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Pain is a complex experience that involves sensory-discriminative and cognitive-emotional neuronal processes. It has long been known across cultures that pain can be relieved by mindful breathing (MB). There is a common assumption that MB exerts its analgesic effect through interoception. Interoception refers to consciously refocusing the mind’s attention to the physical sensation of internal organ function.
In this study, we dissect the cortical analgesic processes by imaging the brains of healthy subjects exposed to traditional MB (TMB) and compare them with another group for which we augmented MB to an outside sensory experience via virtual reality breathing (VRB).
The VRB protocol involved in-house–developed virtual reality 3D lungs that synchronized with the participants’ breathing cycles in real time, providing them with an immersive visual-auditory exteroception of their breathing.
We found that both breathing interventions led to a significant increase in pain thresholds after week-long practices, as measured by a thermal quantitative sensory test. However, the underlying analgesic brain mechanisms were opposite, as revealed by functional near-infrared spectroscopy data. In the TMB practice, the anterior prefrontal cortex uniquely modulated the premotor cortex. This increased its functional connection with the primary somatosensory cortex (S1), thereby facilitating the S1-based sensory-interoceptive processing of breathing but inhibiting its other role in sensory-discriminative pain processing. In contrast, virtual reality induced an immersive 3D exteroception with augmented visual-auditory cortical activations, which diminished the functional connection with the S1 and consequently weakened the pain processing function of the S1.
In summary, our study suggested two analgesic neuromechanisms of VRB and TMB practices—exteroception and interoception—that distinctively modulated the S1 processing of the ascending noxious inputs. This is in line with the concept of dualism (Yin and Yang).
With the development of functional neuroimaging, our understanding of pain has matured to a concept of multidimensional experience in which the brain integrates inputs from sensory-discriminative and cognitive-emotional systems as a central hub [
Mindful breathing (MB) is widely accepted as an authentic treatment for pain relief by patients and society in general [
However, the brain mechanisms for the MB practice in pain modulation are poorly understood [
An existing problem with current MB training is the difficulty of long-time attention focusing, especially for beginners, as this is a subjective interoception process. Therefore, there is an urgent need for a tangible method that can provide an immersive sensory guide to facilitate mental control and match the expectations of the current tech-savvy generation. Recently, the development of virtual reality (VR) has enabled the implementation of such methods. VR is a computer-simulated 3D and interactive experience [
Although proven to be effective in pain modulation, the underlying brain mechanisms of the two processes—abstract sensory-interoception and VR-based sensory-exteroception—remain unclear. This study compared the effectiveness of the two methods in modulating the patients’ pain thresholds in the same study design and clinical environment. We used a week-long protocol in which the participants practiced the traditional MB (TMB) and VR breathing (VRB) in the lab on the first and seventh day, respectively, intercalated by five daily MB practices at home. During the in-lab sessions, we measured the participants’ pain threshold using a facial thermal quantitative sensory test (tQST) after their breathing practices. We used functional near-infrared spectroscopy (fNIRS) as a neuroimaging technique to measure participants’ cortical connectivity and activation. fNIRS is a novel optical brain imaging technique that uses near-infrared light to monitor oxygen levels at multiple cortical locations [
We recruited 40 healthy adult participants in this study (women: 21/40, 52%; age: mean 28 years, SD 4 years). Our exclusion criteria included significant hearing or visual impairment, a history of chronic pain or recent acute pain, significant medical conditions, or current evidence of respiratory distress or asthma. The recruited participants were randomly divided into 2 groups. The first group had interoceptive breathing focusing sessions using an in-house–developed, visual-auditory, 3D VR technology aid (VRB: n=20; women: 11/20, 55%; age: mean 26 years, SD 4 years), whereas the second group had abstract MB (TMB: n=20; women: 10/20, 50%; age: mean 29 years, SD 4 years). This study was approved by the institutional review board of the University of Michigan.
We designed a week-long protocol for both groups. Within the seven days of the protocol, we scheduled each participant for two in-person appointments in the lab on the first and seventh days. From the second to the sixth day, we asked the participants to practice home self-guided exercises following the instructions (
For both in-lab sessions, we asked each participant to complete a set of McGill Pain Questionnaire and the Positive and Negative Affect Schedule (PANAS) questionnaire. Participants were then seated in a dental chair, and we helped them with the comfortable placement of headphones, Oculus Rift virtual imaging equipment (Oculus VR), and a plethysmography belt. Finally, we set up the fNIRS imaging sensors and thermal quantitative sensory thermode, as indicated in
As indicated in
Next, we administered 20 trials of the tQST (Medoc Pathway System). We used 20 times repeated measurements and used the averaged temperature thresholds for further analysis to ensure the test-retest. We placed a single unilateral thermode on the left mandibular nerve branch of the trigeminal cranial nerve (V3 division) for each participant. Within each trial of the 20 trials, the thermode temperature controlled by the controlling device increased from a baseline of 30 °C (86 °F) to a maximum temperature of 50 °C (122 °F), with an increase rate of 1 °C per second. We instructed participants to click the button on the mouse at the first detection of pain, as it stopped the temperature from increasing. The thermode temperature then returned to its baseline and gave the subject a 10-second rest period before the next thermal trial. We also collected fNIRS brain data during the tQST session.
Upon completion of all 20 tQST trials, we asked participants to relax for another 5 minutes for a final collection of resting-state fNIRS data. In addition, we asked participants to complete another set of PANAS and McGill pain questionnaires. Following the completion of the first session, we gave participants a sheet of at-home breathing practice prompt and instructed them to read and complete this exercise for 5 minutes three times a day (after waking, midday, and before bed). Finally, we asked participants to repeat the same protocol during their second in-lab visit on day 7.
(A) The experimental setup with all the technologies integrated. (B) The virtual 3D lungs in the Oculus Rift headset from participants’ view, which moved in synchronization with their breathing cycles in real time (inhaling and exhaling). (C) The experiment protocol. FNIRS: functional near-infrared spectroscopy; QST: quantitative sensory test; TQST: thermal quantitative sensory test.
We used a TechEN-CW6 fNIRS system (TechEn, Inc) with wavelengths of 690 and 830 nm. The fNIRS cap setup included eight emitters of near-infrared light and 28 detectors spaced 3 cm apart, yielding 45 data channels (CHs) deployed at the bilateral aPFC, premotor cortex (PMC), supplementary motor area (SMA), motor cortex, primary somatosensory cortex (S1), and visual cortex (V1), as indicated in
The probe holding cap was established and applied consistently for each participant using the international 10-10 transcranial system positioning [
The designed functional near-infrared spectroscopy cap for functional near-infrared spectroscopy light emitters and detectors with channel (emitter-detector pairs) localization estimation.
We estimated the HRV data using time-domain methods by calculating the SD of the normal-to-normal parameter using MATLAB software (MathWorks). We calculated the parameters based on the optical density data of 830 wavelengths, bandpass filtered with a cutoff frequency of 0.01-2 Hz. The parameters were then calculated using the formulas also available in the paper by Wang and Huang [
where N is the total number of R peaks and
We analyzed fNIRS data using the near-infrared spectroscopy–toolbox [
We applied a generalized linear model with prewhitening and robust least squares [
where
Group-level analysis was conducted using a linear mixed-effects model based on the regression coefficients derived from the individual-level analysis. The model can be expressed as follows:
where
where
To study the brain mechanism during breathing practice, we calculated the associated functional connectivity patterns using the pipelines in the near-infrared spectroscopy–toolbox [
We inspected the relationship between brain connectivity during breathing practice and the temperature threshold measured during the tQST session. We ran an elastic net regression to select the best region-to-region connections for the temperature thresholds. This selection process was performed using the Lasso toolbox in MATLAB (MathWorks). Specifically, we iteratively varied the weight controlling the lasso versus ridge optimization from 0 to 1 in increments of 0.1 to achieve a minimum squared error. With each weight, we applied 10-fold cross-validation with Monte Carlo repetitions (100 times) to guarantee a converged output. Next, we calculated the Pearson correlation coefficient (
Our first observation was that the average temperature threshold measured by the tQST increased from 45.4 to 46.0 °C (
(A) Temperature thresholds measured in the thermal quantitative sensory test sessions for traditional mindful breathing and virtual reality breathing groups. (B) Serenity score (Positive and Negative Affect Schedule) in pre- and postbreathing practices in the traditional mindful breathing group. (C) Fatigue score (Positive and Negative Affect Schedule) in pre- and postbreathing practices in the traditional mindful breathing group. (D) Serenity score (Positive and Negative Affect Schedule) in pre- and postbreathing practices in the virtual reality breathing group. (E) Fatigue score (Positive and Negative Affect Schedule) in pre- and postbreathing practices in the virtual reality breathing group. TMB: traditional mindful breathing; VRB: virtual reality breathing. The asterisks indicate statistical difference between the scores collected from two groups.
(A) The extracted heartbeat signal from the functional near-infrared spectroscopy signal. (B) The estimated SDNN parameter for the prebreathing resting-state sessions, traditional mindful breathing, and virtual reality breathing practice sessions. SDNN: SD of normal to normal; TMB: traditional mindful breathing; VRB: virtual reality breathing.
To study and compare the mechanisms of the two breathing practices, we then investigated the brain connectivity during both breathing practices (pre-tQST) and brain activation during the tQST sessions (thermal pain challenge). As shown in
We further investigated the correlation between brain connectivity and temperature thresholds across participants. As shown in
Functional connectivity patterns during the breathing practices. (A) Significant connectivity patterns (
Next, we examined cortical activation during the tQST session to study how the brain processes pain after the two types of practices. As indicated in
Brain activation map for the thermal quantitative sensory test sessions on visit days 1 and 7. aPFC: anterior prefrontal cortex; DLPFC: dorsolateral prefrontal cortex; M1: motor cortex; PMC: premotor cortex; S1: primary somatosensory cortex; SMA: supplementary motor area; STG: superior temporal gyrus; TPJ: temporal-parietal junction.
Our second observation was the activation of the aPFC region in both groups, as indicated in
Next, for the TMB group, we found activations in the PMC: visit 1, CH 13, t72=2.4 (
Finally, we performed a contrast analysis between the two groups by combining the two visits, as shown in
Between-group contrast analysis results (virtual reality breathing group [+Red]; traditional mindful breathing group [−Blue]). DLPFC: dorsolateral prefrontal cortex; STG: superior temporal gyrus; TPJ: temporal-parietal junction.
It is commonly assumed that MB exerts its analgesic effect through abstract interoception [
Our first finding was that both groups attained a raised pain threshold after one week of breathing practice without significantly different HRV measurements. The results suggested that both TMB and VRB techniques effectively increased pain thresholds in the participants. It is worth noting that the pain-evaluation (tQST) sessions were conducted after the breathing practices, which reproduced their application in the clinical environment, as before a medical/dental procedure. Thus, the analgesic effects were postbreathing effects. The 0.6 °C pain threshold increase in both groups is considered significant, as the human nociceptive sensation thresholds for warmth can be as low as 1.5 °C above the baseline at around 30 °C [
Following the observed temperature threshold changes, we first analyzed the brain activation patterns during the tQST sessions. Our results first confirmed the activation of the contralateral S1 region to noxious thermal stimulation. The S1 has been studied intensively for its critical function in pain and intensity processing [
To further study the brain mechanisms during the two types of breathing practices, we then analyzed their associated functional connectivity. The TMB group demonstrated a closer working relationship among areas, including the aPFC, PMC, and S1 regions. In contrast, we observed fewer connections to the visual and auditory regions in the VRB group. The immersive 3D, sensory-exteroceptive, virtual experience reinforced the participants’ cortical audio-visual activations, thus depriving the S1 processing of the ascending pain inputs. To study whether functional connectivity is related to pain sensitivity, we examined the correlations between the observed connectivity strength and the pain thresholds measured during the tQST session. Interestingly, we found that the connections among the aPFC, PMC, and S1 regions in the TMB group were associated with pain thresholds across visits. In contrast, in the VRB group, we found that the functional connections among the auditory/visual regions, PMC, inferior parietal lobe, and S1 were associated with temperature thresholds. A previous resting-state fMRI study found lower pain sensitivity in meditators with decoupled executive and pain-relevant brain regions [
On the basis of these findings, we propose two possible mechanisms for the TMB and VRB practice—in the TMB group, the aPFC modulated attention [
There were some caveats in this study. First, we asked the participants to mimic the VR experience for at-home practices between day 1 and day 7 lab visits. However, the at-home practice was not as immersive as the in-lab VR practice (owing to the noncompletely portable apparatus of the technologies), which might have dampened its effect. We will use a mobile VR device that works with smartphones in our future studies to address this issue. Next, instead of a nonintervention control group, we used the TMB group as the active control group. Although we found different brain activation and connectivity patterns, in contrast to the VRB group, we still need to compare both groups with a nonintervention control group and evaluate the effects of both the TMB and VRB breathing practices in the future.
In conclusion, as shown in
Schematic plots of the mechanisms under traditional mindful breathing and virtual reality breathing accompanied by the temperature thresholds measured by the thermal quantitative sensory test in this study. S1: primary somatosensory cortex; PMC: premotor cortex.
Breathing practice instructions.
Brain activation during the thermal quantitative sensory test session.
anterior prefrontal cortex
channel
dorsolateral prefrontal cortex
false discovery rate
functional near-infrared spectroscopy
oxyhemoglobin
deoxyhemoglobin
heart rate variability
mindful breathing
Positive and Negative Affect Schedule
prefrontal cortex
premotor cortex
primary somatosensory cortex
supplementary motor area
superior temporal gyrus
traditional mindful breathing
temporal-parietal junction
thermal quantitative sensory test
visual cortex
virtual reality
virtual reality breathing
The authors would like to thank Sumer Panesar and Nathan Wigington for their help with data collection and experiment preparation. The authors would also like to thank Jacqueline Dobson for her help with proofreading the manuscript.
The content described in this study was developed at the University of Michigan and disclosed to the University of Michigan Office of Technology Transfer. All intellectual property rights, including but not limited to patents or patent applications, trademarks, and copyright of software, algorithms, reports, displays, and visualizations, are owned by the Regents of the University of Michigan.