Exploring the kynurenine pathway in mild traumatic brain injury: A longitudinal study.

A potential source of novel biomarkers for mTBI is the kynurenine pathway (KP), a metabolic pathway of tryptophan (Trp), that is up-regulated by neuroinflammation and stress. Considering that metabolites of the KP (kynurenines) are implicated in various neuropsychiatric diseases, exploration of this pathway could potentially bridge the gap between physiological and psychological factors in the recovery process after mTBI. This study, therefore, set out to characterize the KP after mTBI and to examine associations with long-term outcome. Patients were prospectively recruited at the emergency department (ED), and blood samples were obtained in the acute phase (<24 h; N = 256) and at 1-month follow-up (N = 146). A comparison group of healthy controls (HC; N = 32) was studied at both timepoints. Trp, kynurenines, and interleukin (IL)-6 and IL-10 were quantified in plasma. Clinical outcome was measured at six months post-injury. Trp, xanthurenic acid (XA), and picolinic acid (PA) were significantly reduced in patients with mTBI relative to HC, corrected for age and sex. For Trp (d = -0.57 vs. d = -0.29) and XA (d = -0.98 vs. d = -0.32), larger effects sizes were observed during the acute phase compared to one-month follow-up, while for PA (d = -0.49 vs. d = -0.52) effect sizes remained consistent. Findings for other kynurenines (e.g., kynurenine, kynurenic acid, and quinolinic acid) were non-significant after correction for multiple testing. Within the mTBI group, lower acute Trp levels were significantly related to incomplete functional recovery and higher depression scores at 6 months post-injury. No significant relationships were found for Trp, XA, and PA with IL-6 or IL-10 concentrations. In conclusion, our findings indicate that perturbations of the plasma KP in the hyperacute phase of mTBI and 1 month later are limited to the precursor Trp, and glutamate system modulating kynurenines XA and PA. Correlations between acute reductions of Trp and unfavorable outcomes may suggest a potential substrate for pharmacological intervention.

Neurophysiological signatures of mild traumatic brain injury in the acute and subacute phase.

BACKGROUND: Mild traumatic brain injury (mTBI) affects 48 million people annually, with up to 30% experiencing long-term complaints such as fatigue, blurred vision, and poor concentration. Assessing neurophysiological features related to visual attention and outcome measures aids in understanding clinical symptoms and prognostication. METHODS: We recorded EEG and eye movements in mTBI patients during a computerized task performed in the acute (< 24 h, TBI-A) and subacute phase (4-6 weeks thereafter). We estimated the posterior dominant rhythm, reaction times (RTs), fixation duration, and event-related potentials (ERPs). Clinical outcome measures were assessed using the Head Injury Symptom Checklist (HISC) and the Extended Glasgow Outcome Scale (GOSE) at 6 months post-injury. Similar analyses were performed in an age-matched control group (measured once). Linear mixed effect modeling was used to examine group differences and temporal changes within the mTBI group. RESULTS: Twenty-nine patients were included in the acute phase, 30 in the subacute phase, and 19 controls. RTs and fixation duration were longer in mTBI patients compared to controls (p < 0.05), but not between TBI-A and TBI-S (p < 0.05). The frequency of the posterior dominant rhythm was significantly slower in TBI-A (0.6 Hz, p < 0.05) than TBI-S. ERP mean amplitude was significantly lower in mTBI patients than in controls. Neurophysiological features did not significantly relate to clinical outcome measures. CONCLUSION: mTBI patients demonstrate impaired processing speed and stimulus evaluation compared to controls, persisting up to 6 weeks after injury. Neurophysiological features in mTBI can assist in determining the extent and temporal progression of recovery.

Identification of At-Risk Patients That Need More Intensive Treatment Following mTBI: Post-Hoc Insights From the UPFRONT-Study.

OBJECTIVE: To investigate which factors within an at-risk group make patients less likely to benefit from preventive treatment following mild traumatic brain injury (mTBI). SETTING: Inclusion in 3 level I trauma centers in the Netherlands. Data collection through surveys as outpatients. PARTICIPANTS: mTBI patients (18-66 years), reporting 3 or more complaints 2 weeks postinjury (at-risk status). Eighty-four patients included and randomized (39 patients cognitive behavioral therapy, 45 patients telephonic counseling). Eighty patients filled out the questionnaires 12 months postinjury. Post hoc analysis investigating 80 patients as 1 at-risk group receiving psychological treatment. DESIGN: Post hoc study of a randomized controlled trial (RCT). Binomial logistic regression performed determining which variables 2 weeks postinjury contributed strongly to unsuccessful return to work/study (RTW) and unfavorable outcome at 12 months. MAIN MEASURES: RTW and functional outcome as measured with the Glasgow Outcome Scale-Extended (GOSE) at 12 months postinjury. RESULTS: Out of 80 patients, 43 (53.8%) showed a favorable functional outcome at 12 months, and 56 (70%) patients had a full RTW. Patients with unfavorable outcome had a higher age and higher reports of anxiety, depression at 2 weeks and 12 months postinjury. Patients with an unsuccessful RTW had a higher age and higher reports of depression, and posttraumatic stress disorder at 2 weeks and 12 months postinjury. A logistic regression model for functional outcome (GOSE) was statistically significant (χ²7 = 40.30, P < .0001). Of 6 predictor variables, 3 were significant: anxiety, depression, and treatment condition. For RTW, logistic regression was also statistically significant (χ²7 = 19.15, P = .008), with only 1 out of 6 predictor variables (ie, age) being significant. CONCLUSION: Main findings comprise differences in demographic and psychological measures between patients with favorable and unfavorable outcomes and patients with RTW versus no RTW. Prediction models of outcome and RTW showed several psychological measures at 2 weeks greatly determining patients' likelihood benefitting from the preventive treatment. Results suggest that from the beginning there are some patients for whom a short preventive treatment is not sufficient. Selection and treatment of at-risk patients might be better based on psychological symptoms instead of posttraumatic complaints.

Trajectories of Fatigue, Psychological Distress, and Coping Styles After Mild Traumatic Brain Injury: A 6-Month Prospective Cohort Study.

OBJECTIVE: To analyze fatigue after mild traumatic brain injury (TBI) with latent class growth analysis (LCGA) to determine distinct recovery trajectories and investigate influencing factors, including emotional distress and coping styles. DESIGN: An observational cohort study design with validated questionnaires assessing fatigue, anxiety, depression, posttraumatic stress, and coping at 2 weeks and 3 and 6 months postinjury. SETTING: Three level 1 trauma centers. PARTICIPANTS: Patients with mild TBI (N=456). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Fatigue was measured with the fatigue severity subscale of the Checklist Individual Strength, including 8 items (sum score, 8-56). Subsequently, 3 clinical categories were created: high (score, 40-56), moderate (score, 26-38), and low (score, 8-25). RESULTS: From the entire mild TBI group, 4 patient clusters with distinct patterns for fatigue, emotional distress, and coping styles were found with LCGA. Clusters 1 and 2 showed favorable recovery from fatigue over time, with low emotional distress and the predominant use of active coping in cluster 1 (30%) and low emotional distress and decreasing passive coping in cluster 2 (25%). Clusters 3 and 4 showed unfavorable recovery, with persistent high fatigue and increasing passive coping together with low emotional distress in cluster 3 (27%) and high emotional distress in cluster 4 (18%). Patients with adverse trajectories were more often women and more often experiencing sleep disturbances and pain. CONCLUSIONS: The prognosis for recovery from posttraumatic fatigue is favorable for 55% of mild TBI patients. Patients at risk for chronic fatigue can be signaled in the acute phase postinjury based on the presence of high fatigue, high passive coping, and, for a subgroup of patients, high emotional distress. LCGA proved to be a highly valuable and multipurpose statistical method to map distinct courses of disease-related processes over time.

Coping with stress before and after mild traumatic brain injury: a pilot hair cortisol study.

Background: Cortisol is a crucial hormone for adaptation to challenging and stressful situations. Hair cortisol measurement is used to determine chronic stress; the growth rate of hair allows to determine averaged cortisol levels for a longer period. Objective: Pre- and post-injury measures of hair cortisol were compared in patients with mild traumatic brain injury (mTBI), and related to their coping styles.Methods: For 46 patients with mTBI, 3 cm scalp hair samples were collected 4-6 weeks post-injury, resulting in two 1 cm segments, pre- and post-injury. Hair samples were also collected for 11 healthy controls. Hair cortisol was quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Complaints, anxiety, depression and coping style were measured two weeks post-injury and long term (six-twelve months), added with measures for post-traumatic stress and functional outcome.Results: There were no differences between patients' pre- and post-injury cortisol levels, nor between cortisol levels of patients and controls. However, pre- and post-injury cortisol levels of patients were negatively correlated with both passive and an avoidant coping style.Conclusions: Our findings suggest that mTBI has no separate impact on chronic long-term cortisol levels, possibility indicating that variability in cortisol levels reflects individuals' premorbid characteristics determining coping with stress in general.

Patients with mild traumatic brain injury and acute neck pain at the emergency department are a distinct category within the mTBI spectrum: a prospective multicentre cohort study.

BACKGROUND: Acute neck pain (ANP) has recently been demonstrated to be a predictor of persistent posttraumatic complaints after mild traumatic brain injury (mTBI). The aim of this study was to determine specific characteristics of patients with ANP following mTBI, their posttraumatic complaints and relationship with functional outcome. METHODS: Data from a prospective follow-up study of 922 mTBI patients admitted to the emergency department (ED) in three level-one trauma centres were analysed. Patients were divided into two groups: 156 ANP patients and 766 no acute neck pain (nANP) patients. Posttraumatic complaints were evaluated 2 weeks and 6 months post-injury using standardized questionnaires and functional outcome was evaluated at 6 months with the Glasgow Outcome Scale Extended (GOSE). RESULTS: ANP patients were more often female (p < 0.01), younger (38 vs. 47 years, p < 0.01) with more associated acute symptoms at the ED (p < 0.05) compared to nANP patients. More motor vehicle accidents (12% vs. 6%, p = 0.01) and less head wounds (58% vs. 73%, p < 0.01) in ANP patients indicated 'high-energy low-impact' trauma mechanisms. ANP patients showed more posttraumatic complaints 2 weeks and 6 months post-injury (p < 0.05) and more often incomplete recovery (GOSE < 8) was present after 6 months (56% vs. 40%, p = 0.01). CONCLUSIONS: MTBI patients with acute neck pain at the ED constitute a distinct group within the mTBI spectrum with specific injury and demographic characteristics. Early identification of this at risk group already at the ED might allow specific and timely treatment to avoid development of incomplete recovery.

Early Predictors for Long-Term Functional Outcome After Mild Traumatic Brain Injury in Frail Elderly Patients.

OBJECTIVE: To identify the effect of frailty and early postinjury measures on the long-term outcome after mild traumatic brain injury in elderly patients. SETTING: Patients admitted to 3 Dutch hospitals designated as level 1 trauma centers. PARTICIPANTS: The elderly (≥60 years) with mild traumatic brain injury (N = 161). DESIGN: A prospective observational cohort study. MAIN MEASURES: Posttraumatic complaints and the Hospital Anxiety and Depression Scale determined 2 weeks postinjury; the Glasgow Outcome Scale Extended and Groningen frailty indicator determined 1 to 3 years postinjury. RESULTS: A total of 102 nonfrail (63%) and 59 frail elderly (37%) patients, mean age of 70.8 (6.3) years were included. Most patients (54%; 72% nonfrail and 24% frail) recovered completely 1 to 3 years postinjury. Two weeks postinjury, 81% had posttraumatic complaints (83% frail and 80% nonfrail elderly), and 30% showed emotional distress (50% frail and 20% nonfrail). Frailty (odds ratio, 2.1; 95% confidence interval, 1.59-2.77) and presence of early complaints (odds ratio, 1.13; 95% confidence interval, 1.01-1.27) (Nagelkerke R = 46%) were found to predict long-term outcome, whereas age was not a significant predictor. CONCLUSION: The frail elderly had worse long-term outcome, and early complaints were found to be a stronger predictor of unfavorable outcome than age. Understanding the implications of frailty on outcome could help clinicians recognize patients at risk of a poor outcome and allocate care more efficiently.

Brain network dysregulation, emotion, and complaints after mild traumatic brain injury.

OBJECTIVES: To assess the role of brain networks in emotion regulation and post-traumatic complaints in the sub-acute phase after non-complicated mild traumatic brain injury (mTBI). EXPERIMENTAL DESIGN: Fifty-four patients with mTBI (34 with and 20 without complaints) and 20 healthy controls (group-matched for age, sex, education, and handedness) were included. Resting-state fMRI was performed at four weeks post-injury. Static and dynamic functional connectivity were studied within and between the default mode, executive (frontoparietal and bilateral frontal network), and salience network. The hospital anxiety and depression scale (HADS) was used to measure anxiety (HADS-A) and depression (HADS-D). PRINCIPAL OBSERVATIONS: Regarding within-network functional connectivity, none of the selected brain networks were different between groups. Regarding between-network interactions, patients with complaints exhibited lower functional connectivity between the bilateral frontal and salience network compared to patients without complaints. In the total patient group, higher HADS-D scores were related to lower functional connectivity between the bilateral frontal network and both the right frontoparietal and salience network, and to higher connectivity between the right frontoparietal and salience network. Furthermore, whereas higher HADS-D scores were associated with lower connectivity within the parietal midline areas of the bilateral frontal network, higher HADS-A scores were related to lower connectivity within medial prefrontal areas of the bilateral frontal network. CONCLUSIONS: Functional interactions of the executive and salience networks were related to emotion regulation and complaints after mTBI, with a key role for the bilateral frontal network. These findings may have implications for future studies on the effect of psychological interventions.

Pathways of care the first year after moderate and severe traumatic brain injury-discharge destinations and outpatient follow-up.

PRIMARY OBJECTIVE: To determine the pathways of care within the first year after traumatic brain injury (TBI) and to explore whether provided care is related to residual impairments. RESEARCH DESIGN: Retrospective study of 343 patients with moderate and severe TBI admitted to a Level-1 trauma centre. METHODS AND PROCEDURES: Discharge destinations from hospital to home and frequency of outpatient visits were determined. Outcome was defined 1 year after injury by the Extended Glasgow Outcome Scale and Return to Work. RESULTS: Most (94%) patients had returned home 1-year after injury despite cognitive (76%), behavioural (67%) and physical (55%) impairments. One in four patients was severely disabled and 32% had resumed work on a previous level. Two-thirds of all patients went home as secondary discharge destination and 50% needed inpatient rehabilitation. Almost half of patients needed outpatient care, mostly for behavioural and cognitive impairments. One in 10 patients consulted a psychiatrist, with 55% unfavourable outcome. Of those patients initially discharged to home without follow-up, eventually 10% needed outpatient rehabilitation. CONCLUSIONS: One-year after injury most patients had returned home with residual impairments and frequent medical consultations. This finding warrants further investigation to define appropriate aftercare by various medical specialists aimed at long-term community integration.

Primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma (NHL) manifesting in the brain, spinal cord, cerebrospinal fluid and/or eyes, in the absence of systemic manifestations. With an increasing incidence and a 30% 5-year overall survival if promptly treated, timely diagnosis and subsequent treatment is paramount. The typical MRI appearance for PCNSL is a solitary or multiple T2-hypointense, homogeneous gadolinium-enhancing lesion with restricted diffusion. Dexamethasone treatment might compromise and delay the diagnosis. Hallmark of treatment is induction with intravenous high-dose methotrexate consisting polychemotherapy followed by consolidation treatment. Consolidation treatment consists of either whole brain radiotherapy (WBRT) or autologous stem cell transplantation (ASCT). Given the (cognitive) side effects of WBRT, ASCT is increasingly being used as the first choice of treatment.

Evaluation of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 Using a Rapid Point of Care Test for Predicting Head Computed Tomography Lesions After Mild Traumatic Brain Injury in a Dutch Multi-Center Cohort.

Mild traumatic brain injury (mTBI) is a common condition seen in emergency departments worldwide. Blood-based biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) are recently U.S. Food and Drug Administration-approved for the prediction of intracranial lesions on head computed tomography (CT) scans in mTBI. We evaluated the diagnostic performance of GFAP and UCH-L1 in a Dutch cohort using the i-STAT TBI assay. In a multi-center observational study, we enrolled 253 mTBI patients. Head CT scans were scored using the Marshall classification system. Logistic regression models were used to assess the contribution of biomarkers and clinical parameters to diagnostic performance. Detection of UCH-L1 and GFAP resulted in a sensitivity of 97% and specificity of 19% for CT positivity in mTBI patients, along with a negative predictive value of 95% (88-100%) and a positive predictive value of 27% (21-33%). Combining biomarker testing with loss of consciousness and time to sample increased specificity to 46%. Combined testing of UCH-L1 and GFAP testing resulted in possibly more unnecessary CT scans compared with GFAP testing alone, with only limited increase in sensitivity. This study confirmed high sensitivity of GFAP and UCH-L1 for CT abnormalities in mTBI patients using the i-STAT TBI test. The results support the potential use of GFAP and UCH-L1 as tools for determining the indication for CT scanning in mTBI patients, possibly offering a cost- and time-effective approach to management of patients with mTBI. Prospective studies in larger cohorts are warranted to validate our findings.

Good Health-Related Quality of Life in Older Patients One Year after mTBI despite Incomplete Recovery: An Indication of the Disability Paradox?

Background: Older adults (OAs) with mild traumatic brain injury (OA-mTBI) are a growing population, but studies on long-term outcomes and quality of life are scarce. Our aim was to determine the health-related quality of life (HRQoL) in OA-mTBI one year after injury and to assess the early predictors of HRQoL. Methods: Data from a prospective follow-up study of 164 older (≥60 years) and 289 younger mTBI patients (<60 years) admitted to the emergency department were analyzed. Post-traumatic complaints, emotional distress and coping were evaluated 2 weeks post-injury using standardized questionnaires. At 12 months post-injury, HRQoL and functional recovery were determined with the abbreviated version of the World Health Organization Quality of Life scale and Glasgow Outcome Scale Extended (GOSE), respectively. Results: One year post-injury, 80% (n = 131) of the OA-mTBI rated their HRQoL as "good" or "very good", which was comparable to younger patients (79% (n = 226), p = 0.72). Incomplete recovery (GOSE <8) was present in 43% (n = 69) of OA-mTBI, with 67% (n = 46) reporting good HRQoL. Two weeks post-injury, fewer OA-mTBI had (≥2) post-traumatic complaints compared to younger patients (68% vs. 80%, p = 0.01). In the multivariable analyses, only depression-related symptoms (OR = 1.20 for each symptom, 95% CI = 1.01-1.34, p < 0.01) were predictors of poor HRQoL in OA-mTBI. Conclusions: Similar to younger patients, most OA-mTBI rated their HRQoL as good at one year after injury, although a considerable proportion showed incomplete recovery according to the GOSE, suggesting a disability paradox. Depression-related symptoms emerged as a significant predictor for poor HRQoL and can be identified as an early target for treatment after mTBI.

An exploratory study on the association between blood-based biomarkers and subacute neurometabolic changes following mild traumatic brain injury.

BACKGROUND AND OBJECTIVES: Blood-based biomarkers and advanced neuroimaging modalities such as magnetic resonance spectroscopy (MRS) or diffusion tensor imaging (DTI) have enhanced our understanding of the pathophysiology of mild traumatic brain injury (mTBI). However, there is limited published data on how blood biomarkers relate to neuroimaging biomarkers post-mTBI. METHODS: To investigate this, 30 patients with mTBI and 21 healthy controls were enrolled. Data was collected at two timepoints postinjury: acute, < 24 h, (blood) and subacute, four-to-six weeks, (blood and imaging). Interleukin (IL) 6 and 10 (inflammation), free thiols (systemic oxidative stress) and neurofilament light (NF-L) (axonal injury) were quantified in plasma. The neurometabolites total N-acetyl aspartate (tNAA) (neuronal energetics), Myo-Inositol (Ins) and total Choline (tCh) (inflammation) and, Glutathione (GSH, oxidative stress) were quantified using MRS. RESULTS: Concentrations of IL-6 and IL-10 were significantly elevated in the acute phase post-mTBI, while NF-L was elevated only in the subacute phase. Total NAA was lowered in patients with mTBI, although this difference was only nominally significant (uncorrected P < 0.05). Within the patient group, acute IL-6 and subacute tNAA levels were negatively associated (r = - 0.46, uncorrected-P = 0.01), albeit not at a threshold corrected for multiple testing (corrected-P = 0.17). When age was added as a covariate a significant increase in correlation magnitude was observed (ρ = - 0.54, corrected-P = 0.03). CONCLUSION: This study demonstrates potential associations between the intensity of the inflammatory response in the acute phase post-mTBI and neurometabolic perturbations in the subacute phase. Future studies should assess the longitudinal dynamics of blood-based and imaging biomarkers after injury.

Dynamic phase-locking states and personality in sub-acute mild traumatic brain injury: An exploratory study.

Research has shown that maladaptive personality characteristics, such as Neuroticism, are associated with poor outcome after mild traumatic brain injury (mTBI). The current exploratory study investigated the neural underpinnings of this process using dynamic functional network connectivity (dFNC) analyses of resting-state (rs) fMRI, and diffusion MRI (dMRI). Twenty-seven mTBI patients and 21 healthy controls (HC) were included. After measuring the Big Five personality dimensions, principal component analysis (PCA) was used to obtain a superordinate factor representing emotional instability, consisting of high Neuroticism, moderate Openness, and low Extraversion, Agreeableness, and Conscientiousness. Persistent symptoms were measured using the head injury symptom checklist at six months post-injury; symptom severity (i.e., sum of all items) was used for further analyses. For patients, brain MRI was performed in the sub-acute phase (~1 month) post-injury. Following parcellation of rs-fMRI using independent component analysis, leading eigenvector dynamic analysis (LEiDA) was performed to compute dynamic phase-locking brain states. Main patterns of brain diffusion were computed using tract-based spatial statistics followed by PCA. No differences in phase-locking state measures were found between patients and HC. Regarding dMRI, a trend significant decrease in fractional anisotropy was found in patients relative to HC, particularly in the fornix, genu of the corpus callosum, anterior and posterior corona radiata. Visiting one specific phase-locking state was associated with lower symptom severity after mTBI. This state was characterized by two clearly delineated communities (each community consisting of areas with synchronized phases): one representing an executive/saliency system, with a strong contribution of the insulae and basal ganglia; the other representing the canonical default mode network. In patients who scored high on emotional instability, this relationship was even more pronounced. Dynamic phase-locking states were not related to findings on dMRI. Altogether, our results provide preliminary evidence for the coupling between personality and dFNC in the development of long-term symptoms after mTBI.

An integrated perspective linking physiological and psychological consequences of mild traumatic brain injury.

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.

Executive functioning in relation to coping in mild versus moderate-severe traumatic brain injury.

OBJECTIVE: To examine associations between executive functioning (EF) and coping styles, separately for mild and moderate-severe traumatic brain injury (TBI) in the chronic phase postinjury. METHOD: Patients with mild (n = 47) and moderate-severe TBI (n = 59) were included, in addition to healthy controls (HCs; n = 51). Assessment consisted of EF tests (Trail Making Test, Zoo Map Test, Controlled Oral Word Association Test) and questionnaires examining EF (Dysexecutive Questionnaire) and coping styles (Utrecht Coping List). RESULTS: Moderate-severe TBI patients showed significant more EF deficits, lower active coping and higher passive coping than mild TBI patients and HCs, whereas mild TBI patients did not differ from HCs. In the moderate-severe TBI group, a higher number of self-reported EF problems was related to lower levels of active coping, r = -.43, p < .01 and higher levels of passive coping, r = .58, p < .001, with proxy-reports relating to lower levels of active coping, r = -.33, p < .05. For mild TBI, a higher amount of self-reported EF problems was related to lower levels of active coping, r = -.38, p < .05 and higher levels of passive coping, r = .55, p < .001, with proxy-reports relating to higher levels of passive coping, r = .39, p < .05. Except for mental flexibility, EF performances were not associated with coping. CONCLUSIONS: This study shows strong associations between reported EF problems in daily life and coping styles. For moderate-severe TBI, proxy-reports may reflect EF impairments that complicate active problem-solving. However, reported EF problems by mild and moderate-severe TBI patients are also likely to reflect a psychological distress related to the way patients are inclined to deal with stressing situations that put a demand on their executive abilities. (PsycINFO Database Record

The Default Mode Network as a Biomarker of Persistent Complaints after Mild Traumatic Brain Injury: A Longitudinal Functional Magnetic Resonance Imaging Study.

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.

Prediction of work resumption and sustainability up to 1 year after mild traumatic brain injury.

OBJECTIVE: To study return to work (RTW) after mild traumatic brain injury (mTBI) at several intervals after injury and to predict RTW on the basis of occupational factors in addition to demographic, personality, and injury-related factors at 6 and 12 months after injury. METHODS: This was a prospective cohort study (UPFRONT study, n = 1,151) of patients with mTBI admitted to the emergency department. Patients received questionnaires at 2 weeks and 3, 6, and 12 months after injury. RTW was divided into 3 levels: complete (cRTW), partial (pRTW), and no RTW. RESULTS: Rates of cRTW increased from 34% at 2 weeks to 77% at 12 months after injury, pRTW varied from 8% to 16% throughout the year. Logistic regression (complete vs incomplete RTW) demonstrated that apart from previously identified predictors such as demographics (e.g., age and education) and injury characteristics (e.g., cause and severity of injury) and indicators of psychological distress, occupational factors were of influence on work resumption after 6 months (area under the curve [AUC] = 0.82), At 12 months, however, the model was based solely on the presence of extracranial injuries and indicators of maladaptation after injury (AUC = 0.81). CONCLUSIONS: RTW after mTBI is a gradual process, with varying levels of RTW throughout the first year after injury. Different predictors were relevant for short- vs long-term work resumption, with occupational factors influencing short-term RTW. However, for both short- and long-term RTW, posttraumatic complaints and signs of psychological distress early after injury were relevant predictors, allowing early identification of patients at risk for problematic work resumption.

Non-Hospitalized Patients with Mild Traumatic Brain Injury: The Forgotten Minority.

Non-hospitalized mild traumatic brain injury (mTBI) patients comprise a substantial part of the trauma population. For these patients, guidelines recommend specialized follow-up only in the case of persistent complaints or problems in returning to previous activities. This study describes injury and outcome characteristics of non-hospitalized mTBI patients, and the possibility of predicting which of the non-hospitalized patients will return to the outpatient neurology clinic. Data from all non-hospitalized mTBI patients (Glasgow Coma Scale [GCS] score 13-15, n = 462) from a prospective follow-up study on mTBI (UPFRONT-study) conducted in three level 1 trauma centers were analyzed. At 2 weeks, and 3 and 6 months after injury, patients completed questionnaires on post-traumatic complaints, depression, anxiety, outpatient follow-up, and resumption of activities. Most patients were male (57%), with a mean age of 40 years (range 16-91 years). Injuries were most often caused by traffic accidents (32%) or falls (39%). Six months after injury, 36% showed incomplete recovery as defined by the Glasgow Outcome Scale - Extended (GOS-E). Twenty-five percent of the non-hospitalized patients returned to the outpatient neurology clinic within 6 months after injury, of which one third had not completely resumed pre-injury activities. Regression analyses showed an increased risk for outpatient follow-up for patients scoring above the cutoff value for anxiety (odds ratio [OR] = 3.0), depression (OR = 3.5), or both (OR = 3.7) 2 weeks after injury. Our findings underline that clinicians and researchers should be aware of recovery for all mTBI patients, preventing their transition into a forgotten minority.

Patients "At Risk" of Suffering from Persistent Complaints after Mild Traumatic Brain Injury: The Role of Coping, Mood Disorders, and Post-Traumatic Stress.

Although most patients recover fully following mild traumatic brain injury (mTBI), a minority (15-25%) of all patients develop persistent post-traumatic complaints (PTC) that interfere with the resumption of previous activities. An early identification of patients who are at risk for PTC is currently performed by measuring the number of complaints in the acute phase. However, only part of this group will actually develop persisting complaints, stressing the need for studies on additional risk factors. This study aimed to compare this group of patients with many complaints with patients with few and no complaints to identify potential additional discriminating characteristics and to evaluate which of these factors have the most predictive value for being at risk. We evaluated coping style, presence of psychiatric history, injury characteristics, mood-related symptoms, and post-traumatic stress. We included 820 patients (Glasgow Coma Scale [GCS] score 13-15) admitted to three level-1 trauma centers as part of the UPFRONT-study. At 2 weeks after injury, 60% reported three or more complaints (PTC-high), 25% reported few complaints (PTC-low), and 15% reported no complaints (PTC-zero). Results showed that PTC-high consisted of more females (78% vs. 73% and 52%, p < 0.001), were more likely to have a psychiatric history (7% vs. 2% and 5%), and had a higher number of reported depression (22% vs. 6% and 3%, p < 0.001), anxiety (25% vs. 7% and 5%), and post-traumatic stress (37% vs. 27% and 19%, p < 0.001) than the PTC-low and PTC-zero groups. We conclude that in addition to reported complaints, psychological factors such as coping style, depression, anxiety, and post-traumatic stress symptoms had the highest predictive value and should be taken into account in the identification of at-risk patients for future treatment studies.