The management of chronic pelvic pain in women with endometriosis is complex and includes the long-term use of opioids. Patients not fully responsive to drugs or ineligible for surgical treatments need efficient alternatives to improve their quality of life and avoid long-term sequelae.This randomized controlled trial aimed to assess the effects of repeated at-home administrations of a 20-minute virtual reality (VR) solution (Endocare) compared with a sham condition on pain in women experiencing pelvic pain due to endometriosis.Patients were instructed to use the VR headsets twice daily for at least 2 days and for up to 5 days starting on their first day of painful periods. Pain perception was measured using a numerical scale (0-10) before and 60, 120, and 180 minutes after each treatment administration. General pain, stress, fatigue, medication intake, and quality of life were reported daily by patients.P=.48). Pain intensity decreased in both groups from day 1 to day 5 along with a decrease in medication use. Maximum pain intensity reduction of 51.58% (SD 35.33) occurred at day 2, 120 minutes after treatment for the Endocare group and of 27.37% (SD 27.23) at day 3, 180 minutes after treatment for the control group. Endocare was significantly superior to the sham on day 1 , day 2 , and day 3 . Similarly, the mean perceived pain relief was significantly higher with Endocare on day 1  and day 2  compared to the control. No adverse event was reported.A total of 102 patients with endometriosis were included in the final analysis . The mean age was 32.88 years (SD 6.96) and the mean pain intensity before treatment was 6.53 (SD 1.74) and 6.22 (SD 1.69) for the Endocare group and the sham control group, respectively (This study confirmed the effectiveness and safety of self-repeated administrations of a VR immersive treatment used at home while reducing overall pain medication intake in women diagnosed with endometriosis experiencing moderate-to-severe pelvic pain.ClinicalTrials.gov NCT05172492; https://clinicaltrials.gov/ct2/show/NCT05172492 Chronic pelvic pain is the main symptom of women suffering from endometriosis . SeverelEndometriosis is characterized by the occurrence of lesions with behavior comparable to that of the endometrium, including cyclic bleeding during periods, followed by inflammation and proliferation of the conjunctive and muscular cells outside the uterus, mainly on the pelvic peritoneum, ovaries, and rectovaginal septum . EndometThe most common painful symptom of endometriosis is dysmenorrhea 80%), followed by deep dyspareunia (30%) 0%, follo. Thus, tMedical treatments, including combined hormonal contraceptives, progestin, and gonadotropin-releasing hormone agonists, are generally effective in treating endometriosis-related pain -15, whilSurgery is usually not considered as a first-line treatment  but is rTherefore, the management of patients with endometriosis who are not eligible, are refractory, or not fully responsive to hormonal therapies or drug treatments, or are ineligible for surgical treatment  remains a problem. Accordingly, nonpharmacological alternatives are urgently needed to increase the chronic pelvic pain therapeutic arsenal..Studies have shown that virtual reality (VR) is an effective mode to reduce acute pain such as that experienced by burn victims, in cases of lumbar puncture, women during labor, or dental surgery -21, as wP=.04), and was effective for up to 4 hours after administration [Endocare is a class I medical device, or digital therapeutic (DTx), consisting of visual and auditory therapeutic procedures administered using a VR headset to treat pelvic-perineal pain in patients with endometriosis at home. Promising results of the use of Endocare were reported in a single-dose pilot study conducted in a controlled hospital setting in women with pelvic-perineal pain of ≥4/10 intensity: the study treatment provided pain relief and decreased pain intensity by a maximum of 42% compared with only 22% in the control group  to reduce chronic pelvic pain when used at home in full autonomy without medical supervision compared to a digital control in a double-blinded, randomized, sham-controlled clinical trial. The objective of the study was to evaluate the effects of Endocare compared to a digital control on the mean change in pain intensity 1, 2, and 3 hours after daily use during the 5 most painful consecutive days of the month in women with chronic pelvic-perineal pain associated with endometriosis.The “Endocare for Pelvic-perineal Pain Related to Endometriosis Used at Home” study was a randomized, sham-controlled, double-blinded, two-parallel-group, single-site, interventional clinical trial evaluating the efficacy of software as a medical device (SaMD) product on reducing endometriosis-related pain at home compared to a digital control. The study was conducted between December 2021 and October 2022 at the Franco-European Multidisciplinary Endometriosis Institute, Tivoli-Ducos Clinic in Bordeaux, France.Patients included in the study were women over 18 years old with a diagnosis of endometriosis and/or adenomyosis; willing to participate in the study; and women with at least 2 consecutive days per month of endometriosis-related pelvic-perineal pain of moderate to severe intensity , including women without amenorrhea (pain around the onset of menstruation) and women with amenorrhea (in which the most intense pain of the month should last for at least 2 days). Pregnant or nursing women were not eligible for inclusion in the study, along with women who were participating or had participated in an interventional study within the last 30 days before inclusion. Those with severe visual, auditory, or cognitive impairment; color blindness, photosensitivity, epilepsy, or motion sickness; women whose pain is occasional and not present at each menstrual period; those who had previously received VR treatments; and women under judicial protection, guardianship, curatorship, or a protective mandate were also excluded.The impact of the study treatment on patients’ pain relief and quality of life was evaluated using a visual analog scale (stress) , Pichot Treatment adherence, tolerance, Patient's Global Impression of Change (PGIC) , and patEndocare is a class I software medical device developed by Lucine  associated with a VR headset intended to decrease pelvic pain related to endometriosis. The software consists of a 20-minute treatment combining auditory and visual therapeutic stimulations integrated in a 3D VR environment, including binaural beats, verbal hypnotic injunction, nature-based sounds, distraction of attention, and bilateral alternative stimulations.The digital control (control) was also developed by Lucine as a 20-minute audio-video composition similar to Endocare  with exposure to nature sounds, but without Endocare’s stimulations, as previously described . The shaUpon inclusion, eligible patients were randomized to either the Endocare or control arm, were given the study devices and a follow-up diary, and instructed on how to use these materials during their 5 days of participation. Patients were asked to use the treatment starting on their first day of painful periods (next cycle after study inclusion) and up to twice a day with a minimum of 3 hours between exposures. Patients were given the possibility to stop their study treatment after 2 days in case of pain relief and to continue using their usual medications while reporting their uses in their follow-up diary .For the baseline assessment, once enrolled, patients were invited to complete 2 questionnaires to assess their baseline profiles: EHP-5 questionnaire and PCS. The 11 items from the EHP-5 questionnaire were rated from “never” to “always,” while dramatization (PCS) was evaluated on a 5-point Likert-type scale ranging from 0  to 4 .Subsequently, on their first day of pain, patients informed the investigating staff of their treatment initiation (day 1) and started completing their daily follow-up diary for 5 days.Pain intensity was evaluated on an 11-point numeric rating scale  at wakeup, before and after each treatment , and at bedtime. Pain relief was evaluated on a 5-point categorical scale  after each treatment at 60, 120, and 180 minutes. Patients were also asked to report any adverse event that could have occurred during their 5 days of participation.Participants were allowed the use of pain medications in case of an insufficient analgesic effect of the study treatment. In such cases, they were invited to report their medication intake  in their follow-up diaries.Fatigue and stress were reported by patients twice a day at wakeup and bedtime, using the Pichot scale with 8 items ranging from 0 to 4   and the On day 6, patients were contacted by the study staff to perform a remote end-of-study visit by telephone. Patients were invited to complete different questionnaires: the EHP-5 after study participation, the PGIC, and to rate their global level of satisfaction.The sample size was calculated based on data from the “Single Care” pilot study . Considet-tests and ANOVA were used to compare means between groups, and the Pearson test was used to evaluate the correlation between PCS score and pain intensity at 60 minutes after treatment on day 1. Differences between the percentages of patients achieving defined targets of pain reduction were analyzed using bilateral proportion tests. For categorical variables, independence between treatment arms was evaluated using χ2 and Fisher-exact tests, depending on the sample sizes. Differences in pain intensity between the two groups were assessed using a linear mixed model for repeated measures with a 2×2 design (nlme R package), including the effects of group (Endocare vs control), time , along with a random effect on the intercept of each participant. Evaluation of the group×time interaction served as a measure of the efficacy of the study treatment. A contrast analysis (emmeans package) was also performed to test the differences before and after treatments  in both groups. Differences in pain intensity, fatigue, and stress were also assessed using a linear mixed model for repeated measures (2×2 design) at wakeup and bedtime on days 1 and 2. P values were adjusted using the Tukey method. Missing data at several time points were not replaced. False discovery rate corrections were used to adjust for multiple testing when needed.Descriptive statistics were used to describe the sample with respect to demographics, medical history, and pain history. Parametric Student The study was conducted in compliance with the 1964 Declaration of Helsinki and later amendments, ISO 14155:2020, Medical Device Regulation (EU) 2017/745, and ICH-GCP E6. The study received approval on October 26, 2021, by the Comité de Protection des Personnes, Région Ouest, Ouest 1 . All patients signed an informed consent form before inclusion and performing any study-related procedure. The study is registered at ClinicalTrials.gov under registration number NCT05172492.Of the 120 patients screened, 120 were randomized to the Endocare (n=60) and control (n=60) arms, and 103 completed the study. As study procedures were set to start within 1 month following patients’ inclusion, 14 patients prematurely ended their participation after randomization: 11 experienced no more pain before the start of the study (noninclusion criteria) and 3 became pregnant (exclusion criteria). Additionally, 1 patient did not perform the study procedures due to a lack of time. Two patients were considered as lost to follow-up and 1 patient did not return her questionnaire after completing her participation.P=.03), the weight difference between groups was deemed inconsequential, as this parameter was not correlated to any aspect of the treatment.Thus, 102 of the 120 recruited patients (85.0%) were included in the study analyses, including 51 in the Endocare group and 51 in the control group. Patients’ demographic characteristics were similar between groups, with the exception of weight . Albeit The patients’ medical history was also similar between the groups, enabling effective comparison  and 3. CDue to their endometriosis and the pain related to their condition, most of the patients declared using chronic drug treatments at baseline, including analgesics, antiemetics, and antinauseants; anti-inflammatory and antirheumatic products; and drugs for gastrointestinal disorders . No diffOn study day 1, 102 patients used both study treatments and correctly filled in their follow-up diaries. Study device use started to decrease on day 2 , significantly decreased on day 3 , and decreased even more on day 4  and day 5 . Some participants who stopped using the study treatments continued to complete their follow-up diary until the end of the study period.Patients were advised to use the treatment  starting on the first painful day of their cycle. The use of the study treatment was mandatory for at least 2 days , and patients had the possibility of continuing the treatment for the next 3 days if they experienced pain .Differences in pain intensity between baseline (prior to treatment initiation on day 1) and after treatment  over the first 2 days was assessed in the two groups and the results are summarized in As the number of active treatment users was drastically reduced from day 3 onward, only the first 2 days were included in the mixed model. Moreover, no difference was observed in the number of daily self-administrations between the two groups. On days 1 and 2, the mean pain intensity decrease at 60 minutes was 1.48 (SD 1.68) in patients using Endocare and was 0.92 (SD 1.28) in the control group.Compared to the initial (pretreatment) pain intensity levels, pain intensity reduction reached 51.6% (SD 35.34) at 120 minutes and 51.2% (SD 37.33) at 180 minutes on day 2 in the Endocare group versus 21.2% (SD 30.12) and 23.9% (SD 36.06), respectively, in the control group. Maximum pain intensity reduction was achieved on day 2 at 120 minutes after Endocare treatment administration.F100=0.514, P=.48), but significant effects of time  and of the group×time interaction  were identified. Detailed analysis of interactions revealed significant group×time interactions at day 1, 120 minutes ; day 1, 180 minutes ; day 2, before treatment ; day 2, 60 minutes ; day 2, 120 minutes ; and day 2, 180 minutes . In all cases, pain reduction from the baseline was significantly higher in the Endocare group from day 1 at 120 minutes to day 2 at 180 minutes after treatment compared to that of the control group  between the two groups.No significant group effect was observed (ol group . No diffP<.001). For the control group, except for the comparison between day 1 and day 2 before treatment , all other reductions were significant .Contrast analysis revealed that pain intensity reduction was significant for each time point for the Endocare group compared to levels reported at day 1 before treatment and day 2 before treatment . Nevertheless, patients in the Endocare group reported significantly lower pain intensity at day 3 60, 120, and 180 minutes after treatment compared to the control group. No difference was observed on days 4 and 5.Despite the decrease in the number of participants on day 3, compared to the initial (pretreatment) pain intensity levels, pain intensity reduction at 60, 120, and 180 minutes after treatment was significantly higher in the Endocare group at 24.2% (SD 33.59), 41.8% (SD 40.68), and 46.6% (SD 36.02), respectively, compared to that of the control group at 12.0% (SD 22.47), 23.4% (SD 29.43), and 27.4% (SD 27.23), respectively. No difference was observed between the groups on days 4 and 5 .Patients were free to use the study treatment at any time of the day, but not more than twice daily. Therefore, measurements were also analyzed for each day independently to focus solely on the pain intensity reduction from the baseline to 180 minutes, without the influence of the varying delay between consecutive treatment uses.P<.001), day 2 (P<.001), and day 3 (P=.04). No significant difference was observed for days 4 and 5.From days 1 to 5, the mean pain intensity decrease at 60 minutes was 1.33 (SD 1.60) in the Endocare group compared to a 0.88 (SD 1.27) reduction in the control, and 30% of assessments reported a pain reduction of ≥40% 1 hour after the session compared to the daily baseline. Results of the comparison between both treatment arms for days 1-5 using a linear model for repeated measures are detailed in F100=0.261, P=.61) nor for bedtime . In addition, there was no effect of the group×day interaction for wakeup  or bedtime . However, a significant effect of day was found for both wakeup  and bedtime . These results indicated a reduction in pain intensity at both wakeup and bedtime, but that this reduction was not different between the two groups.Pain intensity was also measured each day at wakeup and bedtime for the 5 days of the study and compared using mixed models . Our rest96.6312=–1.149, P=.25).Similar to the pain intensity analysis, pain relief was evaluated both on days 1-2 and days 3-5. Differences in pain relief between baseline (prior to treatment initiation on day 1) and after study treatment use  were assessed in the two groups. As shown in Although not statistically significant, patients from the Endocare group had higher pain relief on day 3 and day 4 but not on day 5 when compared to the control group .During their participation, patients were allowed to use rescue pain medication and asked to report their use during the 5 days of treatment. Some patients stopped using the study treatments after day 2, but still reported their medication use until day 5. Considering days 1 and 2, only 1 patient in the control group stopped the study treatment but reported her drug intake on day 2.t99.9089=–0.994, P=.32). However, a significant but minor correlation between the PCS score at baseline and pain intensity at day 1, 60 minutes was observed  using the same linear mixed model as used for pain intensity. Both patients in the Endocare and control groups declared reduced fatigue and reduced stress between day 1 and day 5 at wakeup and bedtime  with no F100=0.180, P=.67; bedtime: F99=0.041, P=.84) or the stress evaluation , and there was also no significant group×day interaction for the fatigue evaluation  or the stress evaluation . However, significant effects were identified for day in the fatigue evaluation  and the stress evaluation .Considering wakeup and bedtime, no effect of the group was observed for either the fatigue evaluation . In accordance with this result, patients from the Endocare group were significantly more satisfied than patients in the control group .Both PGIC and satisfaction were assessed at the end of the study (day 6), which were compared between the Endocare and control groups. Patients from the Endocare group reported higher improvement of their clinical condition compared to the control group  until day 5 in the two study groups. Compared to the control group, significantly higher pain intensity reduction was observed in the Endocare group from the baseline up to day 3 (maximum on day 2 of 51.6% reduction in the Endocare group vs 21.2% in the control group). Concomitantly, a significant increase in pain relief was declared by the patients exposed to Endocare on days 1 and 2 compared to those using the digital sham control device. In contrast to usual pain medications, there are no particular safety risks associated with repeated use of a VR solution as confirmed in this trial.These results confirmed the previously observed analgesic effects of the self-administered Endocare treatment (maximum pain intensity reduction of 42%)  and patiDuring their participation, patients were free to use concomitant rescue pain medications as usual considering that the device efficacy may differ between participants. The objective was to evaluate patients’ adherence to a DTx, the integration of the device in their daily routine care, and its impact on pain medication intake. Unfortunately, only short-term data were collected and additional investigations would be needed to also demonstrate a long-term impact of the DTx on long-term medication use habits. Nevertheless, at equivalent medication use between groups, higher pain reduction was observed with Endocare.Compared to baseline levels, patients declared increased use of medications. This was an expected result, as day 1 represents the patient’s first day of painful periods when they need pain relief the most. Despite the lack of difference in medication intake observed between the groups, looking at the analgesics used by the women to relieve their pain, the percentage of patients using any kind of analgesic medication decreased in the Endocare group by 14.7% (41.2% to 26.5%) against only 3.3% (37.3% to 34.0%) in the control group between day 1 and day 2 . These rNo difference in stress, fatigue, and quality of life was observed between the two study arms. Although evaluated in the context of the study, it was expected that the impact of the experimental treatments on quality of life (stress and fatigue) would be only minimally observable over a 5-day period, as this type of analysis is generally performed over longer periods . As for medications, long-term data would be needed and more criteria should be investigated to assess the overall impact of the DTx on patients’ quality of life. Postmarket clinical studies should allow collecting such information to improve the solution.Previous studies have shown that VR is effective in reducing acute pain in different types of populations or interventions -23. WhilGiving patients the opportunity to self-manage their pain treatment using an over-the-counter solution should increase their quality of life and have an impact on their pain medication intake, but should also have a beneficial impact on reducing medical staff and health care provider workload.To our knowledge, only a few VR solutions to manage chronic pain exist that are also designed to be used at home. One device has been a game changer in the home-based treatment of chronic low back pain ,50,51, wThe duration of the analgesic effect of VR may vary between studies  , but theThe effect of Endocare evaluated in this study was assessed up to 3 and 4 hours in a previous study , confirmThe medical device evaluated in this study relies both on a hardware and a proprietary software. It was designed to be accessible to all individuals and to treat their pelvic pain anywhere at any time. To complete the circle, the solution needs to be economically affordable. One must be aware that an important part of the costs is attributable to the hardware (VR headset manufacturer). As of today, the product is not yet on the market and multiple plans are envisaged, including  new “presentations/forms” to increase accessibility and usability, while minimizing the financial impact on patients.The main limitation of this study is the drop of 18 patients after the randomization procedure for various reasons mentioned above. This event could have altered the comparability of the two groups, and it is the reason for which we compared the characteristics of patients included in the analysis. To check whether or not the comparability was altered, we also compared the 102 patients included in the analysis to the 18 patients who were not, and we observed their characteristics to be strictly comparable.Moreover, from treatment initiation, while the patient cohort was quite stable on the first 2 days of participation, the participant number decreased continuously until day 5. In addition to the smaller group size, which affects the power of the statistical analysis, patients dropping out can affect patients’ randomization (from day 3 onward). The findings therefore describe the best available data. Reasons for stopping treatments were not collected and such a decrease did not allow a sufficient sample size to conclude on the main objective of the study from days 3 to 5.Further, patients were exposed to only one 20-minute scenario: the same environment repeated up to twice a day may have induced some boredom in exposed patients and may have led some to discontinue the study treatments. This emphasizes the importance of patients’ engagement in this type of new home treatment and the need to develop strategies to ensure treatment adherence over time. Gamification and diversification may play a positive role in this aspect.Finally, considering the objectives, this study was not conducted in a standardized hospital setting but rather at patients’ homes without strict medical supervision and based on declarative data. However, as a reminder, the device is intended to be used at home (over the counter) where and when patients need it the most. Chronic pain is constant and cannot only be treated during hospital consultations. Patients were also given the possibility to use the study treatments at any time of the day without a strict schedule, which may have had an impact on the treatment efficacy depending on their stress level and pain intensity that may vary during the day. The impact of the weekend versus weekdays has not been investigated and may have an influence on multiple parameters, including treatment adherence.This is the first study to report the home use, without medical supervision, of a VR solution designed to reduce pain in patients suffering from chronic pelvic pain associated with endometriosis. Although the study has some limitations due to its conduct at patients’ homes and not in a hospitalized, controlled environment, the results clearly demonstrated the feasibility and effectiveness of VR software use without medical supervision. The decrease of analgesic use and of pain intensity observed in the study provides evidence for the integration of VR in multimodal chronic pelvic pain treatment strategies and may help to avoid the potential opioid dependence observed in the long-term treatment of chronic pain. Long-term data would enable collecting more information about the effect of Endocare on analgesics use. Aside from its efficacy on reducing pain intensity, patients’ lifestyle will play an important role, as taking a pill remains easier than performing a 20-minute VR session.Further studies are still needed to evaluate the efficacy of the VR software in other indications and to compare its efficacy versus traditional medications. Moreover, strategies should be implemented to increase adherence to the VR treatment as it may still be considered, despite its efficacy, as recreative and not therapeutic .


Cancer pain represents a challenge for cancer patients and their family members. Despite progression in pain management, pain is still underreported and undertreated, and there is limited information on the related needs that patients and caregivers may have. Online platforms represent a fundamental tool for research to reveal the unmet needs of these users and their emotions outside the medical setting.This study aimed to (1) reveal the unmet needs of both patients and caregivers and (2) detect the emotional activation associated with cancer pain by analyzing the textual patterns of both users.A descriptive and quantitative analysis of qualitative data was performed in RStudio v.2022.02.3 (RStudio Team). We analyzed 679 posts (161 from caregivers and 518 from patients) published over 10 years on the “cancer” subreddit of Reddit to identify unmet needs and emotions related to cancer pain. Hierarchical clustering, and emotion and sentiment analysis were conducted.unmet needs included the following clusters: (1A) reported experiences, with the subclusters (a) relationship with doctors/spouse and (b) reflections on physical features; and (1B) changes observed over time, with the subclusters (a) regret and (b) progress. For caregivers (agglomerative coefficient=0.80), the main clusters were as follows: (1A) social support and (1B) reported experiences, with the subclusters (a) psychosocial challenges and (b) grief. Moreover, comparison between the 2 groups (entanglement coefficient=0.28) showed that they shared a common cluster labeled uncertainty. Regarding emotion and sentiment analysis, patients expressed a significantly higher negative sentiment than caregivers . On the contrary, caregivers expressed a higher positive sentiment compared with patients , with trust  and joy  being the most prevalent positive emotions.The language used for describing experiences related to cancer pain and expressed needs differed between patients and caregivers. For patients (agglomerative coefficient=0.72), the large cluster labeled Our study emphasized different perceptions of cancer pain in patients and caregivers. We revealed different needs and emotional activations in the 2 groups. Moreover, our study findings highlight the importance of considering caregivers in medical care. Overall, this study increases knowledge about the unmet needs and emotions of patients and caregivers, which may have important clinical implications in pain management. Cancer pain represents a challenge for cancer patients at different time points of their medical path, from diagnosis to long-term survivorship and palliative care. In a recent meta-analysis , cancer From a psychological point of view, cancer pain may represent a source of emotional distress, anxiety, depression, fear of suffering, and even suicidal thoughts ,4-6. Socwe disease” since both patients and caregivers share the stress related to pain and coping with it. Specifically, the STM assumes that an interdependence exists between 2 partners in a relationship and postulates that stressors interfere directly or indirectly with both partners in a close relationship  to 0 [no entanglement]).The labels of each cluster were attributed after agreement between the authors CF and MC. For details, see the guidelines provided by Galili  and KassFinally, we interpreted the product clusters and labeled them depending on the hierarchical clustering performed, considering the context from which the words come.Interrater reliability for manual coding indicated perfect agreement (from 0.98 to 1) for all broad categories and codes .A total of 783 public comments between April 2011 and November 2021 were identified. Of the 783 comments, 679 (161 from caregivers and 518 from patients) were included in the final database since our aim was to focus on the perspectives of patients and caregivers. Therefore, 104 posts were excluded from the analysis since the user type was unknown (n=93) or there was a referral to a health care professional (n=11). Details are provided in Among the 679 comments included, 518 (76.3%) were posted by patients. Regarding cancer pain, the most frequent dimension was the physical dimension . In comparison, 23.7% (123/518) of the comments were focused on both dimensions of pain , and only 7.1% (37/518) were focused on the psychological dimension.Among the 518 comments, 219 (42.3%) did not specify the type of pain. Among the comments that did specify the type of pain, the most frequent type was neuropathy , followed by chronic , acute , somatic , and visceral  pain. Regarding neuropathy, we found that 10.0% (52/518) of posts involved chronic neuropathy, while 3.5% (18/518) involved acute neuropathy.In most posts , patients shared their first-hand experiences and provided information to others in a similar condition. A smaller portion of posts  provided advice, and some posts  posed a question. Further details are provided in Among the 679 comments included, 161 (23.7%) were posted by caregivers. Most caregiver posts discussed pain, focusing on the psychological and physical dimensions . Some focused only on the physical dimension , and others focused only on the psychological dimension .Among the 161 comments, 123 (76.4%) did not specify the type of pain. Among the comments that did specify the type of pain, the most frequent type was chronic pain , followed by neuropathy  and acute pain . Somatic and visceral pain was not found in their comments. Regarding neuropathy, we found that only 2.5% (4/161) of posts involved chronic neuropathy, while 0.6% (1/161) involved acute neuropathy.In general, caregivers mostly shared the experience of their loved ones with cancer in their posts . Caregivers shared their experience as well as provided information in 11.2% (18/161) of posts, and they only provided advice in 8.1% (13/161) of posts. Further details are provided in A word cloud comparing patients’ and caregivers’ words when discussing the cancer pain experience is presented in The word cloud was created by analyzing the most frequent words. Patients more frequently used terms describing the physical aspects of pain , causes of pain related to treatment  or a specific procedure to detect cancer (“biopsy” and “scan”), aspects related to pharmacological treatments taken for managing pain , and their related side effects  compared with caregivers. The only psychological terms used frequently in relation to pain were “worry” and “scary.”On the other hand, caregivers used words related to psychosocial aspects of pain  more frequently compared with patients. In their case, the physical aspects or related side effects of pain and treatments were described less frequently .Based on the associations with target words, the negative sentiment (mean=0.83) was higher than the positive one (mean=0.58), with sadness (mean=0.57) and fear (mean=0.56) being the most prevalent negative emotions, followed by anger (mean=0.30) and disgust (mean=0.26). On the other hand, trust (mean=0.40) and anticipation (mean=0.35) were the most pervasive positive emotions, followed by joy (mean=0.25). The least prevalent emotion was surprise (mean=0.17).The following extracted sentences (from post IDs P2 and P258) well exemplify these sentiments and emotions:Sentences extracted from post ID P2The worst thing about cancer is the fear, and the fear is driven by lack of knowledge.The more you know about your situation -- and the treatment options, and the side effects, and the medical team, and the support services -- the easier it is to handle it.I'm not saying it becomes easy, full-stop, but it does make it easier.Knowledge is power, it pushes back the darkness.And that goes for the people you love, too, the ones you're trying to spare from pain and worry.If they don't know what's going on, they'll worry more.Giving yourself and them, information will make things less opaque and scary.Having a skilled team of medical experts and a support system will, too.Finally, it is TOTALLY NATURAL to feel the way you're feeling!And as always, #FUCKCANCER.Sentences extracted from post ID P258My cancer returned when I was 22, my leg was amputated a week later.I had an endless supply of drugs to deal with the pain, both” real” and phantom limb pains.I’ve felt a lot of the things you currently feel.I hate feeling weak, and I hate relying on people around me.Some days is worse than others, but I have something I can look back on and use as a reference that it can get better.I initially got the cancer diagnosis when I was 14, after 5 years of unexplainable pain. I did chemo for 2 years, radiation therapy for 6 weeks, and 6 surgeries in total.One of these surgeries involved temporarily cutting off the blood supply between my leg and the rest of my body, pumping my leg with extremely toxic chemo that took my leg to 47C (or 117F) degrees.I was a kid when I lost everything.I experienced insane amounts of pain between 14-17.But after treatment, my foot was still broken, and I suffered from osteoporosis in my lower leg; I was shattering bones in my foot just from walking.I’ve had chronic pain for 14 years and I’m 24 years old.I can vividly remember all of the times I nearly died.I remember bleeding in my mouth from eating, waking up in the middle of the night screaming in pain from the full-body cramps, the painful wound on my foot from the radiation therapy, and a seemingly endless list of side effects.Based on the associations with target words, the negative sentiment (mean=0.78) was higher than the positive one (mean=0.64), with sadness (mean=0.61) and fear (mean=0.55) being the most prevalent negative emotions, followed by anger (mean=0.31) and disgust (mean=0.25). On the other hand, trust (mean=0.45) and anticipation (mean=0.38) were the most pervasive positive emotions, followed by joy (mean=0.28). The least prevalent emotion was surprise (mean=0.16).The following extracted sentences (from post IDs C717 and C100) well exemplify these sentiments and emotions:Sentences extracted from post ID C717My gf has stage IV lung cancer, and I cried a few times  but I feel like I am mostly in a “functioning” mode that keeps me going, but I am absolutely over the top overwhelmed with emotions and thoughts, but I know I am no good for my gf either if I just give up.With long times of sickness and going through all that with someone, some people even feel relieved when their loved ones die and feel very guilty, but I think in most cases it is a relief that their loved one don´t have to suffer anymore, I didn´t cry when my dad died after months of being in and out of the hospital and intensive care, but it hit me later.Sentences extracted from post ID C100I lost my husband 47 days ago (this is day 48), and as devastatingly painful as it was to lose him after 24 years together, every time I: 1) remember his struggles in the two months prior to losing him; 2) remember all the times he said he didn't want to be sicker from the treatment from the disease; 3) look at pictures and videos from his final days; it helps me accept that he is gone.I absolutely loathe the “he's no longer in pain” sentiment, but I've realized what I actually miss most of all are the times before he got sick.Truth be told, his last two months were increasingly terrible with every passing day.I can't tell you how many times he said to me, «this is not living».I share this in case it helps.If your mom is not yet hospitalized and can take care of her own needs, there is still hope for her.In my husband's case, that hope evaporated early, though, and if and when it begins evaporating for your mom, the best thing you can do is remind yourself that « keeping her alive » doesn't mean she's actually «living».That could help you let her go.The Wilcoxon rank sum test was used to analyze the differences in emotion and sentiment scores between patients and caregivers.P_rank=3845.24 vs meanC_rank=3732.81; z=−2.14; P<.001), whereas caregivers expressed a positive sentiment more often than patients , with trust  and joy  being the most prevalent positive emotions. Details are provided in The test showed that patients expressed a negative sentiment more often than caregivers (meanunmet needs and (2) cause of pain. This first cluster of unmet needs included 2 nodes named (1A) reported experiences, with the subclusters (a) relationship with doctors/spouse and (b) reflections on physical features; and (1B) changes observed over time, with the subclusters (a) regret and (b) progress. The second cluster of cause of pain included 2 nodes named (2A) radiation and side effects and (2B) othercancer treatments.In the case of patients, the 2 main clusters were labeled as (1) Regarding patients’ reported experiences (cluster 1A), the relationship with the spouse (subcluster a of cluster 1A) is well represented in the following post (post ID P478):I got diagnosed about 5 weeks ago with stage IV. It has completely changed the relationship…From my end, I now see my spouse as a caregiver instead of a spouse. I feel horrible about it and try and remind myself that he is my sexy husband who I adore, but when he is wiping my butt and stuff, it's hard to remember that. Sometimes I see him and just cry because I want to see him as my sexy husband, but it just seems impossible right now.The relationship with doctors (subcluster a of cluster 1A) was related to the need of reassurance. This is evident in the following post (post ID P399):I know how bone cancer feels and how recovery feels.This is cancer. But everyone thinks I'm just “imagining” it because I'm afraid of it returning. But I truly know I'm not. I know my body.I'm just waiting for my doctor to tell me so I can get on with treatment.Regarding physical features (subcluster b of cluster 1A), patients shared the impact of pain on different parts of their bodies. Moreover, they described the physical symptoms  experienced.Had Stage 0 breast cancer (DCIS) and a lumpectomy with a scar on the side of my breast, but close to the armpit. Has been a year and it was slightly painful/sensitive for many months afterward. Even now I still get some pain where the scar tissue is (burning and/or aching). From what I have read in blogs/chatrooms online, this is normal and can last for many years .... Glad to hear you do NOT have cancer. :-)Post ID P429Concerning the changes observed over time (cluster 1B), patients reported regret (subcluster a of cluster 1B) about the action taken during recovery because of the difficulty of waiting and wish to have quick progress (subcluster b of cluster 1B) regarding the right time and the need to be as they were before the diagnosis.I’m hoping to move on to using a stationary bike soon but like you said I have to take it easy. I’ve been pushing myself and regretting it afterwards. Progress is never fast enough.Post ID P127unmet needs. This cluster included 2 nodes named (1A) social support and (1B) reported experiences, with the subclusters (a) psychosocial challenges and (b) grief. The second cluster was labeled (2) patient-relatedcare. This cluster included 2 nodes named (2A) disease and (2B) management.As for caregivers, the first large cluster was labeled (1) Regarding social support (cluster 1A), caregivers expressed this need due to the responsibility they felt in relation to making a choice for the patients. For example, a caregiver wrote:I would do ask for support and make his time as comfortable as possible. It is not your fault and you need to remember that. It is no ones fault. I do hope he is comfortable, and whatever choice you make, I’m sure will be the right one.Post ID C128Regarding their experiences (cluster 1B), caregivers also shared the need to be understood for the burden related to the psychosocial challenges (subcluster a of cluster 1B) of pain management, the care of their loved ones, and the grief related to losing someone (subcluster b of cluster 1B).The following extracted posts are some examples of what caregivers shared on the platform with other caregivers:I’m so terribly sorry for your loss. I lost my mom to cancer in August too. I wish I could say it gets easier but I found it comes to you in waves. One second you’ll be fine and the next second you’ll be crying. Followed by numbness. It’s hard to watch them slowly fade away from us. And there’s nothing we could’ve done to help save them. It’s hard. Reach out for help with extended family to see if they can help take some of the burden off of you. If you ever need someone to talk to you can always shoot me a message here.Post ID C697…Not many people can verbalize what I am feeling…Our pains and struggles are different but hauntingly similar…. Often people don’t and cannot understand. Even worse, they often don’t *want* to understand, especially when you’re young….My grief and suffering make people uncomfortable. My husband’s suffering and mortality make them uncomfortable…They don’t want to see it, so they only see what they want to see. They see a young guy that looks good for having cancer. They dismiss his deficits as “well sometimes I forget things, get lost, or have brain farts! Totally normal!” This isn’t a brain fart or a slight delay in finding words. This isn’t a “shit I forgot to bring my lunch today.” It’s much deeper and more consistent than that. This isn’t normal…Post ID C356uncertainty. See Additionally, the comparison between the 2 dendrograms demonstrated good entanglement (entanglement coefficient=0.28), with only partial similarity regarding the clade consisting of the 2 words “help” and “may” in both the patient and caregiver dendrograms. Based on the dictionary of Loughran and Mcdonald , both wowhat if) related to the disease condition and unpredictable future. This uncertainty can bring worries and fears.For example, patient #340 reported uncertainty  is, that there are a lot of What ifs attached to cancer and the anxiety that comes with it. What if my cancer spreads?, What if it won't go away?, What if it comes back?, What if they find something on my next scan?, or my personal favorite: What if they overlook something on my next scan?. But for every What if we will worry about, there is an infinite number of What ifs we don't even think about. We can't predict the future or how it will develop but if we worry what bad could happen, we might miss the good that can happen too. Or frankly speaking if it's a beautiful sunny day outside, I won't run around with an open umbrella because it might start raining or a I could get shit on by a bird.As for caregivers, uncertainty was related to the grief and fear of losing a loved one. For example, caregiver #159 expressed these feelings by supporting another caregiver.Your story caught my attention immediately. I know the pain, fear and the uncertainty you are going through. You see, my daughter died 3 weeks ago after a 3 1/2 year battle with leukemia. She was 12 years and 5 months old to the day. I will elaborate some, not to compound anything you are going through, but to let you know, you are not alone.This study aimed to investigate the whole representation of cancer pain, considering the perspective of patients and caregivers. Overall, we found that patients and caregivers shared 3 types of content on the Reddit cancer social group about pain: experience, advice, and questions. The most frequent type of shared content in both groups was experience, followed by advice. The questions asked were only by patients. Moreover, different types of pain were covered in the narratives of both users. The most frequent types of pain discussed were neuropathy, chronic pain, and acute pain.The language used to describe the experiences differed in these 2 groups. This was expected since the experiences of patients and caregivers differ regarding cancer pain. While patients have first-hand experience of pain, the experience of caregivers refers to their reaction to it. This said, patients described pain focusing more on the physical dimension , causes of pain related to treatment  or a specific procedure to detect cancer (“biopsy” and “scan”), side effects of treatment , and aspects related to pharmacological treatments taken for managing pain . As for caregivers, they described the experience in terms of the reaction to the suffering of their care and the impact that the experience had in their life, discussing the psychosocial aspects when confronting other caregivers . Coherently, regarding patients’ posts, 69.3% (359/518) covered the physical aspects of pain solely, whereas only 31.1% (50/161) of caregivers’ posts discussed them. As for the psychological dimension of the pain experience, 27.3% (44/161) of caregivers’ posts covered this dimension, whereas this percentage was only 7.1% (37/518) for patients.According to the STM, each disease may be viewed as a “we disease,” affecting patients and their family members. This process results from the interdependence between the 2 actors . SpecifiAs for those witnessing his pain: I'm sorry, I am so sorry … My only advice is to take turns. Everyone experiencing this needs some distance from it from time to time…. If I don't spend some time away from the pain, I will lose my mind.Post ID C261While being a heavy burden, the way in which caregivers deal and cope with caregiving can also be affected by the quality of their relationship with the patient. The closeness between the partners, the time spent together, and the general strength of their relationship may impact multiple aspects of both patients’ and caregivers’ experiences. As the STM suggests , the carOne could certainly have that reaction of hating every bit of the lifestyle change, and perhaps at times it may seem just 100% detestable and harrowing, but as is the case with any event that occurs in life, a significant amount depends on how you participate in it and how you experience it.I am 32 years old and my husband was 31 when he passed away in early March. We were together for over ten years and got married just before he passed away. My one advice to you is, be the hero you can be. Our job isn’t to treat their cancer, medically that is. That’s the job of the doctors, rightfully so. Instead, focus on doing what you are capable of doing, which is being her partner, being her companion through this new life…So in a way, I wanted him to think that it was both of us who got diagnosed. He had to bear the brunt of it obviously... but no one can survive cancer alone. […]. I was there to listen to him and empathize with him as he expressed the different types of pain he was feeling. We both knew I couldn’t cure his symptoms, but I did what I could— […].Reading through some of his notes he left behind, I realized I did the right thing. I was so relieved when I read how much it meant to him that I was there for him.Post ID C376Even if the literature has recently focused more on caregivers’ experiences as well ,50, theiA person’s significant need that is not fulfilled is referred to as an unmet need . Our firrelationships with the doctors/spouse  and reflections on the physical features of pain . Therefore, patients emphasized the physical aspects of pain. Several reasons may explain this narrowed focus.Regarding patients, the hierarchical cluster analysis showed that their pain-related primary needs were causes of pain), in which patients mainly discussed radiation and its related side effects and other cancer treatments  as the primary causes of pain. Consequently, it may be intuitive for patients to assume that having physical roots, pain would only have physical outcomes.The first and most obvious reason is that the pain experienced by patients involves physical aspects. It is related to tissue damage from oncological treatments, surgery, or cancer itself . This alHowever, the physical sensation of pain is not the only reason for patients to mostly speak about pain in terms of physical symptoms. Patients are generally directed by their physicians to focus on their physical characteristics during consultation sessions ,52, withI just kept adjusting and moving in my seat. My doctor said it was probably the normal side effect of bone pain, but I never thought the pain was that bad until he prescribed me some painkillers, and I fully relaxed and could sit still.Post ID P1changes observed over time), they tended to go further. They also shared their psychological needs, such as the desire to return to their old self before the pain, influencing them to push themselves to be more active. This led them to regret the action taken and realize that progress is never fast enough.However, interestingly, when patients retrospectively reflected on their pain  and grief .As for caregivers, the primary needs discussed were the Grief is a familiar feeling experienced by caregivers, and if not well managed, it could remain after 6 months to 1 year following the loss of their loved ones . HoweverThereby, caregivers mainly focused on the psychological dimension of pain rather than the physical dimension .psychological challenges). Third, to avoid getting overwhelmed, caregivers may need to seek support from others and create a sense of community as represented in the cluster of social support. Social support has been demonstrated to be one of the most critical unmet needs for caregivers and patients [The reasons for this may be multiple. First and most obvious, they are not experiencing cancer pain in the first person, and they live these experiences through the lens of a caregiver. Second, their primary role is to provide care and support to reduce the impact of pain in the patients. However, when this goal is not fully achieved, family members may experience anger, helplessness, powerlessness, exhaustion, spiritual distress, lack of confidence, self-blame, and burden from caring ,27. All patients , which cpatients ,55 and mpatients . Still, patients , as the patients  explainsuncertainty. Uncertainty is a familiar feeling among patients with cancer pain [what if” in relation to the condition’s progression and their future, as reported above. It has been demonstrated that cancer patients with pain compared to those without pain showed a higher level of uncertainty. In these patients with pain, uncertainty predicted a lower level of hope [Despite caregivers and patients having different concerns and expressing different needs, we found that they share a common theme. This theme is represented by cer pain ,58,59. Acer pain , it comeMoreover, it may lead the patients to lose control of the situation and may worsen their pain management . As for As shown in a recent systematic review , uncertaIn this study, our second aim was to detect the emotional activation associated with cancer pain in the textual patterns of both patients and caregivers. It is worth noting that there existed a disparity in the number of posts made by patients and caregivers, with patients’ posts being twice as many as those made by caregivers. Thus, in the subsequent sections pertaining to the outcomes, we compared the emotional proportions and distributions between the 2 groups. The comparison was not intended to be numerical but rather proportional, focusing on the emotional distribution between patient and caregiver posts.Overall, we found that the emotional activation in both users’ narratives was high. Compared with caregivers, the negative sentiment expressed by patients was significantly higher. Contrarily, caregivers more frequently expressed positive feelings than patients. The prevalence of negative sentiments among patients with cancer is in line with other findings in the literature ,5,15. StThe differences in positive and negative sentiments in our groups may be due to the divergent experiences and the roles that patients and caregivers adopt to cope with pain. Patients live the experience of pain in the first person. They may have to confront the difficulty of managing their disease over time from diagnosis to long-term survivorship . Therefore, they focus more on the negative aspects. On the other hand, caregivers often have to adopt the role of a supporter, who maintains an optimistic mindset for both of them, and they sometimes underestimate the difficulties that may emerge on the medical pathway. Indeed, our data showed that caregivers expressed significantly higher trust and joy among positive emotions than patients, representing an optimistic outlook.As for the specific emotions  primarily associated with negative sentiment, we did not find significant differences between the 2 groups, with a homogeneity in terms of the negative emotions felt. Looking at each group separately, the 2 most frequently expressed negative emotions were sadness and fear in patients’ and caregivers’ narratives. This finding aligns with the fear-avoidance model ,68, whicOur study has some limitations. First, given that the data were retrieved from an online social network, demographics and user personal characteristics  were missing from our analyses.As for interpersonal characteristics, we could not match patients to their caregivers. The source of the data (the cancer subreddit) did not provide such information. Even though some descriptors of the relationship were described in some comments , the number of such comments was too small for creating separate variables for relationship characteristics.Another consideration we would like to make is regarding the users’ cultural backgrounds. Reddit users are mostly based in the United States, followed by the United Kingdom and Canada . This shMoreover, it is important to note that we used word clouds as a descriptive analysis in this study. While word clouds can provide a visual summary of frequently mentioned words, they may not fully capture the nuanced nature of individuals’ experiences or account for contextual factors and connotations associated with specific words. We would like to emphasize the need for caution in interpreting word clouds, as they may oversimplify or misunderstand the intricacies of the data. By discussing these limitations, we aim to provide a more balanced understanding of the strengths and weaknesses of word clouds. Finally, information about cancer type and treatment type was lacking (variables that may have specific implications for the patients’ pain). Therefore, we could not consider these variables in our analyses. This may impact the generalizability of the findings.Overall, the lack of participant characteristics represents the primary limitation of not just this study but most studies that use online public data. However, simultaneously, such data allows for anonymity and invisibility, which have been demonstrated to facilitate self-disclosure . This isCancer pain is an “emotional provoker”  that mayFurther studies are still needed to understand the interconnectedness of the behavioral and emotional reactions of caregivers and patients to cancer pain. Given that these reactions are formed in dyadic (or family) relationships , dyadic analyses should be implemented to explore the mutual influence between two or more actors -77.


Frozen shoulder (FS) is a chronic pain condition and has been shown to be associated with pain sensitization. However, the underyling brain mechanisms remain unclear. Here, we aimed to explore brain alterations and their association with pain sensitization in patients with FS.A total of 54 FS patients and 52 healthy controls (HCs) were included in this study. Here, we applied both structural and functional magnetic resonance imaging (MRI) techniques to investigate brain abnormalities in FS patients. Voxel-wise comparisons were performed to reveal the differences in the gray matter volume (GMV) and amplitude of low-frequency fluctuation (ALFF) between FS patients and HCs. Furthermore, the region of interest (ROI) to whole-brain functional connectivity (FC) was calculated and compared between groups. Finally, Pearson's correlation coefficients were computed to reveal the association between clinical data and brain alterations.Four main findings were observed: (1) FS patients exhibited decreased thalamus GMV, which correlated with pain intensity and pain threshold; (2) relative to HCs, FS patients exhibited a higher level of ALFF within the anterior cingulate cortex (ACC) and the thalamus; (3) FS patients exhibited a significant increase in Tha-S1 FC compared to HCs; and (4) the effect of thalamus GMV on pain intensity was mediated by pain threshold in FS patients.The dysfunctional thalamus might induce pain hypersensitivity, which further aggravates the pain in FS patients. Frozen shoulder (FS), also referred to as adhesive capsulitis, is a condition that manifests as severe spontaneous shoulder pain and night pain, accompanied by gradual restrictions of both active and passive movements of the affected shoulder –3. FS haWe, therefore, aim to elucidate the relationship between brain abnormalities and pain sensitization in FS patients based on resting-state fMRI data. It is hypothesized that FS patients have higher levels of pain sensitivity associated with abnormal brain function compared to healthy adults. Our study investigates the brain functional and structural alterations in FS patients, which may offer insights into the mechanisms of central pain sensitization in FS.The Institutional Review Board of Tianjin Medical University General Hospital approved the current study, and each participant gave written informed consent before each procedure. A total of 54 primary FS patients along with 52 healthy controls were included during 2022–2023. All participants were right-handed.The inclusion criteria for FS patients were as follows: (1) the reduction of external rotation of the affected shoulder ; (2) 25% reduction in the range of motion of at least two planes of movement compared to the unaffected shoulder; (3) the duration of pain and movement restriction was over at least 3 months; and (4) normal shoulder X-rays. The exclusion criteria were as follows: (1) patients with secondary FS and other shoulder conditions  were excluded; (2) other chronic pain conditions including fibromyalgia and rheumatic diseases; (3) other co-morbidities ; (4) patients who were taking antidepressants and anticonvulsants; and (5) those unable to finish the fMRI scan.For healthy participants, the same exclusion criteria applied with the exception of the FS diagnosis.last month) using a standardized numerical rating scale (NRS) ranging from 0 to 100 (10 = no pain (warm); 20 = threshold pain; and 100 = intolerable pain) and report the duration of pain (month).All FS patients were assessed prior to fMRI scanning. All FS patients were instructed clearly to rate their trait pain intensity  , and theTo determine the pain threshold for both FS patients and healthy controls, electrical stimulation  with a bipolar probe was used, similar to our previous study . The anoA 3T MR scanner  with a 64-channel phase-array head-neck coil was used for obtaining fMRI data. To reduce unconscious movement, participants were given a sponge pad for head support and instructed to stay still. Additionally, participants were told to close their eyes and keep their thoughts neutral, while remaining awake. The simultaneous multi-slice gradient-echo echo-planar imaging (EPI) sequence was used for fMRI scanning using the following parameters: repetition time (TR) = 800 ms, echo time (TE) = 30 ms, in-plane resolution = 3 mm × 3 mm, field of view (FOV) = 222 mm × 222 mm, flip angle (FA) = 54 degrees, matrix = 74 × 74, slice thickness = 3 mm, number of slices = 48, bandwidth = 1,690 Hz/pixel, no gap, PAT  mode, slice orientation = transversal, slice acceleration factor = 4, and phase encoding acceleration factor = 2. A total of 450 functional images were taken in 6 min. A high-resolution 3D T1 structural image was acquired using the two-inversion contrast magnetization prepared rapid gradient echo sequence (MP2RAGE), with a duration of 6 min and 42 s. The parameters used were inversion times (TI1/TI2) = 700 ms/2,110 ms, TR/TE = 4,000 ms/3.41 ms, matrix = 256 × 240, FA1/FA2 = 4 degree/5 degree, FOV = 256 mm × 240 mm, number of slices = 192, slice thickness = 1 mm, slice orientation = sagittal, and in-plane resolution = 1 mm × 1 mm.http://www.restfmri.net/forum/DPARSF) toolbox was used in our current study for data preprocessing. The preprocessing steps were as follows: (1) Due to the acclimatization to the scanner environment, magnetization stabilization, the first ten timepoints were excluded from each functional scan; (2) in order to eliminate the effect of head movement, motion corrections were performed; (3) brain functional images were first coregistered to T1 images and then normalized to the standard space using the Montreal Neurological Institute (MNI) template; (4) the voxels of functional images were resampled to 3 × 3 × 3 mm3; after normalization, the normalized images were visually checked; (5) the linear drift, along with physiological noise  and friston-24 parameters, were regressed out to minimize non-neural signals as covariates; (6) subsequently, a scrubbing procedure was conducted on timepoints with high motion; and (7) finally, the filter step was performed across 0.01–0.08 Hz to remove high-frequency noise and then smoothed with a 5-mm full-width-half-maximum isotropic Gaussian kernel. The resulting data were used for further analysis.The Data Processing Assistant for rs-fMRI  for statistical analysis.Voxel-based morphometry (VBM) analyses were performed to obtain whole-brain gray matter volume in both FS and healthy participants using T1-weighted images. The high-resolution T1-weighted images were processed with the Computational Anatomy Toolbox (CAT12) and SPM12 with the following preprocessing steps: (1) The T1 images were first manually set to the anterior commissure orientation for better registration after screening for artifacts and gross anatomical abnormalities; (2) the reorientated images were segmented into the gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) after signal inhomogeneities correction; (3) DARTEL was used with non-linear registration to standard space, and intensity modulation was conducted using the linear and non-linear components of the Jacobian determinant derived from the deformation fields; and (4) the intracranial volume was calculated by summing the volumes of the segmented gray matter, white matter, and cerebrospinal fluid compartments.http://www.restfmri.net/forum/DPARSF) toolbox was used for FC analysis.After performing the between-group comparison of the ALFF and GMV for identifying significant regions, a follow-up functional connectivity (FC) analysis was conducted on three ROIs. First, the resultant cluster of VBM analysis was first downsampled and registered to functional space (61 × 73 × 61). Subsequently, the overlap between significant clusters of structural and functional analysis was used as a region of interest for functional connectivity analysis. The mean time series across all voxels in the ROIs were extracted, and the voxel-wise functional connectivity was calculated. The resultant ROI-to-whole-brain FC maps were then Z-scored for further statistical analyses. The Data Processing Assistant for rs-fMRI  . The gray matter mask was generated based on the anatomical automatic labeling (AAL) template. Correlation analyses were performed to reveal the association among clinical measures. To further explore the association between brain alterations and clinical measures, Pearson's correlation coefficients were computed for the FS group in brain regions that exhibited significant between-group differences.Voxel-wise two-sample www.processmarcro.org, version 2.16.3) in Statistical Product Service Solutions  was used with 2000 bootstrap samples, which identified 95% confidence intervals for model components. The mediation analysis aimed to evaluate whether there was a significant difference between the total effect (path c) and the direct effect (path c′) that account for the mediator (M). Taking the pain threshold as the mediator, we tested the model with thalamus GMV as the independent variable and pain intensity ratings as the dependent variable based on the previously illustrated pathway, such that the atrophy of the thalamus increased the sensitivity to pain in chronic patients. A significant mediation occurs when bootstrapped upper and lower 95% confidence intervals (CIs) do not include zero.Furthermore, after performing the between-group comparison of the ALFF and GMV for identifying a significant association between clinical metrics and brain abnormalities in the FS group, the mediatory relationship was assessed using a bootstrapped mediation analysis of the GMV with left thalamus , pain threshold, and pain intensity similar to a previous study . The PROp > 0.05).Demographic information and clinical evaluations are displayed in Relative to HCs, FS patients exhibited a significantly higher level of PCS and PVAQ and a significantly lower pain threshold . The assR = 0.56, P < 0.001) and pain threshold  in FS patients  was significantly increased in FS patients and correlated with pain threshold in FS patients, while no significant association between pain intensity and Tha-S1 FC was observed.p < 0.05; 95% confidence interval: , We found that the effect of the thalamus GMV on pain intensity was mediated by pain threshold in FS patients  FS patients exhibited hypersensitivity to pain, which was correlated with the GM atrophy within the thalamus compared to HCs; (2) relative to HCs, FS patients exhibited a higher level of ALFF within the ACC and the thalamus; (3) relative to HCs, FS patients exhibited a significant increase in Tha-S1 FC; and (4) the effect of the thalamus GMV on pain intensity was mediated by pain threshold in FS patients.Compared with HCs, we found a significantly higher level of PCS and PVAQ ratings in FS patients, along with a lower pain threshold . In patients with chronic pain, the pain negatively impacts health-related quality of life , 31. PreWe observed a significant decrease in GMV in the thalamus and an increase in ALFF in the thalamus and the anterior cingulate cortex (ACC). The Tha-S1 FC was also increased in FS patients. Furthermore, the GMV reduction in the thalamus was correlated with pain intensity and pain threshold in FS patients. The thalamus, which is the primary relay station for afferent transmission of nociceptive information to cortical regions, has been shown to be essential in developing and maintaining neuropathic pain –46 e.g.–49. An eIt is noteworthy that our study has several limitations. First, all the participants received analgesics before enrolling in our current study. There is a possibility that this may have affected our results. Second, there are heterogenous sub-regions within the thalamus, and in our current study, we have not explored the functional and structural alterations in sub-regions of the thalamus. This limited the illustration of detailed mechanisms. Third, the question remains as to whether the functional and structural alterations are a “brain signature” of FS or whether they are shared by other chronic pain conditions. It remains unclear whether pain is sensitized at the spinal cord level, which can be clarified with spinal cord functional magnetic resonance imaging. Finally, vertex analysis (FSL-FIRST vertex) would be of assistance in illustrating which part of the thalamus is the most affected. In future experiments, we will pay particular attention to this.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Tianjin Hospital. The patients/participants provided their written informed consent to participate in this study.XC and JZ designed the study. TL, RZ, and JL analyzed the data and wrote the manuscript. All authors contributed to the article and approved the submitted version.


Anterior lumbar interbody fusion (ALIF) is a well-established surgical treatment option for various diseases of the lumbar spine, including spondylolisthesis. This study aimed to evaluate the postoperative correction of spondylolisthesis and restoration of lumbar and segmental lordosis after ALIF.Patients with spondylolisthesis who underwent ALIF between 2013 and 2019 were retrospectively assessed. We assessed the following parameters pre-and postoperatively (6-months follow-up): Visual Analogue Scale (VAS) for pain, Oswestry Disability Index (ODI), lumbar lordosis (LL), segmental lordosis (SL), L4/S1 lordosis, and degree of spondylolisthesis.96 patients were included. In 84 cases (87.50%), additional dorsal instrumentation was performed. The most frequent diagnosis was isthmic spondylolisthesis (73.96%). VAS was reduced postoperatively, from 70 to 40, as was ODI (50% to 32%). LL increased from 59.15° to 64.45°, as did SL (18.95° to 28.55°) and L4/S1 lordosis (37.90° to 44.00°). Preoperative spondylolisthesis was 8.90 mm and was reduced to 6.05 mm postoperatively. Relative spondylolisthesis was 21.63% preoperatively and 13.71% postoperatively. All clinical and radiological improvements were significant . No significant difference considering the lordosis values nor spondylolisthesis was found between patients who underwent ALIF surgery without dorsal instrumentation and patients who received additional dorsal instrumentation. Venous laceration was the most frequent complication (10.42%).With ALIF, good clinical results and safe and effective reduction of spondylolisthesis and restoration of lordosis can be achieved. Additional dorsal instrumentation does not significantly affect postoperative lordosis or spondylolisthesis. Individual vascular anatomy must be reviewed preoperatively before considering ALIF. Anterior lumbar interbody fusion (ALIF) is a well-established surgical treatment option for various lumbar spine pathologies. Advantages compared to posterior approaches to the spine are reduced trauma to the paraspinal muscles and avoidance of entrance into the spinal canal and retraction of nerve roots, and consequently, no postoperative epidural fibrosis and scarring. Also, good visualization of the anterior column with easy access for complete discectomy is possible .ALIF is an effective treatment for spondylolisthesis as it stabilizes the spinal column and decompresses nerve roots indirectly through the restoration of disc height . ALIF caMost studies investigating ALIF and the extent of correction of spondylolisthesis and lordosis have a low case number. Also, studies comparing ALIF alone and ALIF with additional dorsal instrumentation are rare. Therefore, this retrospective, monocentric study aimed, firstly, to evaluate the reduction of spondylolisthesis and restoration of lordosis in a real-life selection of patients who underwent single-level ALIF surgery, either alone or combined with dorsal instrumentation, and secondly, to describe differences between the standalone and with dorsal instrumentation groups.The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee. We obtained approval for the study from the ethics committee of the Federal State of Upper Austria (1273/2019). We carried out a retrospective analysis of patients who underwent ALIF at our department between 1.1.2013 and 10.12.2019. Only patients who showed a measurable amount of spondylolisthesis in the affected segment were included. Patients where additional dorsal instrumentation using pedicle screws and rods was performed, were also included. Patients who underwent multisegmental ALIF surgery and patients where additionally another interbody fusion procedure like transforaminal lumbar interbody fusion (TLIF) or posterior lumbar interbody fusion (PLIF) was performed were excluded. Altogether, 131 patients underwent ALIF surgery between 1.1.2013 and 10.12.2019. Thirty-five patients had to be excluded. In eight patients, a multisegmental ALIF was carried out. In nine patients, a combined procedure using ALIF and PLIF/TLIF was performed, and in one case, an intraoperative switch from ALIF to TLIF was performed. In 17 patients, there was no spondylolisthesis. Therefore, a total of 96 patients were included.The assessed parameters were gender, age, BMI, type of procedure , diagnosis, type of interbody device used, type of instrumentation used, type of interbody graft used, duration of surgery, and complications. Vascular injury was defined as any injury of the iliac vessels. Regarding clinical outcomes, preoperative and postoperative (6 months after operation) Visual Analogue Scale  for pain and Oswestry Disability Index  were assessed.All radiographic measurements were taken from a lateral radiograph of the lumbar spine in a standing position Fig. .A. All pThe patient is positioned supine under general anesthesia. First, a median, subumbilical skin incision or a Pfannenstiel incision was performed. Then, sharp dissection through the subcutaneous fat was performed. After incision of the anterior rectus sheath and dissection of the rectus abdominis muscle, the approach was continued using a retroperitoneal approach, usually on the left side, with dissection towards the promontory. After identification of the iliac arteries and veins, the vessels were mobilized, and the L5 and S1 vertebrae, along with the corresponding intervertebral disc, were visualized. These steps were performed by an access surgeon. A self-retaining retractor system was then fixed into the bone with pins. The correct height of the intervertebral disc L5/S1 was then verified under fluoroscopy. Then the disc space is revised, and intervertebral cage probes are inserted. After identifying a suitable cage size, another radiographic control was performed to verify the appropriate size and the depth of insertion. The final cage was then implanted and fixed with screws into the vertebral bodies of L5 and S1. A final anteroposterior and lateral fluoroscopy control was performed. Afterward, closure was performed using sutures for the fascia and subcutaneous tissue and staples for the skin.Additional dorsal instrumentation was performed after the anterior fusion procedure. Sterile drapes from the anterior procedure were removed after wound closure, and the patient position was switched then from supine to prone. An intraoperative x-ray system for 2D fluoroscopy and 3D imaging  was then set up. Using the fluoroscopy function of the O-arm™, the correct level was identified and, after skin disinfection and sterile draping, a median incision was performed, and the patient reference was then fixed to a spinous process. Intraoperative images were obtained and transferred to the navigation unit. The desired screw trajectories were then planned on the navigation unit. The skin incision was planned with the navigated pedicle access kit. The skin incision was then performed, and under navigational control, the PAK needle was inserted through the pedicle into the vertebral body. A K-wire was then inserted, and the PAK needle removed. After performing this for each screw position, another intraoperative scan was performed to verify the correct positioning of all K-wires. The screws were then inserted via the wires and brought into their final positions under fluoroscopic control. A final anteroposterior and lateral radiograph was taken. The navigation reference was then removed from the spinous process, followed by wound closure.Nominal variables are described with absolute and relative frequencies. Median and IQR (interquartile range) are reported for ordinal and non-normal metric variables and mean and standard deviation for normal metric variables. The normality of metric variables is tested with the Shapiro-Wilk-test. For variables measured at different time points, median and IQR are reported for the preoperative, the postoperative values, and their differences.Differences in metric variables between standalone and dorsal instrumentation groups are tested with Mann-Whitney-U-tests. Spearman’s correlation coefficient (ρ) is used to describe the association between two non-normal metric variables, e.g., blood loss and operation time. Differences in metric variables such as VAS and ODI scores or lumbar and segmental lordosis are tested with the Wilcoxon-signed-rank-test.Association between nominal variables measured preoperatively and postoperatively such as Meyerding grade is tested with a generalized McNemar’s test. Scores of VAS, ODI, LL, SL, and spondylolisthesis pre- and postoperatively are visualized by boxplots with lines showing changes of these measurements per individual. The level of significance was set to 0.05. The statistical software package R (version 4.1.0) was used for the statistical analysis .Altogether, 96 patients – 55 female (57.29%), 41 male (42.71%) – were included. Baseline patient characteristics are shown in Table The median VAS score for preoperative pain was 70.00 IQR: 20.00), while the median postoperative VAS score was 40.00 (IQR: 53.50) . The Wilcoxon signed-rank test shows a significant difference in VAS score pre- to postoperative (p < 0.001). The median preoperative ODI score was 50.00% (IQR: 18.00), and the median postoperative ODI score was 32.00% (IQR: 35.00), with a median reduction of 22.00% (IQR: 28.25). Again, the difference was significant . Figure 0.00, whiMean blood loss was 384.38ml . Blood loss was categorized into five groups. 31 (32.29%) patients had a blood loss lower than 50ml, 34 (35.42%) between 50 and below 250ml, 16 (16.67%) between 250 and below 500ml, 7 (7.29%) between 500 and less than 1000ml, and 8 (8.33%) of at least 1000ml.Complications occurred in 18 patients. Absolute and relative numbers of complications are shown in Table The occurrence of complications also led to a higher operation time, with median total operation times of 139.50 min (IQR: 60.25) in the group without complications and 204.00 min (IQR: 112.00) in the group with complications. The difference was significant (p = 0.0001). Higher blood loss was also significantly associated with a longer operation time .Table Median vertebral body length on the preoperative lateral lumbar spine x-ray was 40.05 mm (IQR: 7.92), compared to 41.65 (IQR: 6.95) postoperatively. Median preoperative spondylolisthesis was 8.90 mm (IQR: 6.50) which was reduced to 6.05 (IQR: 4.55 mm) postoperatively (median absolute reduction of 3 mm (IQR: 4.08), median relative reduction of 33.71%). Details on this development of spondylolisthesis are provided in the form of boxplots and individual evolvements in Fig. Patients who underwent ALIF standalone are compared to patients who also received additional dorsal instrumentation. Neither the change of ODI (median (IQR); dorsal instrumentation, n = 57: -24.00 (26.00); standalone, n = 7: -8.00 (24.50); p = 0.3953) nor of VAS significantly differed (median (IQR); dorsal instrumentation, n = 53: -35.00 (42.00), standalone, n = 6: -15.00 (26.50); p = 0.2531) between the groups. Hence, the tendency of better results of the dorsal instrumentation group compared to the standalone group is not significantly different from zero. No significant association between complications and the performance of standalone procedures is observed (p-= 0.4536).The comparison of the standalone group (n = 12) and the dorsal instrumentation group (n = 84) revealed that the pre- to postoperative differences in LL (p = 0.6941), SL (p = 0.9602), and L4/S1 lordosis (p = 0.7147) did not differ significantly between the groups. The observed difference of the correction of spondylolisthesis between the standalone group and the dorsal instrumentation group is not significant (p = 0.0829).We present the results of 96 patients who underwent ALIF for degenerative spine pathologies where spondylolisthesis was present. In most cases, the procedure was combined with additional dorsal instrumentation using pedicle screws and rods.Most patients  were not rated as having high-grade spondylolisthesis (Meyerding III or IV). This finding is in accordance with the results of other studies, as all our patients were adults with degenerative diseases of the spine, which are typically associated with lower grades of spondylolisthesis. Viglione et al. (2017) state that adult low-grade spondylolisthesis and adolescent high-grade spondylolisthesis should be clearly distinguished, suggesting different pathological entities in these age groups . High-grIn our sample, median spondylolisthesis was significantly reduced postoperatively, by 3.00 mm IQR: 4.08), along with a reduction of the relative subluxation from 21.63% (IQR: 17.10) to 13.71% IQR: 11.61). This is a 33.71% reduction from the preoperative value. Our findings are similar to the reductions reported in the literature. In 2020, Kalani et al. reported a mean reduction of spondylolisthesis by 58.7% in combined procedures with anterior fusion and dorsal instrumentation [.61. This.08, alonMost studies investigating the reduction of spondylolisthesis after ALIF have relatively low sample size numbers, with case numbers between 5 and 65 participants , 14, 17 Additional dorsal instrumentation did not significantly change the lordosis values’ postoperative outcome or the amount of spondylolisthesis reduction. As in most cases of spondylolisthesis, dorsal instrumentation is recommended for reasons of stability and good results concerning bony fusion. Studies comparing standalone procedures with dorsal instrumentation are scarce, and to our knowledge, we present one of the first studies to show that the anterior procedure is the main contributor to the improvement of spondylolisthesis and lordosis.Knowledge and research on the sagittal alignment of the spine have multiplied over the last few years. Sagittal alignment and LL are of significant importance when treating patients with spondylolisthesis , as sagiThe finding that L4/S1 and SL in the operating segment are postoperatively more increased than the total LL might indicate that the lumbar spine as a whole partly compensates for correction of the SL within the segment where fusion was performed. However, further research on this topic should be conducted, as specific physiological mechanisms are not described in the literature leading to these results.A meta-analysis from 2016 comparing complication rates in ALIF and extreme lateral interbody fusion procedures found an overall complication rate of 26.47% for ALIF versus 16.61% for extreme lateral interbody fusion . Most ofOur study was limited by several factors. First, the results may be biased due to the retrospective study design. Also, the sample size of the patients who underwent standalone ALIF was relatively small. We recommend conducting prospective, multi-center studies with large sample sizes to investigate sagittal alignment and spondylolisthesis after ALIF surgery.Good clinical results can be achieved with ALIF, and effective reduction of spondylolisthesis and restoration of LL is possible. We present one of the most extensive single-center studies investigating this topic. Additional dorsal instrumentation did not significantly affect postoperative lordosis or spondylolisthesis compared to the standalone group. As vascular injury is a frequent complication with potentially fatal consequences, individual vascular anatomy must be analyzed on MRI or CT before considering ALIF. Therefore, in patients where the fusion of the lower lumbar spine is indicated in the presence of spondylolisthesis and suitable anatomy, we recommend the performance of ALIF surgery combined with additional dorsal instrumentation.