Edited by: Francisco R. Nieto, University of Granada, Spain
Reviewed by: Sulev Kõks, University of Tartu, Estonia; Bin Gu, University of North Carolina at Chapel Hill, United States
†These authors share the first position.
Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neurology
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Chronic visceral pain (CVP) syndromes are persistently painful disorders with a remarkable lack of effective treatment options. This study aimed at evaluating the effects of different neuromodulation techniques in patients with CVP on cortical activity, through electreocephalography (EEG) and on pain perception, through clinical tests.
A pilot crossover randomized controlled study.
Out-patient.
Adults with CVP (>3 months).
Participants received four interventions in a randomized order: (1) transcranial pulsed current stimulation (tPCS) and active transcranial direct current stimulation (tDCS) combined, (2) tPCS alone, (3) tDCS alone, and (4) sham condition. Resting state quantitative electroencephalography (qEEG) and pain assessments were performed before and after each intervention. Results were compared with a cohort of 47 healthy controls.
We enrolled six patients with CVP for a total of 21 visits completed. Compared with healthy participants, patients with CVP showed altered cortical activity characterized by increased power in theta, alpha and beta bands, and a significant reduction in the alpha/beta ratio. Regarding tES, the combination of tDCS with tPCS had no effect on power in any of the bandwidths, nor brain regions. Comparing tPCS with tDCS alone, we found that tPCS induced higher increase in power within the theta and alpha bandwidths.
This study confirms that patients with CVP present abnormal EEG-indexed cortical activity compared with healthy controls. Moreover, we showed that combining two types of neurostimulation techniques had no effect, whereas the two interventions, when applied individually, have different neural signatures.
Visceral pain results from nociceptor activation in thoracic, pelvic, or abdominal visceral organs (
This paucity of knowledge regarding neural correlates of CVP further undermines treatment interventions. CVP is characterized by high level of disability and discomfort (
In this scenario, we conducted a pilot study with a twofold aim: first, we wanted to assess baseline cortical activity of CVP patients; results are compared with those obtained by a normative sample of neurological healthy participants, published elsewhere (
The inclusion criteria were as follows: (1) age between 18 and 65; (2) history of visceral pain for at least 3 months; (3) an average pain ≥4 in the past 3 months, as measured by the visual analog scale (VAS); (4) no history of neurologic or psychiatric conditions and no current unstable medical conditions; (5) no contraindications to tES; and (6) no current pregnancy. The study was approved by the Institutional Review Board of Spaulding Rehabilitation Hospital and performed in accordance with the Declaration of Helsinki. Healthy subjects’ cohort data have been published elsewhere (
We conducted a pilot randomized, double-blind, sham-controlled crossover trial. Participants received the following four interventions in a randomized order separated by a minimum of 5 days: (1) active tPCS/active tDCS; (2) active tPCS/sham tDCS; (3) sham tPCS/active tDCS, and (4) sham tPCS/sham tDCS. Each stimulation condition was preceded and followed by EEG and clinical assessments.
Transcranial direct current stimulation was delivered with the anode electrode positioned over the left primary motor cortex (M1) and the cathode electrode over the contralateral right supra orbital region (Soterix Medical, NY, USA). Stimulation parameters were as follows: 20 min at 2 mA, 30-s fade-in and fade-out.
We used an investigational, custom-made, battery-powered and high-frequency tPCS device (Lab 8Tron AG) that delivered a quadratic biphasic alternating current using periauricular ear-clip electrodes. Stimulation parameters for tPCS were as follows: 20 min of stimulation at a fixed current intensity of 2 mA and a random noise frequency of 6–10 Hz [as previously described (
We used a 64-channel, high-density Electrical Geodesic Incorporated EEG device (Electrical Geodesics, OR, USA). EEG was recorded for 6 min eyes-closed. Data were sampled at 250 Hz, amplified and filtered using a bandpass of 0.1–70 Hz. For offline analysis, we used a low-pass filter of 40 Hz and high-pass of 1 Hz, followed by manual artifact detection and rejection by a blind assessor. Power and coherence were calculated using EEGLab (
We calculated interhemispheric coherence for these bands and sub-bands using two different electrode pairs: E19–E56 and E14–E57, located in the frontotemporal junction and including their reciprocal location in the contralateral hemisphere. Welch’s averaged modified periodogram method was used to find the estimated coherence of signal
Visual analog scale for pain, anxiety, depression, stress, and sleepiness was collected. Von Frey Hair Assessment (North Coast Medical, Inc., Morgan Hill, CA, USA), comprised of monofilaments (0.008–300 g) was used to determine subjects’ perception threshold. This assessment was performed on the patient’s most painful region and over the ipsilateral hand to serve as a control. Pressure pain threshold (PPT) was also performed to measure subjects’ pain threshold (Commander Algometer, JTECH Medical, UT, USA). PPT was measured over the thenar eminence of both hands, namely, both ipsi- and contralateral to the most painful body area. For the evaluation of conditioned pain modulation (CPM), the same test applied for the PPT (
To compare neurophysiological and behavioral data of healthy controls (HCs) with that of CVP patients, we used baseline data of the first visit for each participant. Continuous variables (i.e., age and years of education) were compared using a
For patients only, Kruskal–Wallis test was used to evaluate the effects of stimulation on power and coherence variables (difference between pre- and post-stimulation values) with
Six patients (2 males and 4 females) were included in the present study (see Table
Demographical and clinical data of the patients.
ID | Age/gender | Diagnosis | Race | Level of education | DI (months) | Pain medication |
---|---|---|---|---|---|---|
1 | 51/F | CP | Caucasian | College | 36 | Fentanyl |
2 | 24/M | CP | Caucasian | College | 5 | Oxycodone |
3 |
36/F | CP | Caucasian | College | 24 | Paracetamol, Ibuprophen |
4 | 33/M | CP | Caucasian | Bachelor | 108 | Oxycotin |
5 | 31/F | CP | African-American | Bachelor | 61 | Lidocaine, Ibuprophen, Hydromorphone |
6 | 44/F | CP | Caucasian | College | 61 | Tapentadol |
Chronic visceral pain patients and HC were similar for age (
Power spectra.
Group | Theta (μV2) | Alpha (μV2) | Low alpha (μV2) | High alpha (μV2) | Beta (μV2) | Ratio α/β |
---|---|---|---|---|---|---|
CVP | 0.10 ± 0.08 |
0.19 ± 0.28 |
0.29 ± 0.56 |
0.13 ± 0.10 | 0.016 ± 0.01 |
12.83 ± 5.9 |
HC | 0.05 ± 0.08 | 0.15 ± 0.17 | 0.19 ± 0.23 | 0.12 ± 0.19 | 0.012 ± 0.01 | 18.6 ± 20.1 |
There were no differences in the baseline power spectrum in the frontal, central, parietal, temporal, or occipital brain regions (all
Differences in absolute power between groups. Mean differences (pre- versus post-intervention) of power for theta and low-alpha bandwidths. The bars represent the standard error. * Significant difference between groups.
Topoplots showing the topographic distribution of the different bandwidths for a representative individual before and after each intervention. Red areas represent higher activity, while blue areas represent lower activity.
As shown in Figure
Transcranial direct current stimulation induced higher reduction in power of theta (
Transcranial pulsed current stimulation induced a decrease in power in the high-alpha bandwidth for global (
No group effect for any bandwidths or brain regions was found (all
Individual power and coherence data can be found in Supplementary Material.
No differences were found in either depression VAS (χ2 = 3.86;
Similarly, no significant differences were found for PPT (χ2 = 0.4;
Individual clinical data can be found in Supplementary Material.
The present study yielded interesting findings: (1) patients with CVP display abnormal neural activity compared with healthy controls, as indexed by qEEG; (2) EEG captured cortical changes following tES, similar to what was observed in healthy controls, while no clinical improvement was noticed; (3) combining tDCS with tPCS does not induce specific changes in neural activity; (4) tDCS and tPCS have different neural signature.
So far, only few studies have investigated the neurophysiological patterns of patients with CVP. For instance, EEG measures in patients with chronic pancreatitis show an increase in power in the theta and alpha frequency bands as well (
Baseline cortical activity could serve as a biomarker for treatment effects and as a predictor of response when using tES and other neuromodulatory techniques. As seen in patients with spinal cord injury and chronic pain, increased theta power at baseline was associated with greater response to analgesic treatment; in this case, hypnosis (
An important mechanism that deserves further investigation in the context of these results is the interaction between pain, immune system and electrical stimulation. It has been discussed before that pain may trigger also immune mechanisms in a two-way brain response to injury (
While no changes were observed clinically, neurophysiologically, the combination of tDCS with tPCS did not lead to any changes in brain activity, while the application of the two techniques separately induced different cortical modifications, as already demonstrated (
Considering each technique individually, tPCS has shown promising and reproducible results as a neuromodulatory tool given the reported effects on coherence and power (
Our results showed that tPCS induced a higher increase in power within these two specific frequency bands compared with tDCS. We also identified a decrease in power for high-alpha bandwidth after tPCS and a decrease in power for theta and low-alpha bandwidths after tDCS, as compared with sham. This reduction in EEG power may represent a cortical modulation reducing a putative pathological over-excitability in patients suffering from chronic forms of pain. In fact, baseline EEG power of the main frequency bands is increased in CVP as compared with HC, suggesting a pathological over-activity in patients, especially over the sensorimotor cortex (i.e., central region). Therefore, the decrease here found can be interpreted as a normalization of the cortical oscillations, leading to a pattern more similar to healthy conditions.
No clinical changes were observed after tDCS, tPCS, or both interventions combined. Evidence shows that repeated tES sessions, and tDCS in particular, are required to induce long-lasting and significant clinical effects in psychiatric (
Present findings, although preliminary, appear promising regarding the potentiality of tES techniques in modulating pathological cortical activity in CVP. Notwithstanding, they should be considered cautiously. When studying patients suffering from chronic pain, the effect of medications on spontaneous brain oscillations should be considered. In the present study, all patients but one were under one or more opioids drugs (see Table
Regarding the sham intervention, an important placebo component was identified (i.e., increase in theta and alpha and a decrease in beta bandwidths following the sham intervention). This could be interpreted in two different ways: (1) the observed increase in theta and alpha power and decrease in high-frequency bands could be related to relaxation. A similar pattern has been observed, for instance, under meditation (
With respect to tES techniques, our preliminary data suggest that the combination of tDCS with tPCS, applied simultaneously, does not lead to improvements in cortical oscillations, similarly to what has been observed in healthy population (
The study was approved by the Institutional Review Board of Spaulding Rehabilitation Hospital and performed in accordance with the Declaration of Helsinki. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the local institutional review board. Healthy subjects’ cohort data have been published elsewhere.
AT, CR, AD, and AH collected data. AT and CR analyzed the data, interpreted the results, and drafted the manuscript. FF designed the study, interpreted the results, and critically reviewed the manuscript. AD, AH, JM-Q, JP, and SF critically reviewed the manuscript and had substantial intellectual contributions. All authors approved the last version of the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This research was supported by the Labuschagne Foundation; the Belgian American Educational Foundation (BAEF) and the Fonds Leon Fredericq Foundation (to AT); Institutional National Research Service Award from the National Center for Complementary and Integrative Health (grant number T32AT000051 to JM-Q); the Ryoichi Sasakawa Fellowship Fund; the Program in Placebo Studies at Beth Israel Deaconess Medical Center; the Coordination for the Improvement of Higher Education Personnel––CAPES; International Cooperation General Program––PGCI (grant number 023/11 to AD); and NIH RO1 (grant number 1R01HD082302-01A1 to FF).
The Supplementary Material for this article can be found online at