Gamma Band Oscillations Reflect Sensory and Affective Dimensions of Pain

Pain is a multidimensional process, which can be modulated by emotions; however, the mechanisms underlying this modulation are unknown. We used pictures with different emotional valence (negative, positive, and neutral) as primes and applied electrical painful stimuli as targets to healthy participants. We assessed pain intensity and unpleasantness ratings and recorded electroencephalograms (EEGs). We found that pain unpleasantness and not pain intensity ratings were modulated by emotion, with increased ratings for negative and decreased ratings for positive pictures. We also found two consecutive gamma band oscillations (GBOs) related to pain processing from time frequency analyses of the EEG signals. The early GBO had a cortical distribution contralateral to the painful stimulus and its amplitude was positively correlated with intensity and unpleasantness ratings, but not with prime valence. The late GBO had a centroparietal distribution and its amplitude was larger for negative compared to neutral and positive pictures. The emotional modulation effect (negative vs. positive) of the late GBO amplitude was positively correlated with pain unpleasantness. The early GBO might reflect the overall pain perception, possibly involving the thalamocortical circuit, while the late GBO might be related to the affective dimension of pain and top-down-related processes.

Human ventromedial prefrontal cortex lesions enhance expectation-related pain modulation

Pain is strongly modulated by expectations and beliefs. Research across species indicates that subregions of the ventromedial prefrontal cortex (VMPFC) play a fundamental role in learning and generating predictions about valued outcomes. Consistent with this overarching framework, neuroimaging studies of experimental pain indicate that VMPFC activation tracks expectations of pain relief and statistically mediates expectation-related reductions in responses to painful stimuli across a distributed pain processing network. However, lesion studies in preclinical models and in humans with refractory chronic pain suggest that VMPFC may play a more general role in representing the affective and motivational qualities of pain that contribute to its strong aversive drive. To test whether VMPFC is necessary for pain processing in general, or instead plays a more specific role in the modulation of pain by expectations, we studied responses to experimental heat pain in five adults with bilateral surgical lesions of VMPFC and twenty healthy adults without brain damage.All participants underwent quantitative sensory testing (QST) to characterize pain sensitivity, followed by a pain expectancy task. Participants were instructed that auditory cues would be followed by heat calibrated to elicit low or high pain. Following a conditioning phase, each cue was intermittently paired with a single temperature calibrated to elicit moderate pain. We compared ratings of moderate heat stimuli and subjective expectancy ratings as a function of cue to evaluate whether VMPFC lesions impact cue-based expectancy and expectancy effects on pain intensity and unpleasantness. We also analyzed QST measures to evaluate whether VMPFC lesions were associated with overall shifts in pain sensitivity.Compared to adults without brain damage, individuals with VMPFC lesions reported larger differences in expectations as a function of pain-predictive cues, and stronger cue-based modulation of pain ratings, particularly for ratings of pain unpleasantness. There were no group differences in pain sensitivity, nor in the relationship between pain and autonomic arousal, indicating that the impact of VMPFC lesions is specific to expectancy-based modulation of pain unpleasantness.Our findings suggest that the VMPFC is not essential for basic subjective and physiological responses to painful stimuli. Rather, our findings of significantly enhanced cue- related expectancy effects may suggest that VMPFC plays an important role in updating expectations or integrating sensory information with expectations to guide subjective judgements about pain. Taken together, these results expand our understanding VMPFC’s contribution to pain and highlight the role of VMPFC in integrating cognitive representations with sensory information to yield affective responses.

Guided Relaxation-Based Virtual Reality for Acute Postoperative Pain and Anxiety: A Pilot Study in a Pediatric Population (Preprint)

BACKGROUND Distraction-based therapies, such as virtual reality (VR), have been used to reduce pain during acutely painful procedures. However, distraction alone cannot produce the prolonged pain reduction required to manage sustained postoperative pain. Integration of VR with other pain reducing therapies, like guided relaxation, may enhance their clinical impact. OBJECTIVE The goal of this pilot study was to assess the association of a single guided relaxation-based VR (VR-GR) session with a reduction in postoperative pain and anxiety in children. We also explored whether pain catastrophizing and anxiety sensitivity influenced this association. METHODS A total of 51 children and adolescents (7-21 years) with postoperative pain followed by the Acute Pain Service at Cincinnati Children’s Hospital were recruited over an 8-month period to undergo a single VR-GR session. Prior to VR, patients completed pain catastrophizing (PCS-C) and anxiety sensitivity (CASI) questionnaires. The primary outcome was changes in pain intensity following VR-GR (immediately, 15, and 30 minutes). Secondary outcomes included changes in pain unpleasantness and anxiety. RESULTS VR-GR decreased pain intensity immediately (p < 0.001) and 30 minutes (p = 0.04) after the VR session, but not at 15 minutes (p = 0.16) post-session. Reductions in pain unpleasantness were observed during all time intervals (p < 0.001 at all intervals). Anxiety was reduced immediately (p = 0.02) but not at 15- (p = 0.08) or 30- (p = 0.30) minutes following VR-GR. Patients with higher CASI reported greater reductions in pain intensity (p = 0.04) and unpleasantness (p = 0.01) following VR-GR. Pain catastrophizing was not associated with changes in pain and anxiety. CONCLUSIONS A single, short VR-GR session showed transient reductions in pain intensity, pain unpleasantness, and anxiety in children and adolescents with acute postoperative pain. These results encourage a future randomized clinical trial assessing efficacy of VR-GR. CLINICALTRIAL NCT04556747

Guided relaxation-based virtual reality versus distraction-based virtual reality or passive control for postoperative pain management in children and adolescents undergoing Nuss repair of pectus excavatum: protocol for a prospective, randomised, controlled trial (FOREVR Peds trial)

IntroductionVirtual reality (VR) offers an innovative method to deliver non-pharmacological pain management. Distraction-based VR (VR-D) using immersive games to redirect attention has shown short-term pain reductions in various settings. To create lasting pain reduction, VR-based strategies must go beyond distraction. Guided relaxation-based VR (VR-GR) integrates pain-relieving mind–body based guided relaxation with VR, a novel therapy delivery mechanism. The primary aim of this study is to assess the impact of daily VR-GR, VR-D and 360 video (passive control) on pain intensity. We will also assess the impact of these interventions on pain unpleasantness, anxiety and opioid and benzodiazepine consumption. The secondary aim of this study will assess the impact of psychological factors (anxiety sensitivity and pain catastrophising) on pain following VR.Methods and analysisThis is a single centre, prospective, randomised, clinical trial. Ninety children/adolescents, aged 8–18 years, presenting for Nuss repair of pectus excavatum will be randomised to 1 of 3 study arms (VR-GR, VR-D and 360 video). Patients will use the Starlight Xperience (Google Daydream) VR suite for 10 min. Patients randomised to VR-GR (n=30) will engage in guided relaxation/mindfulness with the Aurora application. Patients randomised to VR-D (n=30) will play 1 of 3 distraction-based games, and those randomised to the 360 video (n=30) will watch the Aurora application without audio instructions or sound. Primary outcome is pain intensity. Secondary outcomes include pain unpleasantness, anxiety and opioid and benzodiazepine consumption.Ethics and disseminationThis study follows Standard Protocol Items: Recommendations for Interventional Trials guidelines. The protocol was approved by the Cincinnati Children’s Hospital Medical Center’s institutional review board. Patient recruitment began in July 2020. Written informed consent will be obtained for all participants. All information acquired will be disseminated via scientific meetings and published in peer-reviewed journals.Trial registration numberNCT04351776.

Pain Intensity and Unpleasantness in People with Vascular Dementia: A Cross Sectional Study

Pain is a multidimensional sensory and affective experience. People with Vascular Dementia (VaD) experience pain more intensely and have negative emotional responses. Further investigation is needed to understand the neurobiology of pain in VaD. We used experimental thermal pain in a cross-sectional design to determine if adults (age&gt;64) with probable VaD experience increased pain intensity and increased pain unpleasantness during “mild” and “moderate” thermal pain. The final sample included 46 sex- and age-matched adults (23 VaD; 12 female) and controls (23 cognitively intact; 12 female) with an average age of 76.5 years (SD=7.5). Participants reported no daily analgesic use. We used a thermode placed on the thenar eminence to assess temperatures perceived as mild and moderate pain (°C) followed by unpleasantness ratings (0-20 scale). We assessed cognition and depression with the Mini-Mental State Exam (MMSE) and the Geriatric Depression Scale. After controlling for depression, and relative to controls, there was no statistically significant difference in the temperature at which people with VaD perceived mild or moderate pain (p = .086; Cohen’s d: mild=0.55, moderate=0.27). However, there was a statistically significant effect of VaD status on pain unpleasantness (p = .003). People with VaD reported mild and moderate pain as more unpleasant than controls (Cohen’s d = 0.79 and 0.60, respectively). Findings support previous work that people with VaD are at risk of experiencing more pain. Assessing pain intensity and affect can avoid under-treated pain in those with VaD.

Alpha entrainment drives pain relief using visual stimulation in a sample of chronic pain patients. A proof-of-concept controlled study.

One-third of the population in the UK and worldwide struggle with chronic pain. Entraining brain alpha activity through non-invasive visual stimulation has been shown to reduce experimental pain in healthy volunteers. Neural oscillations entrainment offers a potential non-invasive and non-pharmacological intervention for patients with chronic pain, which can be delivered in the home setting and has the potential to reduce use of medications. However, evidence supporting its use in patients with chronic pain is lacking. This study explores whether a) alpha entrainment increase alpha power in patients and b) whether this increase in alpha correlates with analgesia.28 patients with chronic pain sat in a comfortable position and underwent 4-minute visual stimulation using customised goggles at 10 Hz (alpha) and 7 Hz (control) frequency blocks in a randomised cross-over design. 64-channel Electroencephalography (EEG) and 11-point Numeric Rating Scale (NRS) pain intensity and pain unpleasantness scores were recorded before and after stimulation.EEG analysis revealed frontal alpha power was significantly higher when stimulating at 10 Hz when compared to 7 Hz. There was a significant positive correlation between increased frontal alpha and reduction in pain intensity (r=0.33, p&lt;0.05) and pain unpleasantness (r=0.40, p&lt;0.05) in the 10 Hz block.This study provides the first proof of concept that changes in alpha power resulting from entrainment correlate with an analgesic response in patients with chronic pain. Further studies are warranted to investigate dose-response parameters and equivalence to analgesia provided by medications.

Guided relaxation-based virtual reality transiently reduces acute postoperative pain and anxiety in a pediatric population

Background: Virtual reality (VR)-based immersive games and content can distract or redirect attention. Distraction-based therapies, such as VR, have been used to reduce pain from acutely painful procedures. However, it is unlikely that distraction alone can produce the prolonged pain reduction required to manage sustained postoperative pain. Integration of VR with other pain reducing therapies, including mind-body techniques, may enhance their clinical impact. Slow breathing and relaxation techniques are used clinically to reduce pain in children. Incorporating techniques such as these into the immersive audio-visual VR experience has the potential to produce synergistic effects. The current pilot study assessed the ability of a single guided relaxation-based VR (VR-GR) session to decrease acute postoperative pain and anxiety in children and adolescents. We also explored whether pain catastrophizing and anxiety sensitivity influenced the ability of VR-GR to reduce these outcomes. Methods: A total of 51 children and adolescents (ages 7-21 years) with postoperative pain followed by the Acute Pain Service at Cincinnati Childrens Hospital Medical Center were recruited over an 8-month period to undergo a single VR-GR session. Prior to VR, patients completed pain catastrophizing (PCS-C) and anxiety sensitivity (CASI) questionnaires. The primary outcome was changes in pain intensity following VR-GR (immediately, 15, and 30 minutes). Secondary outcomes included changes in pain unpleasantness and anxiety. Results: Based on mixed effects models, VR-GR decreased pain intensity immediately (p < 0.001) and 30 minutes (p = 0.04) after the VR session, but not at 15 minutes (p = 0.16) post-session. Reductions in pain unpleasantness were observed during all time intervals (p < 0.001 at all intervals). Anxiety was reduced immediately (p = 0.02) but not at 15- (p = 0.08) or 30- (p = 0.30) minutes following VR-GR. Adjustment for covariates showed that patients with higher CASI reported greater reductions in pain intensity (p = 0.04) and unpleasantness (p = 0.01) following VR-GR. Pain catastrophizing did not impact changes in pain and anxiety following the VR session (all ps > 0.10). Conclusion: A single, short VR-GR session produced immediate and acute reductions in pain intensity, pain unpleasantness, and anxiety in children and adolescents with acute postoperative pain. These results encourage future randomized clinical trials to compare the effectiveness of VR-GR and mind-body based treatments to reduce postoperative pain outcomes and to reduce requirements for opioid medications during this period.

Transient reductions in postoperative pain and anxiety using virtual reality in children

Objective: Virtual reality (VR) is a promising method to manage pain. Distraction-based VR (VR-D) is thought to reduce pain by redirecting attention. While VR-D can reduce pain associated with acutely painful procedures, it is unclear if VR-D can reduce pain after surgery. We assessed the ability of a single VR-D session to decrease acute postoperative pain and anxiety and explored if pain catastrophizing and anxiety sensitivity influenced the ability of VR-D to reduce these outcomes in children following surgery. Design: Single-center, prospective, pilot study Setting: Cincinnati Childrens Hospital Medical Center (CCHMC) Subjects: 50 children/adolescents (age 7-21 years) with postoperative pain followed by the Acute Pain Service Methods: Patients received a single VR-D session following surgery. Prior to the VR-D session, patients completed pain catastrophizing (PCS-C) and anxiety sensitivity (CASI) questionnaires. Primary outcome consisted of changes in pain intensity following VR-D (immediately, 15, and 30 minutes). Secondary outcomes included changes in pain unpleasantness and anxiety. Results: VR-D decreased pain intensity immediately and 15-minutes after VR-D. Reductions in pain unpleasantness were observed up to 30 minutes following VR-D. Anxiety was also reduced immediately and at 15-minutes following VR-D. While patients with higher pain catastrophizing had higher baseline pain intensity and unpleasantness, they did not show larger pain reductions following VR-D compared to those with lower pain catastrophizing. Conclusions: VR-D is beneficial in transiently reducing pain intensity, unpleasantness, and anxiety in children with acute postoperative pain. This study informs design of larger, controlled study assessing VR-D for acute postoperative pain and anxiety.

Underpredicting Pain: An experimental investigation into the benefits and risks - Preprint

Expectancies can shape pain and other experiences. Generally, experiences change in the direction of what is expected (i.e., assimilation effects), as seen with placebo effects. However, in case of large expectation-experience discrepancies, experiences might change away from what is expected (i.e., contrast effects). Previous research has demonstrated contrast effects on various outcomes, but not pain. We investigated the effects of strong underpredictions of pain on experienced pain intensity. Additionally, we assessed related outcomes including (certainty of) expectations, fear of pain, pain unpleasantness, autonomic responses, and trust. Healthy participants (Study 1: n=81, Study 2: n=123) received verbal suggestions that subsequent heat stimuli would be moderately or highly painful (correct prediction), mildly painful (medium underprediction; Study 2 only), or non-painful (strong underprediction). Both studies showed that participants experienced less intense pain upon strong underprediction than upon correct prediction (i.e., assimilation). Expected pain, fear of pain, and pain unpleasantness were generally also lowered. However, strong underprediction simultaneously lowered certainty of expectations and trust in the experimenter. Study 2 indicated that the effects of strong underprediction versus medium underprediction generally did not differ. Moreover, Study 2 provided some indications for reduced heart rate and skin conductance levels, but increased skin conductance responses upon strong underprediction. In conclusion, even strong underpredictions of pain can reduce pain (i.e., cause assimilation), although not significantly more than medium underpredictions. However, strong underpredictions can cause uncertainty and undermine trust. These findings suggest that healthcare providers may wish to be cautious with providing overly positive information about painful medical procedures.