{"paper_id":"34a18a87-b5d4-4102-8478-4c4edef065a0","body_text":"Assessing the impact of immersive virtual reality technology on the psychological recovery of patients with Parkinson’s disease depression: study protocol of a randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Assessing the impact of immersive virtual reality technology on the psychological recovery of patients with Parkinson’s disease depression: study protocol of a randomized controlled trial Xinyan Chen, Lina Chen, Xiaochun Chen, Qinyong Ye, Guoen Cai, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3067437/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Depression in Parkinson’s disease (DPD) has a high incidence rate in Parkinson's patients. It is common non-motor symptom of Parkinson's disease, which seriously affects patients’ quality of life. Thus, improving Parkinson's depression is important for improving patients’ quality of life. Psychotherapy for depression is limited for many reasons, and only a few patients are able to benefit. Many studies have proven that relaxation therapy, play, and exercise therapy are effective treatment for depression. VR has rapidly developed as a form of rehabilitation in recent years, due to its immersive characteristics and accessibility. Further, it has been applied to the psychological treatment of phobia and anxiety. However, there is no relevant research on the treatment of Parkinson's depression with VR, The aim of this study is to assess the effect of immersive VR-assisted training on DPD patients. Methods: The study design is a single-blind randomized controlled trial. Seventy-four DPD patients will be recruited and chosen as subjects, then randomly allocated into two groups. The VR group (n=37) will accept VR-assisted training (40min) 3 times/week for 8 weeks. The non-VR training group (n= 37) will receive treatment as usual (TAU). The outcome measures will be measured before intervention, at 8 weeks, at 3 months, and at 6 months post-intervention. The primary outcomes will include Hamilton Depression Scale-24 (HAM-D24). The secondary outcomes will include the short-form 36 item health survey questionnaire (SF-36), neuroinflammation factors (BDNF, IL-6, CRP), and functional magnetic resonance imaging (fMRI). Discussion: The traditional treatment of depression has limited resources and requires a lot of time and energy. It is not suitable for PD patients with mobility difficulties and in remote areas. VR is able to make up for limitations in traditional treatment methods. An advantage of VR is that it makes patients more invested in active participation. This study may provide an improved method for the clinical treatment of DPD patients, which is helpful for clinical decision-making and future practice. Trial registration: The study has been registered in the Chinese Clinical Trial Registry ChiCTR2200065843, 16 November 2022. Immersive virtual reality Depression in Parkinson’s disease psychological rehabilitation Randomized controlled trials Figures Figure 1 Figure 2 Figure 3 Background Parkinson’s disease (PD) is the second most common chronic neurodegenerative disease with heterogeneous symptomatology [ 1 ] . The clinical features of PD are rigidity, bradykinesia, tremor, and postural disorders, and has the non-motor symptoms, such as mood disorder, sleep disorder, and recognition disorder. Depression is the most common non-motor symptom of Parkinson’s disease, however, the pathogenesis of depression in Parkinson’s disease (DPD) remains undetermined. The incidence of DPD reported in the literature is 40–50% [ 2 , 3 ] . DPD peaks in the early stage of Parkinson’s disease. Clinical manifestations of DPD are persistent depression, difficulty concentrating, decreased interest in work and life, etc [ 4 – 6 ] . Recent research shows that psychological problems are an important factor affecting the quality of life of Parkinson’s patients, with a quality of life contribution rate around 42% [ 7 – 9 ] . Long-term depression can aggravate motor symptoms of PD, forming a vicious circle, seriously, affecting patients’ quality of life, and increase the burden on family and the social economy. Therefore, it is important to improve the quality of life of Parkinson’s patients by intervening and improving their depressive symptoms. Antidepressant pharmacotherapy and/or cognitive behavioral therapy (CBT) and interpersonal psychotherapy (IPT) are the current mainstays of treatment for depression. However, approximately 40% of depressed patients do not adequately respond to these treatments [ 10 , 11 ] . Therefore, many researchers continue to explore and develop auxiliary therapeutic treatment methods for depression. Previous research has confirmed that physical and mental exercise training such as Yoga, Tai Chi, and relaxation meditation are important auxiliary means of rehabilitation from depression [12,13] . As a therapeutic tool, video games have recently been favored by researchers due to the advantages of entertainment and convenience. Some studies have shown that video games, such as Wii games, mobile games, commercial games, and other auxiliary treatments of depression, achieve a good intervention effect for improving the symptoms of patients with depression [ 14 – 17 ] . Older patients, in addition to adolescents, can benefit from game interventions [ 18 – 22 ] . Virtual Reality (VR) is a revolutionary assistant physical therapy technology developed in recent years [ 23 , 24 ] . It has been considered a cost-effective tool in psychotherapy [ 25 ] . VR immersion expands the game space, increases patient participation in the game, improves the pleasure of the treatment process, and thus improves negative psychological symptoms [ 26 ] . VR associated studies have confirmed that VR treatment is a significantly effective treatment in anxiety and phobia [ 25 ] . VR technology can successfully treat delusions, hallucinations, and other psychiatric symptoms, and researchers have concluded that VR therapy is safe and acceptable for patients, and has long-term effects [ 27 ] . While there is no dedicated research about VR-assisted training in DPD, it should be investigated. The immersive characteristic of VR devices can be a powerful research tool [ 28 , 29 ] . This study will use VR-assisted training to intervene in DPD patients, in order to assess the improvement of DPD symptoms and the strength of the effect. Materials and Methods Study design The study is a randomized single-blind controlled trial. It has been authorized by the Medical Ethics Committee of Union Hospital of Fujian Medical University, and is registered on the Chinese Clinical Trial Registry (registration number ChiCTR2200065843). The participant flow of the research procedure is depicted in Fig.1. We use the Standard Protocol Items to describe the study procedure. The checklist of Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) is depicted in Fig.2. Objectives The primary objective of the study is to evaluate the effect of VR-assisted training for DPD patients and, whether immersive VR can improve the mood of DPD patients. The secondary objective is to evaluate the strength of the effect. Participants Inclusion criteria: (1) participants have been diagnosed with idiopathic PD using the Movement Disorder Society Clinical Diagnostic Criteria at Hoehn and Yahr stages1-3 [30,31] , (2) participants were required to have scores of 8-20 with the 24-item Hamilton Rating Scale for Depression (HAM-D) [32] , (3) patients were less than 80years of age. Exclusion criteria: (1) patients with other mental disorders or bipolar disorder, (2) patients with another serious disease, such as vital organ failure, or malignant tumor. (3) poor adherence to medication. Setting The study training and evaluation will be carried out in the Neurology ward of Union Hospital of Fujian Medical University, China. Recruitment The study executes the recruitment and consent program according to our research team’s previous VR related study [33] . Subjects recruited in the study will be from outpatients in the Neurology department of Union Hospital of Fujian Medical University. If the patient agrees to participate, the attending physician will introduce the patient to the research team. The research team will describe the trial to patients in detail and obtain written consent from patients. Randomization and blinding Eligible participants will be allocated to either the VR training group or the non-VR training group randomly in a 1:1 ratio. The study coordinator will assess baseline information, then inform the attending physician to refer participants to a research team. The study coordinator will not attend to recruit participants. A computerized random number generator will be used by a biostatistician in random allocation sequence. The biostatistician will be not involved in this trial. The allocation is blind to the attending physician, and the participants will be instructed not to tell the attending physician and the outcome assessors about the allocation. Interventions As shown in Table 1, the research intervention description of VR-assisted training in this study is based on the TIDieR template. During the trial relevant care and interventions are permitted. VR system The VR system used in this study is consistent with the VR system used by Huihui Cai, et al in the study of VR-assisted gait rehabilitation in stroke patients. The scenarios of VR-assisted training are shown in Fig.3. VR training group Concurrently with daily treatment, participants receive the adjunct VR training 40 min per day, 3 times per week, for 8 weeks of VR depression training. The specific VR training process is as follows: first, participants will receive training on the 6mⅹ5m flat ground; then, participants will wear HTC Vive virtual glasses. Four series VR training scene (relaxing training, Yoga training, completing tasks training, aerobic exercise training) will be available for subjects. VR scenes are immersive, giving the subjects a relaxing feeling. All three series scenes will be completed in one training. The virtual scenes could be displaced in one series according to participant needs and preferences. Non-VR training group Participants in the non-VR training group will receive the treatment as usual (TAU). TAU participants will receive routine medical and psychiatric treatment, without the research team’s input [34] . Outcome measures All participants will be measured: at baseline (before the beginning of the study), at the end of the intervention, and at the 3 month and 6 month follow-up. All evaluation indicators are depicted in Table 2. Primary outcomes Hamilton Depression Scale-24(HAM-D24) We will use the 24-item Hamilton Depression Rating Scale (HAMD24), authorized by Hamilton in 1960, to assess intervention response. It is one of the most commonly used scales in rating depression status [35] . Secondary outcomes The MOS item short form health survey ( SF - 36) The Short-Form 36-item Health Survey（SF-36）is specialized for depressed elderly patients. It provides additional information about functional health, general well-being, and general health perceptions [36] . Neuroinflammation factors Hormonal changes associated with stress and depression may be involved in key physiological processes during immune activation [37] . The hypothalamic-pituitary-adrenal(HPA)axis is an important component of a large physiological network involved in stress activation [38,39] .Importantly, dysregulation of the immune system and persistent inflammation are inherent characteristics of recurrent depression [40] . Brain-derived neurotrophic factor(BDNF) is a protein that mainly exists in specific brain regions, such as the hippocampus, cerebral cortex, hypothalamus, cerebellum and peripheral nervous system. BDNF is related to neuronal growth, memory consolidation and, storage, and long-term memory impairment [9] . Some studies have shown that BDNF is related to cognition and emotion, which decreases in the serum of depressed patients and increases with exercise [10,41] . Therefore, BDNF is one of the most frequently used serum evaluation factors in depression intervention related studies. Interleukin-6（IL-6）and C-reactive protein（CRP）are related to the inflammatory response caused by hyperactivity of HPA axis. Several studies have shown that CRP and IL-6 are increased in the serum of depressed patients and are related to depression severity [8,11] . Therefore, CRP and IL-6 are also commonly used serological evaluation indicators in depression related studies. Functional magnetic resonance imaging (fMRI) Existing studies have shown that depressed patients have functional abnormalities in different brain regions [12] .Virtual reality only requires minimal exercise and cardio-pulmonary stimulation. 3D spatial perception, motion, and navigation are closely related to spatial memory and requires permanent visual tracking of direction and distance reference points or landmarks. The mapping is performed by integration of hippocampal and entorhinal network mechanisms by grid cells [42] . Therefore, this study will use fMRI as a physiological index to evaluate intervention effectiveness, and judge changes in brain neural network function before and after the intervention. Sample size calculation A recent meta-analysis shows that effects of VR-based treatments were more effective than the control in the post-depression test [25] and the meta-analysis reports an overall effect on depressive symptoms, with Hedges’g=0.73. Considering that the probability of type I error is 5% , the probability of type II error is 20%, the estimated sample size is [43] 62 participants (31 per group) using the program PASS. To allow a dropout rate of 20%, this study will recruit at least 74 participants. Statistical analysis We will use SPSS to build and collect all data. We will use a paired t test to assess the differences of improvement indicators between groups, both before and after intervention, and use an independent sample t test to measure the data between two groups. The measure of statistical significance is set at the standard of P <0.05. In addition, we will use the covariance method to analyze significant demographic and clinical imbalances. We will also analyze differences between subgroups. All data will be collected electronically to guarantee security. Study organization and oversight The research team will administer the study. Research staff will also take charge of VR scene design and VR-assisted intervention. The study will be supervised by the hospital safety supervision committee, which will take charge of study design re-evaluation, procedure execution, medical ethics, participant safety, and data management. Participant information will be protected; we use anonymity to ensure the rights of each participant. All participant data will be stored in a highly secured database to ensure safety. Participant safety during intervention VR related products have been gradually developed and have received high acceptance in recent years. To date, only 2 RCTS have reported adverse events of VR exergames in older adults, such as VR sickness (i.e., headaches, discomfort, dizziness, and fatigue) [44] . During the VR training process, subjects will be in safe surroundings with family and our research team. If a subject feels uncomfortable, they will be able to take a rest. All adverse events (i.e., falls, pains, headaches, dizziness, and fatigue) that occur during the procedure will be taken seriously and registered in order, to decide whether the event is related to the intervention. We will take the following measures to ensure research safety: 1. During the 8-week training, each subject will receive a strict training plan every week. The training plan will be adjusted according to the specific situation of the subject; 2. VR training will be taken in a safe environment. We will pay close attention to participant feedback during use of the VR intervention training; 3. Subjects that withdraw from the study will receive full support. Others The steering committee is composed of authors Xinyan Chen, and Guoen Cai. Committee members participated in the design study and provided suggestions for the experiment. The data security monitoring committee is independent of the host organization, including statistician and Prof. Qinyong Ye as the chairman. Supervision and management department can conduct audits to assess the clinical research behavior and compliance with the protocol, SOPs, GCP, and applicable regulatory requirements. Protocol amendment The research team will discuss amendments to the protocol, first notifying the PI. The PI will have the copy of the modified agreement. Any behaviors that deviate from the agreement will be recorded with the reporting form. Discussion In this study, we will carry out an 8-week VR-assisted training for PD patients with mild to moderate depression, then evaluate the effect of training on the improvement of PD patients with mild to moderate depression through a 6-month follow-up. Since the traditional treatment of depression requires a lot of time and energy, and has limited resources, it is not suitable for PD patients in remote areas or with mobility difficulties. VR is able to make up for these problems with traditional treatment methods. This protocol aims to accumulate data for the effect of VR-assisted training on PD patients with depression, and explore the clinical application of VR. One difference between VR and traditional game therapy is that VR provides a fully immersive virtual real environment scene, which allows patients to have a feeling of immersion and the ability to interact with the scene in the virtual real space. It not only has the reward feedback and entertainment of traditional games, but also involves more physical and mental participation. The advantage of VR will make patients feel more relaxed, immersed, and interested in the VR exercise. Moreover, patients can choose from a variety of VR scenarios, depending on their individual environment requirements. Some studies show that depressed patients have poor participation in the intervention study and high withdrawal rate [ 11 ] . However, the multi-selectivity and immersive advantages of VR can increase active participation and participant stability and reduce the withdrawal rate. Previous studies have confirmed that VR is a suitable treatment method for psychological disorders such as anxiety and phobia, and that VR has a relaxing effect on depressed patients [ 25 ] . Studies have confirmed the effectiveness of VR therapy compared to conventional treatment, and has no side effects for patients, including those who are resistant to conventional drug treatment [ 27 ] . Interestingly, some studies have found that a small amount of VR training can achieve a similar therapeutic effect to continuous physical training, and that intermittent training is more effective than long-term continuous training [ 45 ] . Study status Recruitment will start on July 1, 2023 and will close on July 1, 2026.The entire study-phase and data analysis is expected to be completed within 24 to 36 months. Abbreviations DPD: Major depressive disorder; VR: Virtual reality; TAU: Treatment as usual; RCT: Randomized controlled trial; HAMD: Hamiltion depression scale; fMRI: Functional magnetic resonance imaging. Declarations Acknowledgements The authors thank all study participants. Authors’ contributions XYC, GEC and YQZ were involved in the research conception and design. XYC, YQZ and QYY obtained ethics approval. XYC, XYC and GEC drafted the manuscript. XYC, QYY and XYC participated in the statistical analysis plan. All authors edited and revised the manuscript. All authors approved the final version of the manuscript. Funding This study is supported by grants from the National Key Clinical Specialty Project (No.05029001). The funding agency only provides funding and does not participate in the experimental process. Availability of data and materials For interested researchers, the data from the study can be provided on request. Please contact Dr.Cai. Ethics approval and consent to participate The study is being conducted in compliance of the Declaration of Helsinki. It was approved by the ethics committee of Fujian Medical University Union Hospital(ethics approval number: 2022YF053-01). Informed consent were obtained prior to the study. When necessary, the informed consent of the subject’s family was obtained. Consent for publication Written informed consent for publication was obtained from all participants. All the authors approved the final manuscript and agreed to publish it .All participants agreed to publish images associated with them. Competing interests The authors state that they have no competing interests. Author details 1 Department of Neurology, Fujian Medical University Union Hospital, Institute of Clinical Neurology, Fujian Medical University, Fuzhou 350001, Fujian,China. 2 Department of Clinical Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China. 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Supplementary Files Table1.xlsx Table2.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-3067437\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Study protocol\",\"associatedPublications\":[],\"authors\":[{\"id\":215152606,\"identity\":\"37c5ea79-b271-4f72-9688-a34f37aac9d8\",\"order_by\":0,\"name\":\"Xinyan Chen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fujian Medical University Union 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Zeng\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYPACG37GBhDNRryWNMlGUrUclgTrIEqLfHvv4dc8ZeclmKedMWD4UHaYgX92A34tjD3n0qx5zt2WYJydY8A449xhBok7B/BrYZbIMTPmbbtdB9LCzNt2mMFAIgG/Fjb5NyAt58C2MP8lRguPBI/xY962AxAtjMRokeDJMWOccy4ZqCWt4GDPuXQeiRsEtMi3nzH+8KbMTsJwdvLGBz/KrOX4ZxDQAvKOFA8wOgwbGBgOgFxKUD0QMH/8AdQiT4zSUTAKRsEoGJkAAAhiPnLNfbGgAAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"Fujian Medical University Union Hospital\",\"correspondingAuthor\":true,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yuqi\",\"middleName\":\"\",\"lastName\":\"Zeng\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2023-06-15 10:59:25\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-3067437/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-3067437/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":39643437,\"identity\":\"4111dc11-6999-410d-80da-f90b3fdc3d3b\",\"added_by\":\"auto\",\"created_at\":\"2023-07-06 14:38:09\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":57920,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eResearch flow chart of the experiment\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3067437/v1/84e8239a5dc0195fbf504c0b.jpg\"},{\"id\":39643814,\"identity\":\"0a6a477f-caa7-41ef-a3e6-e9d304b97a24\",\"added_by\":\"auto\",\"created_at\":\"2023-07-06 14:46:09\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":83932,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eStandard Protocol Items: Recommendations for Interventional Trials（SPIRIT）figure (numbers beside \\u003cem\\u003et\\u003c/em\\u003e represent weeks)\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3067437/v1/ccb00e3dbe8e8112195f6792.jpg\"},{\"id\":39642042,\"identity\":\"b9f7f7e8-6f83-4d8d-9b2d-a37f6de15872\",\"added_by\":\"auto\",\"created_at\":\"2023-07-06 14:30:09\",\"extension\":\"jpg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":121776,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eVirtual reality (VR) system and virtual scene.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003ea.b\\u003c/strong\\u003e The VR training scene. \\u0026nbsp;\\u003cstrong\\u003ec\\u003c/strong\\u003e A participant is carrying out riding training\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3067437/v1/d5f36bc46a2f243b9a8521bc.jpg\"},{\"id\":39643823,\"identity\":\"8c4965ab-292a-45be-b82b-cb52892f0d73\",\"added_by\":\"auto\",\"created_at\":\"2023-07-06 14:46:14\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":574272,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3067437/v1/17039249-b01f-4ba7-afd4-9bc0af6da22f.pdf\"},{\"id\":39642046,\"identity\":\"efe57a41-da8c-438a-a704-6ed6629cfba2\",\"added_by\":\"auto\",\"created_at\":\"2023-07-06 14:30:09\",\"extension\":\"xlsx\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":10984,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table1.xlsx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3067437/v1/877a7c347dc4952f4a723848.xlsx\"},{\"id\":39643436,\"identity\":\"303257e8-5255-49b6-9921-a8a0f130673e\",\"added_by\":\"auto\",\"created_at\":\"2023-07-06 14:38:09\",\"extension\":\"xlsx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":12533,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table2.xlsx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3067437/v1/ffe5a8c11397d87d7e0e11b3.xlsx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Assessing the impact of immersive virtual reality technology on the psychological recovery of patients with Parkinson’s disease depression: study protocol of a randomized controlled trial\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eParkinson\\u0026rsquo;s disease (PD) is the second most common chronic neurodegenerative disease with heterogeneous symptomatology\\u003csup\\u003e[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]\\u003c/sup\\u003e. The clinical features of PD are rigidity, bradykinesia, tremor, and postural disorders, and has the non-motor symptoms, such as mood disorder, sleep disorder, and recognition disorder. Depression is the most common non-motor symptom of Parkinson\\u0026rsquo;s disease, however, the pathogenesis of depression in Parkinson\\u0026rsquo;s disease (DPD) remains undetermined. The incidence of DPD reported in the literature is 40\\u0026ndash;50%\\u003csup\\u003e[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]\\u003c/sup\\u003e. DPD peaks in the early stage of Parkinson\\u0026rsquo;s disease. Clinical manifestations of DPD are persistent depression, difficulty concentrating, decreased interest in work and life, etc\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR5\\\" citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]\\u003c/sup\\u003e. Recent research shows that psychological problems are an important factor affecting the quality of life of Parkinson\\u0026rsquo;s patients, with a quality of life contribution rate around 42%\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR8\\\" citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]\\u003c/sup\\u003e. Long-term depression can aggravate motor symptoms of PD, forming a vicious circle, seriously, affecting patients\\u0026rsquo; quality of life, and increase the burden on family and the social economy. Therefore, it is important to improve the quality of life of Parkinson\\u0026rsquo;s patients by intervening and improving their depressive symptoms.\\u003c/p\\u003e \\u003cp\\u003eAntidepressant pharmacotherapy and/or cognitive behavioral therapy (CBT) and interpersonal psychotherapy (IPT) are the current mainstays of treatment for depression. However, approximately 40% of depressed patients do not adequately respond to these treatments \\u003csup\\u003e[\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]\\u003c/sup\\u003e. Therefore, many researchers continue to explore and develop auxiliary therapeutic treatment methods for depression. Previous research has confirmed that physical and mental exercise training such as Yoga, Tai Chi, and relaxation meditation are important auxiliary means of rehabilitation from depression \\u003csup\\u003e[12,13]\\u003c/sup\\u003e. As a therapeutic tool, video games have recently been favored by researchers due to the advantages of entertainment and convenience. Some studies have shown that video games, such as Wii games, mobile games, commercial games, and other auxiliary treatments of depression, achieve a good intervention effect for improving the symptoms of patients with depression\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR15 CR16\\\" citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]\\u003c/sup\\u003e. Older patients, in addition to adolescents, can benefit from game interventions\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR19 CR20 CR21\\\" citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eVirtual Reality (VR) is a revolutionary assistant physical therapy technology developed in recent years\\u003csup\\u003e[\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]\\u003c/sup\\u003e. It has been considered a cost-effective tool in psychotherapy \\u003csup\\u003e[\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]\\u003c/sup\\u003e. VR immersion expands the game space, increases patient participation in the game, improves the pleasure of the treatment process, and thus improves negative psychological symptoms \\u003csup\\u003e[\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]\\u003c/sup\\u003e. VR associated studies have confirmed that VR treatment is a significantly effective treatment in anxiety and phobia\\u003csup\\u003e[\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]\\u003c/sup\\u003e. VR technology can successfully treat delusions, hallucinations, and other psychiatric symptoms, and researchers have concluded that VR therapy is safe and acceptable for patients, and has long-term effects\\u003csup\\u003e[\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eWhile there is no dedicated research about VR-assisted training in DPD, it should be investigated. The immersive characteristic of VR devices can be a powerful research tool\\u003csup\\u003e[\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e]\\u003c/sup\\u003e. This study will use VR-assisted training to intervene in DPD patients, in order to assess the improvement of DPD symptoms and the strength of the effect.\\u003c/p\\u003e\"},{\"header\":\"Materials and Methods\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eStudy design \\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study is a randomized single-blind controlled trial. It has been authorized by the Medical Ethics Committee of Union Hospital of Fujian Medical University, and is registered on the Chinese Clinical Trial Registry (registration number ChiCTR2200065843). The participant flow of the research procedure is depicted in Fig.1. We use the Standard Protocol Items to describe the study procedure. The checklist of Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) is depicted in Fig.2.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eObjectives\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe primary objective of the study is to evaluate the effect of VR-assisted training for DPD patients and, whether immersive VR can improve the mood of DPD patients. The secondary objective is to evaluate the strength of the effect.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eParticipants \\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eInclusion criteria: (1) participants have been diagnosed with idiopathic PD using the Movement Disorder Society Clinical Diagnostic Criteria at Hoehn and Yahr stages1-3\\u003csup\\u003e[30,31]\\u003c/sup\\u003e, (2) participants were required to have scores of 8-20 with the 24-item Hamilton Rating Scale for Depression (HAM-D)\\u003csup\\u003e[32]\\u003c/sup\\u003e, (3) patients were less than 80years of age.\\u003c/p\\u003e\\n\\u003cp\\u003eExclusion criteria: (1) patients with other mental disorders or bipolar disorder, (2) patients with another serious disease, such as vital organ failure, or malignant tumor. (3) poor adherence to medication.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSetting\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study training and evaluation will be carried out in the Neurology ward of Union Hospital of Fujian Medical University, China.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRecruitment \\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study executes the recruitment and consent program according to our research team\\u0026rsquo;s previous VR related study\\u003csup\\u003e[33]\\u003c/sup\\u003e. Subjects recruited in the study will be from outpatients in the Neurology department of Union Hospital of Fujian Medical University. If the patient agrees to participate, the attending physician will introduce the patient to the research team. The research team will describe the trial to patients in detail and obtain written consent from patients.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRandomization and blinding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eEligible participants will be allocated to either the VR training group or the non-VR training group randomly in a 1:1 ratio. The study coordinator will assess baseline information, then inform the attending physician to refer participants to a research team. The study coordinator will not attend to recruit participants. A computerized random number generator will be used by a biostatistician in random allocation sequence. The biostatistician will be not involved in this trial. The allocation is blind to the attending physician, and the participants will be instructed not to tell the attending physician and the outcome assessors about the allocation.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eInterventions \\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAs shown in Table 1, the research intervention description of VR-assisted training in this study is based on the TIDieR template. During the trial relevant care and interventions are permitted.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eVR system\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe VR system used in this study is consistent with the VR system used by Huihui Cai, et al in the study of VR-assisted gait rehabilitation in stroke patients. The scenarios of VR-assisted training are shown in Fig.3.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eVR training group \\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eConcurrently with daily treatment, participants receive the adjunct VR training 40 min per day, 3 times per week, for 8 weeks of VR depression training. The specific VR training process is as follows: first, participants will receive training on the 6mⅹ5m flat ground; then, participants will wear HTC Vive virtual glasses. Four series VR training scene (relaxing training, Yoga training, completing tasks training, aerobic exercise training) will be available for subjects. VR scenes are immersive, giving the subjects a relaxing feeling.\\u003c/p\\u003e\\n\\u003cp\\u003eAll three series scenes will be completed in one training. The virtual scenes could be displaced in one series according to participant needs and preferences.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eNon-VR training group\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eParticipants in the non-VR training group will receive the treatment as usual (TAU). TAU participants will receive routine medical and psychiatric treatment, without the research team\\u0026rsquo;s input\\u003csup\\u003e[34]\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eOutcome measures \\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll participants will be measured: at baseline (before the beginning of the study), at the end of the intervention, and at the 3 month and 6 month follow-up. All evaluation indicators are depicted in Table 2.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003ePrimary outcomes\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eHamilton Depression Scale-24(HAM-D24)\\u003c/strong\\u003e \\u003c/p\\u003e\\n\\u003cp\\u003eWe will use the 24-item Hamilton Depression Rating Scale (HAMD24), authorized by Hamilton in 1960, to assess intervention response. It is one of the most commonly used scales in rating depression status\\u003csup\\u003e[35]\\u003c/sup\\u003e. \\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eSecondary outcomes\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eThe MOS item short form health survey\\u003c/strong\\u003e(\\u003cem\\u003eSF\\u003c/em\\u003e-\\u003cem\\u003e36)\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe Short-Form 36-item Health Survey（SF-36）is specialized for depressed elderly patients. It provides additional information about functional health, general well-being, and general health perceptions\\u003csup\\u003e[36]\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eNeuroinflammation factors\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eHormonal changes associated with stress and depression may be involved in key physiological processes during immune activation\\u003csup\\u003e[37]\\u003c/sup\\u003e. The hypothalamic-pituitary-adrenal(HPA)axis is an important component of a large physiological network involved in stress activation\\u003csup\\u003e[38,39]\\u003c/sup\\u003e.Importantly, dysregulation of the immune system and persistent inflammation are inherent characteristics of recurrent depression\\u003csup\\u003e[40]\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003eBrain-derived neurotrophic factor(BDNF) is a protein that mainly exists in specific brain regions, such as the hippocampus, cerebral cortex, hypothalamus, cerebellum and peripheral nervous system. BDNF is related to neuronal growth, memory consolidation and, storage, and long-term memory impairment\\u003csup\\u003e[9]\\u003c/sup\\u003e. Some studies have shown that BDNF is related to cognition and emotion, which decreases in the serum of depressed patients and increases with exercise\\u003csup\\u003e[10,41]\\u003c/sup\\u003e. Therefore, BDNF is one of the most frequently used serum evaluation factors in depression intervention related studies.\\u003c/p\\u003e\\n\\u003cp\\u003eInterleukin-6（IL-6）and C-reactive protein（CRP）are related to the inflammatory response caused by hyperactivity of HPA axis. Several studies have shown that CRP and IL-6 are increased in the serum of depressed patients and are related to depression severity\\u003csup\\u003e[8,11]\\u003c/sup\\u003e. Therefore, CRP and IL-6 are also commonly used serological evaluation indicators in depression related studies.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunctional magnetic resonance imaging \\u003c/strong\\u003e\\u003cstrong\\u003e(fMRI)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eExisting studies have shown that depressed patients have functional abnormalities in different brain regions\\u003csup\\u003e[12]\\u003c/sup\\u003e.Virtual reality only requires minimal exercise and cardio-pulmonary stimulation. 3D spatial perception, motion, and navigation are closely related to spatial memory and requires permanent visual tracking of direction and distance reference points or landmarks. The mapping is performed by integration of hippocampal and entorhinal network mechanisms by grid cells\\u003csup\\u003e[42]\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003eTherefore, this study will use fMRI as a physiological index to evaluate intervention effectiveness, and judge changes in brain neural network function before and after the intervention.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSample size calculation\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA recent meta-analysis shows that effects of VR-based treatments were more effective than the control in the post-depression test\\u003csup\\u003e[25]\\u003c/sup\\u003e and the meta-analysis reports an overall effect on depressive symptoms, with Hedges\\u0026rsquo;g=0.73. Considering that the probability of type I error is 5% , the probability of type II error is 20%, the estimated sample size is\\u003csup\\u003e[43] \\u003c/sup\\u003e62 participants (31 per group) using the program PASS. To allow a dropout rate of 20%, this study will recruit at least 74 participants.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStatistical analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe will use SPSS to build and collect all data. We will use a paired \\u003cem\\u003et\\u003c/em\\u003e test to assess the differences of improvement indicators between groups, both before and after intervention, and use an independent sample \\u003cem\\u003et\\u003c/em\\u003e test to measure the data between two groups. The measure of statistical significance is set at the standard of\\u003cem\\u003e P\\u003c/em\\u003e\\u0026lt;0.05. In addition, we will use the covariance method to analyze significant demographic and clinical imbalances. We will also analyze differences between subgroups. All data will be collected electronically to guarantee security.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStudy organization and oversight\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe research team will administer the study. Research staff will also take charge of VR scene design and VR-assisted intervention. The study will be supervised by the hospital safety supervision committee, which will take charge of study design re-evaluation, procedure execution, medical ethics, participant safety, and data management.\\u003c/p\\u003e\\n\\u003cp\\u003eParticipant information will be protected; we use anonymity to ensure the rights of each participant. All participant data will be stored in a highly secured database to ensure safety.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eParticipant safety during intervention\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eVR related products have been gradually developed and have received high acceptance in recent years. To date, only 2 RCTS have reported adverse events of VR exergames in older adults, such as VR sickness (i.e., headaches, discomfort, dizziness, and fatigue)\\u003csup\\u003e[44]\\u003c/sup\\u003e. During the VR training process, subjects will be in safe surroundings with family and our research team. If a subject feels uncomfortable, they will be able to take a rest. All adverse events (i.e., falls, pains, headaches, dizziness, and fatigue) that occur during the procedure will be taken seriously and registered in order, to decide whether the event is related to the intervention. We will take the following measures to ensure research safety:\\u003c/p\\u003e\\n\\u003cp\\u003e1. During the 8-week training, each subject will receive a strict training plan every week. The training plan will be adjusted according to the specific situation of the subject;\\u003c/p\\u003e\\n\\u003cp\\u003e2. VR training will be taken in a safe environment. We will pay close attention to participant feedback during use of the VR intervention training;\\u003c/p\\u003e\\n\\u003cp\\u003e3. Subjects that withdraw from the study will receive full support.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eOthers\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe steering committee is composed of authors Xinyan Chen, and Guoen Cai. Committee members participated in the design study and provided suggestions for the experiment. The data security monitoring committee is independent of the host organization, including statistician and Prof. Qinyong Ye as the chairman. Supervision and management department can conduct audits to assess the clinical research behavior and compliance with the protocol, SOPs, GCP, and applicable regulatory requirements. \\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eProtocol amendment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe research team will discuss amendments to the protocol, first notifying the PI. The PI will have the copy of the modified agreement. Any behaviors that deviate from the agreement will be recorded with the reporting form.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this study, we will carry out an 8-week VR-assisted training for PD patients with mild to moderate depression, then evaluate the effect of training on the improvement of PD patients with mild to moderate depression through a 6-month follow-up. Since the traditional treatment of depression requires a lot of time and energy, and has limited resources, it is not suitable for PD patients in remote areas or with mobility difficulties. VR is able to make up for these problems with traditional treatment methods. This protocol aims to accumulate data for the effect of VR-assisted training on PD patients with depression, and explore the clinical application of VR.\\u003c/p\\u003e \\u003cp\\u003eOne difference between VR and traditional game therapy is that VR provides a fully immersive virtual real environment scene, which allows patients to have a feeling of immersion and the ability to interact with the scene in the virtual real space. It not only has the reward feedback and entertainment of traditional games, but also involves more physical and mental participation. The advantage of VR will make patients feel more relaxed, immersed, and interested in the VR exercise. Moreover, patients can choose from a variety of VR scenarios, depending on their individual environment requirements. Some studies show that depressed patients have poor participation in the intervention study and high withdrawal rate\\u003csup\\u003e[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]\\u003c/sup\\u003e. However, the multi-selectivity and immersive advantages of VR can increase active participation and participant stability and reduce the withdrawal rate.\\u003c/p\\u003e \\u003cp\\u003ePrevious studies have confirmed that VR is a suitable treatment method for psychological disorders such as anxiety and phobia, and that VR has a relaxing effect on depressed patients\\u003csup\\u003e[\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]\\u003c/sup\\u003e. Studies have confirmed the effectiveness of VR therapy compared to conventional treatment, and has no side effects for patients, including those who are resistant to conventional drug treatment\\u003csup\\u003e[\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]\\u003c/sup\\u003e. Interestingly, some studies have found that a small amount of VR training can achieve a similar therapeutic effect to continuous physical training, and that intermittent training is more effective than long-term continuous training\\u003csup\\u003e[\\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec26\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy status\\u003c/h2\\u003e \\u003cp\\u003eRecruitment will start on July 1, 2023 and will close on July 1, 2026.The entire study-phase and data analysis is expected to be completed within 24 to 36 months.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eDPD: Major depressive disorder; VR: Virtual reality; TAU: Treatment as usual; RCT: Randomized controlled trial; HAMD: Hamiltion depression scale; fMRI: Functional magnetic resonance imaging.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors thank all study participants.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors\\u0026rsquo; contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eXYC, GEC and YQZ were involved in the research conception and design. XYC, YQZ and QYY obtained ethics approval. XYC, XYC and GEC drafted the manuscript. XYC, QYY and XYC participated in the statistical analysis plan. All authors edited and revised the manuscript. All authors approved the final version of the manuscript.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study is supported by grants from the National Key Clinical Specialty Project (No.05029001). The funding agency only provides funding and does not participate in the experimental process.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eFor interested researchers, the data from the study can be provided on request. Please contact Dr.Cai.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study is being conducted in compliance of the Declaration of Helsinki. It was approved by the ethics committee of Fujian Medical University Union Hospital(ethics approval number: 2022YF053-01). Informed consent were obtained prior to the study. When necessary, the informed consent of the subject\\u0026rsquo;s family was obtained.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWritten informed consent for publication was obtained from all participants. All the authors approved the final manuscript and agreed to publish it .All participants agreed to publish images associated with them.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors state that they have no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor details\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003csup\\u003e1\\u0026nbsp;\\u003c/sup\\u003eDepartment of Neurology, Fujian Medical University Union Hospital, Institute of Clinical Neurology, Fujian Medical University, Fuzhou 350001, Fujian,China.\\u003csup\\u003e2\\u0026nbsp;\\u003c/sup\\u003eDepartment of Clinical Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eKwok JYY,Jackie C.Y,MSocSc,et al.Effects of mindfulness Yoga vs Stretching and resistance training exercises on anxiety and depression for people with Parkinson disease:a randomized clinical trial.JAMA Neurology.2019. doi:10.1001/jamaneurol.2019.0534\\u003c/li\\u003e\\n\\u003cli\\u003eYang Ni,Liu Weiguo, Ning Houxu,et al.Expert consensus on diagnosis and treatment of depression in Parkinson\\u0026rsquo;s desease with integrated traditional Chinese and Western medicine(2021 edition).Chin J Contemp Neurol Neurosurg.2021;21(12):1027-1035.\\u003c/li\\u003e\\n\\u003cli\\u003eWeintraub D,Mamikonyan E.The neuropsychiatry of Parkinson disease:a perfect storm.Am J Geriatr Psychiatry.2019;27:998-1018.\\u003c/li\\u003e\\n\\u003cli\\u003eRaskind MA.Diagnosis and treatment of depression comorbid with neurologic disorders.Am J Med,2008,121(11Suppl 2):28-37.doi:10.1016/j.amjmed.2008.09.011\\u003c/li\\u003e\\n\\u003cli\\u003eRavina B,Camicioli R,Como PG,et al.The impact of depressive symptoms in early Parkinson disease.Neurology,2007,69:342-347. doi:10.1212/01.wnl.0000268695.63392\\u003c/li\\u003e\\n\\u003cli\\u003ePablo.M,Susana A,Jose M,et al.Burden,perceived health status,and mood among caregivers of parkinson\\u0026rsquo;s diserse patients.Movement Disorders.2008;23(12):1673-1680.doi:10.1002/mds.22106\\u003c/li\\u003e\\n\\u003cli\\u003eKwok JYY,Auyeung M,Chan HYL.Examining factors related to health-related quality of life in people with Parkinson\\u0026rsquo;s disease.Rehabil Nurs.2018.doi:10.1097/rnj. 0000000000000179\\u003c/li\\u003e\\n\\u003cli\\u003eConnolly BS,Lang AE.Pharmacological treatment of Parkinson disease:a review.JAMA.2014;311(16):1670-1683. doi:10.1001/jama.2014.3654\\u003c/li\\u003e\\n\\u003cli\\u003eCorcos DM,Robichaud JA,David FJ,et al.A two-year randomized controlled trial of progressive resistance exercise for Parkinson\\u0026rsquo;s disease.Mov Disord.2013;28(9):1230-1240. doi:10.1002/mds.25380\\u003c/li\\u003e\\n\\u003cli\\u003eDimidjian S, Hollon SD, Dobson KS, Schmaling KB, Kohlenberg RJ, Addis ME,et al. Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the acute treatment of adults with major depression. J Consult Psychol. 2006;74(4):658\\u0026ndash;70. doi:10.1037/0022-006X.74.4.658\\u003c/li\\u003e\\n\\u003cli\\u003eFrank K,Marijke H.R,Artjan T.F.B,et al.Effort-D:results of a randomized controlled trial testing the effect of running therapy on depression.BMC Psychiatry.2019;19:170. doi:org/10.1186/s12888-019-2156-x\\u003c/li\\u003e\\n\\u003cli\\u003eChan CH,Ji XW,Chan JS,et al.Effects of the integrative mind-body intervention on depression,sleep disturbances and plasma IL-6.Psychother Psychosom.2017;86(1):54-56.doi:10.1159/000447541\\u003c/li\\u003e\\n\\u003cli\\u003eKwok JY,Choi KC,Chan HY.Effects of mind-body exercises on the physiological and psychosocial well-being of individuals with Parkinson\\u0026rsquo;s disease:a systematic review and meta-analysis.Complement Ther Med.2016:29:121-131.doi:10.1016/j.ctim.2016.09.016\\u003c/li\\u003e\\n\\u003cli\\u003eHiggins JPT,Altman DG,Gotzsche PC,et al.The Cochrane Collaboration\\u0026rsquo;s tool for assessing risk of bias in randomized trials.BMJ.2014;343(7829).doi:10.1186/2046-4053-3-37\\u003c/li\\u003e\\n\\u003cli\\u003eGrant S,Spears A,Pedersen ER,et al.Video Games as a potential modality for behavioral healthe services for young adult veterans:exploratory analysis.JMIR serious games.2018;6(3):e15. doi: 10.2196/games.9327\\u003c/li\\u003e\\n\\u003cli\\u003eKnox M,Lentin J,Cummings TS,et al.Game-based biofeedback for paediatric anxiety and depression.Ment Health Fam Med.2011;8(3):195.\\u003c/li\\u003e\\n\\u003cli\\u003eKuhn S,Berna F,Ludtke T,et al.Fighting depression:action video game play may reduce rumination and increase subjective and objective cognition in depressed patients.Front Psychol.2018;12(9):129.\\u003c/li\\u003e\\n\\u003cli\\u003eMarta R,Manon M,Braulio G.S,et al.Winning the game against depression:a systematic review of video games for the treatment of depressive disorders.Current Psychiatry Reports.2022;24:23-35.doi:10.1007/s11920-022-01314-7\\u003c/li\\u003e\\n\\u003cli\\u003eYing-Yu Chao,GNP-BC,Yvonne K.S,et al.Effects of using Nintendo Wii exergames in older adults:a review of the literature.Joural of aging and health.2015;27(3):379-402.doi:10.1177/0898264314551171\\u003c/li\\u003e\\n\\u003cli\\u003ePhilip P.Foster.Role of physical and mental training in brain network configuration.Frontiers in Aging Neuroscience.2015;7.doi:10.3389/fnagi.2015.00117\\u003c/li\\u003e\\n\\u003cli\\u003eAynur C.Arzu R.O,Ela T.Interactive video game-based approaches improve mobility and mood in older adults:a nonrandomized,controlled trial.Journal of Bodywork and Movement Therapies.2020;24:252-259.doi:10.1016/j.jbmt.2020.01.005\\u003c/li\\u003e\\n\\u003cli\\u003eKiran K,Shafaq A,Nasir S,et al.Role Wii Fit exer-games in improving balance confidence and quality of life in elder population.J Pak Med Assoc.2021.71(9):2130-2134.doi:10.47391/JPMA.319\\u003c/li\\u003e\\n\\u003cli\\u003eMoreira M,de Amorim Lima A,Ferraz.K,et al.Use of virtual reality in gait recovery among post stroke patients-a systematic literature review.Disabil Rehabil Assist Technol.2013;8(5):357-362. doi:10.3109/17483107.2012.749428\\u003c/li\\u003e\\n\\u003cli\\u003eD.Freeman,S.Reeve,A.Robinson,et al.Virtual reality in the assessment,understanding,and treatment of mental health disorders.Psychological Medicine.2017;47:2393-2400. doi:10.1017/S003329171700040X\\u003c/li\\u003e\\n\\u003cli\\u003eLiviu A.F,Carmen D.C,Pim C,et al.The effectiveness of virtual reality based interventions for symptoms of anxiety and depression:a meta analysis.Scientific Reports.2018;8:10323.doi:10.1038/s41598-018-28113-6\\u003c/li\\u003e\\n\\u003cli\\u003eZeng N,Pope Z,Lee J,Gao,Z. Virtual reality exercise for anxiety and depression:a preliminary review of current research in an emerging field.J Clin Med.2018,7:42.doi:10.3390/jcm7030042\\u003c/li\\u003e\\n\\u003cli\\u003eBisso, E.; Signorelli, M.S.; Milazzo, M.; Maglia, M.; Caponnetto, P. Immersive Virtual Reality Applications in Schizophrenia Spectrum Therapy: A Systematic Review. Int. J. Environ. Res. Public Health 2020, 17, 6111.doi:10.3390/ijerph17178111\\u003c/li\\u003e\\n\\u003cli\\u003eEgger J, Gall M, Wallner J, Boechat P, Hann A, Li X, Chen X, Schmalstieg DJP.HTC Vive MeVisLab integration via OpenVR for medical applications. PLoSOne. 2017;12(3):e0173972.\\u003c/li\\u003e\\n\\u003cli\\u003eNiehorster D, Li L, Lappe MJ-P. The accuracy and precision of position and orientation tracking in the HTC vive virtual reality system for scientific research. Iperception. 2017;8(3):2041669517708205.\\u003c/li\\u003e\\n\\u003cli\\u003ePostuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson\\u0026rsquo;s disease: MDS-PD Clinical Diagnostic Criteria. Mov Disord 2015;30(12):1591\\u0026ndash;601.\\u003c/li\\u003e\\n\\u003cli\\u003eHoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. 1967.Neurology 2001;57(10 Suppl 3):S11\\u0026ndash;26.\\u003c/li\\u003e\\n\\u003cli\\u003eSchrag A]Schrag A, Barone P, Brown RG, Leentjens AFG, McDonald WM, Starkstein S,et al. Depression rating scales in Parkinson\\u0026rsquo;s disease: Critique and recommendations. Mov Disord 2007;22(8):1077\\u0026ndash;92.\\u003c/li\\u003e\\n\\u003cli\\u003eHuihui Cai,Tao Lin,Lina Chen,et al.Evaluating the effect of immersive virtual reality technology on gait rehabilitation in stroke patients: a study protocol for a randomized controlled trial.BMC Open.2021;22:91\\u003c/li\\u003e\\n\\u003cli\\u003eRoseanne D.Dobkin,Sarah L.Mann,Michael A.G,et al. Telephone-based cognitive behavioral therapy for depression in Parkinson disease. Neruology.2020;94(16):e1764-1773.\\u003c/li\\u003e\\n\\u003cli\\u003eHamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967;6:278\\u0026ndash;296.\\u003c/li\\u003e\\n\\u003cli\\u003eBeusterien K.M,Steinwald B.,John E.Ware Jr.Usefulness of the SF-36 Health Survey in Measuring Health Outcomes in the Depressed Elderly.Journal of Geriatric Psychiatry and Neurology.1996;9:13-21.\\u003c/li\\u003e\\n\\u003cli\\u003eGądek-Michalska A, Tadeusz J, Rachwalska P, Bugajski J.Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems. Pharmacol Rep.2013; 65(6):1655\\u0026ndash;1662\\u003c/li\\u003e\\n\\u003cli\\u003eTsigos C, Chrousos GP.Physiology of the hypothalamic-pituitary-adrenal axis in health and dysregulation in psychiatric and autoimmune disorders. Endocrinol Metab Clin N Am.1994; 23:451\\u0026ndash;466.\\u003c/li\\u003e\\n\\u003cli\\u003eChrousos GP.Stress and disorders of the stress system. Nat Rev Endocrinol.2009; 5(7):374\\u0026ndash;381.\\u003c/li\\u003e\\n\\u003cli\\u003eZ.M.lgnacio,R.S.da Silva.M.E.Plissari,et al.al.Physical exercise and neuroinflammation in major depressive disorder.Molecular Neurobiology.2019;56:8323-8335.\\u003c/li\\u003e\\n\\u003cli\\u003eK.L.Szuhany,M.W.Otto.Assessing BDNF as a mediator of the effects of exercise on depression.Jonrnal of Psychiatric Research.2020;123:114-118.\\u003c/li\\u003e\\n\\u003cli\\u003eHafting, T., Fyhn, M., Molden, S., Moser, M. B., and Moser, E. I. (2005).Microstructure of a spatial map in the entorhinal cortex. Nature 436, 801\\u0026ndash;806.doi: 10.1038/nature03721\\u003c/li\\u003e\\n\\u003cli\\u003eAndre R.Brunoni,Leandro Valiengo,Alessandra Baccaro,et al.The Sertraline vs electrical current therapy for treating depression clinical study.JAMA Psychiatry.2013;70(4):383-391.\\u003c/li\\u003e\\n\\u003cli\\u003eChao YY, Scherer YK, Montgomery CA. Effects of using nintendo wii TM exergames in older adults: A review of the literature. J Aging Health 2015;27:379e402.\\u003c/li\\u003e\\n\\u003cli\\u003eLee H,Park Y.Park S.The effects of virtual reality training on function in chronic stroke patients:a systematic review and Meta-analysis. BioMed Research International.2019;2019:7595639.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003eTables 1 and 2 are available in the Supplementary Files section.\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Immersive virtual reality, Depression in Parkinson’s disease, psychological rehabilitation, Randomized controlled trials\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-3067437/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-3067437/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground: \\u003c/strong\\u003eDepression in Parkinson’s disease (DPD) has a high incidence rate in Parkinson's patients. It is common non-motor symptom of Parkinson's disease, which seriously affects patients’ quality of life. Thus, improving Parkinson's depression is important for improving patients’ quality of life. Psychotherapy for depression is limited for many reasons, and only a few patients are able to benefit. Many studies have proven that relaxation therapy, play, and exercise therapy are effective treatment for depression. VR has rapidly developed as a form of rehabilitation in recent years, due to its immersive characteristics and accessibility. Further, it has been applied to the psychological treatment of phobia and anxiety. However, there is no relevant research on the treatment of Parkinson's depression with VR, The aim of this study is to assess the effect of immersive VR-assisted training on DPD patients.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods:\\u003c/strong\\u003e The study design is a single-blind randomized controlled trial. Seventy-four DPD patients will be recruited and chosen as subjects, then randomly allocated into two groups. The VR group (n=37) will accept VR-assisted training (40min) 3 times/week for 8 weeks. The non-VR training group (n= 37) will receive treatment as usual (TAU). The outcome measures will be measured before intervention, at 8 weeks, at 3 months, and at 6 months post-intervention. The primary outcomes will include Hamilton Depression Scale-24 (HAM-D24). The secondary outcomes will include the short-form 36 item health survey questionnaire (SF-36), neuroinflammation factors (BDNF, IL-6, CRP), and functional magnetic resonance imaging (fMRI).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eDiscussion:\\u003c/strong\\u003e The traditional treatment of depression has limited resources and requires a lot of time and energy. It is not suitable for PD patients with mobility difficulties and in remote areas. VR is able to make up for limitations in traditional treatment methods. An advantage of VR is that it makes patients more invested in active participation. This study may provide an improved method for the clinical treatment of DPD patients, which is helpful for clinical decision-making and future practice.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTrial registration:\\u003c/strong\\u003e The study has been registered in the Chinese Clinical Trial Registry ChiCTR2200065843, 16 November 2022.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Assessing the impact of immersive virtual reality technology on the psychological recovery of patients with Parkinson’s disease depression: study protocol of a randomized controlled trial\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2023-07-06 14:30:04\",\"doi\":\"10.21203/rs.3.rs-3067437/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"b1e77e3d-5c39-466b-9cf2-b7a88f9fb629\",\"owner\":[],\"postedDate\":\"July 6th, 2023\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2023-07-06T14:30:06+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2023-07-06 14:30:04\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-3067437\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-3067437\",\"identity\":\"rs-3067437\",\"version\":[\"v1\"]},\"buildId\":\"WrCJVZZCHTDjtuVLN7oU0\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}