
==== Front
Curr Gastroenterol Rep
Curr Gastroenterol Rep
Current Gastroenterology Reports
1522-8037
1534-312X
Springer US New York

39136889
940
10.1007/s11894-024-00940-w
Article
The Role of Virtual Reality in the Management of Irritable Bowel Syndrome
Suchak Karisma K. karisma.suchak@cshs.org

12
Almario Christopher V. 123
Liran Omer 124
Chernoff Robert 4
Spiegel Brennan R. 123
1 grid.50956.3f 0000 0001 2152 9905 Division of Health Sciences Research, Department of Medicine, Cedars-Sinai Health System, Pacific Theatre Building 116 N. Robertson Blvd, Suite 800, Los Angeles, CA 90048 USA
2 Cedars-Sinai Center for Outcomes Research and Education (CS-CORE), Los Angeles, CA USA
3 Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai, Los Angeles, CA USA
4 Cedars-Sinai Department of Psychiatry and Behavioral Sciences, Los Angeles, CA USA
13 8 2024
13 8 2024
2024
26 11 294303
16 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Purpose of Review

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction that significantly impacts health-related quality of life (HRQOL). This article explores the potential role of virtual reality (VR)-based cognitive behavioral therapy (CBT) in treating patients with IBS.

Recent Findings

While CBT is a proven, skills-based therapy approach that modifies behaviors and alters dysfunctional thinking patterns to influence the gut-brain axis and improve IBS symptoms, it is rarely prescribed given a paucity of CBT-trained clinicians. We developed a novel VR program that delivers a standardized CBT program over an 8-week period to help patients manage their symptoms. In initial qualitative validation testing, patients expressed positive perceptions about using VR CBT for IBS.

Summary

Home-based, standardized VR CBT has the potential to be an effective and scalable treatment option for patients with IBS. While initial studies have shown proof-of-concept definitive randomized controlled trials are needed to demonstrate the efficacy of self-administered VR CBT in IBS.

Keywords

Irritable bowel syndrome
Virtual reality
Cognitive behavioral therapy
Cedars-Sinai Medical CenterOpen access funding provided by SCELC, Statewide California Electronic Library Consortium

issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2024
==== Body
pmcIntroduction

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction (DGBI) that is characterized by chronic, recurrent abdominal pain and abnormal bowel habits [1]. IBS significantly impacts biopsychosocial functioning, and individuals diagnosed with IBS experience substantial health-related quality of life (HRQOL) decrements similar to those with diabetes, end-stage renal disease, and congestive heart failure [2–4]. Due to the high disease prevalence and marked impact on HRQOL, the economic burden and healthcare utilization related to IBS are enormous; 2.3 M outpatient visits each year are due to IBS [5–7].

While there are many medications used to treat IBS (e.g., neuromodulators, secretagogues, antibiotics) [8], medical therapy often falls short in delivering meaningful, sustained improvements in symptoms and HRQOL. The average number needed to treat (NNT) for US Food and Drug Administration (FDA)-approved IBS medications is 9 [9]. Many of the therapies also have significant side effects that lead patients to discontinue therapy. For example, patients are commonly prescribed tricyclic antidepressants which can cause somnolence, severe dry mouth, and constipation, among other side effects. Hence, there is a critical gap in managing IBS; it is vital to develop and test novel behavioral strategies. In this article, we discuss the evolving role of virtual reality (VR) as a treatment option for IBS, and focus on a novel, on-demand virtual reality VR-based cognitive behavioral therapy (CBT) program that our team developed for patients with IBS.

CBT in IBS

In the biopsychosocial model of IBS pathogenesis, there are interactions between biology (e.g., genetic predisposition, intestinal dysmotility, gut microbiome changes), behavior (e.g., illness behavior, symptom avoidance), cognitive processes (e.g., brain-gut dysregulation, visceral anxiety), and environment (e.g., childhood trauma, stress) [4, 10]. Dysregulation in any of these factors can lead to IBS symptoms, particularly alterations in the gut-brain axis; central nervous system alterations (e.g., chronic stress, anxiety, depression) can lead to symptoms via changes in tight junction and intestinal permeability that cause inflammation, edema, and changes in visceral neuromuscular function [8, 11, 12]. The above findings combined with the well-established overlap of IBS with psychological comorbidities, coupled with evidence that neuromodulators and psychotherapies are effective, indicate that IBS is a disorder of gut-brain interaction [13–16].

Cognitive processes such visceral hypersensitivity and visceral anxiety underlie symptoms for many patients with IBS [10, 12]. CBT is a skills-based therapy approach that targets these cognitive processes by modifying behaviors and altering dysfunctional thinking patterns to influence the gut-brain axis and improve IBS symptoms [10, 17, 18]. Moreover, CBT has been well-studied in IBS with greater than 30 randomized clinical trials (RCTs) demonstrating its efficacy [13–15, 17, 19–21]. For example, Lackner et al. performed a pioneering RCT comparing standard CBT (10 clinic sessions covering: brain-gut interactions; monitoring of symptoms, triggers, and consequences; muscle relaxation; problem solving; relapse prevention training) vs. home-based CBT with minimal therapist contact (4 therapist sessions and home materials on the same topics as standard CBT) vs. IBS education (4 support and informational sessions about IBS and lifestyle factors) [19]. At week 12, more people had global improvement in IBS symptoms in both the standard CBT (55%; p < 0.05) and home-based CBT with minimal therapist contact (61%; p < 0.01) arms vs. the education arm (44%; ref) [19]. They also found that the effects were durable at 1 year [22].

These data led the American College of Gastroenterology (ACG) and American Gastroenterological Association (AGA) in their IBS clinical guidelines to suggest use of CBT in conjunction with other treatments, as it is low risk and efficacious with a NNT of 4 [9, 15, 23]. Yet, despite the strength of evidence showing its efficacy and endorsement in national guidelines, CBT is rarely prescribed given a paucity of clinicians trained in behavioral techniques; self-administered options are needed to bridge the growing gap between supply and demand of CBT practitioners for IBS and other DGBI. On-demand, standardized CBT programs delivered via VR at home has the potential to bridge this gap.

VR in IBS and Hypothesized Mechanisms

VR is unlike other audiovisual technologies in its ability to generate meaningful emotional experiences and durable clinical responses [24, 25]. Users of VR wear a head-mounted display that creates a vivid perception of being transported into immersive and emotionally evocative worlds. The effect of VR is mediated through several mechanisms, most notably presence—the ability of VR to convey a compelling sense of “just being there,” wherever there happens to be [26, 27]. For example, VR can simulate relaxing on a beach, flying over nature scenes, or swimming with dolphins, among countless other environments. Research has shown that these virtual journeys can durably impact clinical outcomes even 18–24 months post treatment [25, 28].

In the context of IBS, VR has the potential to administer an on-demand, standardized CBT program to teach patients skills to manage the maladaptive cognitive processes (e.g., visceral hypersensitivity, visceral anxiety) contributing to their brain-gut axis symptoms. Over time, patients may employ the new skills they learned in VR in everyday life without requiring ongoing VR exposure, similar to the long-term benefits achieved for somatic pain up to 24 months after discontinuing VR CBT therapy [28]. Simultaneously, use of VR as the delivery mechanism for CBT may also lead to “virtual analgesia” for patients’ abdominal pain—the principal driver of IBS symptom severity and the cornerstone of the IBS illness experience [29–33]. Notably, therapeutic VR has long been used to manage the cognitive, affective, and sensory aspects of pain across diverse conditions [34–45]. By stimulating the visual cortex in a way that standard two-dimensional (2D) apps are unable to achieve, VR distracts users from processing nociceptive stimuli that do not require continued use of VR once cognitive skills are transferred [25]. Studies and meta-analyses reveal that VR helps manage chronic pain conditions such as complex regional pain syndrome, chronic neck pain, chronic lower back pain, and cancer pain, among other conditions [37, 40, 42, 46–49].

Our team at Cedars-Sinai has employed virtual analgesia in over 3,000 patients and demonstrated that it is feasible and practical for patients to use the equipment [50]. For instance, we performed a non-randomized trial in 2017 testing VR analgesia in 100 participants with diverse forms of pain; the study demonstrated a 24% reduction in pain that outperformed a 2D relaxation video [51]. Moreover, 65% of VR participants achieved a clinically significant decrease in pain vs. 40% of controls (p = 0.01; NNT = 4) [51]. In a follow-up RCT published in 2019, we found additional evidence supporting the analgesic benefits of VR across a wide range of pain conditions (N = 120) [52]. This study found that VR was effective across ages [52], and from an ongoing NIH HEAL study we are observing similar VR acceptability and effectiveness by gender, race, and ethnicity.

In short, the use of virtual analgesia has gained traction on the strength of less expensive, more scalable, and higher quality VR equipment, meaningful advances in the science of therapeutic VR, dissemination of methodological guidance for VR trials [53], and patient acceptability of VR.

Central Nervous System Effects of VR on IBS Abdominal Pain

Although IBS is a multi-symptom disorder, abdominal pain is its defining characteristic and a predominant feature of the IBS illness experience [29–33]. Unlike other IBS symptoms, such as bloating or bowel habit changes, research from our team found that abdominal pain independently drives HRQOL decrements in IBS [32] and is the principal driver of patient-reported symptom severity [31, 33]. In a study of 755 patients with IBS, we discovered that abdominal pain was the strongest predictor of IBS severity among over 25 tested clinical factors [31].

Research indicates that VR reduces pain through 2 foundational mechanisms of action (MOAs), herein labeled MOA1 and MOA2 (Fig. 1). First, by stimulating the visual cortex while engaging other senses (e.g., auditory, proprioceptive), VR acts as a distraction to limit the user’s processing of nociceptive stimuli (MOA1) [54]. The result is a form of “inattentional blindness” where attentional bandwidth is redirected to the virtual world, lessening one’s ability to attend to pain signals outside the “spotlight of attention.” [55] By overwhelming the visual, auditory, and vestibular senses, VR creates an immersive distraction that restricts the brain from processing pain. The ability of VR to occupy attention also creates an illusion of time acceleration, thus shortening the perception of pain episodes [56–58]. For example, RCTs reveal that VR reduces the perceived length of labor during childbirth, episiotomy repair, endoscopic procedures, and chemotherapy infusions by an average of 30–50% [56–58]. In addition to modifying attention to pain through distraction and time acceleration, VR offers an immersive platform through which people acquire and begin to master specific skills and cultivate adaptive cognitive patterns that reduce pain processing in the central nervous system (MOA2) [59, 60].

Fig. 1 Conceptual model of VR analgesia depicting MOAs and their proposed primary and secondary effects in IBS

The net effect of MOA1 and MOA2 is to centrally modulate pain, promote positive affect, and downregulate physical and emotional components of pain. These effects, in turn, leverage the gate control theory of Melzack and Wall [61], wherein VR activates descending inhibitory pathways and dampens spinal transmission of peripheral afferent pain signals [62–64]. Further, distraction-based VR affects pain processing in the sensory and insular cortex, indicating it can reduce both the intensity of pain and the emotional response to pain [65, 66]. Moreover, data indicates that VR produces similar functional MRI effects as hydromorphone and is as effective as opioids at alleviating pain [64].

Taken together, the conceptual framework in Fig. 1 suggests that VR may reduce IBS pain via central pain modulation coupled with diminished spinal transmission of pain signals. Based on data that VR offers comparable or adjunctive analgesia to opioids [65], combined with robust RCT data showing that non-VR CBT is effective for IBS [13–15, 19], we hypothesize that using VR-administered CBT may reduce abdominal pain, which will then lead to improved overall physical, psychological, and social functioning. As chronic and recurrent abdominal pain is a defining characteristic and predominant feature of the IBS experience [29–33], use of VR to deliver CBT may lead to incremental benefits for IBS associated abdominal pain over that achieved with traditional CBT alone.

Enteric Nervous System Effects of VR on IBS Abdominal Pain

Although VR was initially thought to mainly address pain through central nervous system effects, it is now known that there are reciprocal interactions between the central and enteric nervous systems. This is supported by a study from Schneider et al. that demonstrated how the enteric nervous system acts as a relay between psychological stress and gut inflammation and dysmotility [11]. The investigators found that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes intestinal inflammation [11]. Glucocorticoids also cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and subsequently GI dysmotility [11]. By reducing stress and anxiety—both of which are highly prevalent in people with IBS—through VR CBT, a reduction intestinal inflammation and dysmotility may occur, thus leading to improvements in abdominal pain and HRQOL.

A Novel, On-Demand, VR-Based CBT Program for IBS

Development

Using the ORBIT Model for Developing Behavioral Treatments for Chronic Diseases framework, our Cedars-Sinai team developed a VR program that delivers CBT over an 8-week period to help patients manage their gut symptoms [67]. As part of the ORBIT Model Phase I (Design), the program was defined and refined by a multidisciplinary team (CBT psychologist, gastroenterologist, psychiatrist, biomedical visualization specialist, VR programmer and developer, human-centered design expert, and digital health researchers) in partnership with patients [68].

While actual techniques and foci can vary between CBT frameworks, the VR program includes the following essential CBT components as described by Kinsinger [10]: (i) psychoeducation; (ii) relaxation strategies; (iii) cognitive restructuring; (iv) problem-solving skills; and (v) exposure techniques. Each component maps to 4 VR environments (i.e., “treatment rooms”) that users encounter within the program: (i) Exam Room → psychoeducation; (ii) Chill Room → relaxation strategies and talk therapy; (iii) Theater of the Mind → cognitive restructuring; problem-solving skills; exposure techniques; (iv) Zoom Out Room → psychoeducation; cognitive restructuring; problem-solving skills. Figure 2 shows representative images from each VR treatment room. To optimize accessibility across educational levels, the voiceover scripts were written at an elementary school level with an average Flesch-Kincaid Grade Level score of 6 and Simple Measure Gobbledygook (SMOG) readability score of 5 across the treatment rooms; these scores correspond to 5th-6th grade reading levels.

Fig. 2 Select images from VR treatment rooms and their CBT components

Program Structure and CBT Modules

The standardized CBT program is self-administered and includes a network of environments arranged in a virtual clinic that participants experience at home though a protocolized, 8-week program. Figure 3 presents the activities for each day. Depending on the module, daily treatments last between 5 and 20 minutes. The VR modules are reinforced with daily messages and CBT exercises delivered by a webapp that is available on any smartphone or computer along with emails. Messages have been programmed in a way to reinforce cognitive restructuring. The program progressively builds new skills and culminates in transitioning from using VR to applying the skills learned in VR to everyday life:

Fig. 3 8-week CBT treatment protocol as delivered in VR. See text for details

CBT Skill 1—Psychoeducation

In the Exam Room, participants virtually embody the role of a doctor to examine a patient with pain and discover anatomical and functional aspects of the GI tract. They learn about visceral hypersensitivity and engage in an immersive experience about the brain-gut axis. In the Zoom Out Room, participants journey through a series of “zoom out” maneuvers to gain perspective about the global community of people with IBS and, in the process, gain new perspective about themselves as a person with IBS. In the Chill Room, another therapeutic opportunity emerges from the combination of immersive VR environments with advances in conversational artificial intelligence (AI) via the Mobile Artificially Intelligent Ally (MAIA). The integration of AI within VR offers an unprecedented opportunity for patients to participate in talk therapy, which usually requires one-on-one sessions with a licensed therapist, a resource that is not always available or affordable for many people.

CBT Skill 2—Relaxation Strategies

In the Chill Room, which has been extensively used at Cedars-Sinai in over 200 participants in our inpatient VR consult service, participants practice biofeedback-enabled breath training, experience gut-directed hypnotherapy based on published studies using this technique for IBS, [17, 69–71] and learn to relax in nature environments that leverage the known therapeutic benefits of “biophilia,” which refers to the innate connection that humans have with natural environments, particularly green spaces [72–74]. Prior research has employed biophilic VR programs to reduce stress and support positive psychology [74, 75].

CBT Skill 3—Cognitive Restructuring

In the Theater of the Mind, participants learn principles of CBT, namely, that thoughts about gastrointestinal symptoms can be maladaptive and unhelpful and contribute to perceptions of gut pain, that such thoughts can be challenged and “restructured,” and that changing such thoughts can help alleviate gut pain and the negative emotions associated with it. Users enter a movie theater representing their own mind. Scenes on the screen depict thoughts as participants learn to identify or “catch” the thoughts associated with gut pain, to recognize when such thoughts contain distortions or errors, and to dispute such thoughts with challenging questions. Participants then learn to restructure such unhelpful thoughts about gut pain and replace them with thoughts that are more accurate, fact-based, balanced, and helpful, thereby leading to reductions in negative emotions and GI pain.

CBT Skill 4—Problem-Solving Techniques

In the Theater of the Mind, participants are provided with opportunities to practice applying the principles and techniques of CBT to challenge their perceptions of GI pain. In the Zoom Out Room, participants engage in avatar-based self-chat, through a validated technique called “virtual embodiment,” [76–84] to explore ways to manage their pain, combat the stigma often experienced by people with IBS, and learn to manage biopsychosocial distress through a process of self-discovery.

CBT Skill 5—Exposure Techniques

In the Theater of the Mind Exposure Modules, users practice CBT skills they learned in the earlier Theater of the Mind activities. Within the immersive VR environment, participants are visually “exposed” to the kind of stressful life situations associated with common DGBI symptoms that they might encounter in the real world. For example, for a patient with IBS, they are exposed to being in a public restroom with someone in the adjacent stall, experiencing pain while eating, or being in a meeting with other people while experiencing gut pain. Participants are prompted to practice and use the CBT skills they learned in earlier modules so that they can achieve a sense of mastery about how to handle such situations when they experience them in their lives.

Initial Qualitative Assessment with IBS Patients

As part of Phase I (Design) in the ORBIT Model, we performed qualitative validation with 15 patients using the VR software [68]. Recruited patients met Rome IV criteria for IBS [1] and were receiving care at gastroenterology clinics at Cedars-Sinai. Patients who consented agreed to experience the VR and participate in debriefing sessions. Sessions were led by a qualitative research expert and discussions lasted 2 hours and were audiotaped and transcribed. Patients answered open-ended “think aloud” questions along with scripted probes. The questions focused on global perceptions, module length, instructional clarity, graphics quality, perceived effectiveness, and opportunities for improvement. Afterwards, we used an inductive thematic analysis in which debriefing transcripts were coded and labels identified within the unstructured data. After sorting, combining, and refining the codes and labels, inductive themes were defined and justified with verbatim quotes. Thematic saturation was achieved after interviews with 15 patients. The average age was 47 years and they had IBS for a median duration of 10 years. Fourteen (93%) patients had no, a little bit, or some experience with VR. No patients reported VR-related vertigo (“cybersickness”). Table 1 presents sample user feedback for each treatment room. Across demographics, VR experience, and years with IBS, patients expressed positive perceptions about using VR for IBS; all 15 (100%) said they would recommend VR to other people with IBS. The full methods and results of this Phase I qualitative validation study are available at this 2022 citation published in the American Journal of Gastroenterology [68].

Table 1 Patient perceptions of VR treatment rooms in initial qualitative validation testing [68]

Room	CBT Components	IBS Patient Perceptions	
Exam Room	• Psychoeducation	• Visuals helped “better understand the connection between the gut and the mind.”

• Patients appreciated “the visualization of how the gut and the brain interact.”

• The module helped people envision “what doctors talk about when explaining IBS.”

	
Chill Room	• Relaxation strategies	• The Chill Room was “powerful,” “calming,” “serene,” and “soothing.”

• Helped patients relax as “breathing slowed down with the expansion and contraction of the mandala”; “It was very helpful for me…the graphics, the calmness….”

• Meditation was “helpful in bringing anxiety down” and to “feel better in the long run.”

	
Theater of the Mind	• Cognitive restructuring

• Problem-solving skills

• Exposure techniques

	• CBT content was “valuable,” “easy to understand,” and “relatable”; “it’s reassuring … seeing how accurate you have the mental process of somebody with IBS.”

• Experience caused some to reassess their IBS-related cognitions: “I am reflecting on two things I’ve picked up; saying the thought out loud and replacing it.”

• Put patients’ minds “at ease” and helped them feel “less alone with intrusive thoughts.”

• Helped people “realize how destructive self-blame thoughts can be.”

	
Zoom Out Room	• Psychoeducation

• Cognitive restructuring

• Problem-solving skills

	• The perspective-taking content was considered “straightforward” and “self-driven.”

• Engaging in self-talk helped patients go “beyond themselves” and “be more self-compassionate.”

• Hearing themselves talk led to self-reflection and reconsideration of their IBS cognitions.

• Some patients felt less alone: “When you see from space that there’s a lot of people with IBS…it makes me feel like one of many.”

	

Iterative Updates to VR Program After Initial Qualitative Validation

After completion of the initial 12 patient interviews, 23 software changes were made to enhance the program. For example, in the Exam Room, patients recommended additional education on the role that the heart and cardiovascular system may have in the Management of Irritable Bowel Syndromeathogenesis of IBS and visceral pain. The voiceover script was thus expanded to introduce an example of developing “stomach cramps” while exercising, and illustrated how gut hypoperfusion can cause visceral pain. For the Chill Room, some participants thought that the desert scene felt “desolate” and requested a water environment, leading us to develop a lake scene. As for Theater of the Mind, patients recommended “trigger scenes” to practice CBT in stressful situations, such as being in a public restroom, being in the middle of a meeting when IBS symptoms occur, or flying in an airplane and needing to bother people to access the restroom; such trigger Management of Irritable Bowel Syndrome the VR program. Finally, for the Zoom Out Room, patients suggested adding “conversation starter” topics to help initiate the self-chat feature. We thus added questions such as: “Do you ever feel embarrassed about having IBS?”; “What steps can you take to gain control over your IBS?” After making the changes, we conducted 3 more interviews, which confirmed thematic saturation.

Conclusion

While IBS is very common and overwhelmingly impacts HRQOL, current pharmacologic treatments often fall short in delivering meaningful improvements in symptoms and are commonly limited by side effects. Robust evidence indicates that CBT can improve symptoms and HRQOL in IBS but is rarely used and often inaccessible to patients due to the paucity of CBT-trained clinicians. Hence, it is vital to develop, test, and validate novel behavioral strategies that are effective, durable, safe, inexpensive, and accessible.

Use of a home-based, standardized, VR CBT program, has potential to bridge this gap. We are currently in Phase II of the ORBIT Model and are planning pilot RCTs to gather preliminary data assessing VR’s efficacy and feasibility in IBS. Based on what we observe in these pilot studies from patients and clinicians, additional enhancements will be made to the VR software and its integration in clinical workflows before subjecting it to a definitive, adequately powered efficacy trial. Moreover, data from these studies can inform future research examining VR CBT treatments for other DGBIs (e.g., functional dyspepsia, functional heartburn), Crohn’s disease, and ulcerative colitis, among other GI conditions. Given the high prevalence of IBS and other GI conditions combined with the paucity of effective medical therapies and marked shortage of trained CBT practitioners, the development and validation of novel self-administered approaches are needed.

Author Contributions

K.S. co-wrote the main manuscript text, prepared figures and tables. C.A. co-wrote the main manuscript text, prepared figures and tables. R.C. co-wrote the main manuscript text. O.L. co-wrote the main manuscript text, and co-developed the software program. B.S. co-wrote the main manuscript text, prepared figures and tables, and co-developed the software program.All authors reviewed and edited the manuscript for important intellectual content.

Disclosures

Drs. Brennan Spiegel and Omer Liran co-developed SynerGI using internal resources from Cedars-Sinai Medical Center with additional support from the Marc and Sheri Rapaport Fund for Digital Health Science and Precision Health at Cedars-Sinai. Drs. Spiegel and Liran are co-founders of VRx Health. Dr. Christopher Almario consulted for Exact Sciences, Greenspace Labs and Owlstone Medical; has stock options in My Total Health. Dr. Spiegel consulted for Ardelyx, Exact Sciences, Ferring; has leadership roles in the American College of Gastroenterology (Governor for Southern California); has research grants to his institution from Abbvie, Amgen, Ironwood, Salix/Bausch, Takeda; has patents for My Nutrition Health, digital manometry, AbStats sensor. Dr. Robert Chernoff and Dr. Karisma Suchak do not have any relevant conflicts of interest to disclose.

Open access funding provided by SCELC, Statewide California Electronic Library Consortium

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing Interests

Drs. Brennan Spiegel and Omer Liran co-developed SynerGI using internal resources from Cedars-Sinai Medical Center with additional support from the Marc and Sheri Rapaport Fund for Digital Health Science and Precision Health at Cedars-Sinai. Drs. Spiegel and Liran are co-founders of VRx Health. Dr. Christopher Almario consulted for Exact Sciences, Greenspace Labs and Owlstone Medical; has stock options in My Total Health. Dr. Spiegel consulted for Ardelyx, Exact Sciences, Ferring; has leadership roles in the American College of Gastroenterology (Governor for Southern California); has research grants to his institution from Abbvie, Amgen, Ironwood, Salix/Bausch, Takeda; has patents for My Nutrition Health, digital manometry, AbStats sensor. Dr. Robert Chernoff and Dr. Karisma Suchak do not have any relevant conflicts of interest to disclose.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Mearin F Lacy BE Chang L Chey WD Lembo AJ Simren M Bowel Disorders Gastroenterol 2016 10.1053/j.gastro.2016.02.031
Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, et al. Bowel Disorders Gastroenterol. 2016. 10.1053/j.gastro.2016.02.031.10.1053/j.gastro.2016.02.031
2. Whitehead WE, Burnett CK, Cook EW 3rd, Taub E. Impact of irritable bowel syndrome on quality of life. Dig Dis Sci. 1996;41(11):2248–53. 10.1007/bf02071408.
3. Gralnek IM Hays RD Kilbourne A Naliboff B Mayer EA The impact of irritable bowel syndrome on health-related quality of life Gastroenterology 2000 119 3 654 60 10.1053/gast.2000.16484 10982758
Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. The impact of irritable bowel syndrome on health-related quality of life. Gastroenterology. 2000;119(3):654–60.10982758 10.1053/gast.2000.16484
4. Van Oudenhove L Crowell MD Drossman DA Halpert AD Keefer L Lackner JM Biopsychosocial aspects of Functional Gastrointestinal disorders Gastroenterology 2016 10.1053/j.gastro.2016.02.027 27144624
Van Oudenhove L, Crowell MD, Drossman DA, Halpert AD, Keefer L, Lackner JM, et al. Biopsychosocial aspects of Functional Gastrointestinal disorders. Gastroenterology. 2016. 10.1053/j.gastro.2016.02.027.27144624 10.1053/j.gastro.2016.02.027
5. Peery AF Crockett SD Barritt AS Dellon ES Eluri S Gangarosa LM Burden of gastrointestinal, liver, and pancreatic diseases in the United States Gastroenterology 2015 149 7 1731 e413 10.1053/j.gastro.2015.08.045 26327134
Peery AF, Crockett SD, Barritt AS, Dellon ES, Eluri S, Gangarosa LM, et al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology. 2015;149(7):1731–e413. 10.1053/j.gastro.2015.08.045.26327134 10.1053/j.gastro.2015.08.045
6. Lacy BE Weiser KT Kennedy AT Crowell MD Talley NJ Functional dyspepsia: the economic impact to patients Aliment Pharmacol Ther 2013 38 2 170 7 10.1111/apt.12355 23725230
Lacy BE, Weiser KT, Kennedy AT, Crowell MD, Talley NJ. Functional dyspepsia: the economic impact to patients. Aliment Pharmacol Ther. 2013;38(2):170–7. 10.1111/apt.12355.23725230 10.1111/apt.12355
7. Aro P Talley NJ Agréus L Johansson SE Bolling-Sternevald E Storskrubb T Functional dyspepsia impairs quality of life in the adult population Aliment Pharmacol Ther 2011 33 11 1215 24 10.1111/j.1365-2036.2011.04640.x 21443537
Aro P, Talley NJ, Agréus L, Johansson SE, Bolling-Sternevald E, Storskrubb T, et al. Functional dyspepsia impairs quality of life in the adult population. Aliment Pharmacol Ther. 2011;33(11):1215–24. 10.1111/j.1365-2036.2011.04640.x.21443537 10.1111/j.1365-2036.2011.04640.x
8. Ford AC, Sperber AD, Corsetti M, Camilleri M. Irritable bowel syndrome. Lancet. 2020.
9. Lacy BE, Pimentel M, Brenner DM, Chey WD, Keefer LA, Long MD et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021;116(1):17–44. doi: 10.14309/ajg.0000000000001036.
10. Kinsinger SW Cognitive-behavioral therapy for patients with irritable bowel syndrome: current insights Psychol Res Behav Manag 2017 10 231 7 10.2147/prbm.S120817 28790872
Kinsinger SW. Cognitive-behavioral therapy for patients with irritable bowel syndrome: current insights. Psychol Res Behav Manag. 2017;10:231–7. 10.2147/prbm.S120817.28790872 10.2147/prbm.S120817
11. Schneider KM, Blank N, Alvarez Y, Thum K, Lundgren P, Litichevskiy L et al. The enteric nervous system relays psychological stress to intestinal inflammation. Cell. 2023;186(13):2823-38.e20. 10.1016/j.cell2023.05.001.
12. Ford AC Mahadeva S Carbone MF Lacy BE Talley NJ Functional dyspepsia Lancet 2020 396 10263 1689 702 10.1016/S0140-6736(20)30469-4 33049222
Ford AC, Mahadeva S, Carbone MF, Lacy BE, Talley NJ. Functional dyspepsia. Lancet. 2020;396(10263):1689–702. 10.1016/S0140-6736(20)30469-4.33049222 10.1016/S0140-6736(20)30469-4
13. Black CJ Thakur ER Houghton LA Quigley EMM Moayyedi P Ford AC Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis Gut 2020 69 8 1441 51 10.1136/gutjnl-2020-321191 32276950
Black CJ, Thakur ER, Houghton LA, Quigley EMM, Moayyedi P, Ford AC. Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis. Gut. 2020;69(8):1441–51. 10.1136/gutjnl-2020-321191.32276950 10.1136/gutjnl-2020-321191
14. Drossman DA Tack J Ford AC Szigethy E Törnblom H Van Oudenhove L Neuromodulators for Functional Gastrointestinal disorders (disorders of Gut-Brain Interaction): a Rome Foundation Working Team Report Gastroenterology 2018 154 4 1140 e711 10.1053/j.gastro.2017.11.279 29274869
Drossman DA, Tack J, Ford AC, Szigethy E, Törnblom H, Van Oudenhove L. Neuromodulators for Functional Gastrointestinal disorders (disorders of Gut-Brain Interaction): a Rome Foundation Working Team Report. Gastroenterology. 2018;154(4):1140–e711. 10.1053/j.gastro.2017.11.279.29274869 10.1053/j.gastro.2017.11.279
15. Ford AC Quigley EM Lacy BE Lembo AJ Saito YA Schiller LR Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis Am J Gastroenterol 2014 109 9 1350 65 10.1038/ajg.2014.148 24935275
Ford AC, Quigley EM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(9):1350–65. 10.1038/ajg.2014.148. quiz 66.24935275 10.1038/ajg.2014.148
16. Whitehead WE Palsson O Jones KR Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology 2002 122 4 1140 56 10.1053/gast.2002.32392 11910364
Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002;122(4):1140–56. 10.1053/gast.2002.32392.11910364 10.1053/gast.2002.32392
17. van Tillburg MAL. Cognitive Behavioral Therapy for Disorder of Brain-Gut Interaction. In: Faure C, Thapar N, Di Lorenzo C, editors. Pediatric Neurogastroenterology: Gastrointestinal Motility Disorders and Disorders of Gut Brain Interaction in Children. Cham: Springer International Publishing; 2022. pp. 599–605.
18. Keefer L Ballou SK Drossman DA Ringstrom G Elsenbruch S Ljótsson B A Rome Working Team Report on Brain-Gut Behavior therapies for disorders of Gut-Brain Interaction Gastroenterology 2022 162 1 300 15 10.1053/j.gastro.2021.09.015 34529986
Keefer L, Ballou SK, Drossman DA, Ringstrom G, Elsenbruch S, Ljótsson B. A Rome Working Team Report on Brain-Gut Behavior therapies for disorders of Gut-Brain Interaction. Gastroenterology. 2022;162(1):300–15. 10.1053/j.gastro.2021.09.015.34529986 10.1053/j.gastro.2021.09.015
19. Lackner JM Jaccard J Keefer L Brenner DM Firth RS Gudleski GD Improvement in gastrointestinal symptoms after cognitive behavior therapy for refractory irritable bowel syndrome Gastroenterology 2018 155 1 47 57 10.1053/j.gastro.2018.03.063 29702118
Lackner JM, Jaccard J, Keefer L, Brenner DM, Firth RS, Gudleski GD, et al. Improvement in gastrointestinal symptoms after cognitive behavior therapy for refractory irritable bowel syndrome. Gastroenterology. 2018;155(1):47–57. 10.1053/j.gastro.2018.03.063.29702118 10.1053/j.gastro.2018.03.063
20. Laird KT Tanner-Smith EE Russell AC Hollon SD Walker LS Comparative efficacy of psychological therapies for improving mental health and daily functioning in irritable bowel syndrome: a systematic review and meta-analysis Clin Psychol Rev 2017 51 142 52 10.1016/j.cpr.2016.11.001 27870997
Laird KT, Tanner-Smith EE, Russell AC, Hollon SD, Walker LS. Comparative efficacy of psychological therapies for improving mental health and daily functioning in irritable bowel syndrome: a systematic review and meta-analysis. Clin Psychol Rev. 2017;51:142–52. 10.1016/j.cpr.2016.11.001.27870997 10.1016/j.cpr.2016.11.001
21. Laird KT Tanner-Smith EE Russell AC Hollon SD Walker LS Short-term and long-term efficacy of psychological therapies for irritable bowel syndrome: a systematic review and Meta-analysis Clin Gastroenterol Hepatol 2016 14 7 937 e474 10.1016/j.cgh.2015.11.020 26721342
Laird KT, Tanner-Smith EE, Russell AC, Hollon SD, Walker LS. Short-term and long-term efficacy of psychological therapies for irritable bowel syndrome: a systematic review and Meta-analysis. Clin Gastroenterol Hepatol. 2016;14(7):937–e474. 10.1016/j.cgh.2015.11.020.26721342 10.1016/j.cgh.2015.11.020
22. Lackner JM Jaccard J Radziwon CD Firth RS Gudleski GD Hamilton F Durability and decay of Treatment Benefit of cognitive behavioral therapy for irritable bowel syndrome: 12-Month Follow-Up Am J Gastroenterol 2019 114 2 330 8 10.1038/s41395-018-0396-x 30429592
Lackner JM, Jaccard J, Radziwon CD, Firth RS, Gudleski GD, Hamilton F, et al. Durability and decay of Treatment Benefit of cognitive behavioral therapy for irritable bowel syndrome: 12-Month Follow-Up. Am J Gastroenterol. 2019;114(2):330–8. 10.1038/s41395-018-0396-x.30429592 10.1038/s41395-018-0396-x
23. American Gastroenterological Association. Clinical Decision Support Tool: IBS Treatment. https://gastro.org/press-releases/aga-issues-clinical-guidelines-outlining-drug-treatment-plans-for-patients-with-irritable-bowel-syndrome-ibs/ (2022). Accessed Sept 12 2023.
24. Spiegel B. VRx: How virtual therapeutics will revolutionize Medicine. Basic Books; 2020.
25. Maddox T, Garcia H, Ffrench K, Maddox R, Garcia L, Krishnamurthy P, et al. In-home virtual reality program for chronic low back pain: durability of a randomized, placebo-controlled clinical trial to 18 months post-treatment. Reg Anesth Pain Med. 2022;rapm–2022. 10.1136/rapm-2022-104093.
26. Lombard M Ditton T At the heart of it all: the concept of presence JCMC 1997 3 2 JCMC321 10.1111/j.1083-6101.1997.tb00072.x
Lombard M, Ditton T. At the heart of it all: the concept of presence. JCMC. 1997;3(2):JCMC321. 10.1111/j.1083-6101.1997.tb00072.x.10.1111/j.1083-6101.1997.tb00072.x
27. Heater C Being there: the subjective experience of presence Presence (Camb) 1992 1 2 262 71 10.1162/pres.1992.1.2.262
Heater C. Being there: the subjective experience of presence. Presence (Camb). 1992;1(2):262–71. 10.1162/pres.1992.1.2.262.10.1162/pres.1992.1.2.262
28. Maddox T Sparks C Oldstone L Maddox R Ffrench K Garcia H Durable chronic low back Pain reductions to 24-Months post-treatment for an accessible, 8-Week, In-Home behavioral skills-based virtual reality program: a Randomized Controlled Trial Pain Med 2023 10.1093/pm/pnad070 37220894
Maddox T, Sparks C, Oldstone L, Maddox R, Ffrench K, Garcia H, et al. Durable chronic low back Pain reductions to 24-Months post-treatment for an accessible, 8-Week, In-Home behavioral skills-based virtual reality program: a Randomized Controlled Trial. Pain Med. 2023. 10.1093/pm/pnad070.37220894 10.1093/pm/pnad070
29. Whitehead WE, Crowell MD, Bosmajian L, Zonderman A, Costa PT Jr., Benjamin C, et al. Existence of irritable bowel syndrome supported by factor analysis of symptoms in two community samples. Gastroenterology. 1990;98(2):336–40. doi: S0016508590000476 [pii].
30. Taub E, Cuevas JL, Cook EW 3rd, Crowell M, Whitehead WE. Irritable bowel syndrome defined by factor analysis. Gender and race comparisons. Dig Dis Sci. 1995;40(12):2647–55.
31. Spiegel B, Strickland A, Naliboff BD, Mayer EA, Chang L. Predictors of Patient-Assessed Illness Severity in Irritable Bowel Syndrome. Am J Gastroenterol. 2008. doi: AJG1997 [pii] 10.1111/j.1572-0241.2008.01997.x.
32. Spiegel BM Gralnek IM Bolus R Chang L Dulai GS Mayer EA Clinical determinants of health-related quality of life in patients with irritable bowel syndrome Arch Intern Med 2004 164 16 1773 80 10.1001/archinte.164.16.1773 15364671
Spiegel BM, Gralnek IM, Bolus R, Chang L, Dulai GS, Mayer EA, et al. Clinical determinants of health-related quality of life in patients with irritable bowel syndrome. Arch Intern Med. 2004;164(16):1773–80. 10.1001/archinte.164.16.1773.15364671 10.1001/archinte.164.16.1773
33. Lembo A Ameen VZ Drossman DA Irritable bowel syndrome: toward an understanding of severity Clin Gastroenterol Hepatol 2005 3 8 717 25 10.1016/S1542-3565(05)00157-6 16233998
Lembo A, Ameen VZ, Drossman DA. Irritable bowel syndrome: toward an understanding of severity. Clin Gastroenterol Hepatol. 2005;3(8):717–25. doi: S1542-3565(05)00157-6 [pii].16233998 10.1016/S1542-3565(05)00157-6
34. Ahern MM Dean LV Stoddard CC Agrawal A Kim K Cook CE The effectiveness of virtual reality in patients with spinal pain: a systematic review and meta-analysis Pain Pract 2020 20 6 656 75 10.1111/papr.12885 32196892
Ahern MM, Dean LV, Stoddard CC, Agrawal A, Kim K, Cook CE, et al. The effectiveness of virtual reality in patients with spinal pain: a systematic review and meta-analysis. Pain Pract. 2020;20(6):656–75. 10.1111/papr.12885.32196892 10.1111/papr.12885
35. Brea-Gómez B Torres-Sánchez I Ortiz-Rubio A Calvache-Mateo A Cabrera-Martos I López-López L Virtual reality in the treatment of adults with chronic low back pain: a systematic review and meta-analysis of randomized clinical trials Int J Environ Res Public Health 2021 18 22 11806 10.3390/ijerph182211806 34831562
Brea-Gómez B, Torres-Sánchez I, Ortiz-Rubio A, Calvache-Mateo A, Cabrera-Martos I, López-López L, et al. Virtual reality in the treatment of adults with chronic low back pain: a systematic review and meta-analysis of randomized clinical trials. Int J Environ Res Public Health. 2021;18(22):11806. 10.3390/ijerph182211806.34831562 10.3390/ijerph182211806
36. Garrett B Taverner T McDade P Virtual reality as an adjunct home therapy in chronic pain management: an exploratory study JMIR Med Inf 2017 5 2 e11 10.2196/medinform.7271
Garrett B, Taverner T, McDade P. Virtual reality as an adjunct home therapy in chronic pain management: an exploratory study. JMIR Med Inf. 2017;5(2):e11. 10.2196/medinform.7271.10.2196/medinform.7271
37. Goudman L Jansen J Billot M Vets N De Smedt A Roulaud M Virtual reality applications in chronic pain management: systematic review and meta-analysis JMIR Serious Games 2022 10 2 e34402 10.2196/34402 35536641
Goudman L, Jansen J, Billot M, Vets N, De Smedt A, Roulaud M, et al. Virtual reality applications in chronic pain management: systematic review and meta-analysis. JMIR Serious Games. 2022;10(2):e34402. 10.2196/34402.35536641 10.2196/34402
38. Grassini S Virtual reality assisted non-pharmacological treatments in chronic pain management: a systematic review and quantitative meta-analysis Int J Environ Res Public Health 2022 19 7 4071 10.3390/ijerph19074071 35409751
Grassini S. Virtual reality assisted non-pharmacological treatments in chronic pain management: a systematic review and quantitative meta-analysis. Int J Environ Res Public Health. 2022;19(7):4071. 10.3390/ijerph19074071.35409751 10.3390/ijerph19074071
39. Groenveld TD Smits ML Knoop J Kallewaard JW Staal JB de Vries M Effect of a behavioural therapy-based virtual reality application on quality of Life in Chronic Low Back Pain Clin J Pain 2023 10.1097/AJP.0000000000001110 37002877
Groenveld TD, Smits ML, Knoop J, Kallewaard JW, Staal JB, de Vries M, et al. Effect of a behavioural therapy-based virtual reality application on quality of Life in Chronic Low Back Pain. Clin J Pain. 2023. 10.1097/AJP.0000000000001110.37002877 10.1097/AJP.0000000000001110
40. Guo Q Zhang L Gui C Chen G Chen Y Tan H Virtual reality intervention for patients with Neck Pain: systematic review and Meta-analysis of Randomized controlled trials J Med Internet Res 2023 25 e38256 10.2196/38256 37010891
Guo Q, Zhang L, Gui C, Chen G, Chen Y, Tan H, et al. Virtual reality intervention for patients with Neck Pain: systematic review and Meta-analysis of Randomized controlled trials. J Med Internet Res. 2023;25:e38256. 10.2196/38256.37010891 10.2196/38256
41. Huang Q Lin J Han R Peng C Huang A Using virtual reality exposure therapy in pain management: a systematic review and meta-analysis of randomized controlled trials Value Health 2022 25 2 288 301 10.1016/j.jval.2021.04.1285 35094802
Huang Q, Lin J, Han R, Peng C, Huang A. Using virtual reality exposure therapy in pain management: a systematic review and meta-analysis of randomized controlled trials. Value Health. 2022;25(2):288–301. 10.1016/j.jval.2021.04.1285.35094802 10.1016/j.jval.2021.04.1285
42. Kantha P Lin J-J Hsu W-L The effects of interactive virtual reality in patients with Chronic Musculoskeletal disorders: a systematic review and Meta-analysis Games Health J 2023 12 1 1 12 10.1089/g4h.2022.0088 36706260
Kantha P, Lin J-J, Hsu W-L. The effects of interactive virtual reality in patients with Chronic Musculoskeletal disorders: a systematic review and Meta-analysis. Games Health J. 2023;12(1):1–12. 10.1089/g4h.2022.0088.36706260 10.1089/g4h.2022.0088
43. Lier EJ de Vries M Steggink EM Ten Broek RP van Goor H Effect modifiers of virtual reality in pain management: a systematic review and meta-regression analysis Pain 2023 10.1097/j.pain.0000000000002883 36943251
Lier EJ, de Vries M, Steggink EM, Ten Broek RP, van Goor H. Effect modifiers of virtual reality in pain management: a systematic review and meta-regression analysis. Pain. 2023. 10.1097/j.pain.0000000000002883.36943251 10.1097/j.pain.0000000000002883
44. Mallari B Spaeth EK Goh H Boyd BS Virtual reality as an analgesic for acute and chronic pain in adults: a systematic review and meta-analysis J Pain Res 2019 12 2053 85 10.2147/JPR.S200498 31308733
Mallari B, Spaeth EK, Goh H, Boyd BS. Virtual reality as an analgesic for acute and chronic pain in adults: a systematic review and meta-analysis. J Pain Res. 2019;12:2053–85. 10.2147/JPR.S200498.31308733 10.2147/JPR.S200498
45. Wiederhold BK Gao K Sulea C Wiederhold MD Virtual reality as a distraction technique in chronic pain patients Cyberpsychol Behav Soc Netw 2014 17 6 346 52 10.1089/cyber.2014.0207 24892196
Wiederhold BK, Gao K, Sulea C, Wiederhold MD. Virtual reality as a distraction technique in chronic pain patients. Cyberpsychol Behav Soc Netw. 2014;17(6):346–52. 10.1089/cyber.2014.0207.24892196 10.1089/cyber.2014.0207
46. Sato K Fukumori S Matsusaki T Maruo T Ishikawa S Nishie H Nonimmersive virtual reality mirror visual feedback therapy and its application for the treatment of complex regional pain syndrome: an open-label pilot study Pain Med 2010 11 4 622 9 10.1111/j.1526-4637.2010.00819.x 20202141
Sato K, Fukumori S, Matsusaki T, Maruo T, Ishikawa S, Nishie H, et al. Nonimmersive virtual reality mirror visual feedback therapy and its application for the treatment of complex regional pain syndrome: an open-label pilot study. Pain Med. 2010;11(4):622–9. 10.1111/j.1526-4637.2010.00819.x.20202141 10.1111/j.1526-4637.2010.00819.x
47. Bordeleau M Stamenkovic A Tardif P-A Thomas J The use of virtual reality in back pain rehabilitation: a systematic review and meta-analysis J Pain 2022 23 2 175 95 10.1016/j.jpain.2021.08.001 34425250
Bordeleau M, Stamenkovic A, Tardif P-A, Thomas J. The use of virtual reality in back pain rehabilitation: a systematic review and meta-analysis. J Pain. 2022;23(2):175–95. 10.1016/j.jpain.2021.08.001.34425250 10.1016/j.jpain.2021.08.001
48. Wu Y Wang N Zhang H Sun X Wang Y Zhang Y Effectiveness of virtual reality in Symptom Management of Cancer patients: a systematic review and Meta-analysis J Pain Symptom Manage 2023 65 5 e467 c82 10.1016/j.jpainsymman.2023.01.023 36758907
Wu Y, Wang N, Zhang H, Sun X, Wang Y, Zhang Y. Effectiveness of virtual reality in Symptom Management of Cancer patients: a systematic review and Meta-analysis. J Pain Symptom Manage. 2023;65(5):e467–c82. 10.1016/j.jpainsymman.2023.01.023.36758907 10.1016/j.jpainsymman.2023.01.023
49. Eldaly AS, Avila FR, Torres-Guzman RA, Maita KC, Garcia JP, Serrano LP et al. Virtual and augmented reality in management of Phantom Limb Pain: a systematic review. Hand (N Y). 2022:15589447221130093. 10.1177/15589447221130093.
50. Mosadeghi S Reid MW Martinez B Rosen BT Spiegel BMR Feasibility of an immersive virtual reality intervention for hospitalized patients: an observational cohort study JMIR Ment Health 2016 3 2 e28 10.2196/mental.5801 27349654
Mosadeghi S, Reid MW, Martinez B, Rosen BT, Spiegel BMR. Feasibility of an immersive virtual reality intervention for hospitalized patients: an observational cohort study. JMIR Ment Health. 2016;3(2):e28. 10.2196/mental.5801.27349654 10.2196/mental.5801
51. Tashjian VC Mosadeghi S Howard AR Lopez M Dupuy T Reid M Virtual reality for management of pain in hospitalized patients: results of a controlled trial JMIR Ment Health 2017 4 1 e9 10.2196/mental.7387 28356241
Tashjian VC, Mosadeghi S, Howard AR, Lopez M, Dupuy T, Reid M, et al. Virtual reality for management of pain in hospitalized patients: results of a controlled trial. JMIR Ment Health. 2017;4(1):e9. 10.2196/mental.7387.28356241 10.2196/mental.7387
52. Spiegel B Fuller G Lopez M Dupuy T Noah B Howard A Virtual reality for management of pain in hospitalized patients: a randomized comparative effectiveness trial PLoS ONE 2019 14 8 e0219115 10.1371/journal.pone.0219115 31412029
Spiegel B, Fuller G, Lopez M, Dupuy T, Noah B, Howard A, et al. Virtual reality for management of pain in hospitalized patients: a randomized comparative effectiveness trial. PLoS ONE. 2019;14(8):e0219115. 10.1371/journal.pone.0219115.31412029 10.1371/journal.pone.0219115
53. Birckhead B Khalil C Liu X Conovitz S Rizzo A Danovitch I Recommendations for methodology of virtual reality clinical trials in health care by an international working group: iterative study JMIR Ment Health 2019 6 1 e11973 10.2196/11973 30702436
Birckhead B, Khalil C, Liu X, Conovitz S, Rizzo A, Danovitch I, et al. Recommendations for methodology of virtual reality clinical trials in health care by an international working group: iterative study. JMIR Ment Health. 2019;6(1):e11973. 10.2196/11973.30702436 10.2196/11973
54. Li A Montaño Z Chen VJ Gold JI Virtual reality and pain management: current trends and future directions Pain Manag 2011 1 2 147 57 10.2217/pmt.10.15 21779307
Li A, Montaño Z, Chen VJ, Gold JI. Virtual reality and pain management: current trends and future directions. Pain Manag. 2011;1(2):147–57. 10.2217/pmt.10.15.21779307 10.2217/pmt.10.15
55. McCaul KD Malott JM Distraction and coping with pain Psychol Bull 1984 95 3 516 33 10.1037/0033-2909.95.3.516 6399756
McCaul KD, Malott JM. Distraction and coping with pain. Psychol Bull. 1984;95(3):516–33.6399756 10.1037/0033-2909.95.3.516
56. JahaniShoorab N Ebrahimzadeh Zagami S Nahvi A Mazluom SR Golmakani N Talebi M The effect of virtual reality on Pain in Primiparity Women during Episiotomy Repair: a randomize clinical trial Iran J Med Sci 2015 40 3 219 24 25999621
JahaniShoorab N, Ebrahimzadeh Zagami S, Nahvi A, Mazluom SR, Golmakani N, Talebi M, et al. The effect of virtual reality on Pain in Primiparity Women during Episiotomy Repair: a randomize clinical trial. Iran J Med Sci. 2015;40(3):219–24.25999621
57. Frey DP Bauer ME Bell CL Low LK Hassett AL Cassidy RB Virtual reality Analgesia in Labor: the VRAIL Pilot Study-A Preliminary Randomized Controlled Trial Suggesting Benefit of Immersive virtual reality analgesia in unmedicated laboring women Anesth Analg 2018 128 6 e93 6 10.1213/ane.0000000000003649
Frey DP, Bauer ME, Bell CL, Low LK, Hassett AL, Cassidy RB, et al. Virtual reality Analgesia in Labor: the VRAIL Pilot Study-A Preliminary Randomized Controlled Trial Suggesting Benefit of Immersive virtual reality analgesia in unmedicated laboring women. Anesth Analg. 2018;128(6):e93–6. 10.1213/ane.0000000000003649.10.1213/ane.0000000000003649
58. Chirico A Lucidi F De Laurentiis M Milanese C Napoli A Giordano A Virtual reality in Health System: Beyond Entertainment. A Mini-review on the efficacy of VR during Cancer Treatment J Cell Physiol 2016 231 2 275 87 10.1002/jcp.25117 26238976
Chirico A, Lucidi F, De Laurentiis M, Milanese C, Napoli A, Giordano A. Virtual reality in Health System: Beyond Entertainment. A Mini-review on the efficacy of VR during Cancer Treatment. J Cell Physiol. 2016;231(2):275–87. 10.1002/jcp.25117.26238976 10.1002/jcp.25117
59. Seminowicz DA Shpaner M Keaser ML Krauthamer GM Mantegna J Dumas JA Cognitive-behavioral therapy increases prefrontal cortex gray matter in patients with chronic pain J Pain 2013 14 12 1573 84 10.1016/j.jpain.2013.07.020 24135432
Seminowicz DA, Shpaner M, Keaser ML, Krauthamer GM, Mantegna J, Dumas JA, et al. Cognitive-behavioral therapy increases prefrontal cortex gray matter in patients with chronic pain. J Pain. 2013;14(12):1573–84. 10.1016/j.jpain.2013.07.020.24135432 10.1016/j.jpain.2013.07.020
60. Hubbard CS, Khan SA, Keaser ML, Mathur VA, Goyal M, Seminowicz DA. Altered brain structure and function correlate with disease severity and pain catastrophizing in migraine patients. eNeuro. 2014;1(1):e20–14. 10.1523/ENEURO.0006-14.2014.
61. Katz J Rosenbloom BN The golden anniversary of Melzack and Wall’s gate control theory of pain: celebrating 50 years of pain research and management Pain Res Manag 2015 20 6 285 6 10.1155/2015/865487 26642069
Katz J, Rosenbloom BN. The golden anniversary of Melzack and Wall’s gate control theory of pain: celebrating 50 years of pain research and management. Pain Res Manag. 2015;20(6):285–6. 10.1155/2015/865487.26642069 10.1155/2015/865487
62. Gold JI Belmont KA Thomas DA The neurobiology of virtual reality pain attenuation Cyberpsychol Behav 2007 10 4 536 44 10.1089/cpb.2007.9993 17711362
Gold JI, Belmont KA, Thomas DA. The neurobiology of virtual reality pain attenuation. Cyberpsychol Behav. 2007;10(4):536–44. 10.1089/cpb.2007.9993.17711362 10.1089/cpb.2007.9993
63. Keefe FJ Huling DA Coggins MJ Keefe DF Rosenthal MZ Herr NR Virtual reality for persistent pain: a new direction for behavioral pain management Pain 2012 153 11 2163 6 10.1016/j.pain.2012.05.030 22770840
Keefe FJ, Huling DA, Coggins MJ, Keefe DF, Rosenthal MZ, Herr NR, et al. Virtual reality for persistent pain: a new direction for behavioral pain management. Pain. 2012;153(11):2163–6. 10.1016/j.pain.2012.05.030.22770840 10.1016/j.pain.2012.05.030
64. Hoffman HG, Chambers GT, Meyer WJ III, Arceneaux LL, Russell WJ, Seibel EJ, et al. Virtual reality as an adjunctive non-pharmacologic analgesic for acute burn pain during medical procedures. Ann Behav Med. 2011;41(2):183–91. 10.1007/s12160-010-9248-7.
65. Hoffman HG Richards TL Van Oostrom T Coda BA Jensen MP Blough DK The analgesic effects of opioids and immersive virtual reality distraction: evidence from subjective and functional brain imaging assessments Anesth Analg 2007 105 6 1776 83 10.1213/01.ane.0000270205.45146.db 18042882
Hoffman HG, Richards TL, Van Oostrom T, Coda BA, Jensen MP, Blough DK, et al. The analgesic effects of opioids and immersive virtual reality distraction: evidence from subjective and functional brain imaging assessments. Anesth Analg. 2007;105(6):1776–83. 10.1213/01.ane.0000270205.45146.db.18042882 10.1213/01.ane.0000270205.45146.db
66. Hoffman HG Richards TL Bills AR Van Oostrom T Magula J Seibel EJ Using fMRI to study the neural correlates of virtual reality analgesia CNS Spectr 2006 11 1 45 51 10.1017/s1092852900024202 16400255
Hoffman HG, Richards TL, Bills AR, Van Oostrom T, Magula J, Seibel EJ, et al. Using fMRI to study the neural correlates of virtual reality analgesia. CNS Spectr. 2006;11(1):45–51. 10.1017/s1092852900024202.16400255 10.1017/s1092852900024202
67. Czajkowski SM Powell LH Adler N Naar-King S Reynolds KD Hunter CM From ideas to efficacy: the ORBIT model for developing behavioral treatments for chronic diseases Health Psychol 2015 34 10 971 82 10.1037/hea0000161 25642841
Czajkowski SM, Powell LH, Adler N, Naar-King S, Reynolds KD, Hunter CM, et al. From ideas to efficacy: the ORBIT model for developing behavioral treatments for chronic diseases. Health Psychol. 2015;34(10):971–82. 10.1037/hea0000161.25642841 10.1037/hea0000161
68. Spiegel BMR, Liran O, Gale R, Khalil C, Makaroff K, Chernoff R et al. Qualitative Validation of a Novel VR Program for Irritable Bowel Syndrome: A VR1 Study. Am J Gastroenterol. 2022;117(3):495–500. 10.14309/ajg.0000000000001641.
69. Hetterich L Stengel A Psychotherapeutic interventions in irritable bowel syndrome Front Psychiatry 2020 11 286 10.3389/fpsyt.2020.00286 32425821
Hetterich L, Stengel A. Psychotherapeutic interventions in irritable bowel syndrome. Front Psychiatry. 2020;11:286. 10.3389/fpsyt.2020.00286.32425821 10.3389/fpsyt.2020.00286
70. Windgassen S Moss-Morris R Chilcot J Sibelli A Goldsmith K Chalder T The journey between brain and gut: a systematic review of psychological mechanisms of treatment effect in irritable bowel syndrome Br J Health Psychol 2017 22 4 701 36 10.1111/bjhp.12250 28573818
Windgassen S, Moss-Morris R, Chilcot J, Sibelli A, Goldsmith K, Chalder T. The journey between brain and gut: a systematic review of psychological mechanisms of treatment effect in irritable bowel syndrome. Br J Health Psychol. 2017;22(4):701–36. 10.1111/bjhp.12250.28573818 10.1111/bjhp.12250
71. Szigethy E Hypnotherapy for inflammatory bowel disease across the lifespan Am J Clin Hypn 2015 58 1 81 99 10.1080/00029157.2015.1040112 26046718
Szigethy E. Hypnotherapy for inflammatory bowel disease across the lifespan. Am J Clin Hypn. 2015;58(1):81–99. 10.1080/00029157.2015.1040112.26046718 10.1080/00029157.2015.1040112
72. Wilson EO. Biophilia. Cambridge: Harvard University Press; 1984.
73. Wilson EO Kellert SR The Biophilia hypothesis 1993 Washington, DC Island
Wilson EO, Kellert SR. The Biophilia hypothesis. Washington, DC: Island; 1993.
74. Yin J Arfaei N MacNaughton P Catalano PJ Allen JG Spengler JD Effects of biophilic interventions in office on stress reaction and cognitive function: a randomized crossover study in virtual reality Indoor Air 2019 29 6 1028 39 10.1111/ina.12593 31418925
Yin J, Arfaei N, MacNaughton P, Catalano PJ, Allen JG, Spengler JD. Effects of biophilic interventions in office on stress reaction and cognitive function: a randomized crossover study in virtual reality. Indoor Air. 2019;29(6):1028–39. 10.1111/ina.12593.31418925 10.1111/ina.12593
75. Ahn SJ Bostick J Ogle E Nowak KL McGillicuddy KT Bailenson JN Experiencing nature: embodying animals in immersive virtual environments increases inclusion of nature in self and involvement with nature JCMC 2016 21 6 399 419 10.1111/jcc4.12173
Ahn SJ, Bostick J, Ogle E, Nowak KL, McGillicuddy KT, Bailenson JN. Experiencing nature: embodying animals in immersive virtual environments increases inclusion of nature in self and involvement with nature. JCMC. 2016;21(6):399–419. 10.1111/jcc4.12173.10.1111/jcc4.12173
76. Perez-Marcos D Solazzi M Steptoe W Oyekoya O Frisoli A Weyrich T A fully immersive set-up for remote interaction and neurorehabilitation based on virtual body ownership Front Neurol 2012 3 110 10.3389/fneur.2012.00110 22787454
Perez-Marcos D, Solazzi M, Steptoe W, Oyekoya O, Frisoli A, Weyrich T, et al. A fully immersive set-up for remote interaction and neurorehabilitation based on virtual body ownership. Front Neurol. 2012;3:110. 10.3389/fneur.2012.00110.22787454 10.3389/fneur.2012.00110
77. Falconer CJ Slater M Rovira A King JA Gilbert P Antley A Embodying compassion: a virtual reality paradigm for overcoming excessive self-criticism PLoS ONE 2014 9 11 e111933 10.1371/journal.pone.0111933 25389766
Falconer CJ, Slater M, Rovira A, King JA, Gilbert P, Antley A, et al. Embodying compassion: a virtual reality paradigm for overcoming excessive self-criticism. PLoS ONE. 2014;9(11):e111933. 10.1371/journal.pone.0111933.25389766 10.1371/journal.pone.0111933
78. Osimo SA Pizarro R Spanlang B Slater M Conversations between self and self as Sigmund Freud—A virtual body ownership paradigm for self counselling Sci Rep 2015 5 13899 10.1038/srep13899 26354311
Osimo SA, Pizarro R, Spanlang B, Slater M. Conversations between self and self as Sigmund Freud—A virtual body ownership paradigm for self counselling. Sci Rep. 2015;5:13899. 10.1038/srep13899.26354311 10.1038/srep13899
79. Falconer CJ Rovira A King JA Gilbert P Antley A Fearon P Embodying self-compassion within virtual reality and its effects on patients with depression BJPsych Open 2016 2 1 74 80 10.1192/bjpo.bp.115.002147 27703757
Falconer CJ, Rovira A, King JA, Gilbert P, Antley A, Fearon P, et al. Embodying self-compassion within virtual reality and its effects on patients with depression. BJPsych Open. 2016;2(1):74–80. 10.1192/bjpo.bp.115.002147.27703757 10.1192/bjpo.bp.115.002147
80. Bourdin P Barberia I Oliva R Slater M A virtual out-of-body experience reduces fear of death PLoS ONE 2017 12 1 e0169343 10.1371/journal.pone.0169343 28068368
Bourdin P, Barberia I, Oliva R, Slater M. A virtual out-of-body experience reduces fear of death. PLoS ONE. 2017;12(1):e0169343. 10.1371/journal.pone.0169343.28068368 10.1371/journal.pone.0169343
81. Barberia I Oliva R Bourdin P Slater M Virtual mortality and near-death experience after a prolonged exposure in a shared virtual reality may lead to positive life-attitude changes PLoS ONE 2018 13 11 e0203358 10.1371/journal.pone.0203358 30395568
Barberia I, Oliva R, Bourdin P, Slater M. Virtual mortality and near-death experience after a prolonged exposure in a shared virtual reality may lead to positive life-attitude changes. PLoS ONE. 2018;13(11):e0203358. 10.1371/journal.pone.0203358.30395568 10.1371/journal.pone.0203358
82. Matamala-Gomez M Gonzalez AMD Slater M Sanchez-Vives MV Decreasing pain ratings in chronic arm pain through changing a virtual body: different strategies for different pain types J Pain 2019 20 6 685 97 10.1016/j.jpain.2018.12.001 30562584
Matamala-Gomez M, Gonzalez AMD, Slater M, Sanchez-Vives MV. Decreasing pain ratings in chronic arm pain through changing a virtual body: different strategies for different pain types. J Pain. 2019;20(6):685–97. 10.1016/j.jpain.2018.12.001.30562584 10.1016/j.jpain.2018.12.001
83. Slater M Neyret S Johnston T Iruretagoyena G Crespo MÁdlC, Alabèrnia-Segura M An experimental study of a virtual reality counselling paradigm using embodied self-dialogue Sci Rep 2019 9 1 10903 10.1038/s41598-019-46877-3 31358846
Slater M, Neyret S, Johnston T, Iruretagoyena G, Crespo MÁdlC, Alabèrnia-Segura M, et al. An experimental study of a virtual reality counselling paradigm using embodied self-dialogue. Sci Rep. 2019;9(1):10903. 10.1038/s41598-019-46877-3.31358846 10.1038/s41598-019-46877-3
84. Gorisse G Senel G Banakou D Beacco A Oliva R Freeman D Self-observation of a virtual body-double engaged in social interaction reduces persecutory thoughts Sci Rep 2021 11 1 23923 10.1038/s41598-021-03373-x 34907279
Gorisse G, Senel G, Banakou D, Beacco A, Oliva R, Freeman D, et al. Self-observation of a virtual body-double engaged in social interaction reduces persecutory thoughts. Sci Rep. 2021;11(1):23923. 10.1038/s41598-021-03373-x.34907279 10.1038/s41598-021-03373-x
