VISSER, K., M. Koggel, J. Blaauw, H.J.v.d. Horn, B. Jacobs, and J.v.d. Naalt. Blood based biomarkers of inflammation in mild traumatic brain injury: A systematic review. NEUROSCI BIOBEHAV REV XX(X) XXX-XXX, 2021. - Inflammation is an important secondary physiological response to traumatic brain injury (TBI). Most of the current knowledge on this response is derived from research in moderate and severe TBI. In this systematic review we summarize the literature on clinical studies measuring blood based inflammatory markers following mild traumatic brain injury (mTBI) and identify the value of inflammatory markers as biomarkers. Twenty-three studies were included. This review suggests a distinct systemic inflammatory response following mTBI, quantifiable within 6 h up to 12 months post-injury. Interleukin-6 is the most promising biomarker for the clinical diagnosis of brain injury while interleukin-10 is a potential candidate for triaging CT scans. The diagnostic and prognostic utility of inflammatory markers may be more fully appreciated as a component of a panel of biomarkers. However, discrepancies in study design, analysis and reporting make it difficult to draw any definite conclusions. For the same reasons, a meta-analysis was not possible. We provide recommendations to follow standardized methodologies to allow for reproducibility of results in future studies.

Despite the often seemingly innocuous nature of a mild traumatic brain injury (mTBI), its consequences can be devastating, comprising debilitating symptoms that interfere with daily functioning. Currently, it is still difficult to pinpoint the exact cause of adverse outcome after mTBI. In fact, extensive research suggests that the underlying etiology is multifactorial. In the acute and early sub-acute stages, the pathophysiology of mTBI is likely to be dominated by complex physiological alterations including cellular injury, inflammation, and the acute stress response, which could lead to neural network dysfunction. In this stage, patients often report symptoms such as fatigue, headache, unstable mood and poor concentration. When time passes, psychological processes, such as coping styles, personality and emotion regulation, become increasingly influential. Disadvantageous, maladaptive, psychological mechanisms likely result in chronic stress which facilitates the development of long-lasting symptoms, possibly via persistent neural network dysfunction. So far, a systemic understanding of the coupling between these physiological and psychological factors that in concert define outcome after mTBI is lacking. The purpose of this narrative review article is to address how psychophysiological interactions may lead to poor outcome after mTBI. In addition, a framework is presented that may serve as a template for future studies on this subject.

The objective of this study was to examine longitudinal functional connectivity of resting-state networks in patients with and without complaints after uncomplicated mild traumatic brain injury (mTBI). Second, we aimed to determine the value of network connectivity in predicting persistent complaints, anxiety, depression and long-term outcome. Thirty mTBI patients with three or more post-traumatic complaints at 2 weeks post-injury, 19 without complaints, and 20 matched healthy controls were selected for this study. Resting-state functional MRI (fMRI) was performed in patients at 1 month and 3 months post-injury, and once in healthy controls. Independent component analysis (ICA) was used to investigate the default mode, executive and salience networks. Persistent post-traumatic complaints, anxiety, and depression were measured at 3 months post-injury, and outcome was determined at 1 year post-injury. Within the group with complaints, higher functional connectivity between the anterior and posterior components of the default mode network at 1 month post-injury was associated with a greater number of complaints at 3 months post-injury (ρ = 0.59, p = 0.001). Minor longitudinal changes in functional connectivity were found for patients with and without complaints after mTBI, which were limited to connectivity within the precuneus component of the default mode network. No significant results were found for the executive and salience networks. Current results suggest that the default mode network may serve as a biomarker of persistent complaints in patients with uncomplicated mTBI.

Mild traumatic brain injury (mTBI) is one of the most common neurological disorders worldwide. Posttraumatic complaints are frequently reported, interfering with outcome. However, a consistent neural substrate has not yet been found. We used graph analysis to further unravel the complex interactions between functional brain networks, complaints, anxiety and depression in the sub-acute stage after mTBI. This study included 54 patients with uncomplicated mTBI and 20 matched healthy controls. Posttraumatic complaints, anxiety and depression were measured at two weeks post-injury. Patients were selected based on presence (n = 34) or absence (n = 20) of complaints. Resting-state fMRI scans were made approximately four weeks post-injury. High order independent component analysis resulted in 89 neural components that were included in subsequent graph analyses. No differences in graph measures were found between patients with mTBI and healthy controls. Regarding the two patient subgroups, degree, strength, local efficiency and eigenvector centrality of the bilateral posterior cingulate/precuneus and bilateral parahippocampal gyrus were higher, and eigenvector centrality of the frontal pole/ bilateral middle & superior frontal gyrus was lower in patients with complaints compared to patients without complaints. In patients with mTBI, higher degree, strength and eigenvector centrality of default mode network components were related to higher depression scores, and higher degree and eigenvector centrality of executive network components were related to lower depression scores. In patients without complaints, one extra module was found compared to patients with complaints and healthy controls, consisting of the cingulate areas. In conclusion, this research extends the knowledge of functional network connectivity after mTBI. Specifically, our results suggest that an imbalance in the function of the default mode- and executive network plays a central role in the interaction between emotion regulation and the persistence of posttraumatic complaints.