**1. Introduction**

Post-traumatic stress disorder (PTSD) is a chronic debilitating condition that results from having been exposed to trauma. In the current medical field, the diagnostic criteria of PTSD are largely dependent on the clinical symptomatology that outlines the disorder, including cognitive, behavioral, and affective domains [1]. Specifically, the diagnosis for PTSD includes the presence of symptoms of re-experience, avoidance, negative alterations in cognition and mood, and alterations in arousal and reactivity following the trauma [2]. Clinical symptoms of PTSD have been the sole standard for its diagnosis as acquired through self-report and/or structured clinical interview, and have been demonstrated as reliable predictors of a number of important health outcomes. For instance, previous studies have shown that PTSD symptoms predict the degree of functional recovery from pain [3], depressive symptoms [4], risk of substance abuse [5], and factors related to quality of life such as feeling of dissatisfaction [6]. Furthermore, in addition to the psychobehavioral clinical features, PTSD often involves comorbidities with other health problems such as obesity [7], type 2 diabetes mellitus [8], and cardiovascular complications [9]. Considering that all of the above health concerns involve problems in metabolic syndrome which are then closely related to oxidative stress and inflammation, it may then be presumed that the underlying mechanisms of PTSD involves the dysregulation of the immune system.

While psychobehavioral symptoms are the major factors considered when investigating the pathological state and severity of one's PTSD, understanding the immunological alterations that occur in tandem with these symptoms may be informative. For instance, detailed inflammatory responses to various oxidative stress in PTSD such as physical trauma and psychosocial stress may help identify the potentially distinct or diverging pathways towards the development of PTSD, and further reveal the pathophysiology of the disorder [10]. Growing research on PTSD recommends the development and promotion of early treatment strategies for PTSD prior to any clinical symptom development [11], as trauma-exposed individuals with high PTSD symptom severity demonstrated to have less likelihood of seeking treatment [12], resulting in a higher risk of chronic PTSD. For studies that investigated the biological factors associated with the clinical symptoms of a ffective or anxiety disorders, findings have shown that clinical symptoms in patients with depression [13] and anxiety disorders [14] are significantly associated with altered profiles of oxidative stress and inflammation, such as altered serum inflammatory markers. Interestingly, these alterations in inflammatory markers remained significant as compared to individuals in their respective control group, even after adjusting for demographic variables and lifestyle, suggesting that inflammatory response within the central nervous system (CNS) may be partly involved in the pathophysiology of PTSD. Furthermore, some studies have indicated that signs of inflammation may not necessarily correlate with the clinical symptoms of PTSD in a direct manner [15,16], and therefore the inclusion of one's immunological state along with the clinical symptom and severity of PTSD may provide further details of one's diagnostic state for PTSD in a more comprehensive manner. Moreover, considering that PTSD also has a late-onset tendency for clinical symptom development [17], incorporating data on the inflammatory state in the acute aftermath of trauma may help promote various strategies of early prevention and intervention for PTSD, as opposed to being solely dependent on the emergence of clinical symptoms as markers of the disorder.

In recent years, a growing number of studies have investigated the immunological alterations in PTSD as to elucidate the detailed biological pathways that underlie the clinical symptoms of the disorder. In particular, in addition to the abundant number of animal model and in vitro studies on the matter, studies using a human cohort have emerged based on the latest version of the Clinician-Administered PTSD Scale as according to the fifth version of the Diagnostic and Statistical Manual (CAPS-5) [18]. Techniques of neurological assessments including magnetic resonance imaging (MRI) and positron emission tomography (PET) have also emerged, which may allow to investigate the inflammatory responses in PTSD from a deeper, neurological perspective. For instance, previous systematic reviews have been done on MRI-based studies that demonstrated significant structural [19] and neurochemical [20] alterations in specific regions of the brain in association with stress or trauma. Further research that investigate these neurological alterations in PTSD in association with inflammatory responses as well as specific clinical symptoms of PTSD using up-to-date methods of clinical assessment may further reveal the underlying pathways of the disorder in a multi-level perspective.

A number of reviews have also been published that discuss the inflammatory changes in a human PTSD model. In particular, articles investigated inflammation as observable through specific serum inflammatory markers that are known to be in association with PTSD [21,22] and conducted meta-analysis and meta-regression [23] as to summarize elevated systemic levels of oxidative stress and inflammation in individuals with PTSD as compared to healthy controls. However, reviews on the topic of inflammation and PTSD have demonstrated inconsistent findings, which have been suggested to be the result of the heterogeneity of the disorder. While controlling for all the factors that make up the heterogeneity of PTSD across the studies reviewed may be di fficult to conduct, a targeted and structured review that excludes some of the major contributors to the heterogeneity of PTSD may help reveal some of the detailed underlying pathways of PTSD in relation to inflammation, such as the exclusion of PTSD with comorbid complications, and observing for a potential pattern according to

various types of trauma. Moreover, research also indicates that the time between the onset of trauma and the time of assessment may be an important factor that influences the heterogeneity found in inflammatory response in PTSD [24], therefore the distinction between early-onset and later onset of trauma exposure should be considered in addition to recent reviews. A comprehensive and updated review on the growing literature that were recently published on inflammation in PTSD according to various factors that potentially contribute to the heterogeneity may explain for the contrasting findings that were discussed to date. Considering that a few studies in the past have suggested that specific inflammatory markers may play an important role specifically in PTSD [25] and previous articles suggested specific biomarkers as promising for indicating inflammation in PTSD [21], summarizing findings from recent literature on such specified markers may help identify potential biological markers that indicate one's pathophysiology of PTSD.

The current study aims to provide a review of the recent literature on the inflammatory aspect of PTSD in a human model and discuss potential ways to better understand one's state of PTSD through the additional perspective of oxidative stress and inflammation. Specifically, we will review the physiological changes that occur in PTSD as measurable through inflammatory biomarkers, as well as neurological aspects of inflammation in PTSD through neuroimaging methodologies. The summary of the major findings of PTSD with respect to oxidative stress and inflammation may promote further discussion on the potential ways of early detection of those who are at risk for PTSD, as well as early intervention strategies for PTSD.
