effects of transcranial direct current stimulation on esophageal motility in patients with...

Clinical Neurophysiology xxx (2014) xxx–xxx

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Clinical Neurophysiology

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Effects of transcranial direct current stimulation on esophageal motilityin patients with gastroesophageal reflux disease

1388-2457/$36.00 � 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.http://dx.doi.org/10.1016/j.clinph.2013.12.110

⇑ Corresponding author. Address: Department of Experimental Biomedicine andClinical Neuroscience (BioNeC), University of Palermo, Via Gaetano La Loggia 1,90129 Palermo (PA), Italy. Tel.: +39 0916555105; fax: +39 091 6555102.

E-mail address: [email protected] (S. Vigneri).

Please cite this article in press as: Vigneri S et al. Effects of transcranial direct current stimulation on esophageal motility in patients with gastroesopreflux disease. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2013.12.110

Simone Vigneri a,⇑, Sebastiano Bonventre b, Angela Inviati b, Domenico Schifano b, Giuseppe Cosentino a,Angela Puma c, Giuseppe Giglia a, Piera Paladino a, Filippo Brighina a, Brigida Fierro a

a Department of Experimental Biomedicine and Clinical Neurosciences (BioNeC), University of Palermo, Italyb Department of Emergency Surgery – Digestive Motility Section, University of Palermo, Italyc Santa Maria del Prato Hospital, Feltre, Italy

a r t i c l e i n f o h i g h l i g h t s

Article history:Accepted 24 December 2013Available online xxxx

Keywords:tDCSDistal amplitudePathological wavesNERDERDSensitization

� Prolonged excitatory tDCS over the esophageal motor cortical cortex can significantly modifyesophageal peristalsis in gastroesophageal reflux disease (GERD) patients.

� Anodal tDCS have shown a strong effect on distal waves mean amplitude and percentage of patholog-ical waves in patients with non-erosive reflux disease (NERD).

� Erosive reflux disease (ERD) parameters were not significantly modified by tDCS. These datastrengthen the hypothesis of a different pathophysiology and progression into a chronic (i.e.unresponsive) form in patients with ERD.

a b s t r a c t

Objective: To evaluate the effects of transcranial direct current stimulation (tDCS) on esophageal peristal-sis in patients with gastroesophageal reflux disease (GERD).Methods: Patients with GERD preliminary diagnosis were included in a randomized double-blind sham-controlled study. Esophageal manometry was performed before and during transcranial direct currentstimulation (tDCS) of the right precentral cortex. Half of patients were randomly assigned to anodal, halfto sham stimulation. Distal waves amplitude and pathological waves percentage were measured, afterswallowing water boli, for ten subsequent times. Last, a 24 h pH-bilimetry was done to diagnose non-erosive reflux disease (NERD) or functional heartburn (FH). The values obtained before and during anodalor sham tDCS were compared.Results: Sixty-eight patients were enrolled in the study. Distal waves mean amplitude increased signifi-cantly only during anodal tDCS in NERD (p = 0.00002) and FH subgroups (p = 0.008) while percentage ofpathological waves strongly decreased only in NERDs (p = 0.002).Conclusions: Transcranial stimulation can influence cortical control of esophageal motility and improvepathological motor pattern in NERD and FH but not in erosive reflux disease (ERD) patients.Significance: Pathophysiological processes in GERD are not only due to peripheral damage but to centralneural control involvement as well. In ERD patients dysfunctions of the cortico-esophageal circuit seemto be more severe and may affect central nervous system physiology.� 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights

reserved.

1. Introduction

Gastroesophageal reflux disease (GERD) is a widespreaddisorder affecting the 10–20% of population in Western countries

with an increasing prevalence in the last two decades. GERD canbe subdivided into erosive (ERD) and non-erosive (NERD) subtypes,the former being diagnosed if pathological acid exposure andnormal endoscopic examination occur while the latter ifendoscopic evidence of mucosal injury is found. Patients affectedby recurrent chest pain but with negative acid exposure and nor-mal endoscopy are usually considered as functional heartburn(FH). Clinical manifestations include esophageal (e.g. heartburn,regurgitation, dysphagia) and extraesophageal (e.g. cough, asthma,

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2 S. Vigneri et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

hoarseness) symptoms (Lacy et al., 2010). GERD can severelyimpair quality of life and sometimes worsen to life-threateningconditions such as Barrett’s esophagus and esophageal adenocarci-noma (Shaheen and Ransohoff, 2002). Ineffective esophagealmotility (IEM) is the most common manometric finding, definedas distal esophageal hypocontractility in at least 30% of wet swal-lows, characterized either as low-amplitude peristaltic waves(<30 mmHg), low-amplitude simultaneous or not propagatedwaves, or absent peristalsis (Spechler and Castell, 2001).

In early studies with transcranial magnetic stimulation (TMS)on healthy subjects, Aziz et al. (1995) suggested that stimulatedcortico-esophageal pathways share the same population of brain-stem motor neurons activated during swallowing and vagal stimu-lation, while electromyographic responses evoked by focal TMSsucceeded in identifying the topographic representation of theesophagus on the cerebral cortex (Aziz et al., 1996). Transcranialdirect current stimulation (tDCS) is a safe and non-invasive formof neurostimulation involving purely modulatory effects on humancortex and is burdened with fewer technical artifacts such asacoustic noise and muscle twitching in comparison with TMS,making it more suitable for double-blind, sham-controlled studies(Tanaka and Watanabe, 2009). Due to the area of surface electrodesthe device ensure a wide area of cortical stimulation but, on theother hand, low spatial resolution and poorly selective effects. An-odal tDCS applied to the human cortex immediately increases cor-tical excitability while cathodal tDCS results in the opposite effect(Nitsche et al., 2008). Long-lasting sessions (over 10 min) can altercortical excitability for up to 1 h, depending on the intensity of thecurrent and the duration of the stimulation. Short-term effects aredue to an action on membrane polarization thus modulating theconductance of sodium and calcium channels, while long-termeffects are consequential to modulation of N-methyl-D-aspartate(NMDA) receptors resembling long-term potentiation and long-term depression (Nitsche et al., 2003; Antal et al., 2006). A recentstudy using tDCS to modulate pharyngeal motor cortex in healthysubjects showed a positive influence of anodal currents on cortico-bulbar excitability (Jefferson et al., 2009).

Aim of the present study was to investigate the effects of anodaltDCS on esophageal peristalsis in a randomized double-blindsham-controlled study in patients with GERD.

2. Methods

2.1. Patients

We recruited adults between 18 and 65 years of age with GERDsymptoms according to a reflux disease questionnaire (RDQ) score>12 based on symptoms over the previous 2 weeks (Shaw et al.,2001), a positive response to a proton pump inhibitor (PPI) trialand a disease duration not inferior to 6 months. Prior to enrollmenteach patient underwent an esophageal endoscopy in order todifferentiate ERD from NERD, and withdrew PPI therapy at least7 days before. The severity of esophagitis was assessed accordingto the Los Angeles classification (Armstrong et al., 1996). Patientsaffected by neurological, neoplastic or systemic diseases, or takingdrugs which could affect central nervous system or esophagealmotility were excluded from the study. Clinical evaluations andinterviews were conducted by a neurologist and a surgeon expertin digestive motility disorders, who made the final decisions withrespect to eligibility.

2.2. tDCS settings

A continuous current was delivered via two electrodesmeasuring 5 � 7 cm using a battery-driven constant current

Please cite this article in press as: Vigneri S et al. Effects of transcranial direct cureflux disease. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.201

stimulator (Magstim DC Stimulator). All patients comfortablyseated and in a safe environment wore a tight-fitting plastic swim-mer’s cap to mark the optimum site of stimulation. Afterward, thecap was removed and electrodes were fixed thanks to elastic headstraps placed around the head circumference, according tostandard procedures as suggested in several studies (Da Silvaet al., 2011). Cz was located at the vertex using the international‘‘10–20’’ system (Herwig et al., 2003) and, in agreement with pre-vious studies, the active electrode was placed with its center 4 cmin front and 5.5 cm lateral to the vertex on the right hemisphere inorder to stimulate the ‘‘esophageal cortical area’’, while the refer-ence electrode was placed above the contralateral mastoid (Azizet al., 1996). The stimulation side was chosen because esophagealfunction on human cortex has been reported to be asymmetric,prevailing on the right rather than left side in most of studies. Nev-ertheless, previous studies have reported that evoked potentialscan be recorded from esophageal muscles following TMS on bothhemispheres, therefore stimulating the ‘‘non-dominant’’ hemi-sphere should not significantly affect esophageal response (Azizet al., 1996; Hamdy et al., 2001). The mastoid was chosen becauseit ensured a wider and deeper pattern of stimulation in comparisonwith supraorbital montage (Datta et al., 2011). For anodal stimula-tion a current of 1.5 mA intensity was delivered for the wholeduration of the esophageal manometry (on average 20 min). Unfor-tunately, the stimulation time could not be previously set becauseit was determined by the duration of manometry. Nevertheless,differences in stimulation time between subjects were minimaland we evaluated the on-line rather than post-tDCS off-line effects,therefore we believe this variability could unlikely affect results.

The current intensity applied for stimulation is in the range ifcompared with most of recent studies (Brunoni et al., 2012). Forsham stimulation the device was turned off after 30 s of stimula-tion at the same intensity in order to give to the patients a localtemporary tingling sensation and a feeling of stimulation whichhas been reported to be indistinguishable from anodal tDCS(Gandiga et al., 2006; Jaberzadeh et al., 2013). No adverse effectswere observed during and after stimulation.

2.3. Esophageal manometric and pH-metric settings and parameters

An appropriate flexible probe (Mui Scientific, E4555) closed tip,4 radial ways with bearing point, has been used for the tests; per-fusion equipment involves an azotes infusion pump: ‘‘InternationalBiomedical Inc. mod. 745–0100’’; recording of data by an auto-calibrating polygraph ‘‘Narco Bio System MMS 200’’ connected toa PC by a dedicated software for automatic analysis of acquireddata. Lower esophageal sphincter (LES) pressure was obtainedthanks to four pressure sensors separated by intervals of 5 cmand placed internally at different sides of the probe, the distalesophageal body was assessed 3 cm over the LES: both theseparameters were measured in mmHg. Regarding 24 h pH-metry,a Microdigitrapper or a Digitrapper pH recorder were randomly usedfor each patient. Probes (placed 5 cm above the manometricallydetermined upper border of LES) were calibrated in a standardbuffer solution (pH = 7 and 1) either before and after monitoring.A pH Software Analysis Program was used for data analysis. ABilitec 2000 fibreoptic probe was used to detect bile reflux.

2.4. Study protocol

The study was conducted in the digestive motility section in asafe and quiet environment, in accordance with the declarationof Helsinki and was approved by local ethics committee (Rickham,1964). A written informed consent was obtained from each patientbefore starting the protocol. Eligible patients were randomlyassigned in a 1:1 ratio to one of the two groups: one group

rrent stimulation on esophageal motility in patients with gastroesophageal3.12.110


S. Vigneri et al. / Clinical Neurophysiology xxx (2014) xxx–xxx 3

underwent anodal stimulation while the other underwent shamstimulation. The difference in age and gender distribution of thetwo groups was not significant (p > 0.05). While sitting on theexamination table and after tDCS electrode placement, the patientwas asked to bring the chin down to chest and the probe was in-serted through the nose and guided down the esophagus into thestomach. The esophageal manometry was lead by an expert physi-cian unaware of the type of stimulation applied to the patient, andperformed in two conditions: baseline and during anodal or shamcortical stimulation. First LES pressure was evaluated with pull-through technique thanks to four pressure sensors separated byintervals of 5 cm, in order to have four values. Then esophageal dis-tal body was assessed by giving to the subject 5 ml of water with asyringe and asking him for ten subsequent times to swallow, withan interval of 30 s between each swallow in order to prevent a cen-trally mediated inhibition of peristalsis (Hamdy et al., 1999). More-over, if pathological waves resembling IEM (i.e., peristaltic waves<30 mmHg, simultaneous or not propagated waves, or absent peri-stalsis) occurred, the percentage over ten swallows was calculated.Once data had been collected the probe was guided down again tothe stomach, tDCS device was turned on and anodal or sham stim-ulation was started. 2 min after stimulation onset, manometry wasperformed and parameters collected once again. Followingmanometry a 24 h pH-bilimetry was done and results were consid-ered suggestive of significant acid reflux or mucosal sensitivity toacid reflux when De Meester score was >14.72, or lower but witha symptom index (SI) > 50% and/or a symptom association proba-bility (SAP) P 95%, suggesting a diagnosis of hypersensitive esoph-agus (Bredenoord et al., 2005). A bile reflux was consideredpathologic if the fraction time of light absorption value over 0.14was greater than 4% (Vaezi and Richter, 1996). If either endoscopyand pH-bilimetry resulted negative the subject was included in FHcategory.

2.5. Statistical analysis

A repeated measures analysis of variance (ANOVA) was done totest the effects of tDCS on distal waves mean amplitude and LESbasal pressure, with time (pre and during tDCS) as within-patientfactor, stimulation (anodal or sham) and GERD subtype (NERD,ERD or FH) as between-patient factors. A Bonferroni test wasapplied for post hoc analysis. We used the Kruskal–Wallis test inorder to determine differences between median values ofpathological waves percentage in anodal vs. sham group. Post-hoc pairwise comparisons were done with the Wilcoxon’s ranksum test. In order to quantify the association between changes

Table 1Patient demographic and clinical characteristics.

NERD

Anodal Sham

n 16 14Age 38 (12) 43 (12)Women 10 8

Ph-metryAcid reflux 11 (85%) 9 (60%)Mixed/non-acid reflux 5 (42%) 5 (62.5%)

IEMYes 6 (50%) 5 (62.5%)No 10 (43%) 9 (36%)

Decreased LES basal tone 2 4

Data are mean (SD) or n (% of anodal or sham). NERD = non-erosive reflux disease. ERmotility. LES = lower esophageal sphincter.


occurring in distal waves mean amplitude and percentage of path-ological waves, a Spearman’s rank correlation test was performed.We assumed statistical significance if p < 0.05. Data were analyzedusing Statistica 10 (Statsoft).

3. Results

3.1. Effects of stimulation

Seventy-one patients were tested between January 2011 andSeptember 2013. Three patients were excluded due to the manom-etry which showed a motility pattern suggestive of achalasia. Thebaseline characteristics of the groups are shown in Table 1 andstudy profile is described in Fig. 1, while a summary of tDCS effectson evaluated parameters is summarized in Table 2. Only two sub-jects showed bile reflux (one treated with anodal tDCS) and onefulfilled criteria for hypersensitive esophagus, therefore we couldnot reach statistical significance to highlight differences betweenthese groups and acid or mixed refluxes.

Regarding distal waves mean amplitude a significant main ef-fect of interaction between time, stimulation and reflux disease(F(2, 62) = 3.5518, p = 0.03) was found. Post-hoc analysis showeda strong increase in waves amplitude occurring in NERD(p = 0.00002) and FH (p = 0.008) subjects during anodal stimulationcompared with baseline values (Fig. 2).

The Kruskal–Wallis test showed a significant difference in path-ological waves percentage between anodal and sham groups(v2 = 8.64, p = 0.003). After the Wilcoxon test, post-anodal tDCShighlighted a sustained reduction of pathological waves percent-age only in NERD (p = 0.002) although a similar trend was observedalso in FH subjects (Fig. 3). Following anodal stimulation, aninverse association between distal waves amplitude increase andpathological waves decrease was observed in GERD patients withSpearman correlation test (q = �0.36, p = 0.03). A sample size ofn = 16 (NERD) and n = 12 (NERD with dysmotility) allowed us toshow, respectively, a 35% of increase in distal waves amplitudewith 88.1% of power and a 63% of decrease in pathological waveswith 100% of power. Regarding FH (n = 10), distal waves amplitudewas increased of 33% with 72.8% of power. Gender did not signifi-cantly affect response to transcranial stimulation.

Only the 19% of all subjects in this study displayed dysfunc-tional LES due to decreased mean basal tone (i.e., <10 mmHg;Spechler and Castell, 2001). LES basal tone was not modified bytDCS since stimulation did not produce significant effects in anyof the subgroups. Nevertheless this is not surprising because only

ERD FH

Anodal Sham Anodal Sham

9 9 10 1043 (14) 43 (10) 29 (8) 36 (12)4 3 5 5

2 (15%) 6 (40%) –7 (58%) 3 (37.5%) –

4 (33%) 3 (37.5%) 2 (17%) –5 (22%) 6 (24%) 8 (35%) 10 (40%)

1 5 – 1

D = erosive reflux disease. FH = functional heartburn. IEM = ineffective esophageal



71 subjects met eligibility criteria

3 excluded due to an achalasic motility pattern

68 subjects were eligible for tDCS

35 underwent anodal stimulation 33 underwent sham stimulation

10 with negative pH-bilimetry were included in FH and analysed for endpoints

25 with positive pH-bilimetry were included in GERD and analysed for endpoints

23 with positive pH-bilimetry were included in GERD and analysed for endpoints

10 with negative pH-bilimetry were included in FH and analysed for endpoints

Fig. 1. Study profile. tDCS: transcranial direct current stimulation. GERD: gastroesophageal reflux disease. FH: functional heartburn.

Table 2Changes in distal waves mean amplitude and percentage of pathological waves following tDCS.

Distal waves amplitude (mmHg) Pathological waves percentage (%) LES basal tone (mmHg)

Pre During Pre During Pre During

Anodal tDCS – NERD 55 (30.7) 77.3 (28.4) 33 2 14.9 (5.2) 12.7 (3.7)Anodal tDCS – ERD 68.5 (33.2) 70.2 (29.7) 32 23 16.3 (6.9) 15.1 (8.4)Anodal tDCS – FH 62.5 (28.2) 82.5 (28.1) 30 10 15.1 (4.1) 15.3 (4.1)Sham tDCS – NERD 73.9 (41.9) 75.7 (44.9) 38 31 12.6 (6) 13.3 (5.7)Sham tDCS – ERD 61.5 (34.9) 65.8 (41.3) 33 38 11 (5) 11.6 (7.4)Sham tDCS – FH 79.9 (34.5) 80.3 (28.1) 18 23 17.8 (9.4) 16.3 (7)

Data are mean (SD). tDCS = transcranial direct current stimulation. NERD = non-erosive reflux disease. ERD = erosive reflux disease. FH = functional heartburn. LES = loweresophageal sphincter. Pathological waves percentage was calculated only in subjects displaying dysmotility in P1/10 wet swallows.


transient LES relaxation are accounted as a GERD pathophysiolog-ical strong factor (Hershcovici and Fass, 2010).

4. Discussion

This study aimed to explore the effects of tDCS on esophagealmanometric parameters in patients with GERD. Our results con-firm the documented role of cortex in modulating esophagealmotility. Cerebral cortex has a leading role in starting the voluntaryswallowing process directly or through its connection with deepersites. The premotor cortex gives a major contribution to esopha-geal modulation through the convergence of fibers on the brain-stem swallowing pattern generator and then into the nuclei ofdorsal motor nucleus (DMN) of the vagus nerve whose efferentsare in turn conveyed to esophagus (Aziz et al., 1995; Shiina et al.,2010). Nucleus of the tractus solitarius (NTS) and DMN interactionshave also been documented, suggesting a link between NTS andesophageal motoneurons (Broussard et al., 1998). Moreover, recentstudies with functional magnetic resonance imaging (fMRI) con-firmed the precentral cortex as a fundamental area in triggeringthe pharyngo-esophageal swallowing circuit (Martin et al., 2001).Changes observed in distal waves amplitude following volitionalswallowing can be explained by a direct excitatory effect of anodalcurrents on cortex and cortico-esophageal pathway. On the otherhand, the decrease of pathological waves is related to changes indistal amplitude suggesting that tDCS affect low-amplitude as wellas normal-amplitude waves. LES basal tone was not modified by


tDCS probably because it mainly depends on local factors (e.g.,myogenic tone) and enteric nervous system modulation (Farréand Sifrim, 2008). Although most of studies about effects of corticalstimulation are performed with TMS and focused on the proximalpart of esophagus (Aziz et al., 1996; Hamdy et al., 1998), it is likelythat anodal tDCS, modulating the swallowing circuit, may exert itsexcitatory effects also on distal esophagus.

The most intriguing result of this study is the lack of response tostimulation in ERD subjects. Due to evidences of functional neuro-imaging, motility and endoscopic findings, symptoms pattern andresponse to pharmacological treatment showing variability in thespectrum of GERD, several works have suggested different patho-physiology between NERD and ERD (Hershcovici and Fass, 2010;Xu et al., 2010). Patients with erosive esophagitis have been asso-ciated with higher acid exposure in the distal esophagus and lowermean resting LES pressure if compared with NERDs, being theoret-ically more susceptible to mucosal inflammation and acid-relateddamage of peripheral afferents (Altomare et al., 2013). Neverthe-less, IEM has been compared in GERD subgroups, mostly with nomarked variability in NERD vs. ERD (Lemme et al., 2005).

Regarding central nervous system involvement, several factorshave been shown to influence processing of afferent signals tothe brain (Anand et al., 2007). Peripheral and central sensitizationseems likely to be responsible for induction and maintenance ofvisceral hypersensitivity in patients with GERD despite restorationof physiological intraluminal acidity (De Bortoli et al., 2013). Spinalnociceptors and vagal afferent pathway can be sensitized by muco-sal acid exposure or mechanical distension due to reflux, inducing



Fig. 2. Distal waves mean amplitude before (‘‘Pre’’) and during (‘‘Post’’) anodal or sham tDCS in non-erosive (NERD), erosive (ERD) reflux disease and functional heartburn(FH). Bars indicates CI. ‘‘⁄’’ Means statistical significance (p < 0.05).


cortical responses even in absence of a perceived heartburn andcontributing to the development of hyperalgesia and allodynia aswell as contractile hyperreactivity after acid infusion (Dreweset al., 2005). Moreover, two recent fMRI studies highlighted a dif-ferent cortical response in NERD vs. ERD following esophagealchemical stimuli, leading the authors to postulate different centralmechanisms of esophageal visceral sensation in GERD subgroups(Yang et al., 2008; Xu et al., 2010).

The same noxious stimuli can alter cortical motor as well assensory pattern (Shaker, 2007). In fact, esophageal acid exposure,even if unperceived, enhances the activity of the cortical swallow-ing network (Kern et al., 2009), and a prolonged acid mucosalexposure can activate local neural reflexes responsible of de-creased esophageal motility and acid clearance, or even intrinsicneurons imbalance. For instance, patients with IEM express higherdensity of neuronal nitric oxide synthase-positive in the inner cir-cular muscle of the esophagus than controls, leading to dysfunc-tional peristalsis (Kim et al., 2008).

Pathophysiological processes involved in sensitization mighteventually affect neuraxis regulation and responsiveness which,in turn, would worsen esophageal dysfunction and give rise to a vi-cious circle, although it is unclear if central nervous system impair-ment would be primary or secondary (Ang et al., 2008; Shiina et al.,2010). NERD and FH subjects preserve the responsiveness of cor-tico-esophageal drive to anodal tDCS, likely through mutual con-nections of prefrontal gyrus with subcortical areas (Aziz et al.,2000), while ERDs might suffer the harmful effects of prolongedand painful afferents causing alterations of central neural controland severe impairment in avoiding noxious stimuli and starting


visceral motor responses. If erosive forms can be considered a sep-arate disease rather than a simple progression from non-erosiveones is still a matter of debate (Hershcovici and Fass, 2010). Our re-sults does not actually solve the controversy because the worse re-sponse in ERD could either be subsequent to the advanced stage ofprogression in a previously non-erosive ‘‘responder’’ or to a distinctphysiopathological entity. Summarizing, the different ERD profilecould be due to peripheral as well as central factors but, to date,every assumption remains speculative and further studies areneeded to clarify the different grade of systems involvement.

Some limitations of this study must be addressed: first, we didnot considered evaluating esophageal motor evoked potentials inorder to find a precise stimulation site because of tDCS low spatialresolution. Therefore, considering the close cortical representationof pharynx and esophagus and their multiple neural connectionsgiving rise to visceral efferents, we can not rule out facilitationdue to stimulation of adjacent sites or remote effects on deepersystems such as the dopaminergic one (Tanaka et al., 2013). Sec-ond, the use of standard tests rather than esophageal impedancemonitoring and high-resolution manometry. Nevertheless, theadvantage of these tools mostly lies in finding motor abnormalitiesand refluxes hardly detected with conventional equipment, there-fore we believe this issue does not impair our results reliability(Kahrilas and Sifrim, 2008). Third, we did not include healthy sub-jects in the study. However, we considered FHs as controls and thesignificant effects of tDCS on their waves amplitude confirm thatchanges observed in NERD were not by chance. Moreover, severalworks showed the significant effects of non-invasive stimulationon swallowing cortex plasticity in healthy subjects (Hamdy et al.,



Fig. 3. Percentage of pathological waves before (‘‘Pre’’) and during (‘‘Post’’) anodal or sham tDCS in non-erosive (NERD), erosive (ERD) reflux disease and functional heartburn(FH). Bars indicates CI. ‘‘⁄’’ Means statistical significance (p < 0.05).


1998; Shaw et al., 2001; Jefferson et al., 2009). Fourth, the studydesign based on categorization of NERD, ERD and FH according topH-metry resulted in different sample size and gender distributionin GERD subgroups. Nevertheless, several works dealing with gen-der either in healthy (Dantas et al., 1998) and ineffective esopha-geal motility (Haack et al., 2008), showed unremarkablevariability in esophageal peristalsis between men and women.Moreover, in our study no significant difference was observed inthe distribution of gender between subjects who underwent ano-dal and sham stimulation, and sex did not affect response to trans-cranial stimulation.

We believe that performing pH-bilimetry after stimulationcould not normalize acid clearance nor affect reflux monitoring re-sults. In fact, effects of a single 13 min anodal tDCS session usuallydo not exceed 1 h, making it unlikely to be a significant factor in pHvariations during 24 h. Moreover, if tDCS could normalize acidclearance in best responders we would as well expect a significantdifference in motility variations between patients with and with-out dysmotility, which did not occur (Nitsche and Paulus, 2001).

The possible long-term effects on patients symptoms improve-ment only remain speculative. In this regard, repeated sessions ofstimulation and follow-up studies could represent a worth toolin the future. To our knowledge this is the first study evaluatingthe possibility to influence esophageal motility in GERD patientsthrough non-invasive transcranial modulation of cortical control.Although dysmotility is only one of the factors involved in GERD,these data support the hypothesis of a different pathophysiologyin NERD vs. ERD, beyond mucosal damage. Considering the recentuse of tDCS as a therapeutical help in several disease such asimprovement of dysphagia in patients with stroke (Kumar et al.,2011), further studies could increase our knowledge about GERDand eventually lead to a selective new treatment of itssubcategories.


Role of the funding source

No funding sources had any role in study design, collection,analysis and interpretation of data, or writing of the report. Thecorresponding author had full access to all the data of the studyand had final responsibility for the decision to submit it forpublication.

Financial disclosure

None of the authors have any financial interest to disclose.

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