Effect of repetitive transcranial magnetic stimulation on altered
perception of One
’s own face
Simple Futarmal Kothari
a,b,d,*, Lilja Kristin Dagsdottir
a,b, Mohit Kothari
c,d,
Jakob Udby Blicher
e, Abhishek Kumar
b,h, Poul Erik Buchholtz
g, Mahmoud Ashkanian
g,
Peter Svensson
a,b,faDepartment of Dentistry and Oral Health, Aarhus University, Aarhus C, 8000, Denmark bScandinavian Center for Orofacial Neurosciences (SCON), Denmark
cDepartment of Clinical Medicine, Aarhus University, Aarhus N, 8200, Denmark dHammel Neurorehabilitation and University Research Clinic, Hammel, 8450, Denmark eCFIN, Department of Clinical Medicine, Aarhus University, Aarhus N, 8200, Denmark fFaculty of Odontology, Malmø University, Sweden
gDepartment for Depression and Anxiety Disorders, Aarhus University Hospital, Aarhus N, 8200, Denmark hDepartment of Dental Medicine, Karolinska Institutet, Huddinge, 141 04, Sweden
a r t i c l e i n f o
Article history:
Received 30 August 2019 Received in revised form 28 December 2019 Accepted 2 January 2020 Available online 8 January 2020
Keywords:
Perceptual distortion of face Repetitive transcranial magnetic stimulation
Local anesthesia Theta-burst stimulation Orofacial pain
Primary somatosensory cortex
a b s t r a c t
Background: Chronic orofacial pain (COP) patients often perceive the painful face area as “swollen” without clinical signs; such self-reported illusions of the face are termed perceptual distortion (PD). The pathophysiological mechanisms underlying PD remain elusive.
Objective: To test the neuromodulatory effect of repetitive transcranial magnetic stimulation (rTMS) on PD in healthy individuals, to gain insight into the cortical mechanisms underlying PD.
Methods: PD was induced experimentally by injections of local anesthetic (LA) around the infraorbital nerve and measured as perceived size changes of the affected area. Participants were randomly allocated to inhibitory rTMS (n¼ 26) or sham rTMS (n ¼ 26) group. The participants rated PD at baseline, 6 min after LA, immediately, 20 and 40 min after rTMS. The rTMS (inhibitory and sham) was applied to face (lip) representation area of primary somatosensory cortex (SI) as an intervention at 10 min after the LA, when the magnitude of PD is large. As inhibitory rTMS, continuous theta-burst stimulation paradigm (50 Hz) for 40s was employed to inhibit cortical activity.
Results: We demonstrated a significant decrease in the magnitude of PD immediately and 20 min after the application of inhibitory rTMS compared with sham rTMS (P< 0.006). In two control experiments, we also showed that peripheral muscle stimulation and stimulation of a cortical region other than the lip representation area had no effect on the magnitude of the PD.
Conclusions: Inhibitory rTMS applied to a somatotopical-relevant cortical region modulates PD of the face in healthy individuals and could potentially have therapeutic implications for COP patients.
© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Body image is how an individual perceives the physical appearance of his/her own body [1]. An interaction between sen-sory inputs and feedback from peripheral afferents is required for generating the subjective body image [2,3]. When the input from a
body part is removed or disturbed such as after anesthesia or deafferentation, changes at cortical and subcortical levels occur resulting in body image disruptions or distortions of the perceived size of the affected body part, a phenomenon known as“perceptual distortion” (PD) [3e5]. Such PD is well-known in patients suffering from neurological and psychological disorders like phantom sen-sations [6], anorexia nervosa [7], complex regional pain syndrome (CRPS) [8] and chronic back pain [9].
It is of particular importance when such distortions occur in the face region as the face is a unique part of our personal identity. It is a * Corresponding author. Department of Dentistry and Oral Health, Aarhus
Uni-versity, Vennelyst Boulevard 9, DK-8000, Aarhus C, Denmark E-mail address:simple.futarmal@dent.au.dk(S.F. Kothari).
Contents lists available atScienceDirect
Brain Stimulation
j o u r n a l h o m e p a g e :h t t p : / / w w w . j o u r n a l s . e l s e v i e r. c o m/ b r a i n - s t i m u l a t i o n
https://doi.org/10.1016/j.brs.2020.01.001
key feature in showing and detecting emotions [10] and facilitating normal social and sensory interactions. Furthermore, dynamic integration of multisensory inputs is crucial for our perception and identification of our own face [11]. Thus, PD is considered as a multisensory phenomenon [11]. Orofacial pain patients often report that the painful facial area is“swollen” or “feels differently” [12,13]. There are often no clinical signs or physical differences present, hence such self-reported“illusions” may represent a sort of disrupted body image or a“perceptual distortion” of the face, and may contribute to the maintenance of facial pain [12e14]. Unfor-tunately, the mechanisms underlying such pain-related PDs are poorly understood. It is postulated that cortical reorganization of the primary somatosensory cortex (SI) is an associated factor [4,15,16]. The robustness of PD of the face have been illustrated experimentally by Dagsdottir et al., by transiently blocking nerve transduction using local anesthetics (LA) in the orofacial region [11,13,14].
Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique can modulate cortical func-tion using facilitatory and inhibitory paradigms, which in turn can modulate cognition and behavior (i.e., PD) [17,18]. Recently, Giur-gola et al. showed that low-frequency rTMS delivered to the SI hand area results in overestimation of the perceived size of the partici-pant’s own hand [15]. Further, with the use of continuous theta-burst stimulation (cTBS) paradigms, inhibitory responses have been reported that outlast the duration of the conditioning stim-ulus for up to an hour [19]. The approach with inhibitory rTMS stimulation will allow identifying the neural substrate responsible for PD.
Therefore, this study aimed to test the neuromodulatory effect of rTMS on evoked PD in healthy individuals in order to gain an insight into the possible underlying cortical mechanisms important for coding PD. We hypothesized that inhibitory rTMS paradigm applied to the somatotopic relevant cortical region (SI) could block the induction of evoked PD.
Materials and methods Participants
In total, 58 healthy individuals were recruited in the study, however six individuals were excluded as the lip representation area of primary motor cortex (MI) could not be located. Thus, in this study 52 healthy individuals were included who were randomly allocated to either inhibitory rTMS (n ¼ 26; mean ± SD age: 24.7± 4.5 years, 12 females) or Sham rTMS (n ¼ 26; mean ± SD age: 25.3± 6.6 years, 14 females). All participants were right-handed and free from any neurological or psychological disorders, without any pain and history of trauma to face, took no medica-tions, and had no contraindications to TMS and LA. All participants were examined prior to the experiment with a chairside sensory test at the facial region to confirm normal bilateral somatosensory function [20]. All participants gave their written informed consent prior to the study. The study was approved by the local ethics committee in Denmark (no. 1-10-72-72-17) and was performed in accordance with the Helsinki Declaration.
Experimental protocol - main experiment
This study was performed as a single-blinded, randomized, and placebo controlled trial. Here, PD wasfirst induced experimentally in the face region. Following which, rTMS was employed as an intervention to modulate the magnitude of PD. The overview of the study design is presented inFig. 1.
Experimentally evoked perceptual distortion
Perceptual distortion was induced experimentally by unilateral, intraoral LA injections of 1.0 ml of Mepivacaine hydrochloride (20 mg/ml with 10
m
g/ml adrenaline) (Scandonest-Adrenalin, SEPTODONT, Saint-Maur-Des-Fossess, France), around the infraor-bital nerve on the right side of the face in all the participants. PD was defined as a perceived change in the size (e.g. swollenness/ increase or reduction/decrease) in the participant’s midface cor-responding to the infraorbital nerve region involving the upper lip compared with the unaffected contralateral side [11]. A verbal numerical rating scale (VNRS) ranging from 100% through 0% toþ100%, where 0% ¼ “no size change”, 100% ¼ “half the size” and þ100% ¼ “double the size” compared to the non-affected contralateral side of the face was used to rate the PD of the affected face area [11,13]. Further, to confirm the location of PD, the participants were asked to mark/map the area affected by PD on an outlined face drawing (Fig. A.1) [11]. The participants were excluded if they did not perceive any size changes in the injected area.Mechanical and visual stimulations
PD is a multisensory phenomenon [11] so in addition to the LA injection, mechanical and visual stimulations were applied to create a robust illusion of PD. Thus, immediately after mapping the area of perceived changes on the face drawings and rating the PD, visual stimulation was provided. Here, the participants were asked to handle an image of their own face by stopping a slow running film clip of gradual and stepped distortion of their face, according to their current feeling of PD. These computer manipulation warps of the participants face were used as visual stimuli (Fig. A.2) (For a detailed description, see appendix, and Skyt et al.) [13]. Mechanical Fig. 1. Overview of the study design. rTMS¼ repetitive transcranial magnetic stimu-lation; PD¼ perceptual distortion; LA ¼ local anesthesia; VNRS ¼ verbal numerical rating scale; SI¼ primary somatosensory cortex.
stimulation was then given using a non-painful 128 mN von Frey filament, while the participants received visual feedback. This acted as a combined visualþ mechanical stimuli. For mechanical stim-ulation, the von Freyfilament was applied 10 times (1 Hz pace) at the center of the area marked to be distorted on the participant’s individual drawings. The visual feedback consisted of a warped snapshot (still photograph) of the participant’s distorted face on the computer screen, matching their current feeling of PD [11]. Thus, the participants rated for the perceived size changes of the affected face area i.e., PD during three sensory stimulation conditions (a) before applying sensory stimulation (i.e., when the participants mapped the distorted area on face drawings (Fig. A.1) (b) during visual stimulus and (c) after receiving mechanical stimuli together with the visual feedback, i.e., combined visual þ mechanical stimuli. These ratings of PD for all the three sensory stimulation conditions were given atfive different time points: baseline (before injection), 6 min after LA, immediately, 20 and 40 min after rTMS. At baseline, no visual or mechanical stimuli were given. The par-ticipants were simply asked if they experienced any change in the size/shape of the facial area and were asked to rate on the VNRS. Assessment of LA effect on general somatosensory function and its results are presented in appendix.
Repetitive transcranial magnetic stimulation (rTMS)
The rTMS was applied to right face (lip) representation area of SI at 10 min after the LA administration, which was when the magnitude of PD was large (Fig. 1). The rTMS stimulation site and intensity were identified prior to inducing PD i.e., before adminis-tering the LA.
In order to locate the lip representation area of SI, the right hand and thereafter right lip representation area of the contralateral primary motor cortex (MI) was identified using single pulse TMS. TMS (Magventure, Farm, Denmark) was delivered through a 70 mm diameterfigure-of-eight coil over the contralateral MI at the opti-mum scalp position to elicit motor evoked potentials (MEPs) in the first dorsal interosseous (FDI) muscle. The optimum scalp position (“hot spot”) that elicited a maximum FDI response was then
identified [21]. The FDI hotspot was identified to ease the location of the MI lip area. The procedure was repeated for the lip area, with MEPs being recorded in the orbicularis oris, starting from a site 3 cm lateral and 1.5 cm anterior to the hand site (Fig. 2A) [22]. The resting motor threshold (rMT) of lip was determined as the mini-mum stimulus intensity needed to produce MEPs of 10
m
V (peak to peak) or more in at least 5 of 10 consecutive stimuli. The mean± SD rMT for the lip area was 50.3± 3.9% of maximum stimulator output (MSO).At the time of devising this study, no studies were found describing the distance between lip representation area of MI and SI to guide the location of the rTMS. Therefore, we measured the distance between the lip area of MI and SI in four healthy partici-pants using anatomical MRI, and a Neuronavigation system for TMS (eXima NBS, Nexstim Plc., Helsinki, Finland). Specifically, a T1 weighted magnetic resonance image was acquired (3T TimTrio, Siemens Erlangen Germany) and imported into the navigation de-vice. Hand and lip hotspots were identified and marked on the cap as described above. The lip hotspot was identified on the navigation device (in the precentral gyrus), and the coil was moved orthogonal posterior to the postcentral gyrus, and the point was marked on the cap. The distance between the lip-hotspot and the postcentral gy-rus was then measured on the cap. Accordingly, we defined a point 2.2 cm posterior to the orbicularis oris motor“hot spot” to stimu-late the S1. This site corresponded approximately to the lip repre-sentation area of SI.
The rTMS (inhibitory and sham) was applied to the lip repre-sentation area of SI as an intervention. A Magstim X100 stimulator (Magventure, Farm, Denmark) was used with a MCF-B65 figure-of-eight coil (MagVenture) to deliver inhibitory rTMS. High frequency cTBS paradigm which produces inhibitory effect was delivered for 40 s as an inhibitory rTMS. Here 200 bursts of TMS pulses (80% rMT intensity) were applied continuously at 5 Hz rate; each burst con-sisted of 3 pulses delivered at 50 Hz rate. A total of 600 pulses were applied [19]. For placebo stimulation, a sham rTMS was applied using the same stimulation parameters as with real cTBS, but using a placebo coil, which produced similar sound as the real coil. After
Fig. 2. Motor evoked potentials of the right orbicularis oris muscle (A) and tibialis anterior muscle (B) resulting from cortical single-pulse transcranial magnetic stimulation of the contralateral lip and leg primary motor cortex (MI) respectively.
the intervention, participants were asked to rate the sensations caused by the rTMS intervention on a Likert scale: very unpleasant, unpleasant, neither pleasant nor unpleasant, pleasant and very pleasant.
Control experiment 1
This experiment aimed to evaluate the natural course of experimentally induced PD over time. Here no intervention was given, but participants (n¼ 10) simply rated perceived size changes at different time points (baseline, 6, 10, 30 and 50 min after LA) as done in the main experiment. The time points 10, 30 and 50 min after LA corresponded to immediately, 20 and 40 min after rTMS of the main experiment. The ten participants did not take part in the main study.
Control experiment 2
Due to lateral placement of the cortical lip area, the coil was placed quite close to the temporalis and masseter muscle while employing inhibitory rTMS. This consequently resulted in consid-erable direct muscle activation. Thus, this experiment was per-formed to evaluate if there was any effect from the muscle input/ stimulation on the magnitude of the PD. Nine participants from the inhibitory rTMS group were included. Here again, LA was injected into the infraorbital region. The experimental protocol was the same as for the main experiment. However, no inhibitory rTMS was given, but the reported PD scores of the nine participants at different time points were taken from the main experiment and were used for the analysis. As a control intervention, trans-cutaneous electrical nerve stimulation (TENS) (Cefar prima pro, Malmo, Sweden) with a high frequency of 80 Hz was applied simultaneously to the left temporalis and masseter muscle along with the sham rTMS for 40 s. Before the stimulation, circular ad-hesive electrodes (3.2 cm in diameter) were placed on left tem-poralis and masseter muscles. The intensity of the TENS to be applied for each muscle was determined before the start of this experiment based on the ratings given on the Likert scale of the inhibitory rTMS intervention induced sensations during the main experiment. The participants again scored for the perceived size changes at different time points as done in the main experiment. Control experiment 3
This experiment was performed to evaluate if application of cTBS at the cortical region other than the lip had an effect on the magnitude of the PD. Five participants from the inhibitory rTMS group were included. Here again, LA was injected into the infraor-bital region. Experimental protocol was same as the main experi-ment (Fig. 1) except that instead of sham rTMS, participants received cTBS for 40 s at the leg representation area of SI. The re-sults were compared with the inhibitory rTMS session from the main experiment. Localization of the leg SI area (Fig. 2B) is described in detail in appendix. In all the control experiments, all the three sensory stimulation conditions were applied as done in the main experiment. The control experiments were conducted more than 2 months after the main experiment to make sure that the participants did not have carry-over effect of previously ob-tained cTBS on PD.
Statistical analyses
The sample size was determined for this parallel-design study based on the risk of type I and II errors determined as 5% and 20% respectively, with the estimated variance in the PD measures
approximately 20% [13]. Accordingly, a total of 26 participants entered each intervention group.
The data was assessed for normality using descriptive normality tests and Kolmogorov-Smirnov test. To test the hypothesis that inhibitory rTMS paradigm applied to face SI could block the in-duction of evoked PD, below statistical tests were performed. The changes in the magnitude of PD at different time points were compared between the groups using a two-way analysis of variance (ANOVA) with Group (inhibitory and sham) as between group fac-tor and Time (baseline, 6 min after LA, immediately, 20 and 40 min after rTMS) as repeated measures, followed by post-hoc Tukey tests, when appropriate. The above analysis was performed sepa-rately on the VNRS scores of PD obtained during three different sensory stimulation conditions: before applying sensory stimula-tion, after visual stimulus and after visualþ mechanical stimuli. However, on comparing the reported PD scores at each time point between the sensory stimulation conditions, there were no signif-icant differences found in both active (P¼ 0.160) and sham groups (P¼ 0.076). Therefore, only results obtained for the perceived size changes after visualþ mechanical stimuli are presented here. For control experiment 1, the PD scores reported during this experi-ment were compared to the inhibitory and sham rTMS session of the main experiment using ANOVA with Group (no intervention, inhibitory and sham) and Time as factors. Further, for the control experiment 2, the effect of inhibitory rTMS and TENS on the magnitude of PD at different time points were also compared using three separate two-way ANOVAs with Sessions (inhibitory rTMS, TENS) and Time as factors. Finally, for the control experiment 3, the effect of inhibitory rTMS applied at lip and leg area of SI on the magnitude of PD at different time points were also compared similarly with Site (inhibitory rTMS at lip area and leg area) and Time as factors. In the main experiment, there was no main effect of the group. This could be because the baseline values and the PD values 6 min after LA were almost equal in both the groups. Therefore, we performed additional test of the area under the curve (AUC) for the PD scores obtained after the application of rTMS and performed between-group comparison using t-tests. Similar tests of AUC were also performed for control experiments 2 and 3 and the results are presented in appendix. Further, the effect of sensory stimulation on the magnitude of PD in the control experiments were also analyzed using ANOVA with Time (without baseline) and sensory stimulation (before, after visual stimulus and after com-bined visual and mechanical stimuli) as factors.
All data are presented as mean± standard error of the mean (SEM). Statistical significance was set at P < 0.05.
Results
Main experiment: effect of inhibitory and sham rTMS on perceptual distortion
All the participants reported PD in the infraorbital region, including the lip and cheek region after the LA administration. However, there was a consistent report of an increase in size in the right lip region. Therefore, the VNRS scores of the reported PD for the lip region were only taken into account for the analyses.
The results of rTMS intervention on the perceived size changes were similar for all the three sensory stimulation conditions. Moreover, there were no significant differences between the sen-sory stimulation conditions for the PD scores reported at each time point in both the groups (P> 0.160). Thus, the results obtained for the perceived size changes after multisensory input, i.e., combined visual and mechanical stimuli are explicitly presented here. Same was done for the control experiments, as again, no significant dif-ferences were found between the sensory stimulation conditions
for the PD scores reported at each time point (control experiment I: P¼ 0.388; control experiment II: P ¼ 0.653; control experiment III: P¼ 0.959). The results of other two sensory stimulation conditions for all the experiments are shown in appendix, Table A.2-A.5.
The ANOVA showed a significant effect of time (P < 0.001), but not the group (P¼ 0.267) on the PD scores. Importantly, there was a significant interaction between the group and time (P < 0.001). Post-hoc tests showed that the PD scores differed significantly between all the time points (P< 0.004). Interestingly, the post-hoc tests for interaction revealed that the magnitude of PD was significantly lower immediately and 20 min after the application of cTBS compared with sham rTMS (P < 0.004) (Fig. 3). Further, compared with 6 min after LA, the magnitude of perceived size changes were significantly lower immediately, 20 and 40 min after cTBS in the inhibitory rTMS group (P< 0.001) but for the sham rTMS group, the PD was significantly lower only at 40 min after rTMS (P< 0.001) (Fig. 3). With sham rTMS as an intervention, there were no significant differences in the perceived size changes be-tween 6 min after LA, immediately and 20 min after rTMS (P¼ 0.099).
The analysis of the AUC for PD scores obtained after rTMS showed a significant decrease in the perceived size changes for the inhibitory group compared to sham (P¼ 0.035).
Control experiment 1
There was a significant effect of time (P < 0.001) but not group (P¼ 0.115). There was also a significant interaction between group and time (P< 0.001). All the time points were significantly different from the baseline (P < 0.001). Importantly, the post-hoc test showed that the magnitude of PD was significantly lower imme-diately, 20 and 40 min after cTBS compared with the corresponding time points of the no intervention group (P< 0.001). Further, the PD
scores did not differ statistically significantly between the sham rTMS and no intervention group at any time points (P> 0.098) (Fig. 3).
Control experiment 2
ANOVA revealed a main effect of session (P < 0.001) with significantly lower scores of PD reported at the right lip region during the inhibitory rTMS session compared to the TENS session. A main effect of time (P< 0.001) also occurred with baseline signif-icantly different from all other time points (P< 0.001). Interest-ingly, there was also a significant interaction between session and time (P¼ 0.001). Post-hoc tests revealed that the participants re-ported significantly lower magnitude of PD immediately, 20 min and 40 min after the application of cTBS compared with the TENS (P< 0.003) (Fig. 4). Further, compared with 6 min after LA, the magnitude of perceived size changes were significantly lower immediately, 20 and 40 min after the application of inhibitory rTMS (P< 0.011) but not after the application of TENS (P > 0.160) (Fig. 4). Control experiment 3
ANOVA showed a main effect of site and time (P< 0.002) on PD scores. There was also a significant interaction between site and time (P¼ 0.004). Post-hoc tests revealed that the participants re-ported lower perceived size changes at the right lip region when cTBS was applied to the lip representation area of SI compared to the leg representation area (P ¼ 0.002). The PD scores at the baseline were significantly different from all other time points (P< 0.001). The perceived size changes reported at 6 min after LA were significantly higher than the PD scores reported at 20 and 40 min after rTMS (P< 0.001). Importantly, participants reported significantly lower magnitudes of PD immediately, 20 min and
Fig. 3. (A) Effect of inhibitory, sham rTMS and no intervention on the magnitude of experimentally evoked perceptual distortion of the face at different time points. (B) Individual/ actual values of perceived size changes rated by 26 individuals at different time points during inhibitory rTMS session. (C) Individual/actual values of perceived size changes rated by 26 individuals at different time points during sham rTMS session. rTMS¼ repetitive transcranial magnetic stimulation; LA ¼ local anesthesia. * indicates significantly different from sham rTMS.¤ indicates significantly different from no intervention group. # indicates significantly different from 6 min after LA. Dotted line indicates time of intervention. Bold line indicates mean verbal numerical rating scale scores of perceptual distortion. Error bars show standard error of the mean (SEM).
40 min after the application of cTBS at the lip area compared to the leg area of SI (P< 0.010) (Fig. 5). Further, compared with 6 min after LA, the magnitude of perceived size changes significantly decreased 20 and 40 min after the application of cTBS at the lip area of SI (P< 0.011) but with cTBS applied to the leg area of SI, the perceived size changes were significantly lower only at 40 min after inhibitory rTMS compared to 6 min after LA (P< 0.001) (Fig. 5).
Discussion
To our knowledge, this is the first study to employ a non-invasive neuromodulatory intervention to modulate the magni-tude of experimentally induced PD in the face of healthy in-dividuals. The keyfinding was that there was a significant decrease in the magnitude of perceived size changes on application of cTBS at the face (lip) representation area of SI compared to the sham rTMS. Additionally, the control experiments revealed the impor-tance of face SI as the neural substrate responsible for coding PD of the facial region.
Distorted body image or PD has been extensively studied in many conditions such as phantom sensations, anorexia nervosa, chronic back pain and CRPS [6e9]. However, only a few studies have looked into such a phenomenon in the orofacial region [3,13,14], although a study reported that 55% of the chronic orofa-cial pain patients experienced PD [12]. Changes in the facial perception can be studied by employing LA, multisensory stimu-lation or by stimulating the peripheral sensory afferents, resulting in a striking illusion of a measurable changed perception as seen in the present study [5,11,14]. Interestingly, employing low frequency (1 Hz) rTMS to SI hand area in both hemispheres has shown to cause PD of participant’s own hand [15]. Further studies should evaluate the effect of low frequency rTMS on changes in facial perception.
The understanding of neural mechanisms underlying disrupted body image or PD is in an early stage [9,23]. As with other condi-tions mentioned above, the PD following administration of LA has also been linked to neuroplasticity/cortical reorganization (short-term) of the SI [4,24]. It has been proposed that modulation of corticalɤ-aminobutyric acid (GABA) may play an essential role in cortical reorganization that occurs within minutes and hours after manipulation of sensory input [25,26]. Thus, presumably the mechanism of action could also be related to changes in the cortical GABA levels, a key factor in cortical inhibition.
Studies have employed tactile discrimination training, mirror box therapies, and virtual reality applications to normalize the body image disruptions, however, the results are inconsistent [27e29]. Interestingly, for the orofacial region, only one study was found which employed multisensory stimulation as an intervention to experimental PD [11]. Although, in this study there was a sig-nificant decrease in PD at 10, 20 and 30 min after LA, the effect size was small [11]. Moreover, the intervention was provided at all time points unlike the present study [11]. In the present study, appli-cation of cTBS significantly decreased the magnitude of perceived size changes not only compared to sham rTMS, but also compared to 6 min after LA (before intervention) until 40 min after active rTMS applied to lip SI suggesting face SI as cortical structure involved in PD of the face. Moreover, application of cTBS at the leg representation area of SI in the control experiment did not have an effect on the perceived size changes of the affected face area (Fig. 5A). Thus, providing further support that face SI plays a specific role in the processing of PD of the face. The neural basis of inhibi-tory mechanisms induced by cTBS is still under active in-vestigations [30]. It can be speculated that cTBS applied to face SI produces lasting changes in the excitability of the intracortical circuits generating somatosensory evoked potentials (SEPs) by inducing long-term depression-like synaptic plasticity in SI [31]. Fig. 4. Effect of (A) inhibitory rTMS and transcutaneous electric nerve stimulation (TENS) on the magnitude of experimentally evoked perceptual distortion of the face at different time points. (B) Individual/actual values of perceived size changes rated by nine individuals at different time points during inhibitory rTMS session. (C) Individual/actual values of perceived size changes rated by nine individuals at different time points during TENS session. rTMS¼ repetitive transcranial magnetic stimulation; LA ¼ local anesthesia. * indicates significantly different from TENS. # indicates significantly different from 6 min after LA. Dotted line indicates time of intervention. Bold line indicates mean verbal numerical rating scale scores of perceptual distortion. Error bars show standard error of the mean (SEM).
The current study is also associated with some limitations:first, the measurement of PD was mainly based on subjective reports, however, use of computer manipulation warps further confirmed the presence of the facial PD [13]; Second, the sample sizes of the control experiments were small. Nevertheless, thefindings of the control experiments add robustness to the mainfinding that cTBS applied to face S1 can significantly reduce the magnitude of PD; Third, PD was always induced experimentally on the right side of the face in all the participants and rTMS was given on the contra-lateral hemisphere. Studies have shown hemispheric differences in intracortical excitability using TMS. Therefore, it would be inter-esting to evaluate the effect of rTMS on the PD evoked on left side of the face.
Having shown that PD is prevalent in orofacial pain patients and might contribute to the maintenance of orofacial pain [12], this study has important clinical implications. Thefindings of this study may open up new complementary neurocognitive management strategies for chronic facial pain patients and will also aid in better understanding of perceived size changes and chronic pain. If this non-invasive, non-pharmacological neuromodulatory intervention (rTMS) is proven successful in orofacial pain patients, it will open avenues for treating not only other pain conditions showing this unique phenomenon but also other neurological and psychological disorders.
In conclusion, cTBS applied to a somatotopic-relevant cortical region appears to modulate orofacial PD towards a normalized perception. From thefindings of this study, it could be speculated that cTBS might have therapeutic effects in chronic orofacial pain patients. Further research is now needed to evaluate the effect of neuromodulatory interventions on PD and pain in chronic facial pain patients.
Declaration of competing interest
None of the authors has any conflicts of interests.
CRediT authorship contribution statement
Simple Futarmal Kothari: Methodology, Formal analysis, Investigation, Writing - original draft. Lilja Kristin Dagsdottir: Methodology, Writing - review& editing. Mohit Kothari: Meth-odology, Writing - review& editing. Jakob Udby Blicher: Meth-odology, Visualization, Writing - review & editing. Abhishek Kumar: Conceptualization, Methodology, Writing - review & editing. Poul Erik Buchholtz: Methodology, Writing - review& editing. Mahmoud Ashkanian: Methodology, Writing - review& editing. Peter Svensson: Conceptualization, Methodology, Writing - review& editing, Supervision, Funding acquisition.
Acknowledgements
Funding: This study was funded by Det Frie Forskningsråd, Danish council for independent research, Denmark with grant reference number 6110-00156.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
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Fig. 5. Effect of (A) inhibitory rTMS at lip and leg representation area of primary somatosensory cortex (SI) on the magnitude of experimentally evoked perceptual distortion of the face at different time points. (B) Individual/actual values of perceived size changes rated byfive individuals at different time points during inhibitory rTMS session at lip SI. (C) Individual/actual values of perceived size changes rated byfive individuals at different time points during inhibitory rTMS session at leg SI. rTMS ¼ repetitive transcranial magnetic stimulation; LA¼ local anesthesia. * indicates significantly different from inhibitory rTMS at leg SI. # indicates significantly different from 6 min after LA. Dotted line indicates time of intervention. Bold line indicates mean verbal numerical rating scale scores of perceptual distortion. Error bars show standard error of the mean (SEM).
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