Identifying Factors Associated with Post-Traumatic brain injury Depression: The Role of Inflammatory Markers

Identifying Factors Associated with Post-Traumatic brain injury Depression: The Role of Inflammatory Markers | 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 Research Article Identifying Factors Associated with Post-Traumatic brain injury Depression: The Role of Inflammatory Markers Zhen Yang, 德龙 王, Yang Liu, Hongwang Yan, Yuanchi Cheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3859918/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Depression is a common emotional and psychiatric complication of traumatic brain injury (TBI) that has significant negative impacts on patient recovery. Despite the importance of identifying and treating depression in TBI patients, there is currently no simple and standardized system available for assessing the likelihood of post-TBI depression. In this study we are aim to explore the clinical value of peripheral blood inflammatory markers in predicting mental disorders after TBI. Methods A total of 67 TBI patients in this study were included and divided them into Group A (depression group) or Group B (non-depression group) based on the presence or absence of concomitant psychiatric disorders. We collected relevant clinical data and inflammatory markers from both groups to identify factors influencing post-TBI depression and analyzed their diagnostic efficacy and correlations. Results The overall prevalence of mental disorders among TBI patients was found to be 64.18% at the three-month follow-up after injury. Our study revealed that intracranial infection was an independent factor influencing the occurrence of post-TBI depression (OR = 19.873, 95%CI = 6.721 ~ 58.764, P = 0.001). Patients who developed post-TBI depression had significantly higher levels of white blood cells(WBCs), neutrophil percentage, C-reactive protein (CRP), and monocyte levels compared to non-depressed TBI patients. Additionally, WBCs (Pearson = 0.735,P = 0.001), neutrophil percentage (Pearson = 0.742, P = 0.001), and CRP (Pearson = 0.556, P = 0.001) levels were positively correlated with depression severity in TBI patients. Conclusions Our findings suggest a high prevalence of post-TBI depression and highlight peripheral inflammatory markers such as WBCs, neutrophil percentage, and CRP levels as potential early diagnostic indicators for this condition. Identifying these factors can facilitate early diagnosis and intervention for post-TBI depression, improving patient outcomes. This study provides evidence for clinicians to develop effective treatment strategies for post-TBI depression and advance our understanding of its mechanisms. Traumatic brain injury psychiatric disorders intracranial infection inflammatory markers early diagnosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Traumatic brain injury (TBI) is a significant public health issue worldwide and a leading cause of death, disability, and psychiatric disorders. There are nearly 42 million cases of TBI annually globally [1, 2]. Post-traumatic depression and anxiety disorders are the most common, persistent, and challenging psychiatric complications following TBI, with a high prevalence of approximately 60%[3, 4]. The emergence of neurological and psychiatric symptoms has a devastating impact on the long-term recovery of TBI, significantly affecting overall function [5]. This results in the utilization of substantial medical resources [6, 7], and severely damaging the quality of life of patients and their families [8–10]. It has broad social impacts on human health, productivity, and even criminal behavior[11]. The detailed mechanism of the high incidence of psychiatric disorders after TBI is not yet clear, and the main hypothesized mechanisms involve neuroendocrine disorders and abnormal activity in the hypothalamic-pituitary-adrenal axis (HPA)[12, 13]. Previous studies have reported that the occurrence of psychiatric disorders is usually accompanied by changes in immune function, activation of the inflammatory response system, and decreased levels of brain-derived neurotrophic factor (BDNF) [14–16], all of which are detrimental to TBI recovery. Chronic inflammation after TBI is a key factor in the development of neurological and depressive disorders [17, 18]. Neuroinflammation caused by TBI may directly affect the brain through chronic inflammatory signals or indirectly activate the neuroimmune system to overreact to subsequent internal balance challenges, thereby increasing the risk of neurological and psychiatric disorders[18, 19]. It is interesting to note that previous studies have primarily focused on the changes in inflammatory cytokine levels in patients with post-TBI mental disorders and the negative impact of mental disorders on TBI prognosis. However, there is a lack of research on preventing post-TBI mental disorders and the predictive significance of inflammatory markers for their occurrence. Various molecules in the brain can be transported through the blood-brain barrier to the peripheral circulation, including WBCs, CRP, neutrophil percentage, monocytes, and others, which can serve as markers of inflammation. Obtaining blood samples from patients is less invasive and causes less trauma, making the use of peripheral blood inflammatory markers as biomarkers for early diagnosis of mental disorders in TBI patients significant in improving patient outcomes. This study aims to explore the predictive value of inflammatory markers in blood for post-TBI mental disorders and provide insight into the early diagnosis of mental disorders after TBI. 2. Materials and Methods 2.1 Study Design Patients who were diagnosed with TBI and received treatment at the XX Hospital in Shanghai, China from October 2019 to September 2020. All participants provided informed consent. Of 327 patients, 67 were included in the study (Fig. 1 ). Inclusion criteria were as follows: aged 18 to 65 years who had been diagnosed with TBI, conscious and have stable medical conditions, not experienced any other significant stressful events within one year, at least a primary school education level and are able to understand the questionnaire. Exclusion criteria were as follows: Individuals with psychiatric disorders or developmental delay, severe infectious diseases, autoimmune diseases who are receiving immunosuppressive therapy, severe cardiovascular or pulmonary diseases, cancer, or other physical illnesses, personal or family history of psychiatric disorders. The study was reviewed and approved by the Ethics Committee Shanghai Fengxian Central Hospital (Date: 10.21.2019, No: 2019-KY-06) and conducted in accordance with the principles of the Declaration of Helsinki. 2.2 Data Collection and Assessment In this study, a convenient sampling method was employed to collect peripheral venous blood samples from patients upon admission. The collected blood samples were subjected to analysis for the detection of various parameters such as WBCs (3.5 ~ 9.5*10 9 /L), neutrophil granulocytes (1.8 ~ 6.3*10 9 /L), neutrophil granulocyte percentage (40%~75%), lymphocytes (1.1 ~ 3.2*10 9 /L), lymphocyte percentage (20%~50%), monocytes (00.1 ~ 0.6*10 9 /L), monocyte percentage (3%~10%), eosinophil granulocytes (0.02 ~ 0.52*10 9 /L), eosinophil granulocyte percentage (0.4%~8%), basophil granulocytes (0 ~ 0.06*10 9 /L), basophil granulocyte percentage (0%~1%), and CRP (0 ~ 10mg/L). Furthermore, data questionnaires and Hamilton Depression Scale (HAMD) surveys were conducted when the patients were in a conscious state after admission and also at the time of discharge. 2.3 Follow-up Following the patients' discharge, monthly data questionnaires and Hamilton Depression Scale (HAMD) surveys were conducted over a 3-month period. Patients showing no symptoms of depression after 3 months had their venous blood samples collected to detect the level of 5-hydroxytryptamine (5-HT). For those who developed depression during the follow-up period, venous blood samples were collected prior to treatment. Subsequently, based on the clinical symptoms of the patients, the results of scale tests, and the level of 5-HT, the psychiatrist evaluated whether the patients had coexisting depression and categorized them into two groups: the control group and the depression group. The relationship between the difference in inflammatory markers in the blood at the time of admission, including WBCs, neutrophil percentage, lymphocytes, monocytes, and CRP, and the degree of depression was compared between the two groups in order to identify potential biomarkers for early diagnosis of mental disorders following TBI. 2.4 Statistical Analysis In this study, statistical analyses were conducted using SPSS software version 21.0. Normally distributed data were presented as means ± standard deviations, while non-normally distributed data were expressed using medians and interquartile ranges. Group comparisons were performed using t-tests, Mann-Whitney U tests, or chi-square tests, as appropriate. Non-normally distributed data underwent logarithmic transformation prior to Pearson's correlation analysis to examine the relationship between inflammatory markers and mental disorders. Multiple stepwise linear regression analyses were conducted with inflammatory markers as independent variables to elucidate their association with mental disorders. The criterion for statistical significance was set at a P-value less than 0.05 (two-tailed). 3. Results 3.1 Follow Up Analysis: the incidence rate of mental disorders among TBI patients was found to be 64.18% at the three-month follow-up after injury. The study involved 327 patients diagnosed with TBI and treated at our Neurosurgery Department. After applying the inclusion criteria, we found that 171 patients met the requirements. However, a total of 62 patients were excluded from the study due to various reasons. Among these, three patients had psychiatric disorders, six suffered from severe infectious diseases, twelve received immunosuppressive therapy, 36 had severe cardiovascular (n = 3) or pulmonary diseases (n = 5), cancer(n = 2), or other physical illnesses (n = 26), and five had a family history of psychiatric disorders. Additionally, during the follow-up, a further 36 patients were excluded due to missing data. Finally, data from a total of 67 patients consisting of 41 men and 26 women were used for the final analysis. Among 67 patients, including 43 individuals in the depression group (28 males and 15 females) with ages ranging from 46 to 74 years (mean age, 62.65 ± 7.37 years). The depression group comprised 19 individuals with mild depression (HAMD score between 8 and 16), 17 with moderate depression (HAMD score between 17 and 23), and 7 with severe depression (HAMD score ≥ 24). The non-depression group consisted of 24 cases, with individuals aged between 35 and 85 years and no history of stroke. Their HAMD scores were ≤ 7. The results of the follow-up assessment revealed that the incidence rate of depression within three months of TBI was 64.18%, as presented in Table Ⅰ. Tab. Ⅰ Percentage of mental disorders 3 months after TBI Groups N Percentage Non-depression(HAMD ≤ 7 分) 24 35.82% Mild depression(8 ≤ HAMD ≤ 16) 19 28.36% Moderate depression(17 ≤ HAMD ≤ 23) 17 25.37% Severe depression (HAMD ≥ 24) 7 10.45% 3.2 Depression group had significantly lower levels of 5-HT compared to the non-depression group. The 5-HT hypothesis of depression is one of the commonly accepted hypotheses for the biochemical mechanisms of depression, which postulates a reduction in 5-HT levels in individuals with depression [ 20 ] . Our analysis demonstrated that the levels of 5-HT were significantly decreased in the depression group (HAMD score ≥ 8) compared to those in the non-depression group (P < 0.05). Both HAMD scores and 5-HT levels indicated the co-occurrence of depression among TBI patients, as shown in Fig. 2 . 3.3 Univariate analysis of mental disorders after TBI. The findings of the single factor analysis revealed a significant statistical difference in the occurrence rates of intracerebral hematoma and intracranial infection between patients with depression and those without depression. These results are presented in Table Ⅱ and suggest that depression may be associated with an increased risk of such complications. Table Ⅱ Univariate analysis of mental disorders after TBI (‾x ± s) Factors A (depression group) B (Non-depression group) t/ χ2 P Age 44.83 ± 10.28 44.99 ± 12.87 12.790 0.991 Time to hospital after TBI 1.60 ± 0.75 1.47 ± 0.67 1.262 0.209 Intracranial hematoma Yes 23 No 14 Yes 39 No 61 5.848 0.016* Posttraumatic coma Yes 18 No 19 Yes 44 No 56 0.236 0.67 Intracranial infection Yes 24 No 13 Yes 10 No 90 43.571 0.001*** * P ＜0.05, *** P = 0.001 3.4 Multifactor analysis of psychiatric disorders after TBI. The results of the multifactor logistic regression analysis revealed that intracranial infection was an independent factor significantly influencing the occurrence of psychiatric disorders after TBI. These findings, which are presented in Table Ⅲ, suggest that preventing and treating intracranial infections may be crucial in reducing the risk of psychiatric complications following TBI. Table Ⅲ Multivariate analysis of mental disorders after TBI Factors Regression coefficient Wald OR P 95%CI Intracranial infection -2.917 29.207 19.873 0.001*** 6.721 ~ 58.764 Intracranial hematoma -0.672 1.584 2.108 0.208 0.660 ~ 6.734 Posttraumatic coma -0.826 1.981 0.438 0.175 0.133 ~ 1.445 Time to hospital after TBI -0.605 2.924 0.546 0.087 0.273 ~ 1.092 *** P = 0.001 3.5 Elevated Inflammatory Markers in the Depression Group Compared to the Non-Depression Group The present study investigated the potential differences in peripheral inflammatory markers between depressive and non-depressive patients prior to the onset of depression. Our findings revealed that WBCs, neutrophil percentage, monocytes, and CRP were significantly increased in the depression group (P < 0.05), as demonstrated in Fig. 3 . However, there were no significant differences observed in neutrophils, lymphocytes, lymphocyte percentage, monocyte percentage, eosinophils, eosinophil percentage, basophils, or basophil percentage between the two groups. These results suggest that alterations in peripheral immune function may play a role in the pathogenesis of depression. Further research is necessary to better understand the underlying mechanisms and clinical implications of these findings for the diagnosis and treatment of depression. 3.6 Positive Correlation between Depression Severity and WBC Levels in Patients with TBI This study examined the potential association between depression severity and WBC counts in patients with TBI. Previous research has indicated that infection, trauma, and emotional stress can lead to an increase in peripheral WBC counts, and studies have also found that WBC levels are elevated in individuals with depression [21]. To explore the correlation between depression severity and inflammatory markers in TBI patients, we recruited a sample of 67 TBI patients from our hospital and conducted a Pearson analysis on the relationship between inflammatory markers at admission and psychiatric disorders. Our results demonstrated a positive correlation between depression severity and WBC levels in TBI patients, as illustrated in Fig. 4 . These findings suggest that inflammation may play a role in the development of depression following TBI, and highlight the importance of monitoring inflammatory markers in clinical assessments of TBI patients. Further research is needed to elucidate the mechanisms underlying this relationship and to evaluate the potential implications for the diagnosis and treatment of depression in TBI patients. 3.7 Positive Correlation between Depression Severity and Neutrophil Percentage, but Not Monocyte Levels, in Patients with TBI Our previous research found that the percentage of neutrophils and monocytes were significantly higher in the depression group than in the non-depression group after TBI. Additionally, we observed a positive correlation between depression severity and WBC levels in TBI patients. To further explore this correlation, we conducted a Pearson analysis to investigate the relationship between depression severity and neutrophil and monocyte levels in a sample of TBI patients. Our results showed a significant positive correlation between depression severity and neutrophil percentage (Pearson = 0.742**, P = 0.001), as depicted in Fig. 5 . However, we did not observe a significant correlation between depression severity and monocyte levels (Pearson = 0.268, P = 0.001). These findings suggest that changes in peripheral immune function, specifically increases in neutrophil counts, may be involved in the pathogenesis of depression following TBI. Further investigation is necessary to better understand the underlying mechanisms of this relationship and its clinical implications for the diagnosis and treatment of depression in TBI patients. 3.8 Positive Correlation between Depression Severity and CRP Levels in TBI Patients This study aimed to investigate the potential relationship between depression severity and CRP levels in patients with TBI. Previous research has found that ischemia and hypoxia following craniocerebral injury can cause the massive release of inflammatory cytokines and promote the synthesis of CRP in the liver. In addition, previous studies have also reported significant increases in CRP levels in depressed patients after TBI. [ 22 ] 。To examine the correlation between depression severity and CRP levels in TBI patients, we conducted a Pearson analysis on a sample of TBI patients. Our results revealed a positive correlation between depression severity and CRP levels in TBI patients (Pearson = 0.556*, P = 0.001), as illustrated in Fig. 6 . These findings suggest that inflammation may play a role in the development of depression following TBI, and highlight the importance of monitoring CRP levels in clinical assessments of TBI patients. Further research is necessary to elucidate the mechanisms underlying this relationship and to evaluate the potential implications for the diagnosis and treatment of depression in TBI patients. 4. Discussion This study aimed to investigate the factors influencing the occurrence of mental disorders after TBI, focusing on the potential role of peripheral inflammation. Our findings revealed that intracranial infection was a significant independent factor affecting the development of mental disorders after TBI. We also found a strong association between mental disorders after TBI and increased levels of WBCs, neutrophil percentage, CRP, and monocyte levels in patients' peripheral blood. Furthermore, we found that WBC count, neutrophil percentage, and CRP levels were positively correlated with the severity of depression in TBI patients. These results suggest that peripheral inflammatory markers may serve as potential indicators for early identification of mental disorders after TBI. The relationship between peripheral inflammation and mental disorders is not yet fully understood. However, our findings provide valuable insights into its possible underlying mechanisms. Future studies should aim to elucidate the neuroendocrine regulation and hypothalamic-pituitary adrenal axis activity involved in this relationship. Early diagnosis and intervention are crucial for managing mental disorders after TBI, given their significant impact on patient quality of life and prognosis. Our study suggests that monitoring peripheral inflammatory markers could aid early diagnosis and treatment of mental disorders after TBI. This approach has the potential to reduce the incidence of mental disorders and improve the long-term outcomes of TBI patients. In conclusion, our study highlights the importance of screening for intracranial infection and monitoring peripheral inflammatory markers in clinical assessments of TBI patients. The use of peripheral inflammatory markers as potential indicators for mental disorders after TBI warrants further investigation. Ultimately, our findings contribute to the growing body of evidence supporting the critical role of peripheral inflammation in the pathophysiology of mental disorders after TBI. Mental disorders, particularly depression, are prevalent complications that occur after TBI and significantly impact patient outcomes. [ 23 ] 。In fact, depression is one of the most common complications resulting from TBI [ 24 – 26 ] 。Studies show that within a year of experiencing TBI, 30–70% of patients will develop depression [ 27 , 28 ] , with post-traumatic depression prevalence being 7.9 times higher than in the general population [ 29 ] 。Our retrospective analysis of TBI patients admitted to the Neurosurgery Department of XX Hospital in Shanghai from January 2016 to December 2018 revealed that during hospitalization (within 15–30 days), the incidence of depression was about 5%. Furthermore, our follow-up study involving 67 TBI patients recruited between October 2019 and September 2020 found a high occurrence of depression, up to 64.18%, within three months of TBI. Depression following TBI requires long-term rehabilitation and can worsen patient prognosis, increase medical burdens, and profoundly affect families [ 30 ] .Therefore, early diagnosis and intervention for mental disorders in TBI patients are critical. Timely and effective interventions can prevent the development of psychological disorders and promote the patient's early return to society. The underlying mechanisms of mental disorders after TBI are complex, but current hypotheses suggest disruptions in neuroendocrine regulation, abnormalities in hypothalamic-pituitary-adrenal (HPA) axis activity, and dysfunctions in central nervous system (CNS) neurotransmission [ 12 , 13 ] 。The HPA axis is a major pathway involved in the development of psychiatric symptoms [ 31 – 34 ] , with abnormal activation and changes in cortisol levels being important characteristics of patients with mental disorders [ 35 – 37 ] 。Dysfunction in CNS 5-HT neurotransmission has been implicated in emotional disorders [ 38 , 39 ] , with anxiety and depression patients presenting significantly reduced 5-HT levels. Meanwhile, cortisol, adrenaline, and noradrenaline levels are also decreased [ 40 , 41 ] 。 Dopamine neurons are also closely related to mental disorders after TBI, as they are easily damaged, leading to decreased dopamine function and levels in patients with mental disorders [ 42 ] 。Our study found that out of 67 patients, 43 had varying degrees of depression, and depressed patients had significantly lower 5-HT levels than non-depressed patients. Mental disorders following TBI are often accompanied by changes in immune function and activation of the inflammatory response system [ 12 , 13 ] 。However, the causality between inflammation and depression remains controversial [ 43 ] 。Importantly, both may mutually promote each other. Inflammation may promote the onset of depression [ 44 , 45 ] , and depression can exacerbate inflammation [ 46 ] 。Patients with depression often present abnormal expression of inflammatory cytokines, hindering recovery from TBI and prolonging treatment. Depression may increase susceptibility to diseases through distorted immune responses, as patients often have elevated levels of pro-inflammatory cytokines such as IL-1, IL-2, IL-6, and TNF-α in peripheral blood [ 47 ] 。Peripheral blood leukocytes, CRP, neutrophil percentage, monocytes, among others, are indicators of inflammatory reactions. During immune responses, CRP is produced by the liver stimulated by IL-6 and TNF, serving as a sensitive indicator of systemic inflammation [ 22 ] 。Meanwhile, peripheral blood leukocytes increase in response to infection, trauma, and emotional stress.Our study examined factors that may affect the incidence of depression before admission and found that intracranial infection is an independent risk factor for depression after TBI. Comparing all inflammatory markers in depressed patients before depression onset with those of non-depressed patients, we found that WBC count and CRP levels were significantly higher in the depression group. This suggests that the occurrence of depression after TBI may be associated with increased inflammatory markers. In conclusion, the relationship between inflammation and mental disorders after TBI remains unclear, but our findings suggest mutual promotion. Elevated inflammatory markers, such as peripheral blood leukocytes and CRP levels, may serve as potential indicators for diagnosing depression in TBI patients. Further research is needed to elucidate the underlying mechanisms and identify effective interventions that target inflammatory responses in TBI patients with mental disorders. Peripheral blood leukocytes, including neutrophils, eosinophils, basophils, lymphocytes, and monocytes, form the first line of defense mechanisms against inflammatory reactions. In this study, we found that the percentage of neutrophils and monocytes was significantly higher in the depression group among TBI patients, suggesting their potential correlation with depression after TBI. Previous research has also suggested that TBI patients with poor prognosis have higher levels of neutrophils and monocytes [ 48 ] . Moreover, Person's analysis revealed a positive correlation between the degree of depression and WBC count, neutrophil percentage, and CRP level in the recruited TBI patients. This highlights the importance of monitoring changes in peripheral blood leukocyte subsets, particularly neutrophils and monocytes, to aid in early diagnosis of mental disorders in TBI patients. In conclusion, changes in peripheral blood leukocyte subsets, particularly neutrophils and monocytes, may serve as correlates of depression following TBI. Monitoring inflammatory markers such as WBC count, neutrophil percentage, and CRP level may provide insights into the prognosis of TBI patients, including their propensity for psychiatric complications. Further studies are warranted to elucidate the underlying mechanisms and identify effective interventions targeting inflammatory responses in TBI patients with mental disorders. 5. Conclusions In summary, we found that intracranial infection was a significant independent factor affecting the development of mental disorders after TBI. Additionally, we found a strong association between mental disorders after TBI and increased levels of peripheral inflammatory markers. Notably, we also observed a positive correlation between the severity of depression in TBI patients and WBC count, neutrophil percentage, and CRP levels. These findings suggest that monitoring peripheral inflammatory markers could aid in early identification and intervention for mental disorders after TBI. Therefore, screening for intracranial infections and monitoring peripheral inflammatory markers should be included in the clinical assessment of TBI patients. Overall, our study contributes to the growing body of evidence supporting the critical role of peripheral inflammation in the pathophysiology of mental disorders after TBI. Further research is warranted to develop effective interventions targeting inflammatory responses in TBI patients with mental disorders. Declarations Data Sharing Statement The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Author Contributions Study conception and design: CYC, ZY. Data collection:CYC. Analysis and interpretation of results: HWY. Draft manuscript preparation: ZY. Critical revision of the article: CYC. All authors (ZY, HWY, CYC) reviewed the results and approved the final version of the manuscript. Ethics Approval and Consent to Participate The study was reviewed and approved by the Ethics Committee Shanghai XX Hospital and conducted in accordance with the principles of the Declaration of Helsinki. 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Cumulative depression episodes predict later C-reactive protein levels: a prospective analysis. Biol Psychiatry. 2012;71(1):15–21. Cheng Y, Desse S, Martinez A, Worthen RJ, Jope RS, Beurel E. TNFalpha disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice. Brain Behav Immun. 2018;69:556–67. Saber M, Rice AD, Christie I, Roberts RG, Knox KS, Nakaji P, et al. Remote Ischemic Conditioning Reduced Acute Lung Injury After Traumatic Brain Injury in The Mouse. Shock; 2020. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 27 Apr, 2024 Editor assigned by journal 22 Jan, 2024 Submission checks completed at journal 18 Jan, 2024 First submitted to journal 13 Jan, 2024 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-3859918","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":267789868,"identity":"1094de7b-5a37-4994-953e-6b256f30e445","order_by":0,"name":"Zhen Yang","email":"","orcid":"","institution":"Shanghai University of Medicine43 \u0026 Health Science Affiliated Sixth People’s Hospital South Campus","correspondingAuthor":false,"prefix":"","firstName":"Zhen","middleName":"","lastName":"Yang","suffix":""},{"id":267789869,"identity":"d6e73b2f-70fa-43f5-bec8-e90939937a03","order_by":1,"name":"德龙 王","email":"","orcid":"","institution":"Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China","correspondingAuthor":false,"prefix":"","firstName":"德龙","middleName":"","lastName":"王","suffix":""},{"id":267789870,"identity":"78af0f37-ccfb-4d08-9f4d-13c9851481be","order_by":2,"name":"Yang Liu","email":"","orcid":"","institution":"Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Liu","suffix":""},{"id":267789871,"identity":"fc16da09-f9ea-46be-ab2a-dfafd19c0acf","order_by":3,"name":"Hongwang Yan","email":"","orcid":"","institution":"The first people’s hospital of Wenling, Department of Cardiothoracic Surgery, Wenling, 317500, Zhejiang Province, China","correspondingAuthor":false,"prefix":"","firstName":"Hongwang","middleName":"","lastName":"Yan","suffix":""},{"id":267789872,"identity":"cc0d71cd-639a-478e-8e13-4e58a8e0d54d","order_by":4,"name":"Yuanchi Cheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIie3RsWrDMBCA4RMu8nLUq4KHvsKBwGQweRYbg7p46NS1KgJ3CXRVyUtk6qxE1M+QwUsoeE43Dx3qvcV2twz65vsRugMIgmsk2MtQDPlTExvnLpRvliRafG0Ve8W2PNsHVS1IAFaWH9mbraXEy5HpuSLZGS0RXUSuztKcXASx/9hPPtIddIXrjpNrH9OaultApU5TCYlSe8Qe6WDex6SPQGA2lzwb5F6Qhyxdkx+3MZ8YZrmnVXMjJSxJxKlsYFxykSAvz1tSFZ/7S2LvexhPWfC7T+eG73yTxL6dTH7j/xsPgiAI/vIDGjhO8vkPnK4AAAAASUVORK5CYII=","orcid":"","institution":"Southern Medical University Affiliated Fengxian Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yuanchi","middleName":"","lastName":"Cheng","suffix":""}],"badges":[],"createdAt":"2024-01-13 11:14:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3859918/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3859918/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49975930,"identity":"eb735622-5180-474a-afef-f882f5788493","added_by":"auto","created_at":"2024-01-22 14:48:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":33891,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3859918/v1/b651d432a33bdae5a7ab3cec.png"},{"id":49975933,"identity":"2c54a5a2-8c81-4586-8942-f3bc49697eaf","added_by":"auto","created_at":"2024-01-22 14:48:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5720,"visible":true,"origin":"","legend":"\u003cp\u003eBlood levels of 5-HT in the depressed and non-depressed groups\u003c/p\u003e","description":"","filename":"Onlinefloatimage210.png","url":"https://assets-eu.researchsquare.com/files/rs-3859918/v1/e75fe2dc14e78832a4d58346.png"},{"id":49975929,"identity":"03ea03e3-4e33-4fd8-a3e6-11593f6768bd","added_by":"auto","created_at":"2024-01-22 14:48:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":16123,"visible":true,"origin":"","legend":"\u003cp\u003eBlood levels of inflammatory factors in the depressed and non-depressed groups\u003c/p\u003e","description":"","filename":"Onlinefloatimage310.png","url":"https://assets-eu.researchsquare.com/files/rs-3859918/v1/e489dd3f6c999e523877dbdd.png"},{"id":49975932,"identity":"1d570ce6-b127-4419-b7d6-94ea03954a8e","added_by":"auto","created_at":"2024-01-22 14:48:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":7995,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation analysis of depression degree and leucocyte level in patients with TBI\u003c/p\u003e","description":"","filename":"Onlinefloatimage411.png","url":"https://assets-eu.researchsquare.com/files/rs-3859918/v1/016a783cdc82f073c691eb59.png"},{"id":49975931,"identity":"564dd941-0fc8-44e3-9d97-49c977876c5d","added_by":"auto","created_at":"2024-01-22 14:48:43","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":16371,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation analysis of depression degree with neutrophil percentage and monocyte level in patients with TBI\u003c/p\u003e","description":"","filename":"Onlinefloatimage511.png","url":"https://assets-eu.researchsquare.com/files/rs-3859918/v1/168db87164469b1fefb49e06.png"},{"id":49977858,"identity":"4aef388a-b1fb-4455-9acf-48c6002ed4eb","added_by":"auto","created_at":"2024-01-22 14:56:43","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":7732,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation analysis of depression degree and CRP level in patients with TBI\u003c/p\u003e","description":"","filename":"Onlinefloatimage65.png","url":"https://assets-eu.researchsquare.com/files/rs-3859918/v1/d43aaaa36fe140efda8f6e8d.png"},{"id":49978471,"identity":"0c8587f9-85d6-4a7f-941c-2c7fb82289a8","added_by":"auto","created_at":"2024-01-22 15:04:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":660953,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3859918/v1/56449658-ddba-4b9e-bbc6-b7e03b738284.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Identifying Factors Associated with Post-Traumatic brain injury Depression: The Role of Inflammatory Markers","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eTraumatic brain injury (TBI) is a significant public health issue worldwide and a leading cause of death, disability, and psychiatric disorders. There are nearly 42\u0026nbsp;million cases of TBI annually globally [1, 2]. Post-traumatic depression and anxiety disorders are the most common, persistent, and challenging psychiatric complications following TBI, with a high prevalence of approximately 60%[3, 4]. The emergence of neurological and psychiatric symptoms has a devastating impact on the long-term recovery of TBI, significantly affecting overall function [5]. This results in the utilization of substantial medical resources [6, 7], and severely damaging the quality of life of patients and their families [8\u0026ndash;10]. It has broad social impacts on human health, productivity, and even criminal behavior[11].\u003c/p\u003e \u003cp\u003eThe detailed mechanism of the high incidence of psychiatric disorders after TBI is not yet clear, and the main hypothesized mechanisms involve neuroendocrine disorders and abnormal activity in the hypothalamic-pituitary-adrenal axis (HPA)[12, 13]. Previous studies have reported that the occurrence of psychiatric disorders is usually accompanied by changes in immune function, activation of the inflammatory response system, and decreased levels of brain-derived neurotrophic factor (BDNF) [14\u0026ndash;16], all of which are detrimental to TBI recovery. Chronic inflammation after TBI is a key factor in the development of neurological and depressive disorders [17, 18]. Neuroinflammation caused by TBI may directly affect the brain through chronic inflammatory signals or indirectly activate the neuroimmune system to overreact to subsequent internal balance challenges, thereby increasing the risk of neurological and psychiatric disorders[18, 19].\u003c/p\u003e \u003cp\u003eIt is interesting to note that previous studies have primarily focused on the changes in inflammatory cytokine levels in patients with post-TBI mental disorders and the negative impact of mental disorders on TBI prognosis. However, there is a lack of research on preventing post-TBI mental disorders and the predictive significance of inflammatory markers for their occurrence. Various molecules in the brain can be transported through the blood-brain barrier to the peripheral circulation, including WBCs, CRP, neutrophil percentage, monocytes, and others, which can serve as markers of inflammation. Obtaining blood samples from patients is less invasive and causes less trauma, making the use of peripheral blood inflammatory markers as biomarkers for early diagnosis of mental disorders in TBI patients significant in improving patient outcomes. This study aims to explore the predictive value of inflammatory markers in blood for post-TBI mental disorders and provide insight into the early diagnosis of mental disorders after TBI.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study Design\u003c/h2\u003e \u003cp\u003ePatients who were diagnosed with TBI and received treatment at the XX Hospital in Shanghai, China from October 2019 to September 2020. All participants provided informed consent. Of 327 patients, 67 were included in the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInclusion criteria were as follows: aged 18 to 65 years who had been diagnosed with TBI, conscious and have stable medical conditions, not experienced any other significant stressful events within one year, at least a primary school education level and are able to understand the questionnaire.\u003c/p\u003e \u003cp\u003eExclusion criteria were as follows: Individuals with psychiatric disorders or developmental delay, severe infectious diseases, autoimmune diseases who are receiving immunosuppressive therapy, severe cardiovascular or pulmonary diseases, cancer, or other physical illnesses, personal or family history of psychiatric disorders.\u003c/p\u003e \u003cp\u003e The study was reviewed and approved by the Ethics Committee Shanghai Fengxian Central Hospital (Date: 10.21.2019, No: 2019-KY-06) and conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data Collection and Assessment\u003c/h2\u003e \u003cp\u003eIn this study, a convenient sampling method was employed to collect peripheral venous blood samples from patients upon admission. The collected blood samples were subjected to analysis for the detection of various parameters such as WBCs (3.5\u0026thinsp;~\u0026thinsp;9.5*10\u003csup\u003e9\u003c/sup\u003e/L), neutrophil granulocytes (1.8\u0026thinsp;~\u0026thinsp;6.3*10\u003csup\u003e9\u003c/sup\u003e/L), neutrophil granulocyte percentage (40%~75%), lymphocytes (1.1\u0026thinsp;~\u0026thinsp;3.2*10\u003csup\u003e9\u003c/sup\u003e/L), lymphocyte percentage (20%~50%), monocytes (00.1\u0026thinsp;~\u0026thinsp;0.6*10\u003csup\u003e9\u003c/sup\u003e/L), monocyte percentage (3%~10%), eosinophil granulocytes (0.02\u0026thinsp;~\u0026thinsp;0.52*10\u003csup\u003e9\u003c/sup\u003e/L), eosinophil granulocyte percentage (0.4%~8%), basophil granulocytes (0\u0026thinsp;~\u0026thinsp;0.06*10\u003csup\u003e9\u003c/sup\u003e/L), basophil granulocyte percentage (0%~1%), and CRP (0\u0026thinsp;~\u0026thinsp;10mg/L). Furthermore, data questionnaires and Hamilton Depression Scale (HAMD) surveys were conducted when the patients were in a conscious state after admission and also at the time of discharge.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Follow-up\u003c/h2\u003e \u003cp\u003eFollowing the patients' discharge, monthly data questionnaires and Hamilton Depression Scale (HAMD) surveys were conducted over a 3-month period. Patients showing no symptoms of depression after 3 months had their venous blood samples collected to detect the level of 5-hydroxytryptamine (5-HT). For those who developed depression during the follow-up period, venous blood samples were collected prior to treatment. Subsequently, based on the clinical symptoms of the patients, the results of scale tests, and the level of 5-HT, the psychiatrist evaluated whether the patients had coexisting depression and categorized them into two groups: the control group and the depression group. The relationship between the difference in inflammatory markers in the blood at the time of admission, including WBCs, neutrophil percentage, lymphocytes, monocytes, and CRP, and the degree of depression was compared between the two groups in order to identify potential biomarkers for early diagnosis of mental disorders following TBI.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e \u003cp\u003eIn this study, statistical analyses were conducted using SPSS software version 21.0. Normally distributed data were presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations, while non-normally distributed data were expressed using medians and interquartile ranges. Group comparisons were performed using t-tests, Mann-Whitney U tests, or chi-square tests, as appropriate. Non-normally distributed data underwent logarithmic transformation prior to Pearson's correlation analysis to examine the relationship between inflammatory markers and mental disorders. Multiple stepwise linear regression analyses were conducted with inflammatory markers as independent variables to elucidate their association with mental disorders. The criterion for statistical significance was set at a P-value less than 0.05 (two-tailed).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003ch2\u003e3.1 Follow Up Analysis: the incidence rate of mental disorders among TBI patients was found to be 64.18% at the three-month follow-up after injury.\u003c/h2\u003e \u003cp\u003eThe study involved 327 patients diagnosed with TBI and treated at our Neurosurgery Department. After applying the inclusion criteria, we found that 171 patients met the requirements. However, a total of 62 patients were excluded from the study due to various reasons. Among these, three patients had psychiatric disorders, six suffered from severe infectious diseases, twelve received immunosuppressive therapy, 36 had severe cardiovascular (n\u0026thinsp;=\u0026thinsp;3) or pulmonary diseases (n\u0026thinsp;=\u0026thinsp;5), cancer(n\u0026thinsp;=\u0026thinsp;2), or other physical illnesses (n\u0026thinsp;=\u0026thinsp;26), and five had a family history of psychiatric disorders. Additionally, during the follow-up, a further 36 patients were excluded due to missing data. Finally, data from a total of 67 patients consisting of 41 men and 26 women were used for the final analysis.\u003c/p\u003e \u003cp\u003eAmong 67 patients, including 43 individuals in the depression group (28 males and 15 females) with ages ranging from 46 to 74 years (mean age, 62.65\u0026thinsp;\u0026plusmn;\u0026thinsp;7.37 years). The depression group comprised 19 individuals with mild depression (HAMD score between 8 and 16), 17 with moderate depression (HAMD score between 17 and 23), and 7 with severe depression (HAMD score\u0026thinsp;\u0026ge;\u0026thinsp;24). The non-depression group consisted of 24 cases, with individuals aged between 35 and 85 years and no history of stroke. Their HAMD scores were \u0026le;\u0026thinsp;7. The results of the follow-up assessment revealed that the incidence rate of depression within three months of TBI was 64.18%, as presented in Table Ⅰ.\u003c/p\u003e \u003cp\u003eTab. Ⅰ Percentage of mental disorders 3 months after TBI\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePercentage\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-depression(HAMD\u0026thinsp;\u0026le;\u0026thinsp;7 分)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35.82%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild depression(8\u0026thinsp;\u0026le;\u0026thinsp;HAMD\u0026thinsp;\u0026le;\u0026thinsp;16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28.36%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate depression(17\u0026thinsp;\u0026le;\u0026thinsp;HAMD\u0026thinsp;\u0026le;\u0026thinsp;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25.37%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere depression (HAMD\u0026thinsp;\u0026ge;\u0026thinsp;24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.45%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Depression group had significantly lower levels of 5-HT compared to the non-depression group.\u003c/h2\u003e \u003cp\u003eThe 5-HT hypothesis of depression is one of the commonly accepted hypotheses for the biochemical mechanisms of depression, which postulates a reduction in 5-HT levels in individuals with depression\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Our analysis demonstrated that the levels of 5-HT were significantly decreased in the depression group (HAMD score\u0026thinsp;\u0026ge;\u0026thinsp;8) compared to those in the non-depression group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Both HAMD scores and 5-HT levels indicated the co-occurrence of depression among TBI patients, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Univariate analysis of mental disorders after TBI.\u003c/h2\u003e \u003cp\u003eThe findings of the single factor analysis revealed a significant statistical difference in the occurrence rates of intracerebral hematoma and intracranial infection between patients with depression and those without depression. These results are presented in Table Ⅱ and suggest that depression may be associated with an increased risk of such complications.\u003c/p\u003e \u003cp\u003eTable Ⅱ Univariate analysis of mental disorders after TBI (\u0026oline;x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA\u003c/p\u003e \u003cp\u003e(depression group)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eB\u003c/p\u003e \u003cp\u003e(Non-depression group)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003et/ χ2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.83\u0026thinsp;\u0026plusmn;\u0026thinsp;10.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.99\u0026thinsp;\u0026plusmn;\u0026thinsp;12.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.790\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.991\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to hospital after TBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.262\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.209\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntracranial hematoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes 23\u003c/p\u003e \u003cp\u003eNo 14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes 39\u003c/p\u003e \u003cp\u003eNo 61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.848\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.016*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePosttraumatic coma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes 18\u003c/p\u003e \u003cp\u003eNo 19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes 44\u003c/p\u003e \u003cp\u003eNo 56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntracranial infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes 24\u003c/p\u003e \u003cp\u003eNo 13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes 10\u003c/p\u003e \u003cp\u003eNo 90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43.571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*\u003cem\u003eP\u003c/em\u003e＜0.05, ***\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.001\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Multifactor analysis of psychiatric disorders after TBI.\u003c/h2\u003e \u003cp\u003eThe results of the multifactor logistic regression analysis revealed that intracranial infection was an independent factor significantly influencing the occurrence of psychiatric disorders after TBI. These findings, which are presented in Table Ⅲ, suggest that preventing and treating intracranial infections may be crucial in reducing the risk of psychiatric complications following TBI.\u003c/p\u003e \u003cp\u003eTable Ⅲ Multivariate analysis of mental disorders after TBI\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRegression coefficient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eWald\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003e95%CI\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntracranial infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-2.917\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29.207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.873\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.721\u0026thinsp;~\u0026thinsp;58.764\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntracranial hematoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.672\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.584\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.660\u0026thinsp;~\u0026thinsp;6.734\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePosttraumatic coma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.826\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.981\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.133\u0026thinsp;~\u0026thinsp;1.445\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to hospital after TBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.605\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.924\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.546\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.273\u0026thinsp;~\u0026thinsp;1.092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e***\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.001\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Elevated Inflammatory Markers in the Depression Group Compared to the Non-Depression Group\u003c/h2\u003e \u003cp\u003eThe present study investigated the potential differences in peripheral inflammatory markers between depressive and non-depressive patients prior to the onset of depression. Our findings revealed that WBCs, neutrophil percentage, monocytes, and CRP were significantly increased in the depression group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), as demonstrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. However, there were no significant differences observed in neutrophils, lymphocytes, lymphocyte percentage, monocyte percentage, eosinophils, eosinophil percentage, basophils, or basophil percentage between the two groups. These results suggest that alterations in peripheral immune function may play a role in the pathogenesis of depression. Further research is necessary to better understand the underlying mechanisms and clinical implications of these findings for the diagnosis and treatment of depression.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Positive Correlation between Depression Severity and WBC Levels in Patients with TBI\u003c/h2\u003e \u003cp\u003eThis study examined the potential association between depression severity and WBC counts in patients with TBI. Previous research has indicated that infection, trauma, and emotional stress can lead to an increase in peripheral WBC counts, and studies have also found that WBC levels are elevated in individuals with depression [21]. To explore the correlation between depression severity and inflammatory markers in TBI patients, we recruited a sample of 67 TBI patients from our hospital and conducted a Pearson analysis on the relationship between inflammatory markers at admission and psychiatric disorders. Our results demonstrated a positive correlation between depression severity and WBC levels in TBI patients, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. These findings suggest that inflammation may play a role in the development of depression following TBI, and highlight the importance of monitoring inflammatory markers in clinical assessments of TBI patients. Further research is needed to elucidate the mechanisms underlying this relationship and to evaluate the potential implications for the diagnosis and treatment of depression in TBI patients.\u003c/p\u003e \u003ch2\u003e3.7 Positive Correlation between Depression Severity and Neutrophil Percentage, but Not Monocyte Levels, in Patients with TBI\u003c/h2\u003e \u003cp\u003eOur previous research found that the percentage of neutrophils and monocytes were significantly higher in the depression group than in the non-depression group after TBI. Additionally, we observed a positive correlation between depression severity and WBC levels in TBI patients.\u003c/p\u003e \u003cp\u003eTo further explore this correlation, we conducted a Pearson analysis to investigate the relationship between depression severity and neutrophil and monocyte levels in a sample of TBI patients. Our results showed a significant positive correlation between depression severity and neutrophil percentage (Pearson\u0026thinsp;=\u0026thinsp;0.742**, P\u0026thinsp;=\u0026thinsp;0.001), as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. However, we did not observe a significant correlation between depression severity and monocyte levels (Pearson\u0026thinsp;=\u0026thinsp;0.268, P\u0026thinsp;=\u0026thinsp;0.001). These findings suggest that changes in peripheral immune function, specifically increases in neutrophil counts, may be involved in the pathogenesis of depression following TBI. Further investigation is necessary to better understand the underlying mechanisms of this relationship and its clinical implications for the diagnosis and treatment of depression in TBI patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.8 Positive Correlation between Depression Severity and CRP Levels in TBI Patients\u003c/h2\u003e \u003cp\u003eThis study aimed to investigate the potential relationship between depression severity and CRP levels in patients with TBI. Previous research has found that ischemia and hypoxia following craniocerebral injury can cause the massive release of inflammatory cytokines and promote the synthesis of CRP in the liver. In addition, previous studies have also reported significant increases in CRP levels in depressed patients after TBI.\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e。To examine the correlation between depression severity and CRP levels in TBI patients, we conducted a Pearson analysis on a sample of TBI patients. Our results revealed a positive correlation between depression severity and CRP levels in TBI patients (Pearson\u0026thinsp;=\u0026thinsp;0.556*, P\u0026thinsp;=\u0026thinsp;0.001), as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThese findings suggest that inflammation may play a role in the development of depression following TBI, and highlight the importance of monitoring CRP levels in clinical assessments of TBI patients. Further research is necessary to elucidate the mechanisms underlying this relationship and to evaluate the potential implications for the diagnosis and treatment of depression in TBI patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study aimed to investigate the factors influencing the occurrence of mental disorders after TBI, focusing on the potential role of peripheral inflammation. Our findings revealed that intracranial infection was a significant independent factor affecting the development of mental disorders after TBI. We also found a strong association between mental disorders after TBI and increased levels of WBCs, neutrophil percentage, CRP, and monocyte levels in patients' peripheral blood. Furthermore, we found that WBC count, neutrophil percentage, and CRP levels were positively correlated with the severity of depression in TBI patients. These results suggest that peripheral inflammatory markers may serve as potential indicators for early identification of mental disorders after TBI.\u003c/p\u003e \u003cp\u003eThe relationship between peripheral inflammation and mental disorders is not yet fully understood. However, our findings provide valuable insights into its possible underlying mechanisms. Future studies should aim to elucidate the neuroendocrine regulation and hypothalamic-pituitary adrenal axis activity involved in this relationship.\u003c/p\u003e \u003cp\u003eEarly diagnosis and intervention are crucial for managing mental disorders after TBI, given their significant impact on patient quality of life and prognosis. Our study suggests that monitoring peripheral inflammatory markers could aid early diagnosis and treatment of mental disorders after TBI. This approach has the potential to reduce the incidence of mental disorders and improve the long-term outcomes of TBI patients.\u003c/p\u003e \u003cp\u003eIn conclusion, our study highlights the importance of screening for intracranial infection and monitoring peripheral inflammatory markers in clinical assessments of TBI patients. The use of peripheral inflammatory markers as potential indicators for mental disorders after TBI warrants further investigation. Ultimately, our findings contribute to the growing body of evidence supporting the critical role of peripheral inflammation in the pathophysiology of mental disorders after TBI.\u003c/p\u003e \u003cp\u003eMental disorders, particularly depression, are prevalent complications that occur after TBI and significantly impact patient outcomes. \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e。In fact, depression is one of the most common complications resulting from TBI\u003csup\u003e[\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e。Studies show that within a year of experiencing TBI, 30\u0026ndash;70% of patients will develop depression\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e, with post-traumatic depression prevalence being 7.9 times higher than in the general population\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e。Our retrospective analysis of TBI patients admitted to the Neurosurgery Department of XX Hospital in Shanghai from January 2016 to December 2018 revealed that during hospitalization (within 15\u0026ndash;30 days), the incidence of depression was about 5%. Furthermore, our follow-up study involving 67 TBI patients recruited between October 2019 and September 2020 found a high occurrence of depression, up to 64.18%, within three months of TBI. Depression following TBI requires long-term rehabilitation and can worsen patient prognosis, increase medical burdens, and profoundly affect families\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e.Therefore, early diagnosis and intervention for mental disorders in TBI patients are critical. Timely and effective interventions can prevent the development of psychological disorders and promote the patient's early return to society.\u003c/p\u003e \u003cp\u003eThe underlying mechanisms of mental disorders after TBI are complex, but current hypotheses suggest disruptions in neuroendocrine regulation, abnormalities in hypothalamic-pituitary-adrenal (HPA) axis activity, and dysfunctions in central nervous system (CNS) neurotransmission\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e。The HPA axis is a major pathway involved in the development of psychiatric symptoms \u003csup\u003e[\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e, with abnormal activation and changes in cortisol levels being important characteristics of patients with mental disorders\u003csup\u003e[\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e。Dysfunction in CNS 5-HT neurotransmission has been implicated in emotional disorders \u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e, with anxiety and depression patients presenting significantly reduced 5-HT levels. Meanwhile, cortisol, adrenaline, and noradrenaline levels are also decreased\u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e。 Dopamine neurons are also closely related to mental disorders after TBI, as they are easily damaged, leading to decreased dopamine function and levels in patients with mental disorders\u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e。Our study found that out of 67 patients, 43 had varying degrees of depression, and depressed patients had significantly lower 5-HT levels than non-depressed patients.\u003c/p\u003e \u003cp\u003eMental disorders following TBI are often accompanied by changes in immune function and activation of the inflammatory response system\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e。However, the causality between inflammation and depression remains controversial\u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e。Importantly, both may mutually promote each other. Inflammation may promote the onset of depression\u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e, and depression can exacerbate inflammation\u003csup\u003e[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e。Patients with depression often present abnormal expression of inflammatory cytokines, hindering recovery from TBI and prolonging treatment. Depression may increase susceptibility to diseases through distorted immune responses, as patients often have elevated levels of pro-inflammatory cytokines such as IL-1, IL-2, IL-6, and TNF-α in peripheral blood\u003csup\u003e[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e。Peripheral blood leukocytes, CRP, neutrophil percentage, monocytes, among others, are indicators of inflammatory reactions. During immune responses, CRP is produced by the liver stimulated by IL-6 and TNF, serving as a sensitive indicator of systemic inflammation\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e。Meanwhile, peripheral blood leukocytes increase in response to infection, trauma, and emotional stress.Our study examined factors that may affect the incidence of depression before admission and found that intracranial infection is an independent risk factor for depression after TBI. Comparing all inflammatory markers in depressed patients before depression onset with those of non-depressed patients, we found that WBC count and CRP levels were significantly higher in the depression group. This suggests that the occurrence of depression after TBI may be associated with increased inflammatory markers. In conclusion, the relationship between inflammation and mental disorders after TBI remains unclear, but our findings suggest mutual promotion. Elevated inflammatory markers, such as peripheral blood leukocytes and CRP levels, may serve as potential indicators for diagnosing depression in TBI patients. Further research is needed to elucidate the underlying mechanisms and identify effective interventions that target inflammatory responses in TBI patients with mental disorders.\u003c/p\u003e \u003cp\u003ePeripheral blood leukocytes, including neutrophils, eosinophils, basophils, lymphocytes, and monocytes, form the first line of defense mechanisms against inflammatory reactions. In this study, we found that the percentage of neutrophils and monocytes was significantly higher in the depression group among TBI patients, suggesting their potential correlation with depression after TBI. Previous research has also suggested that TBI patients with poor prognosis have higher levels of neutrophils and monocytes\u003csup\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/sup\u003e. Moreover, Person's analysis revealed a positive correlation between the degree of depression and WBC count, neutrophil percentage, and CRP level in the recruited TBI patients. This highlights the importance of monitoring changes in peripheral blood leukocyte subsets, particularly neutrophils and monocytes, to aid in early diagnosis of mental disorders in TBI patients. In conclusion, changes in peripheral blood leukocyte subsets, particularly neutrophils and monocytes, may serve as correlates of depression following TBI. Monitoring inflammatory markers such as WBC count, neutrophil percentage, and CRP level may provide insights into the prognosis of TBI patients, including their propensity for psychiatric complications. Further studies are warranted to elucidate the underlying mechanisms and identify effective interventions targeting inflammatory responses in TBI patients with mental disorders.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn summary, we found that intracranial infection was a significant independent factor affecting the development of mental disorders after TBI. Additionally, we found a strong association between mental disorders after TBI and increased levels of peripheral inflammatory markers. Notably, we also observed a positive correlation between the severity of depression in TBI patients and WBC count, neutrophil percentage, and CRP levels. These findings suggest that monitoring peripheral inflammatory markers could aid in early identification and intervention for mental disorders after TBI. Therefore, screening for intracranial infections and monitoring peripheral inflammatory markers should be included in the clinical assessment of TBI patients. Overall, our study contributes to the growing body of evidence supporting the critical role of peripheral inflammation in the pathophysiology of mental disorders after TBI. Further research is warranted to develop effective interventions targeting inflammatory responses in TBI patients with mental disorders.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Sharing Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy conception and design: CYC, ZY. Data collection:CYC. Analysis and interpretation of results: HWY. Draft manuscript preparation: ZY. Critical revision of the article: CYC. All authors (ZY, HWY, CYC) reviewed the results and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was reviewed and approved by the Ethics Committee Shanghai XX Hospital and conducted in accordance with the principles of the Declaration of Helsinki. All participants provided informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the participants in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author declares no conflicts of interests\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. 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TNFalpha disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice. Brain Behav Immun. 2018;69:556\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaber M, Rice AD, Christie I, Roberts RG, Knox KS, Nakaji P, et al. Remote Ischemic Conditioning Reduced Acute Lung Injury After Traumatic Brain Injury in The Mouse. Shock; 2020.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-trauma-and-emergency-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejot","sideBox":"Learn more about [European Journal of Trauma and Emergency Surgery](http://link.springer.com/journal/68)","snPcode":"68","submissionUrl":"https://submission.nature.com/new-submission/68/3","title":"European Journal of Trauma and Emergency Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Traumatic brain injury, psychiatric disorders, intracranial infection, inflammatory markers, early diagnosis","lastPublishedDoi":"10.21203/rs.3.rs-3859918/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3859918/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDepression is a common emotional and psychiatric complication of traumatic brain injury (TBI) that has significant negative impacts on patient recovery. Despite the importance of identifying and treating depression in TBI patients, there is currently no simple and standardized system available for assessing the likelihood of post-TBI depression. In this study we are aim to explore the clinical value of peripheral blood inflammatory markers in predicting mental disorders after TBI.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 67 TBI patients in this study were included and divided them into Group A (depression group) or Group B (non-depression group) based on the presence or absence of concomitant psychiatric disorders. We collected relevant clinical data and inflammatory markers from both groups to identify factors influencing post-TBI depression and analyzed their diagnostic efficacy and correlations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe overall prevalence of mental disorders among TBI patients was found to be 64.18% at the three-month follow-up after injury. Our study revealed that intracranial infection was an independent factor influencing the occurrence of post-TBI depression (OR\u0026thinsp;=\u0026thinsp;19.873, 95%CI\u0026thinsp;=\u0026thinsp;6.721\u0026thinsp;~\u0026thinsp;58.764, P\u0026thinsp;=\u0026thinsp;0.001). Patients who developed post-TBI depression had significantly higher levels of white blood cells(WBCs), neutrophil percentage, C-reactive protein (CRP), and monocyte levels compared to non-depressed TBI patients. Additionally, WBCs (Pearson\u0026thinsp;=\u0026thinsp;0.735,P\u0026thinsp;=\u0026thinsp;0.001), neutrophil percentage (Pearson\u0026thinsp;=\u0026thinsp;0.742, P\u0026thinsp;=\u0026thinsp;0.001), and CRP (Pearson\u0026thinsp;=\u0026thinsp;0.556, P\u0026thinsp;=\u0026thinsp;0.001) levels were positively correlated with depression severity in TBI patients.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur findings suggest a high prevalence of post-TBI depression and highlight peripheral inflammatory markers such as WBCs, neutrophil percentage, and CRP levels as potential early diagnostic indicators for this condition. Identifying these factors can facilitate early diagnosis and intervention for post-TBI depression, improving patient outcomes. This study provides evidence for clinicians to develop effective treatment strategies for post-TBI depression and advance our understanding of its mechanisms.\u003c/p\u003e","manuscriptTitle":"Identifying Factors Associated with Post-Traumatic brain injury Depression: The Role of Inflammatory Markers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-22 14:48:38","doi":"10.21203/rs.3.rs-3859918/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2024-04-27T08:34:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-22T20:46:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-18T08:24:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Trauma and Emergency Surgery","date":"2024-01-13T11:12:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-trauma-and-emergency-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejot","sideBox":"Learn more about [European Journal of Trauma and Emergency Surgery](http://link.springer.com/journal/68)","snPcode":"68","submissionUrl":"https://submission.nature.com/new-submission/68/3","title":"European Journal of Trauma and Emergency Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7c8f72bd-573d-454b-bc38-f64be16509de","owner":[],"postedDate":"January 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-01-22T14:48:38+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-22 14:48:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3859918","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3859918","identity":"rs-3859918","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}