al., 1996; Moulton et al., 2012). TMS as employed in research, including pain studies, uses long-duration repetitive stimulation (rTMS), intended to modify cortical excitability. The effect is usually obtained after hundreds or thousands of stimuli and is typically quantified as post- versus pre-rTMS changes in behavioural and/or neurophysiological parameters. M1 is one of the main targets for rTMS in pain research. High-frequency rTMS directed to M1 exerts anti-nociception, probably via M1’s inhibitory influence on the nociceptive processing exerted directly at thalamic and spinal levels, and indirectly via activation of limbic, cortical and sub-cortical areas such as the periaqueductal grey (PAG), anterior cingulate cortex (ACC) and amygdala (Garcıa-Larrea and Peyron, 2007; Pagano et al., 2011; Maarrawi et al., 2013). An analgesic effect exerted by rTMS directed to M1 was demonstrated by increase in thermal pain thresholds (Summers et al., 2004; Lefaucheur et al., 2008; Nahmias et al., 2009; Borckardt et al., 2011) and alleviation of capsaicin- and laser stimulationinduced pain (Tamura et al., 2004; Antal and Paulus, 2010; de Tommaso et al., 2010; Mylius et al., 2012). Further, at the clinical level, it was proved as an effective analgesic treatment for pain states of 242 Eur J Pain 20 (2016) 241--249
Y. Granovsky et al.
various etiologies (Lefaucheur, 2004; Zaghi et al., 2011; Marlow et al., 2013; Moreno-Duarte et al., 2014). To date, to the best of our knowledge, the specific mode of ‘VL’-TMS in pain research has only been applied in one study using short rTMS over dorsolateral prefrontal cortex (DLPFC) during experimental capsaicin-induced pain in order to investigate the modulatory effect of the DLPFC on pain (Fierro et al., 2010). No study targeted the primary motor cortex using short ‘VL’-TMS in assessing pain perception. We hypothesized that induction of short ‘VL’-TMS in this cortical area known to be functionally associated with pain modulation, will interrupt processes of pain inhibition, resulting in pain facilitation.
2. Materials and methods 2.1 Subjects Thirty right-handed healthy volunteers, aged 18– 40 years (mean 24.7 2.1 years), 15 men and 15 women, participated in this study. Exclusion criteria included a history of peripheral or central nervous system disorders (including chronic pain, cognitive, epileptic and headache disorders), loss of consciousness after head trauma, cochlear implants or implanted cardiac defibrillators, pregnancy, medication use on a regular basis, and tissue damage in experimented regions. Subjects were also restricted from taking any medication within 24 h prior to experimental session. All subjects provided written informed consent. The Institutional Review Board of Rambam Health Care Campus, Israel, approved the study protocol, in accordance with the Declaration of Helsinki (2008).
2.2 Contact heat stimuli Contact heat stimuli were delivered by a Thermal Sensory Analyzer (TSA) 2001 system (Medoc, Ramat Yishai, Israel) with a 30 9 30 mm Peltier surface stimulator, strapped to the volar forearm of the subject’s dominant (right) hand. Contact-heat baseline temperature was set to 32 °C. Temperature increasing and decreasing rates were set to 2.0 °C/s. The heat pain assessments included measurement of heat pain threshold (HPT) at temperature increase rate of 1 °C via the method of limits (Yarnitsky, 1997), and a delivery of tonic heat stimuli at a fixed (47.5 °C) temperature. The thermode was attached to the skin by a Velcro strap. To avoid pain sensitization/adaptation during tonic heat stimulation, the thermode © 2015 European Pain Federation - EFICâ
Y. Granovsky et al.
was manually moved to an adjacent area after each tonic stimulus. The examiner was informed about possible impact of the pressure against the skin on pain perception, and instructed to maintain a uniform pressure on the skin across all stimulation conditions.
2.3 Transcranial magnetic stimulation A figure-of-eight coil (MCF-B65) with MagPro X100 magnetic stimulator (MagVenture Inc., Farum, Denmark) was used for TMS. The TMS-preparations started with supporting the subject’s neck using an airplane pillow and tightly putting a swimmer’s cap over the head to mark coil location and angulation. Two surface electrodes in a tendon-belly construction were put to the right abductor pollicis brevis (APB) muscle for motor evoked potential (MEP) recordings. Subjects were instructed to recline comfortably, keep eyes open, lean head back and report any pain or discomfort on the head, or muscle twitches in the right hand. The TMS-coil was tangentially placed (anteroposterior direction) above the hand motor cortex with its position marked on the swimming cap as a reference point. The center of the coil was positioned directly above the APB cortical representation in motor cortex (the position which elicited the largest response from the APB muscle; tested at the beginning of each session), approximately 5 cm lateral to the parasagittal axis at a 45° angle (approximately perpendicular to central sulcus). A metal arm fixated the coil in this position. For placebo condition the sham testing was performed using the same TMS-coil flipped upsidedown at the same scalp location without changing stimulus intensity, providing discharge noise without stimulating cortical tissue. The coil used was very wide (due to its passive cooling system) and therefore when it was flipped, a large distance spanned the active part of the coil and the scalp surface. This configuration resulted in considerable stimulation intensity reduction (roughly 60%, according to the manufacturer), while from the subject’s point of view, it resembled active TMS stimulation. The experiment was single-blind; all subjects were blinded to the experimental conditions. The patients were not instructed about the existence of a sham condition, but they were informed that in each session different stimulation parameters would be applied using the same coil. Resting motor threshold (rMT) was defined as the lowest stimulus intensity able to elicit amplitudes of
© 2015 European Pain Federation - EFICâ
TMS-induced ‘virtual lesion’ attenuates heat pain
50 lV in 5 out of 10 stimuli when the muscle is at rest (Rossini et al., 1994). The TMS intensity was reported as the percentage of the maximal TMS machine output. Starting at 30% stimulus intensity, the intensity was increased (at 3% increment steps) until every stimulus resulted in a consistent MEP. Holding this stimulus intensity, the coil was marginally moved over the specific area (inter-stimulus interval 3 s to avoid facilitation) in search of MEP’s with maximal amplitudes. Audiovisual feedback was provided using a 3-lead EEG-system (QuickAmp40; Brain Products GmbH, Munich, Germany) to establish complete APB-relaxation. Coil placement was then marked on the swimmer’s cap. Finally, the stimulus intensity was reduced and rMT established, as defined above, to the closest whole percentage intensity. During TMS, subjects were instructed to report any pain, discomfort or muscle twitches. The investigator continuously verified coil placement (any shift from the reference point) and relaxation of muscles (visual EMG-inspection). In the case of reported or visually observed muscle activation, the stimulus intensity was lowered accordingly and a performance check conducted during the next TMS-train.
2.4 Experimental protocol All subjects were tested in the same setting in a quiet room with an ambient temperature of ~23 °C. Prior to the experiment, subjects were given a routine explanation of the tests. We report the results of two experimental sessions where active (‘VL’) or ‘sham’ primary motor cortex stimulations were performed. This report relates to one part of a larger project, whose other part will be reported separately. Active or ‘sham’ M1 stimulation were performed in separate experimental sessions that were randomly counterbalanced using freely available computerized randomization program. To avoid potential carry-over effects of a previous TMS-session, consecutive sessions were planned with a minimum spacing of 7 days. During each session, two 30 sec-long tonic heat stimuli were delivered. A ‘baseline’ condition of stand-alone (without any active or sham TMS) heat stimulus was administered at the beginning of each experimental session. After 15 min heat stimulus of the same intensity was delivered with either active or sham M1-directed TMS. The heat stimuli were given on the upper-third of the volar forearm. The TMS was 5 sec of 10 Hz-stimulation delivered over the left hemisphere; the active stimulation was given at the intensity of 90% of the individual rMT. Subjects were asked to rate their pain verbally on a 0–100 numerical pain scale (NPS) in
Eur J Pain 20 (2016) 241--249
243
TMS-induced ‘virtual lesion’ attenuates heat pain
which 0 was “no pain” and 100 the “most intense pain imaginable”. Thus, four NPS scores were obtained at the beginning (T0), and at 10 sec (T10), 20 sec (T20) and 30 sec (T30) of heat stimulation. TMS was started at the 17th sec of the heat stimulation, such that the T20 pain score was obtained during the TMS-train. One researcher (K.S.L.) tested all subjects. At the first session, subjects completed several pain-related psychological questionnaires; Pain Catastrophizing Scale (PCS), Perceived Stress Scale (PSS) and Fear of Pain Questionnaire (FPQ). In addition, the HPT was assessed at the beginning of each session.
2.5 Statistical analysis A mixed model (repeated measures) ANOVA (rANOVA) was employed to examine influences of full-factorial combinations of Sex, Stimulation Type (M1-’VL’ or ‘sham’) and Condition (‘baseline’ pain stimulation given stand-alone vs. pain with active or sham TMS) on changes in the pain scores along tonic heat stimulus (T20 vs. T10 and T30 vs. T10), with inclusion of covariates: the scores of PSS, PCS and FPQ, the rMT value and HPT. As part of the diagnostic procedures to validate the analysis, ANOVA residuals were inspected. Subjects were treated as a random factor nested within sex. Tukey–Kramer tests were employed for post-hoc comparisons as appropriate. Least square means and associated standard errors are reported. JMP and SAS (both SAS Institute, Cary, NC) were employed for analyses. In addition, paired t-tests corrected for the multiple comparison were performed in order to assess the differences of pain scores between men and women at each stimulation condition-type combination, and for all aforementioned covariates. Simple descriptive data about the subjects are expressed as mean standard error.
3. Results All recruited subjects completed the whole experimental setup. Mean rMT at the ‘VL’-TMS session was 49.2 8.3% (range: 30–62); the mean applied TMS intensity was 43.7 7.1% (range: 27–54). The mean rMT in the sham-TMS session was 48.6 8.5% (range: 36–64); no significant difference for the rMT values was observed between two session (p = 0.452). In spite of our hypothesis that the maximal change in pain score would be observed at the rating during the ‘VL’ (T20 pain score), rANOVA revealed no significant difference of the T20 versus T10 (taken before the TMS) pain scores. For the T30 244 Eur J Pain 20 (2016) 241--249
Y. Granovsky et al.
versus T10 differences in pain ratings, however, significant effect of Condition (ratings to heat pain delivered stand-alone or with TMS) was observed, pointing to reduction in pain scores along the heat pain with TMS (p < 0.001). This reduction was not related to the Stimulation type (‘VL’ or ‘sham’; p = 0.136). Furthermore, we found a significant Sex effect (p = 0.012); women demonstrated greater reduction in pain scores as compared to men. Importantly, there was a triple Sex X Stimulation type X Condition interaction (p = 0.027). Post-hoc Tukey analysis revealed that while males responded with similar changes in pain scores during the noxious heat at ‘baseline’ (without any TMS intervention) and at the ‘VL’ induction (p = 0.783), women experienced significant pain reduction under the ‘VL’-inducing condition (p = 0.008) compared to the ‘baseline’ noxious heat stimulation. No such reduction in pain scores was observed for the ‘sham’ stimulation in women (p = 0.100) or men (p = 0.315). Fig. 1 depicts the 4 pain scores along each stimulation condition in men and women. The values for the heat pain scores obtained at each stimulation condition in the whole study group, separately for males and females, are presented in Table 1. Importantly, there were no sex differences in the baseline pain scores. Two-way ANOVA did not reveal overall (p = 0.191) or session-related differences in pain perception between men and women (p = 0.932). No effect of the covariates of FPQ, HPT or rMT on changes in pain sores was found (p = 0.354, p = 0.437 and p = 0.691, respectively). However, PSS and PCS had significant impact on the described model (p < 0.001 and p = 0.011, respectively), probably due to positive correlation between the PSS score and the pain ratings during noxious heat (r = 0.386; p = 0.035 for the ‘VL’- stimulation session, and r = 0.320; p = 0.085 for the sham-stimulation session). Moreover, subjects with higher PSS also reported higher PCS scores (r = 0.450; p = 0.012). No sex differences were observed for the rMT or HPT values at any stimulation session. In the active M1-TMS session the rMT values were 48.9 8.9% in women and 49.5 7.9% in men (p = 0.846). The stimulation intensity applied in the M1-TMS session were 43.2 7.2% in women and 44.1 7.1% in men (p = 0.725). The rMT values for the sham-TMS session were 48.4 8.7% and 48.8 8.5% for women and men, respectively (p = 0.900). For the HPT, the values in the active M1-TMS session were 45.1 2.6 °C in women and 45.1 3.2 °C in men (p = 0.977); the values in the sham-TMS session © 2015 European Pain Federation - EFICâ
Y. Granovsky et al.
TMS-induced ‘virtual lesion’ attenuates heat pain
The effect of sham-TMS, females
70
70
60
60
*
50
NPS
NPS
The effect of M1-TMS, females
50
40
40
30
30
20 T0
T10 T20 Heat pain duraon (s)
20
T30
T0
70
60
60
50
50
NPS
NPS
70
40
40
30
30
20 T10 T20 Heat pain duraon (s) Baseline
T30
The effect of sham-TMS, males
The effect of M1-TMS, males
T0
T10 T20 Heat pain duraon (s)
20
T30
Shame TMS
T0
T10 T20 Heat pain duraon (s)
T30
TMS on M1
Figure 1 Heat pain scores in women and men at ‘baseline’ (solid line with diamonds), active TMS (‘VL’) (dotted line with squares) and ‘sham’ TMS (punctate line with squares) conditions. The pain was rated using verbal numerical pain scale (NPS). A TMS schematic is presented as a grey square. *p = 0.008; women demonstrated significant pain reduction at post versus pre-’VL’ conditions as compared to the changes in pain scores along the ‘baseline’.
were 45.3 3.3 °C in women and 44.6 3.5 °C in men (p = 0.578). No sex differences were observed neither for PCS (21.7 9.6, women versus 21.3 9.2, men; p = 0.908), nor for PSS (14.2 7.1, women vs. 11.2 4.9, men; p = 0.191), or for FPQ (80.1 19.5, women vs. 80.1 16.5, men; p = 0.908).
4. Discussion Our results showed that short high-frequency rTMS train disrupted M1 during noxious tonic stimulus and attenuated pain; this analgesic effect was apparent shortly after the end of TMS and was mainly evident in women. Disrupting brain functioning is a well-established concept in neuroscience. ‘VL’ has been demonstrated in speech arrest while stimulating language regions, reduction in visual discrimination while stimulating visual cortex, and memory deficit while stimulating © 2015 European Pain Federation - EFICâ
prefrontal regions (Pascual-Leone et al., 1999; Stewart et al., 2001; Terao and Ugawa, 2006; Silvanto and Muggleton, 2008). The exact underlying mechanism is not yet fully understood. Intensity of magnetic stimuli as well as the context under which stimuli are delivered influences the ‘VL’ effect (Ziemann, 2010). In addition, TMS effects are usually not limited to the site of stimulation but spread either physically to neighbouring areas, or by distant propagation of action potentials along cortico-cortical and cortico-subcortical projections (Siebner et al., 2001; Massimini et al., 2005; Blankenburg et al., 2008; Ruff et al., 2009). Thus, in terms of the ‘VL’ concept this means that TMS effects could be caused directly at the stimulated site, but equally well through modification of neuronal activity at distant sites, or both. M1 is commonly activated in response to pain (Apkarian et al., 2000; Peyron et al., 2000); intracortical recordings in humans support evidence Eur J Pain 20 (2016) 241--249
245
TMS-induced ‘virtual lesion’ attenuates heat pain
Y. Granovsky et al.
Table 1 Descriptive data of the heat pain ratings obtained at ‘baseline’, active (‘VL’) and ‘sham’ TMS in (A) whole study population, and (B) separately in men and women. Stimulation type & condition
T0
T10
T20
T30
A M1, baseline M1, VL Sham, baseline Sham, TMS B Men M1, baseline M1, VL Sham, baseline Sham, TMS Women M1, baseline M1, VL Sham, baseline Sham, TMS
50.4 54.2 49.5 50.6
4.7 4.5 4.4 4.2
56.0 54.6 57.6 55.7
4.1 3.9 4.5 4.2
52.2 43.5 55.9 45.8
4.2 4.0 4.7 4.3
57.3 42.8 57.5 50.0
4.4 4.1 4.9 4.5
43.3 45.7 44.0 47.8
6.1 6.3 5.7 6.6
50.6 49.2 50.5 53.9
5.3 5.4 6.1 6.6
50.9 40.5 50.7 45.3
5.5 5.2 6.3 6.6
51.7 42.7 54.1 46.2
6.4 5.1 6.3 6.7
57.4 62.7 55.0 53.3
6.9 5.8 6.3 5.4
61.5 60.0 64.8 57.5
6.1 5.5 6.3 5.4
53.6 46.5 61.2 46.3
6.5 6.1 6.8 5.7
62.8 42.9 60.9 53.7
5.8 6.7 7.5 6.0
for a spinothalamic-related input to the motor cortex, in parallel with primary somatosensory cortex (SI) activation (Frot et al., 2013). In turn, M1 is involved in pain inhibition; M1 stimulation appears to trigger a rapid and phasic activation in the lateral thalamus, which leads to a cascade of synaptic events influencing activity in the medial thalamus, perigenual ACC, orbitofrontal cortex, and PAG (Garcıa-Larrea et al., 1999; Garcıa-Larrea and Peyron, 2007). Transdural motor cortex stimulation reversed allodynia and hyperalgesia in the neuropathic pain model and increased activity in PAG, ACC and amygdalae (Pagano et al., 2011, 2012). Importantly, increased corticothalamic functional connectivity in response to M1-rTMS was associated with relief of central post-stroke pain (Goto et al., 2008) assumed to be opioid-mediated, as the M1rTMS-related neuropathic pain relief can be predicted by the opioid receptor density in the thalamus, PAG, and contralateral insula (Maarrawi et al., 2013). The described results point to both functional and structural correspondence between M1 and the somatosensory cortices that, together with activation of limbic and subcortical areas, play an important role in the mediation of pain inhibition. It is not clear, however, whether the parameters used in our study explore the same mechanisms. The central finding of our study is sex-related pain reduction due to brief M1-directed high frequency rTMS given on top of experimental pain. These behavioural changes due to TMS indicate a 246 Eur J Pain 20 (2016) 241--249
‘VL’ effect and confirm the functional relevance of M1 in pain modulation. Previous rTMS-pain studies used much longer trains and sessions, resulting in clinical pain reduction after rTMS (Lefaucheur et al., 2010a,b). These rTMS-related findings can be interpreted as (1) interference of M1 activity lasting shortly beyond the time of stimulation, or alternatively, (2) transient augmentation of motor cortex excitability. We delivered short rTMS train during the experimental pain, inducing a ‘VL’ effect i.e. interference with M1 activation. Bearing in mind that M1 neuronal activity is involved in pain inhibition, we would expect pain increase in case of M1 disruption. The observed pain reduction suggests that disruption of the motor cortex activity can lead to pain decrease. Several explanations can be proposed in this regard: (1) The effect of TMS is not local and leads to changes in synaptic activity in adjacent cortical areas and even in the contralateral hemisphere (Lee et al., 2003) activating compensatory other brain regions involved in pain inhibition. This assertion bases, for example, on the reports that activation of nearby motor areas is associated with pain inhibition (Pich e et al., 2009; Moont et al., 2011). Consistent, rTMS to the DLPFC restores deficient intracortical inhibition of the motor cortex, and so reduces pain (Fierro et al., 2010). (2) In parallel with the previous assertion, the disruption of M1 may theoretically result in reduced activity in the brain regions associated with pro-nociception, leading to pain reduction. Kodama et al. (2009) reported reduced amplitude of the somatosensory evoked potentials, a measure for SI excitability, in response to M1-rTMS. In addition, there is evidence of excitatory connectivity between M1 and other brain areas such as the SMA and somatosensory cortices (Fox et al., 1997; Grefkes et al., 2010), and thalamus (Goto et al., 2008) pointing to M1’s interaction with brain regions associated with both proand anti-nociception. (3) The stimulated part of M1 may become less responsive to inputs from other motor areas. Such rapid reorganization of the motor cortex may theoretically lead to increased M1 excitability and, consequently, to pain attenuation. Functional brain reorganization and plasticity of M1 and related areas was widely described in stroke (Jiang et al., 2013), spinal cord injury (Nardone et al., 2013) and chronic pain patients (Seifert and Maih€ ofner, 2011), although these clinical correlates occur during a longer time course. In the same vein, whole-brain changes in functional connectivity were reported for M1-transcranial direct current stimulation (tDCS) (Sehm et al., 2012). (4) Since the © 2015 European Pain Federation - EFICâ
Y. Granovsky et al.
maximal analgesic response was observed not during, but several seconds after TMS, we propose that this effect relates to a delayed increase in M1 neuronal excitability. This is consistent with reports on persisting neuronal activation in a distinct set of motor cortical areas beyond the time of M1-TMS (Siebner et al., 2000) and on a delayed analgesic effect relative to the actual period of motor cortex stimulation (Garcıa-Larrea and Peyron, 2007). Indeed, a similar effect was reported following DLPFC-rTMS preventing further increase in capsaicin-induced pain (Fierro et al., 2010). Each of the proposed mechanisms, alone or in combination, may explain our results of pain reduction in response to M1-directed virtual lesion. Sex differences in pain perception are attributed to various biological and cognitive/affective factors (Fillingim et al., 2009). Nevertheless, consistent with the results of other reports (Cahn et al., 2003; Pitcher et al., 2003; Livingston et al., 2010) our findings pointed to a lack of sex differences in painrelated psychological variables or in heat pain threshold or resting cortical excitability. Diverse results have been reported in relation to tonic pain; while some observed greater heat pain attenuation in women (Defrin et al.,2008; Hashmi and Davis, 2009), others contradicted these findings (Tousignant-Laflamme et al., 2008; Nahmias et al., 2009). Our results are consistent with the former findings; women experienced decreased pain regardless of the type of TMS. Furthermore, the triple Sex, Stimulation type and Condition interaction indicates additional pain attenuation in women to M1-’VL’. There is evidence for sex differences in the responses to TMS application during behavioural tasks and to therapeutic interventions. Knops et al. (2006) found that sex mediated the impact of a TMS-induced ‘VL’ on the intraparietal sulcus for investigating its role in numerical cognition. Further, rTMS on the DLPFC improved cognitive functions in women compared to men (Huber et al., 2003). Moreover, the effects of rTMS applied for achieving antidepressant-like effect in rats was sex-dependent (Yang et al., 2007). In line, treating refractory bipolar/ major depression was found to be associated with female hormones (Huang et al., 2008). Thus, the role of sex differences in pain relief by the TMS treatment needs further investigation, especially in the light of the evidence of sex differences in the modulation of human cortical plasticity tested by tDCS (Kuo et al., 2006; Chaieb et al., 2008). Another possible relating factor to sex disparity is higher transcallosal inhibition in women (De Gen© 2015 European Pain Federation - EFICâ
TMS-induced ‘virtual lesion’ attenuates heat pain
naro et al., 2004), and that this inter-hemispheric interaction was affected by gonadal hormones (Hausmann et al., 2006). As one of the mechanisms underlying ‘VL’ is the disruption of the neural processing (Di Lazzaro et al., 2004; Siebner et al., 2009) and, accordingly, the interactions between remote but inter-connected brain regions, it can be proposed that M1-’VL’ was more effective in women in the present study due to superior baseline interhemispheric connectivity. The main limitation of our study relates to the issues of sham stimulation and blinding. It is known that creating an adequate sham control in TMS is notoriously difficult. The TMS system we used does not have a sham coil, so it was therefore not possible to keep the examiner blinded. However, several precautions were taken to ensure subjects’ blinding: subjects could not see or feel that the coil was flipped, and the same clicking sounds were produced regardless of coil orientation. Sensory confounders of the stimulation could possibly distract from pain in active and sham TMS; we carefully refrained from scalp nociception so subjects could not distinguish between the conditions. In addition, no subjects reported spontaneously any differences in cortical sensation across both stimulation sessions. In summary, we demonstrated that disruption of motor cortex neural activity via induction of ‘virtual lesion’ during exposure to tonic pain is associated with pain reduction, which confirms the functional relevance of ‘VL’ technique in pain research. The association of pain attenuation with sex may point in favour of a more pronounced effect of M1-directed TMS in women. This raises the importance of conducting personalized pain treatment with cortical magnetic stimulation. Acknowledgement Thanks to Dr. Elliot Sprecher for his help in the statistical analysis, and to Dr. Ruth Moont for her help in English editing.
Author contributions Y.G. was responsible for study logistics, preliminary data analysis, manuscript preparation. K.S.L. was responsible for study conduction and data collection, help with the manuscript preparation. I.W-F. was responsible for study logistics, manuscript preparation. D.Y. was responsible for study logistics, help with the manuscript preparation. A.C. was responsible for study logistics. A.S. study logistics, manuscript preparation.
Eur J Pain 20 (2016) 241--249
247
TMS-induced ‘virtual lesion’ attenuates heat pain
References Amassian, V.E., Cracco, R.Q., Maccabee, P.J., Cracco, J.B., Rudell, A., Eberle, L. (1989). Suppression of visual perception by magnetic coil stimulation of human occipital cortex. Electroencephalogr Clin Neurophysiol 74, 458–462. Antal, A., Paulus, W. (2010). Effects of transcranial theta-burst stimulation on acute pain perception. Restor Neurol Neurosci 28, 477– 484. Apkarian, A.V., Gelnar, P.A., Krauss, B.R., Szeverenyi, N.M. (2000). Cortical responses to thermal pain depend on stimulus size: A functional MRI study. J Neurophysiol 83, 3113–3122. Blankenburg, F., Ruff, C.C., Bestmann, S., Bjoertomt, O., Eshel, N., Josephs, O., Weiskopf, N., Driver, J. (2008). Interhemispheric effect of parietal TMS on somatosensory response confirmed directly with concurrent TMS-fMRI. J Neurosci 28, 13202–13208. Borckardt, J.J., Reeves, S.T., Beam, W., Jensen, M.P., Gracely, R.H., Katz, S., Smith, A.R., Madan, A., Patterson, D., George, M.S. (2011). A randomized, controlled investigation of motor cortex transcranial magnetic stimulation (TMS) effects on quantitative sensory measures in healthy adults: Evaluation of TMS device parameters. Clin J Pain 27, 486–494. Cahn, S.D., Herzog, A.G., Pascual-Leone, A. (2003). Paired-pulse transcranial magnetic stimulation: Effects of hemispheric laterality, gender, and handedness in normal controls. J Clin Neurophysiol 20, 371–374. Casey, K.L., Minoshima, S., Morrow, T.J., Koeppe, R.A. (1996). Comparison of human cerebral activation pattern during cutaneous warmth, heat pain, and deep cold pain. J Neurophysiol 76, 571– 581. Chaieb, L., Antal, A., Paulus, W. (2008). Gender-specific modulation of short-term neuroplasticity in the visual cortex induced by transcranial direct current stimulation. Vis Neurosci 25, 77–81. De Gennaro, L., Bertini, M., Pauri, F., Cristiani, R., Curcio, G., Ferrara, M., Rossini, P.M. (2004). Callosal effects of transcranial magnetic stimulation (TMS): The influence of gender and stimulus parameters. Neurosci Res 48, 129–137. Defrin, R., Pope, G., Davis, K.D. (2008). Interactions between spatial summation, 2-point discrimination and habituation of heat pain. Eur J Pain 12, 900–909. Di Lazzaro, V., Oliviero, A., Pilato, F., Saturno, E., Dileone, M., Mazzone, P., Insola, A., Tonali, P.A., Rothwell, J.C. (2004). The physiological basis of transcranial motor cortex stimulation in conscious humans. Clin Neurophysiol 115, 255–266. Epstein, C.M., Meador, K.J., Loring, D.W., Wright, R.J., Weissman, J.D., Sheppard, S., Lah, J.J., Puhalovich, F., Gaitan, L., Davey, K.R. (1999). Localization and characterization of speech arrest during transcranial magnetic stimulation. Clin Neurophysiol 110, 1073–1079. Fierro, B., De Tommaso, M., Giglia, F., Giglia, G., Palermo, A., Brighina, F. (2010). Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) during capsaicin-induced pain: Modulatory effects on motor cortex excitability. Exp Brain Res 203, 31–38. Fillingim, R.B., King, C.D., Ribeiro-Dasilva, M.C., Rahim-Williams, B., Riley, J.L. 3rd (2009). Sex, gender, and pain: A review of recent clinical and experimental findings. J Pain 10, 447–485. Fox, P., Ingham, R., George, M.S., Mayberg, H., Ingham, J., Roby, J., Martin, C., Jerabek, P. (1997). Imaging human intra-cerebral connectivity by PET during TMS. NeuroReport 8, 2787–2791. Frot, M., Magnin, M., Mauguiere, F., Garcia-Larrea, L. (2013). Cortical representation of pain in primary sensory-motor areas (S1/M1)-a study using intracortical recordings in humans. Hum Brain Mapp 34, 2655–2668. Garcıa-Larrea, L., Peyron, R. (2007). Motor cortex stimulation for neuropathic pain: From phenomenology to mechanisms. NeuroImage 37(Suppl 1), S71–S79. Garcıa-Larrea, L., Peyron, R., Mertens, P., Gregoire, M.C., Lavenne, F., Le Bars, D., Convers, P., Mauguiere, F., Sindou, M., Laurent, B. (1999). Electrical stimulation of motor cortex for pain control: A combined PET-scan and electrophysiological study. Pain 83, 259–273.
248 Eur J Pain 20 (2016) 241--249
Y. Granovsky et al.
Goto, T., Saitoh, Y., Hashimoto, N., Hirata, M., Kishima, H., Oshino, S., Tani, N., Hosomi, K., Kakigi, R., Yoshimine, T. (2008). Diffusion tensor fiber tracking in patients with central post-stroke pain; correlation with efficacy of repetitive transcranial magnetic stimulation. Pain 140, 509–518. Grefkes, C., Nowak, D.A., Wang, L.E., Dafotakis, M., Eickhoff, S.B., Fink, G.R. (2010). Modulating cortical connectivity in stroke patients by rTMS assessed with fMRI and dynamic causal modeling. NeuroImage 50, 233–242. Hashmi, J.A., Davis, K.D. (2009). Women experience greater heat pain adaptation and habituation than men. Pain 145, 350–357. Haug, B.A., Schonle, P.W., Knobloch, C., Kohne, M. (1992). Silent period measurements revives a a valuable diagnostic tool with transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol 85, 158–160. Hausmann, M., Tegenthoff, M., Sanger, J., Janssen, F., Gunturkun, O., Schwenkreis, P. (2006). Transcallosal inhibition across the menstrual cycle: A TMS study. Clin Neurophysiol 117, 26–32. Huang, C.C., Wei, I.H., Chou, Y.H., Su, T.P. (2008). Effect of age, gender, menopausal status, and ovarian hormonal level on rTMS in treatment-resistant depression. Psychoneuroendocrinology 33, 821–831. Huber, T.J., Schneider, U., Rollnik, J. (2003). Gender differences in the effect of repetitive transcranial magnetic stimulation in schizophrenia. Psychiatry Res 120, 103–105. Jiang, L., Xu, H. and Yu, C. (2013). Brain connectivity plasticity in the motor network after ischemic stroke. Neural Plast Volume 2013, Article ID 924192, 11 pages. Knops, A., Nuerk, H.C., Sparing, R., Foltys, H., Willmes, K. (2006). On the functional role of human parietal cortex in number processing: How gender mediates the impact of a ‘virtual lesion’ induced by rTMS. Neuropsychologia 44, 2270–2283. Kodama, M., Aono, K., Masakado, Y. (2009). Changes in sensory functions after low-frequency repetitive transcranial magnetic stimulation over the motor cortex. Tokai J Exp Clin Med 34, 122–129. Kuo, M.F., Paulus, W., Nitsche, M.A. (2006). Sex differences in cortical neuroplasticity in humans. NeuroReport 17, 1703–1707. Lee, L., Siebner, H.R., Rowe, J.B., Rizzo, V., Rothwell, J.C., Frackowiak, R.S., Friston, K.J. (2003). Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J Neurosci 23, 5308–5318. Lefaucheur, J.P. (2004). Transcranial magnetic stimulation in the management of pain. Suppl Clin Neurophysiol 57, 737–748. Lefaucheur, J.P., Drouot, X., Menard-Lefaucheur, I., Keravel, Y., Nguyen, J.P. (2008). Motor cortex rTMS in chronic neuropathic pain: Pain relief is associated with thermal sensory perception improvement. J Neurol Neurosurg Psychiatry 79, 1044–1049. Lefaucheur, J.P., Jarry, G., Drouot, X., Menard-Lefaucheur, I., Keravel, Y., Nguyen, J.P. (2010a). Motor cortex rTMS reduces acute pain provoked by laser stimulation in patients with chronic neuropathic pain. Clin Neurophysiol 121, 895–901. Lefaucheur, J.P., Menard-Lefaucheur, I., Goujon, C., Keravel, Y., Nguyen, J.P. (2010b). Predictive value of rTMS in the identification of responders to epidural motor cortex stimulation therapy for pain. J Pain 12, 1102–1111. Livingston, S.C., Goodkin, H.P., Ingersoll, C.D. (2010). The influence of gender, hand dominance, and upper extremity length on motor evoked potentials. J Clin Monit Comput 24, 427–436. Maarrawi, J., Peyron, R., Mertens, P., Costes, N., Magnin, M., Sindou, M., Laurent, B., Garcia-Larrea, L. (2013). Brain opioid receptor density predicts motor cortex stimulation efficacy for chronic pain. Pain 154, 2563–2568. Marlow, N.M., Bonilha, H.S., Short, E.B. (2013). Efficacy of transcranial direct current stimulation and repetitive transcranial magnetic stimulation for treating fibromyalgia syndrome: A systematic review. Pain Pract 13, 131–145. Massimini, M., Ferrarelli, F., Huber, R., Esser, S.K., Singh, H., Tononi, G. (2005). Breakdown of cortical effective connectivity during sleep. Science 309, 2228–2232. Moont, R., Crispel, Y., Lev, R., Pud, D., Yarnitsky, D. (2011). Temporal changes in cortical activation during conditioned pain modulation (CPM), a LORETA study. Pain 152, 1469–1477.
© 2015 European Pain Federation - EFICâ
Y. Granovsky et al.
Moreno-Duarte, I., Morse, L.R., Alam, M., Bikson, M., Zafonte, R., Fregni, F. (2014). Targeted therapies using electrical and magnetic neural stimulation for the treatment of chronic pain in spinal cord injury. NeuroImage 85, 1003–1013. Moulton, E.A., Pendse, G., Becerra, L.R., Borsook, D. (2012). BOLD responses in somatosensory cortices better reflect heat sensation than pain. J Neurosc 32, 6024–6031. Mylius, V., Borckardt, J.J., Lefaucheur, J.P. (2012). Noninvasive cortical modulation of experimental pain. Pain 153, 1350–1363. Nahmias, F., Debes, C., de Andrade, D.C., Mhalla, A., Bouhassira, D. (2009). Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers. Pain 147, 224–232. Nardone, R., H€ oller, Y., H€ oller, P., Thon, N., Thomschewski, A., Brigo, F., Trinka, E. (2013). The role of the ipsilateral primary motor cortex in movement control after spinal cord injury: A TMS study. Neurosci Lett 552, 21–24. Pagano, R.L., Assis, D.V., Clara, J.A., Alves, A.S., Dale, C.S., Teixeira, M.J., Fonoff, E.T., Britto, L.R. (2011). Transdural motor cortex stimulation reverses neuropathic pain in rats: A profile of neuronal activation. Eur J Pain 15, 268, e1-14. Pagano, R.L., Fonoff, E.T., Dale, C.S., Ballester, G., Teixeira, M.J., Britto, L.R. (2012). Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: Possible pathways for antinociception. Pain 153, 2359–2369. Pascual-Leone, A., Bartres-Faz, D., Keenan, J.P. (1999). Transcranial magnetic stimulation: Studying the brain-behaviour relationship by induction of ‘virtual lesions’. Philos Trans R Soc Lond B Biol Sci 354, 1229–1238. Pascual-Leone, A., Walsh, V., Rothwell, J. (2000). Transcranial magnetic stimulation in cognitive neuroscience–virtual lesion, chronometry, and functional connectivity. Curr Opin Neurobiol 10, 232–237. Peyron, R., Laurent, B., Garcıa-Larrea, L. (2000). Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 30, 263–288. Pich e, M., Arsenault, M., Rainville, P. (2009). Cerebral and cerebrospinal processes underlying counterirritation analgesia. J Neurosci 29, 14236–14246. Pitcher, J.B., Ogston, K.M., Miles, T.S. (2003). Age and sex differences in human motor cortex input-output characteristics. J Physiol 546, 605–613. Rossini, P.M., Barker, A.T., Berardelli, A., Caramia, M.D., Caruso, G., Cracco, R.Q., Dimitrijevic, M.R., Hallett, M., Katayama, Y., L€ ucking, C.H., et al. (1994). Noninvasive electrical and magnetic stimulation of the brain, spinal cord and roots: Basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol 91, 79–92. Ruff, C.C., Driver, J., Bestmann, S. (2009). Combining TMS and fMRI: From ‘virtual lesions’ to functional-network accounts of cognition. Cortex 45, 1043–1049. Sehm, B., Sch€ afer, A., Kipping, J., Margulies, D., Conde, V., Taubert, M., Villringer, A., Ragert, P. (2012). Dynamic modulation of intrinsic
© 2015 European Pain Federation - EFICâ
TMS-induced ‘virtual lesion’ attenuates heat pain
functional connectivity by transcranial direct current stimulation. J Neurophysiol 108, 3253–3263. Seifert, F., Maih€ ofner, C. (2011). Functional and structural imaging of pain-induced neuroplasticity. Curr Opin Anaesthesiol 24, 515–523. Siebner, H.R., Peller, M., Willoch, F., Minoshima, S., Boecker, H., Auer, C., Drzezga, A., Conrad, B., Bartenstein, P. (2000). Lasting cortical activation after repetitive TMS of the motor cortex: A glucose metabolic study. Neurology 54, 956–963. Siebner, H., Peller, M., Bartenstein, P., Willoch, F., Rossmeier, C., Schwaiger, M., Conrad, B. (2001). Activation of frontal premotor areas during suprathreshold transcranial magnetic stimulation of the left primary sensorimotor cortex: A glucose metabolic PET study. Hum Brain Mapp 12, 157–167. Siebner, H., Hartwigsen, G., Kassuba, T., Rothwell, J. (2009). How does transcranial magnetic stimulation modify neuronal activity in the brain? Implications for studies of cognition. Cortex 45, 1035– 1042. Silvanto, J., Muggleton, N.G. (2008). New light through old windows: Moving beyond the “virtual lesion” approach to transcranial magnetic stimulation. NeuroImage 39, 549–552. Stewart, L., Ellison, A., Walsh, V., Cowey, A. (2001). The role of transcranial magnetic stimulation (TMS) in studies of vision, attention and cognition. Acta Psychol (Amst) 107, 275–291. Summers, J., Johnson, S., Pridmore, S., Oberoi, G. (2004). Changes to cold detection and pain thresholds following low and high frequency transcranial magnetic stimulation of the motor cortex. Neurosci Lett 368, 197–200. Tamura, Y., Okabe, S., Ohnishi, T., N Saito, D., Arai, N., Mochio, S., Inoue, K., Ugawa, Y. (2004). Effects of 1-Hz repetitive transcranial magnetic stimulation on acute pain induced by capsaicin. Pain 107, 107–115. Terao, Y., Ugawa, Y. (2006). Studying higher cerebral functions by transcranial magnetic stimulation. Suppl Clin Neurophysiol 59, 9–17. de Tommaso, M., Brighina, F., Fierro, B., Francesco, V.D., Santostasi, R., Sciruicchio, V., Vecchio, E., Serpino, C., Lamberti, P., Livrea, P. (2010). Effects of high-frequency repetitive transcranial magnetic stimulation of primary motor cortex on laser-evoked potentials in migraine. J Headache Pain 11, 505–512. Tousignant-Laflamme, Y., Page, S., Goffaux, P., Marchand, S. (2008). An experimental model to measure excitatory and inhibitory pain mechanisms in humans. Brain Res 1230, 73–79. Yang, Y., Li, W., Zhu, B., Liu, Y., Yang, B., Wang, H., Wang, Z. (2007). Sex differences in antidepressant-like effect of chronic repetitive transcranial magnetic stimulation in rats. Prog Neuropsychopharmacol Biol Psychiatry 31, 735–740. Yarnitsky, D. (1997). Quantitative sensory testing. Muscle Nerve 20, 198– 204. Zaghi, S., Thiele, B., Pimentel, D., Pimentel, T., Fregni, F. (2011). Assessment and treatment of pain with non-invasive cortical stimulation. Restor Neurol Neurosci 29, 439–451. Ziemann, U. (2010). TMS in cognitive neuroscience: Virtual lesion and beyond. Cortex 46, 124–127.
Eur J Pain 20 (2016) 241--249
249
‘Virtual lesion’ in pain research; a study on magnetic stimulation of the primary motor cortex Y. Granovsky1,2, K.S. Liem3, I. Weissman-Fogel4, D. Yarnitsky1,2, A. Chistyakov5, A. Sinai1,5 1 2 3 4 5
Department of Neurology, Rambam Medical Center, Haifa, Israel Clinical Neurophysiology Laboratory, Technion Faculty of Medicine, Haifa, Israel Faculty of Medicine, University Utrecht, The Netherlands Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel Neurosurgery Laboratory, Rambam Medical Center, Haifa, Israel
Correspondence Dr. Yelena Granovsky E-mail: [email protected] Funding sources This study was sponsored by the Israel Science Foundation, Grant no. 518/2012. Conflicts of interest No authors declare any conflict of interests.
Accepted for publication 16 March 2015 doi:10.1002/ejp.715
Abstract Background: ‘Virtual lesion’ (‘VL’) is a transient disruption of cortical activity during task performance. It can be induced by single pulses or short trains of transcranial magnetic stimulation (TMS) directed to functionally relevant brain areas. We applied ‘VL’ methodology of a short train of TMS given on top of experimental tonic pain, expecting to see changes in pain scores. Methods: Thirty young healthy subjects (15 women) were assessed with active (‘VL’) or ‘sham’ TMS in different sessions, randomly. In each session, 30 sec-long contact heat (47.5 °C, right forearm) was applied stand-alone (‘baseline’) and with 5 sec-long 10 Hz-TMS over left primary motor cortex (M1) starting at 17 sec of the heat stimulation. Results: Pain scores decreased after ‘VL’ or ‘sham’ (p < 0.001). Independently of the type of TMS, pain reduction was stronger in women (p = 0.012). A triple Sex x Stimulation type (‘VL’ or ‘sham’) x Condition (‘baseline’ heat pain vs. heat pain with TMS) interaction (p = 0.027) indicated stronger pain reduction by ‘VL’ in women (p = 0.008) and not in men (p = 0.78) as compared to ‘baseline’. Pain catastrophizing and perceived stress ratings affected the model (p = 0.010 and p < 0.001, respectively), but without sex differences. Conclusions: This study indicates that interactions between cortical excitability of the motor cortex and nociceptive processing may be gender-related.
1. Introduction One of the methodological approaches to study the involvement of specific brain regions in the neural activity related to various high functions is the induction of a ‘virtual lesion’ (‘VL’) via application of brief transcranial magnetic stimulation (TMS) during task performance (Ziemann, 2010). The effect of ‘VL’ induced by TMS is a transient and reversible interference with cortical processing during the task (Pascual-Leone et al., 2000; Ziemann, 2010). ‘VL’
© 2015 European Pain Federation - EFICâ
can be achieved either by a single TMS pulse timelocked to the stimulus (Amassian et al., 1989) or by using a short high-frequency (>10 Hz) rTMS train (Epstein et al., 1999; Siebner et al., 2009), with both resulting in behavioural changes. Two main mechanisms have been suggested to underlie ‘VL’: (1) silencing of pyramidal neurons probably through activation of GABAergic interneurons (Haug et al., 1992), and (2) disruption of neural processing due to the addition of noise to the ongoing activity (Siebner et al., 2001; Di Lazzaro et al., 2004). The balance between these two mechanisms depends mainly on
Eur J Pain 20 (2016) 241--249
241
TMS-induced ‘virtual lesion’ attenuates heat pain
What is already known about this topic? • Transcranial magnetic stimulation (TMS) can be used to modify the activity in the motor cortex and to induce changes in pain perception. • When used in ‘virtual lesion’ mode (i.e. single pulse or short train of stimuli during the stimulus processing), TMS can interrupt activity in the stimulated motor cortex as well as in distant connected brain areas that are involved in stimulus processing. What does this study add?
• TMS-induced ‘virtual lesion’ directed to the motor cortex changes the experimental pain perception, i.e. reducing the perceived pain intensity. • TMS-induced pain reduction is sex dependent, i.e. more efficient in women.
the stimulus intensity (Di Lazzaro et al., 2004) and on the intrinsic excitability of the neurons. Imaging studies demonstrated pain-related activation of the primary motor cortex (M1), when applying the contact tonic heat paradigms (Casey et al., 1996; Moulton et al., 2012). TMS as employed in research, including pain studies, uses long-duration repetitive stimulation (rTMS), intended to modify cortical excitability. The effect is usually obtained after hundreds or thousands of stimuli and is typically quantified as post- versus pre-rTMS changes in behavioural and/or neurophysiological parameters. M1 is one of the main targets for rTMS in pain research. High-frequency rTMS directed to M1 exerts anti-nociception, probably via M1’s inhibitory influence on the nociceptive processing exerted directly at thalamic and spinal levels, and indirectly via activation of limbic, cortical and sub-cortical areas such as the periaqueductal grey (PAG), anterior cingulate cortex (ACC) and amygdala (Garcıa-Larrea and Peyron, 2007; Pagano et al., 2011; Maarrawi et al., 2013). An analgesic effect exerted by rTMS directed to M1 was demonstrated by increase in thermal pain thresholds (Summers et al., 2004; Lefaucheur et al., 2008; Nahmias et al., 2009; Borckardt et al., 2011) and alleviation of capsaicin- and laser stimulationinduced pain (Tamura et al., 2004; Antal and Paulus, 2010; de Tommaso et al., 2010; Mylius et al., 2012). Further, at the clinical level, it was proved as an effective analgesic treatment for pain states of 242 Eur J Pain 20 (2016) 241--249
Y. Granovsky et al.
various etiologies (Lefaucheur, 2004; Zaghi et al., 2011; Marlow et al., 2013; Moreno-Duarte et al., 2014). To date, to the best of our knowledge, the specific mode of ‘VL’-TMS in pain research has only been applied in one study using short rTMS over dorsolateral prefrontal cortex (DLPFC) during experimental capsaicin-induced pain in order to investigate the modulatory effect of the DLPFC on pain (Fierro et al., 2010). No study targeted the primary motor cortex using short ‘VL’-TMS in assessing pain perception. We hypothesized that induction of short ‘VL’-TMS in this cortical area known to be functionally associated with pain modulation, will interrupt processes of pain inhibition, resulting in pain facilitation.
2. Materials and methods 2.1 Subjects Thirty right-handed healthy volunteers, aged 18– 40 years (mean 24.7 2.1 years), 15 men and 15 women, participated in this study. Exclusion criteria included a history of peripheral or central nervous system disorders (including chronic pain, cognitive, epileptic and headache disorders), loss of consciousness after head trauma, cochlear implants or implanted cardiac defibrillators, pregnancy, medication use on a regular basis, and tissue damage in experimented regions. Subjects were also restricted from taking any medication within 24 h prior to experimental session. All subjects provided written informed consent. The Institutional Review Board of Rambam Health Care Campus, Israel, approved the study protocol, in accordance with the Declaration of Helsinki (2008).
2.2 Contact heat stimuli Contact heat stimuli were delivered by a Thermal Sensory Analyzer (TSA) 2001 system (Medoc, Ramat Yishai, Israel) with a 30 9 30 mm Peltier surface stimulator, strapped to the volar forearm of the subject’s dominant (right) hand. Contact-heat baseline temperature was set to 32 °C. Temperature increasing and decreasing rates were set to 2.0 °C/s. The heat pain assessments included measurement of heat pain threshold (HPT) at temperature increase rate of 1 °C via the method of limits (Yarnitsky, 1997), and a delivery of tonic heat stimuli at a fixed (47.5 °C) temperature. The thermode was attached to the skin by a Velcro strap. To avoid pain sensitization/adaptation during tonic heat stimulation, the thermode © 2015 European Pain Federation - EFICâ
Y. Granovsky et al.
was manually moved to an adjacent area after each tonic stimulus. The examiner was informed about possible impact of the pressure against the skin on pain perception, and instructed to maintain a uniform pressure on the skin across all stimulation conditions.
2.3 Transcranial magnetic stimulation A figure-of-eight coil (MCF-B65) with MagPro X100 magnetic stimulator (MagVenture Inc., Farum, Denmark) was used for TMS. The TMS-preparations started with supporting the subject’s neck using an airplane pillow and tightly putting a swimmer’s cap over the head to mark coil location and angulation. Two surface electrodes in a tendon-belly construction were put to the right abductor pollicis brevis (APB) muscle for motor evoked potential (MEP) recordings. Subjects were instructed to recline comfortably, keep eyes open, lean head back and report any pain or discomfort on the head, or muscle twitches in the right hand. The TMS-coil was tangentially placed (anteroposterior direction) above the hand motor cortex with its position marked on the swimming cap as a reference point. The center of the coil was positioned directly above the APB cortical representation in motor cortex (the position which elicited the largest response from the APB muscle; tested at the beginning of each session), approximately 5 cm lateral to the parasagittal axis at a 45° angle (approximately perpendicular to central sulcus). A metal arm fixated the coil in this position. For placebo condition the sham testing was performed using the same TMS-coil flipped upsidedown at the same scalp location without changing stimulus intensity, providing discharge noise without stimulating cortical tissue. The coil used was very wide (due to its passive cooling system) and therefore when it was flipped, a large distance spanned the active part of the coil and the scalp surface. This configuration resulted in considerable stimulation intensity reduction (roughly 60%, according to the manufacturer), while from the subject’s point of view, it resembled active TMS stimulation. The experiment was single-blind; all subjects were blinded to the experimental conditions. The patients were not instructed about the existence of a sham condition, but they were informed that in each session different stimulation parameters would be applied using the same coil. Resting motor threshold (rMT) was defined as the lowest stimulus intensity able to elicit amplitudes of
© 2015 European Pain Federation - EFICâ
TMS-induced ‘virtual lesion’ attenuates heat pain
50 lV in 5 out of 10 stimuli when the muscle is at rest (Rossini et al., 1994). The TMS intensity was reported as the percentage of the maximal TMS machine output. Starting at 30% stimulus intensity, the intensity was increased (at 3% increment steps) until every stimulus resulted in a consistent MEP. Holding this stimulus intensity, the coil was marginally moved over the specific area (inter-stimulus interval 3 s to avoid facilitation) in search of MEP’s with maximal amplitudes. Audiovisual feedback was provided using a 3-lead EEG-system (QuickAmp40; Brain Products GmbH, Munich, Germany) to establish complete APB-relaxation. Coil placement was then marked on the swimmer’s cap. Finally, the stimulus intensity was reduced and rMT established, as defined above, to the closest whole percentage intensity. During TMS, subjects were instructed to report any pain, discomfort or muscle twitches. The investigator continuously verified coil placement (any shift from the reference point) and relaxation of muscles (visual EMG-inspection). In the case of reported or visually observed muscle activation, the stimulus intensity was lowered accordingly and a performance check conducted during the next TMS-train.
2.4 Experimental protocol All subjects were tested in the same setting in a quiet room with an ambient temperature of ~23 °C. Prior to the experiment, subjects were given a routine explanation of the tests. We report the results of two experimental sessions where active (‘VL’) or ‘sham’ primary motor cortex stimulations were performed. This report relates to one part of a larger project, whose other part will be reported separately. Active or ‘sham’ M1 stimulation were performed in separate experimental sessions that were randomly counterbalanced using freely available computerized randomization program. To avoid potential carry-over effects of a previous TMS-session, consecutive sessions were planned with a minimum spacing of 7 days. During each session, two 30 sec-long tonic heat stimuli were delivered. A ‘baseline’ condition of stand-alone (without any active or sham TMS) heat stimulus was administered at the beginning of each experimental session. After 15 min heat stimulus of the same intensity was delivered with either active or sham M1-directed TMS. The heat stimuli were given on the upper-third of the volar forearm. The TMS was 5 sec of 10 Hz-stimulation delivered over the left hemisphere; the active stimulation was given at the intensity of 90% of the individual rMT. Subjects were asked to rate their pain verbally on a 0–100 numerical pain scale (NPS) in
Eur J Pain 20 (2016) 241--249
243
TMS-induced ‘virtual lesion’ attenuates heat pain
which 0 was “no pain” and 100 the “most intense pain imaginable”. Thus, four NPS scores were obtained at the beginning (T0), and at 10 sec (T10), 20 sec (T20) and 30 sec (T30) of heat stimulation. TMS was started at the 17th sec of the heat stimulation, such that the T20 pain score was obtained during the TMS-train. One researcher (K.S.L.) tested all subjects. At the first session, subjects completed several pain-related psychological questionnaires; Pain Catastrophizing Scale (PCS), Perceived Stress Scale (PSS) and Fear of Pain Questionnaire (FPQ). In addition, the HPT was assessed at the beginning of each session.
2.5 Statistical analysis A mixed model (repeated measures) ANOVA (rANOVA) was employed to examine influences of full-factorial combinations of Sex, Stimulation Type (M1-’VL’ or ‘sham’) and Condition (‘baseline’ pain stimulation given stand-alone vs. pain with active or sham TMS) on changes in the pain scores along tonic heat stimulus (T20 vs. T10 and T30 vs. T10), with inclusion of covariates: the scores of PSS, PCS and FPQ, the rMT value and HPT. As part of the diagnostic procedures to validate the analysis, ANOVA residuals were inspected. Subjects were treated as a random factor nested within sex. Tukey–Kramer tests were employed for post-hoc comparisons as appropriate. Least square means and associated standard errors are reported. JMP and SAS (both SAS Institute, Cary, NC) were employed for analyses. In addition, paired t-tests corrected for the multiple comparison were performed in order to assess the differences of pain scores between men and women at each stimulation condition-type combination, and for all aforementioned covariates. Simple descriptive data about the subjects are expressed as mean standard error.
3. Results All recruited subjects completed the whole experimental setup. Mean rMT at the ‘VL’-TMS session was 49.2 8.3% (range: 30–62); the mean applied TMS intensity was 43.7 7.1% (range: 27–54). The mean rMT in the sham-TMS session was 48.6 8.5% (range: 36–64); no significant difference for the rMT values was observed between two session (p = 0.452). In spite of our hypothesis that the maximal change in pain score would be observed at the rating during the ‘VL’ (T20 pain score), rANOVA revealed no significant difference of the T20 versus T10 (taken before the TMS) pain scores. For the T30 244 Eur J Pain 20 (2016) 241--249
Y. Granovsky et al.
versus T10 differences in pain ratings, however, significant effect of Condition (ratings to heat pain delivered stand-alone or with TMS) was observed, pointing to reduction in pain scores along the heat pain with TMS (p < 0.001). This reduction was not related to the Stimulation type (‘VL’ or ‘sham’; p = 0.136). Furthermore, we found a significant Sex effect (p = 0.012); women demonstrated greater reduction in pain scores as compared to men. Importantly, there was a triple Sex X Stimulation type X Condition interaction (p = 0.027). Post-hoc Tukey analysis revealed that while males responded with similar changes in pain scores during the noxious heat at ‘baseline’ (without any TMS intervention) and at the ‘VL’ induction (p = 0.783), women experienced significant pain reduction under the ‘VL’-inducing condition (p = 0.008) compared to the ‘baseline’ noxious heat stimulation. No such reduction in pain scores was observed for the ‘sham’ stimulation in women (p = 0.100) or men (p = 0.315). Fig. 1 depicts the 4 pain scores along each stimulation condition in men and women. The values for the heat pain scores obtained at each stimulation condition in the whole study group, separately for males and females, are presented in Table 1. Importantly, there were no sex differences in the baseline pain scores. Two-way ANOVA did not reveal overall (p = 0.191) or session-related differences in pain perception between men and women (p = 0.932). No effect of the covariates of FPQ, HPT or rMT on changes in pain sores was found (p = 0.354, p = 0.437 and p = 0.691, respectively). However, PSS and PCS had significant impact on the described model (p < 0.001 and p = 0.011, respectively), probably due to positive correlation between the PSS score and the pain ratings during noxious heat (r = 0.386; p = 0.035 for the ‘VL’- stimulation session, and r = 0.320; p = 0.085 for the sham-stimulation session). Moreover, subjects with higher PSS also reported higher PCS scores (r = 0.450; p = 0.012). No sex differences were observed for the rMT or HPT values at any stimulation session. In the active M1-TMS session the rMT values were 48.9 8.9% in women and 49.5 7.9% in men (p = 0.846). The stimulation intensity applied in the M1-TMS session were 43.2 7.2% in women and 44.1 7.1% in men (p = 0.725). The rMT values for the sham-TMS session were 48.4 8.7% and 48.8 8.5% for women and men, respectively (p = 0.900). For the HPT, the values in the active M1-TMS session were 45.1 2.6 °C in women and 45.1 3.2 °C in men (p = 0.977); the values in the sham-TMS session © 2015 European Pain Federation - EFICâ
Y. Granovsky et al.
TMS-induced ‘virtual lesion’ attenuates heat pain
The effect of sham-TMS, females
70
70
60
60
*
50
NPS
NPS
The effect of M1-TMS, females
50
40
40
30
30
20 T0
T10 T20 Heat pain duraon (s)
20
T30
T0
70
60
60
50
50
NPS
NPS
70
40
40
30
30
20 T10 T20 Heat pain duraon (s) Baseline
T30
The effect of sham-TMS, males
The effect of M1-TMS, males
T0
T10 T20 Heat pain duraon (s)
20
T30
Shame TMS
T0
T10 T20 Heat pain duraon (s)
T30
TMS on M1
Figure 1 Heat pain scores in women and men at ‘baseline’ (solid line with diamonds), active TMS (‘VL’) (dotted line with squares) and ‘sham’ TMS (punctate line with squares) conditions. The pain was rated using verbal numerical pain scale (NPS). A TMS schematic is presented as a grey square. *p = 0.008; women demonstrated significant pain reduction at post versus pre-’VL’ conditions as compared to the changes in pain scores along the ‘baseline’.
were 45.3 3.3 °C in women and 44.6 3.5 °C in men (p = 0.578). No sex differences were observed neither for PCS (21.7 9.6, women versus 21.3 9.2, men; p = 0.908), nor for PSS (14.2 7.1, women vs. 11.2 4.9, men; p = 0.191), or for FPQ (80.1 19.5, women vs. 80.1 16.5, men; p = 0.908).
4. Discussion Our results showed that short high-frequency rTMS train disrupted M1 during noxious tonic stimulus and attenuated pain; this analgesic effect was apparent shortly after the end of TMS and was mainly evident in women. Disrupting brain functioning is a well-established concept in neuroscience. ‘VL’ has been demonstrated in speech arrest while stimulating language regions, reduction in visual discrimination while stimulating visual cortex, and memory deficit while stimulating © 2015 European Pain Federation - EFICâ
prefrontal regions (Pascual-Leone et al., 1999; Stewart et al., 2001; Terao and Ugawa, 2006; Silvanto and Muggleton, 2008). The exact underlying mechanism is not yet fully understood. Intensity of magnetic stimuli as well as the context under which stimuli are delivered influences the ‘VL’ effect (Ziemann, 2010). In addition, TMS effects are usually not limited to the site of stimulation but spread either physically to neighbouring areas, or by distant propagation of action potentials along cortico-cortical and cortico-subcortical projections (Siebner et al., 2001; Massimini et al., 2005; Blankenburg et al., 2008; Ruff et al., 2009). Thus, in terms of the ‘VL’ concept this means that TMS effects could be caused directly at the stimulated site, but equally well through modification of neuronal activity at distant sites, or both. M1 is commonly activated in response to pain (Apkarian et al., 2000; Peyron et al., 2000); intracortical recordings in humans support evidence Eur J Pain 20 (2016) 241--249
245
TMS-induced ‘virtual lesion’ attenuates heat pain
Y. Granovsky et al.
Table 1 Descriptive data of the heat pain ratings obtained at ‘baseline’, active (‘VL’) and ‘sham’ TMS in (A) whole study population, and (B) separately in men and women. Stimulation type & condition
T0
T10
T20
T30
A M1, baseline M1, VL Sham, baseline Sham, TMS B Men M1, baseline M1, VL Sham, baseline Sham, TMS Women M1, baseline M1, VL Sham, baseline Sham, TMS
50.4 54.2 49.5 50.6
4.7 4.5 4.4 4.2
56.0 54.6 57.6 55.7
4.1 3.9 4.5 4.2
52.2 43.5 55.9 45.8
4.2 4.0 4.7 4.3
57.3 42.8 57.5 50.0
4.4 4.1 4.9 4.5
43.3 45.7 44.0 47.8
6.1 6.3 5.7 6.6
50.6 49.2 50.5 53.9
5.3 5.4 6.1 6.6
50.9 40.5 50.7 45.3
5.5 5.2 6.3 6.6
51.7 42.7 54.1 46.2
6.4 5.1 6.3 6.7
57.4 62.7 55.0 53.3
6.9 5.8 6.3 5.4
61.5 60.0 64.8 57.5
6.1 5.5 6.3 5.4
53.6 46.5 61.2 46.3
6.5 6.1 6.8 5.7
62.8 42.9 60.9 53.7
5.8 6.7 7.5 6.0
for a spinothalamic-related input to the motor cortex, in parallel with primary somatosensory cortex (SI) activation (Frot et al., 2013). In turn, M1 is involved in pain inhibition; M1 stimulation appears to trigger a rapid and phasic activation in the lateral thalamus, which leads to a cascade of synaptic events influencing activity in the medial thalamus, perigenual ACC, orbitofrontal cortex, and PAG (Garcıa-Larrea et al., 1999; Garcıa-Larrea and Peyron, 2007). Transdural motor cortex stimulation reversed allodynia and hyperalgesia in the neuropathic pain model and increased activity in PAG, ACC and amygdalae (Pagano et al., 2011, 2012). Importantly, increased corticothalamic functional connectivity in response to M1-rTMS was associated with relief of central post-stroke pain (Goto et al., 2008) assumed to be opioid-mediated, as the M1rTMS-related neuropathic pain relief can be predicted by the opioid receptor density in the thalamus, PAG, and contralateral insula (Maarrawi et al., 2013). The described results point to both functional and structural correspondence between M1 and the somatosensory cortices that, together with activation of limbic and subcortical areas, play an important role in the mediation of pain inhibition. It is not clear, however, whether the parameters used in our study explore the same mechanisms. The central finding of our study is sex-related pain reduction due to brief M1-directed high frequency rTMS given on top of experimental pain. These behavioural changes due to TMS indicate a 246 Eur J Pain 20 (2016) 241--249
‘VL’ effect and confirm the functional relevance of M1 in pain modulation. Previous rTMS-pain studies used much longer trains and sessions, resulting in clinical pain reduction after rTMS (Lefaucheur et al., 2010a,b). These rTMS-related findings can be interpreted as (1) interference of M1 activity lasting shortly beyond the time of stimulation, or alternatively, (2) transient augmentation of motor cortex excitability. We delivered short rTMS train during the experimental pain, inducing a ‘VL’ effect i.e. interference with M1 activation. Bearing in mind that M1 neuronal activity is involved in pain inhibition, we would expect pain increase in case of M1 disruption. The observed pain reduction suggests that disruption of the motor cortex activity can lead to pain decrease. Several explanations can be proposed in this regard: (1) The effect of TMS is not local and leads to changes in synaptic activity in adjacent cortical areas and even in the contralateral hemisphere (Lee et al., 2003) activating compensatory other brain regions involved in pain inhibition. This assertion bases, for example, on the reports that activation of nearby motor areas is associated with pain inhibition (Pich e et al., 2009; Moont et al., 2011). Consistent, rTMS to the DLPFC restores deficient intracortical inhibition of the motor cortex, and so reduces pain (Fierro et al., 2010). (2) In parallel with the previous assertion, the disruption of M1 may theoretically result in reduced activity in the brain regions associated with pro-nociception, leading to pain reduction. Kodama et al. (2009) reported reduced amplitude of the somatosensory evoked potentials, a measure for SI excitability, in response to M1-rTMS. In addition, there is evidence of excitatory connectivity between M1 and other brain areas such as the SMA and somatosensory cortices (Fox et al., 1997; Grefkes et al., 2010), and thalamus (Goto et al., 2008) pointing to M1’s interaction with brain regions associated with both proand anti-nociception. (3) The stimulated part of M1 may become less responsive to inputs from other motor areas. Such rapid reorganization of the motor cortex may theoretically lead to increased M1 excitability and, consequently, to pain attenuation. Functional brain reorganization and plasticity of M1 and related areas was widely described in stroke (Jiang et al., 2013), spinal cord injury (Nardone et al., 2013) and chronic pain patients (Seifert and Maih€ ofner, 2011), although these clinical correlates occur during a longer time course. In the same vein, whole-brain changes in functional connectivity were reported for M1-transcranial direct current stimulation (tDCS) (Sehm et al., 2012). (4) Since the © 2015 European Pain Federation - EFICâ
Y. Granovsky et al.
maximal analgesic response was observed not during, but several seconds after TMS, we propose that this effect relates to a delayed increase in M1 neuronal excitability. This is consistent with reports on persisting neuronal activation in a distinct set of motor cortical areas beyond the time of M1-TMS (Siebner et al., 2000) and on a delayed analgesic effect relative to the actual period of motor cortex stimulation (Garcıa-Larrea and Peyron, 2007). Indeed, a similar effect was reported following DLPFC-rTMS preventing further increase in capsaicin-induced pain (Fierro et al., 2010). Each of the proposed mechanisms, alone or in combination, may explain our results of pain reduction in response to M1-directed virtual lesion. Sex differences in pain perception are attributed to various biological and cognitive/affective factors (Fillingim et al., 2009). Nevertheless, consistent with the results of other reports (Cahn et al., 2003; Pitcher et al., 2003; Livingston et al., 2010) our findings pointed to a lack of sex differences in painrelated psychological variables or in heat pain threshold or resting cortical excitability. Diverse results have been reported in relation to tonic pain; while some observed greater heat pain attenuation in women (Defrin et al.,2008; Hashmi and Davis, 2009), others contradicted these findings (Tousignant-Laflamme et al., 2008; Nahmias et al., 2009). Our results are consistent with the former findings; women experienced decreased pain regardless of the type of TMS. Furthermore, the triple Sex, Stimulation type and Condition interaction indicates additional pain attenuation in women to M1-’VL’. There is evidence for sex differences in the responses to TMS application during behavioural tasks and to therapeutic interventions. Knops et al. (2006) found that sex mediated the impact of a TMS-induced ‘VL’ on the intraparietal sulcus for investigating its role in numerical cognition. Further, rTMS on the DLPFC improved cognitive functions in women compared to men (Huber et al., 2003). Moreover, the effects of rTMS applied for achieving antidepressant-like effect in rats was sex-dependent (Yang et al., 2007). In line, treating refractory bipolar/ major depression was found to be associated with female hormones (Huang et al., 2008). Thus, the role of sex differences in pain relief by the TMS treatment needs further investigation, especially in the light of the evidence of sex differences in the modulation of human cortical plasticity tested by tDCS (Kuo et al., 2006; Chaieb et al., 2008). Another possible relating factor to sex disparity is higher transcallosal inhibition in women (De Gen© 2015 European Pain Federation - EFICâ
TMS-induced ‘virtual lesion’ attenuates heat pain
naro et al., 2004), and that this inter-hemispheric interaction was affected by gonadal hormones (Hausmann et al., 2006). As one of the mechanisms underlying ‘VL’ is the disruption of the neural processing (Di Lazzaro et al., 2004; Siebner et al., 2009) and, accordingly, the interactions between remote but inter-connected brain regions, it can be proposed that M1-’VL’ was more effective in women in the present study due to superior baseline interhemispheric connectivity. The main limitation of our study relates to the issues of sham stimulation and blinding. It is known that creating an adequate sham control in TMS is notoriously difficult. The TMS system we used does not have a sham coil, so it was therefore not possible to keep the examiner blinded. However, several precautions were taken to ensure subjects’ blinding: subjects could not see or feel that the coil was flipped, and the same clicking sounds were produced regardless of coil orientation. Sensory confounders of the stimulation could possibly distract from pain in active and sham TMS; we carefully refrained from scalp nociception so subjects could not distinguish between the conditions. In addition, no subjects reported spontaneously any differences in cortical sensation across both stimulation sessions. In summary, we demonstrated that disruption of motor cortex neural activity via induction of ‘virtual lesion’ during exposure to tonic pain is associated with pain reduction, which confirms the functional relevance of ‘VL’ technique in pain research. The association of pain attenuation with sex may point in favour of a more pronounced effect of M1-directed TMS in women. This raises the importance of conducting personalized pain treatment with cortical magnetic stimulation. Acknowledgement Thanks to Dr. Elliot Sprecher for his help in the statistical analysis, and to Dr. Ruth Moont for her help in English editing.
Author contributions Y.G. was responsible for study logistics, preliminary data analysis, manuscript preparation. K.S.L. was responsible for study conduction and data collection, help with the manuscript preparation. I.W-F. was responsible for study logistics, manuscript preparation. D.Y. was responsible for study logistics, help with the manuscript preparation. A.C. was responsible for study logistics. A.S. study logistics, manuscript preparation.
Eur J Pain 20 (2016) 241--249
247
TMS-induced ‘virtual lesion’ attenuates heat pain
References Amassian, V.E., Cracco, R.Q., Maccabee, P.J., Cracco, J.B., Rudell, A., Eberle, L. (1989). Suppression of visual perception by magnetic coil stimulation of human occipital cortex. Electroencephalogr Clin Neurophysiol 74, 458–462. Antal, A., Paulus, W. (2010). Effects of transcranial theta-burst stimulation on acute pain perception. Restor Neurol Neurosci 28, 477– 484. Apkarian, A.V., Gelnar, P.A., Krauss, B.R., Szeverenyi, N.M. (2000). Cortical responses to thermal pain depend on stimulus size: A functional MRI study. J Neurophysiol 83, 3113–3122. Blankenburg, F., Ruff, C.C., Bestmann, S., Bjoertomt, O., Eshel, N., Josephs, O., Weiskopf, N., Driver, J. (2008). Interhemispheric effect of parietal TMS on somatosensory response confirmed directly with concurrent TMS-fMRI. J Neurosci 28, 13202–13208. Borckardt, J.J., Reeves, S.T., Beam, W., Jensen, M.P., Gracely, R.H., Katz, S., Smith, A.R., Madan, A., Patterson, D., George, M.S. (2011). A randomized, controlled investigation of motor cortex transcranial magnetic stimulation (TMS) effects on quantitative sensory measures in healthy adults: Evaluation of TMS device parameters. Clin J Pain 27, 486–494. Cahn, S.D., Herzog, A.G., Pascual-Leone, A. (2003). Paired-pulse transcranial magnetic stimulation: Effects of hemispheric laterality, gender, and handedness in normal controls. J Clin Neurophysiol 20, 371–374. Casey, K.L., Minoshima, S., Morrow, T.J., Koeppe, R.A. (1996). Comparison of human cerebral activation pattern during cutaneous warmth, heat pain, and deep cold pain. J Neurophysiol 76, 571– 581. Chaieb, L., Antal, A., Paulus, W. (2008). Gender-specific modulation of short-term neuroplasticity in the visual cortex induced by transcranial direct current stimulation. Vis Neurosci 25, 77–81. De Gennaro, L., Bertini, M., Pauri, F., Cristiani, R., Curcio, G., Ferrara, M., Rossini, P.M. (2004). Callosal effects of transcranial magnetic stimulation (TMS): The influence of gender and stimulus parameters. Neurosci Res 48, 129–137. Defrin, R., Pope, G., Davis, K.D. (2008). Interactions between spatial summation, 2-point discrimination and habituation of heat pain. Eur J Pain 12, 900–909. Di Lazzaro, V., Oliviero, A., Pilato, F., Saturno, E., Dileone, M., Mazzone, P., Insola, A., Tonali, P.A., Rothwell, J.C. (2004). The physiological basis of transcranial motor cortex stimulation in conscious humans. Clin Neurophysiol 115, 255–266. Epstein, C.M., Meador, K.J., Loring, D.W., Wright, R.J., Weissman, J.D., Sheppard, S., Lah, J.J., Puhalovich, F., Gaitan, L., Davey, K.R. (1999). Localization and characterization of speech arrest during transcranial magnetic stimulation. Clin Neurophysiol 110, 1073–1079. Fierro, B., De Tommaso, M., Giglia, F., Giglia, G., Palermo, A., Brighina, F. (2010). Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) during capsaicin-induced pain: Modulatory effects on motor cortex excitability. Exp Brain Res 203, 31–38. Fillingim, R.B., King, C.D., Ribeiro-Dasilva, M.C., Rahim-Williams, B., Riley, J.L. 3rd (2009). Sex, gender, and pain: A review of recent clinical and experimental findings. J Pain 10, 447–485. Fox, P., Ingham, R., George, M.S., Mayberg, H., Ingham, J., Roby, J., Martin, C., Jerabek, P. (1997). Imaging human intra-cerebral connectivity by PET during TMS. NeuroReport 8, 2787–2791. Frot, M., Magnin, M., Mauguiere, F., Garcia-Larrea, L. (2013). Cortical representation of pain in primary sensory-motor areas (S1/M1)-a study using intracortical recordings in humans. Hum Brain Mapp 34, 2655–2668. Garcıa-Larrea, L., Peyron, R. (2007). Motor cortex stimulation for neuropathic pain: From phenomenology to mechanisms. NeuroImage 37(Suppl 1), S71–S79. Garcıa-Larrea, L., Peyron, R., Mertens, P., Gregoire, M.C., Lavenne, F., Le Bars, D., Convers, P., Mauguiere, F., Sindou, M., Laurent, B. (1999). Electrical stimulation of motor cortex for pain control: A combined PET-scan and electrophysiological study. Pain 83, 259–273.
248 Eur J Pain 20 (2016) 241--249
Y. Granovsky et al.
Goto, T., Saitoh, Y., Hashimoto, N., Hirata, M., Kishima, H., Oshino, S., Tani, N., Hosomi, K., Kakigi, R., Yoshimine, T. (2008). Diffusion tensor fiber tracking in patients with central post-stroke pain; correlation with efficacy of repetitive transcranial magnetic stimulation. Pain 140, 509–518. Grefkes, C., Nowak, D.A., Wang, L.E., Dafotakis, M., Eickhoff, S.B., Fink, G.R. (2010). Modulating cortical connectivity in stroke patients by rTMS assessed with fMRI and dynamic causal modeling. NeuroImage 50, 233–242. Hashmi, J.A., Davis, K.D. (2009). Women experience greater heat pain adaptation and habituation than men. Pain 145, 350–357. Haug, B.A., Schonle, P.W., Knobloch, C., Kohne, M. (1992). Silent period measurements revives a a valuable diagnostic tool with transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol 85, 158–160. Hausmann, M., Tegenthoff, M., Sanger, J., Janssen, F., Gunturkun, O., Schwenkreis, P. (2006). Transcallosal inhibition across the menstrual cycle: A TMS study. Clin Neurophysiol 117, 26–32. Huang, C.C., Wei, I.H., Chou, Y.H., Su, T.P. (2008). Effect of age, gender, menopausal status, and ovarian hormonal level on rTMS in treatment-resistant depression. Psychoneuroendocrinology 33, 821–831. Huber, T.J., Schneider, U., Rollnik, J. (2003). Gender differences in the effect of repetitive transcranial magnetic stimulation in schizophrenia. Psychiatry Res 120, 103–105. Jiang, L., Xu, H. and Yu, C. (2013). Brain connectivity plasticity in the motor network after ischemic stroke. Neural Plast Volume 2013, Article ID 924192, 11 pages. Knops, A., Nuerk, H.C., Sparing, R., Foltys, H., Willmes, K. (2006). On the functional role of human parietal cortex in number processing: How gender mediates the impact of a ‘virtual lesion’ induced by rTMS. Neuropsychologia 44, 2270–2283. Kodama, M., Aono, K., Masakado, Y. (2009). Changes in sensory functions after low-frequency repetitive transcranial magnetic stimulation over the motor cortex. Tokai J Exp Clin Med 34, 122–129. Kuo, M.F., Paulus, W., Nitsche, M.A. (2006). Sex differences in cortical neuroplasticity in humans. NeuroReport 17, 1703–1707. Lee, L., Siebner, H.R., Rowe, J.B., Rizzo, V., Rothwell, J.C., Frackowiak, R.S., Friston, K.J. (2003). Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J Neurosci 23, 5308–5318. Lefaucheur, J.P. (2004). Transcranial magnetic stimulation in the management of pain. Suppl Clin Neurophysiol 57, 737–748. Lefaucheur, J.P., Drouot, X., Menard-Lefaucheur, I., Keravel, Y., Nguyen, J.P. (2008). Motor cortex rTMS in chronic neuropathic pain: Pain relief is associated with thermal sensory perception improvement. J Neurol Neurosurg Psychiatry 79, 1044–1049. Lefaucheur, J.P., Jarry, G., Drouot, X., Menard-Lefaucheur, I., Keravel, Y., Nguyen, J.P. (2010a). Motor cortex rTMS reduces acute pain provoked by laser stimulation in patients with chronic neuropathic pain. Clin Neurophysiol 121, 895–901. Lefaucheur, J.P., Menard-Lefaucheur, I., Goujon, C., Keravel, Y., Nguyen, J.P. (2010b). Predictive value of rTMS in the identification of responders to epidural motor cortex stimulation therapy for pain. J Pain 12, 1102–1111. Livingston, S.C., Goodkin, H.P., Ingersoll, C.D. (2010). The influence of gender, hand dominance, and upper extremity length on motor evoked potentials. J Clin Monit Comput 24, 427–436. Maarrawi, J., Peyron, R., Mertens, P., Costes, N., Magnin, M., Sindou, M., Laurent, B., Garcia-Larrea, L. (2013). Brain opioid receptor density predicts motor cortex stimulation efficacy for chronic pain. Pain 154, 2563–2568. Marlow, N.M., Bonilha, H.S., Short, E.B. (2013). Efficacy of transcranial direct current stimulation and repetitive transcranial magnetic stimulation for treating fibromyalgia syndrome: A systematic review. Pain Pract 13, 131–145. Massimini, M., Ferrarelli, F., Huber, R., Esser, S.K., Singh, H., Tononi, G. (2005). Breakdown of cortical effective connectivity during sleep. Science 309, 2228–2232. Moont, R., Crispel, Y., Lev, R., Pud, D., Yarnitsky, D. (2011). Temporal changes in cortical activation during conditioned pain modulation (CPM), a LORETA study. Pain 152, 1469–1477.
© 2015 European Pain Federation - EFICâ
Y. Granovsky et al.
Moreno-Duarte, I., Morse, L.R., Alam, M., Bikson, M., Zafonte, R., Fregni, F. (2014). Targeted therapies using electrical and magnetic neural stimulation for the treatment of chronic pain in spinal cord injury. NeuroImage 85, 1003–1013. Moulton, E.A., Pendse, G., Becerra, L.R., Borsook, D. (2012). BOLD responses in somatosensory cortices better reflect heat sensation than pain. J Neurosc 32, 6024–6031. Mylius, V., Borckardt, J.J., Lefaucheur, J.P. (2012). Noninvasive cortical modulation of experimental pain. Pain 153, 1350–1363. Nahmias, F., Debes, C., de Andrade, D.C., Mhalla, A., Bouhassira, D. (2009). Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers. Pain 147, 224–232. Nardone, R., H€ oller, Y., H€ oller, P., Thon, N., Thomschewski, A., Brigo, F., Trinka, E. (2013). The role of the ipsilateral primary motor cortex in movement control after spinal cord injury: A TMS study. Neurosci Lett 552, 21–24. Pagano, R.L., Assis, D.V., Clara, J.A., Alves, A.S., Dale, C.S., Teixeira, M.J., Fonoff, E.T., Britto, L.R. (2011). Transdural motor cortex stimulation reverses neuropathic pain in rats: A profile of neuronal activation. Eur J Pain 15, 268, e1-14. Pagano, R.L., Fonoff, E.T., Dale, C.S., Ballester, G., Teixeira, M.J., Britto, L.R. (2012). Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: Possible pathways for antinociception. Pain 153, 2359–2369. Pascual-Leone, A., Bartres-Faz, D., Keenan, J.P. (1999). Transcranial magnetic stimulation: Studying the brain-behaviour relationship by induction of ‘virtual lesions’. Philos Trans R Soc Lond B Biol Sci 354, 1229–1238. Pascual-Leone, A., Walsh, V., Rothwell, J. (2000). Transcranial magnetic stimulation in cognitive neuroscience–virtual lesion, chronometry, and functional connectivity. Curr Opin Neurobiol 10, 232–237. Peyron, R., Laurent, B., Garcıa-Larrea, L. (2000). Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 30, 263–288. Pich e, M., Arsenault, M., Rainville, P. (2009). Cerebral and cerebrospinal processes underlying counterirritation analgesia. J Neurosci 29, 14236–14246. Pitcher, J.B., Ogston, K.M., Miles, T.S. (2003). Age and sex differences in human motor cortex input-output characteristics. J Physiol 546, 605–613. Rossini, P.M., Barker, A.T., Berardelli, A., Caramia, M.D., Caruso, G., Cracco, R.Q., Dimitrijevic, M.R., Hallett, M., Katayama, Y., L€ ucking, C.H., et al. (1994). Noninvasive electrical and magnetic stimulation of the brain, spinal cord and roots: Basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol 91, 79–92. Ruff, C.C., Driver, J., Bestmann, S. (2009). Combining TMS and fMRI: From ‘virtual lesions’ to functional-network accounts of cognition. Cortex 45, 1043–1049. Sehm, B., Sch€ afer, A., Kipping, J., Margulies, D., Conde, V., Taubert, M., Villringer, A., Ragert, P. (2012). Dynamic modulation of intrinsic
© 2015 European Pain Federation - EFICâ
TMS-induced ‘virtual lesion’ attenuates heat pain
functional connectivity by transcranial direct current stimulation. J Neurophysiol 108, 3253–3263. Seifert, F., Maih€ ofner, C. (2011). Functional and structural imaging of pain-induced neuroplasticity. Curr Opin Anaesthesiol 24, 515–523. Siebner, H.R., Peller, M., Willoch, F., Minoshima, S., Boecker, H., Auer, C., Drzezga, A., Conrad, B., Bartenstein, P. (2000). Lasting cortical activation after repetitive TMS of the motor cortex: A glucose metabolic study. Neurology 54, 956–963. Siebner, H., Peller, M., Bartenstein, P., Willoch, F., Rossmeier, C., Schwaiger, M., Conrad, B. (2001). Activation of frontal premotor areas during suprathreshold transcranial magnetic stimulation of the left primary sensorimotor cortex: A glucose metabolic PET study. Hum Brain Mapp 12, 157–167. Siebner, H., Hartwigsen, G., Kassuba, T., Rothwell, J. (2009). How does transcranial magnetic stimulation modify neuronal activity in the brain? Implications for studies of cognition. Cortex 45, 1035– 1042. Silvanto, J., Muggleton, N.G. (2008). New light through old windows: Moving beyond the “virtual lesion” approach to transcranial magnetic stimulation. NeuroImage 39, 549–552. Stewart, L., Ellison, A., Walsh, V., Cowey, A. (2001). The role of transcranial magnetic stimulation (TMS) in studies of vision, attention and cognition. Acta Psychol (Amst) 107, 275–291. Summers, J., Johnson, S., Pridmore, S., Oberoi, G. (2004). Changes to cold detection and pain thresholds following low and high frequency transcranial magnetic stimulation of the motor cortex. Neurosci Lett 368, 197–200. Tamura, Y., Okabe, S., Ohnishi, T., N Saito, D., Arai, N., Mochio, S., Inoue, K., Ugawa, Y. (2004). Effects of 1-Hz repetitive transcranial magnetic stimulation on acute pain induced by capsaicin. Pain 107, 107–115. Terao, Y., Ugawa, Y. (2006). Studying higher cerebral functions by transcranial magnetic stimulation. Suppl Clin Neurophysiol 59, 9–17. de Tommaso, M., Brighina, F., Fierro, B., Francesco, V.D., Santostasi, R., Sciruicchio, V., Vecchio, E., Serpino, C., Lamberti, P., Livrea, P. (2010). Effects of high-frequency repetitive transcranial magnetic stimulation of primary motor cortex on laser-evoked potentials in migraine. J Headache Pain 11, 505–512. Tousignant-Laflamme, Y., Page, S., Goffaux, P., Marchand, S. (2008). An experimental model to measure excitatory and inhibitory pain mechanisms in humans. Brain Res 1230, 73–79. Yang, Y., Li, W., Zhu, B., Liu, Y., Yang, B., Wang, H., Wang, Z. (2007). Sex differences in antidepressant-like effect of chronic repetitive transcranial magnetic stimulation in rats. Prog Neuropsychopharmacol Biol Psychiatry 31, 735–740. Yarnitsky, D. (1997). Quantitative sensory testing. Muscle Nerve 20, 198– 204. Zaghi, S., Thiele, B., Pimentel, D., Pimentel, T., Fregni, F. (2011). Assessment and treatment of pain with non-invasive cortical stimulation. Restor Neurol Neurosci 29, 439–451. Ziemann, U. (2010). TMS in cognitive neuroscience: Virtual lesion and beyond. Cortex 46, 124–127.
Eur J Pain 20 (2016) 241--249
249
