A cautionary tale on the effects of different covariance structures in linear mixed effects modeling of fMRI data.

With the steadily increasing abundance of longitudinal neuroimaging studies with large sample sizes and multiple repeated measures, questions arise regarding the appropriate modeling of variance and covariance. The current study examined the influence of standard classes of variance-covariance structures in linear mixed effects (LME) modeling of fMRI data from patients with pediatric mild traumatic brain injury (pmTBI; N = 181) and healthy controls (N = 162). During two visits, participants performed a cognitive control fMRI paradigm that compared congruent and incongruent stimuli. The hemodynamic response function was parsed into peak and late peak phases. Data were analyzed with a 4-way (GROUP×VISIT×CONGRUENCY×PHASE) LME using AFNI's 3dLME and compound symmetry (CS), autoregressive process of order 1 (AR1), and unstructured (UN) variance-covariance matrices. Voxel-wise results dramatically varied both within the cognitive control network (UN>CS for CONGRUENCY effect) and broader brain regions (CS>UN for GROUP:VISIT) depending on the variance-covariance matrix that was selected. Additional testing indicated that both model fit and estimated standard error were superior for the UN matrix, likely as a result of the modeling of individual terms. In summary, current findings suggest that the interpretation of results from complex designs is highly dependent on the selection of the variance-covariance structure using LME modeling.

Parkinson's disease cerebrovascular reactivity pattern: A feasibility study.

A mounting body of research points to cerebrovascular dysfunction as a fundamental element in the pathophysiology of Parkinson's disease (PD). In the current feasibility study, blood-oxygen-level-dependent (BOLD) MRI was used to measure cerebrovascular reactivity (CVR) in response to hypercapnia in 26 PD patients and 16 healthy controls (HC), and aimed to find a multivariate pattern specific to PD. Whole-brain maps of CVR amplitude (i.e., magnitude of response to CO2) and latency (i.e., time to reach maximum amplitude) were computed, which were further analyzed using scaled sub-profile model principal component analysis (SSM-PCA) with leave-one-out cross-validation. A meaningful pattern based on CVR latency was identified, which was named the PD CVR pattern (PD-CVRP). This pattern was characterized by relatively increased latency in basal ganglia, sensorimotor cortex, supplementary motor area, thalamus and visual cortex, as well as decreased latency in the cerebral white matter, relative to HC. There were no significant associations with clinical measures, though sample size may have limited our ability to detect significant associations. In summary, the PD-CVRP highlights the importance of cerebrovascular dysfunction in PD, and may be a potential biomarker for future clinical research and practice.

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.

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.

Acute serum free thiols: a potentially modifiable biomarker of oxidative stress following traumatic brain injury.

Serum concentrations of free thiols (key components of the extracellular antioxidant machinery) reflect the overall redox status of the human body. The objective of this exploratory study was to determine the concentrations of serum free thiols in the acute phase after traumatic brain injury (TBI) and their association with long-term outcome. In this observational cohort study, patients with TBI of various severity were included from a biobank of prospectively enrolled TBI patients. Further eligibility criteria included an available blood sample and head computed tomography data, obtained within 24 h of injury, as well as a functional outcome assessment (Glasgow Outcome Scale Extended (GOSE)) at 6 months post-injury. Serum free thiol concentrations were markedly lower in patients with TBI (n = 77) compared to healthy controls (n = 55) (mean ± standard deviation; 210.3 ± 63.3 vs. 301.8 ± 23.9 µM, P < 0.001) indicating increased oxidative stress. Concentrations of serum free thiols were higher in patients with complete functional recovery (GOSE = 8) than in patients with incomplete recovery (GOSE < 8) (median [interquartile range]; 235.7 [205.1-271.9] vs. 205.2 [173-226.7] µM, P = 0.016), suggesting that patients with good recovery experience less oxidative stress in the acute phase after TBI or have better redox function. Acute TBI is accompanied by a markedly lower concentration of serum free thiols compared to healthy controls indicating that serum free thiols may be a novel biomarker of TBI. Future studies are warranted to validate our findings and explore the clinical applicability and prognostic capability of this candidate-biomarker.

Long-Term Stability of Blood Serum Biomarkers in Traumatic Brain Injury: A Feasibility Study.

Few studies on traumatic brain injury (TBI) have investigated the stability of blood serum biomarkers after long-term storage at low temperatures. In the current feasibility study we analyzed acute phase serum samples from patients with mild TBI as well as patients with moderate and severe TBI that were collected more than 10 years ago (old samples). We were particularly interested in mild TBI, because injury effects are more subtle in this category as compared to moderate-severe TBI. Therefore, the primary objective was to find out whether several biomarkers were still detectable for these patients. Additionally, we examined whether biomarker levels varied as a function of injury severity. For comparison, we also analyzed samples from an ongoing mTBI cohort (new samples) and healthy controls. Samples were treated with care and were not being subjected to freeze-thaw cycles. We measured concentrations of interleukins (IL6 and 10) and brain specific markers (total tau, UCH-L1, GFAP, and NF-L). No significant differences in biomarker concentrations were found between old and new mild TBI samples. For IL6, IL10, and UCH-L1 higher concentrations were found in moderate and severe TBI as compared to mild TBI. In conclusion, our study shows that long-term storage does not rule out the detection of meaningful biomarker concentrations in patients with TBI, although further research by other laboratories is warranted.

Effects of Mild Traumatic Brain Injury on Resting State Brain Network Connectivity in Older Adults.

Older age is associated with worsened outcome after mild traumatic brain injury (mTBI) and a higher risk of developing persistent post-traumatic complaints. However, the effects of mTBI sequelae on brain connectivity at older age and their association with post-traumatic complaints remain understudied.We analyzed multi-echo resting-state functional magnetic resonance imaging data from 25 older adults with mTBI (mean age: 68 years, SD: 5 years) in the subacute phase (mean injury to scan interval: 38 days, SD: 9 days) and 20 age-matched controls. Severity of complaints (e.g. fatigue, dizziness) was assessed using self-reported questionnaires. Group independent component analysis was used to identify intrinsic connectivity networks (ICNs). The effects of group and severity of complaints on ICNs were assessed using spatial maps intensity (SMI) as a measure of within-network connectivity, and (static) functional network connectivity (FNC) as a measure of between-network connectivity.Patients indicated a higher total severity of complaints than controls. Regarding SMI measures, we observed hyperconnectivity in left-mid temporal gyrus (cognitive-language network) and hypoconnectivity in the right-fusiform gyrus (visual-cerebellar network) that were associated with group. Additionally, we found interaction effects for SMI between severity of complaints and group in the visual(-cerebellar) domain. Regarding FNC measures, no significant effects were found.In older adults, changes in cognitive-language and visual(-cerebellar) networks are related to mTBI. Additionally, group-dependent associations between connectivity within visual(-cerebellar) networks and severity of complaints might indicate post-injury (mal)adaptive mechanisms, which could partly explain post-traumatic complaints (such as dizziness and balance disorders) that are common in older adults during the subacute phase.

A Decentralized ComBat Algorithm and Applications to Functional Network Connectivity.

Recent studies showed that working with neuroimage data collected from different research facilities or locations may incur additional source dependency, affecting the overall statistical power. This problem can be mitigated with data harmonization approaches. Recently, the ComBat method has become commonly adopted for various neuroimage modalities. While open neuroimaging datasets are becoming more common, a substantial amount of data is still unable to be shared for various reasons. In addition, current approaches require moving all the data to a central location, which requires additional resources and creates redundant copies of the same datasets. To address these issues, we propose a decentralized harmonization approach that does not create redundant copies of the original datasets and performs remote operations on the datasets separately without sharing any individual subject data, ensuring a certain level of privacy and reducing regulatory hurdles. We proposed a novel approach called "Decentralized ComBat" which can harmonize datasets separately without combining the datasets. We tested our model by harmonizing functional network connectivity datasets from two traumatic brain injury studies in a decentralized way. Also, we used simulations to analyze the performance and scalability of our model when the number of data collection sites increases. We compare the output with centralized ComBat and show that the proposed approach produces similar results, increasing the sensitivity of the functional network connectivity analysis and validating our approach. Simulations show that our model can be easily scaled to many more datasets based on the requirement. In sum, we believe this provides a powerful tool, further complementing open data and allowing for integrating public and private datasets.

Blood-based biomarkers of inflammation in mild traumatic brain injury: A systematic review.

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.

Postural and gait symptoms in de novo Parkinson's disease patients correlate with cholinergic white matter pathology.

INTRODUCTION: The postural instability gait difficulty motor subtype of patients with Parkinson's disease (PIGD-PD) has been associated with more severe cognitive pathology and a higher risk on dementia compared to the tremor-dominant subtype (TD-PD). Here, we investigated whether the microstructural integrity of the cholinergic projections from the nucleus basalis of Meynert (NBM) was different between these clinical subtypes. METHODS: Diffusion-weighted imaging data of 98 newly-diagnosed unmedicated PD patients (44 TD-PD and 54 PIGD-PD subjects) and 10 healthy controls, were analysed using diffusion tensor imaging, focusing on the white matter tracts associated with cholinergic projections from the NBM (NBM-WM) as the tract-of-interest. Quantitative tract-based and voxel-based analyses were performed using FA and MD as the estimates of white matter integrity. RESULTS: Voxel-based analyses indicated significantly lower FA in the frontal part of the medial and lateral NBM-WM tract of both hemispheres of PIGD-PD compared to TD-PD. Relative to healthy control, several clusters with significantly lower FA were observed in the frontolateral NBM-WM tract of both disease groups. Furthermore, significant correlations between the severity of the axial and gait impairment and NBM-WM FA and MD were found, which were partially mediated by NBM-WM state on subjects' attentional performance. CONCLUSIONS: The PIGD-PD subtype shows a loss of microstructural integrity of the NBM-WM tract, which suggests that a loss of cholinergic projections in this PD subtype already presents in de novo PD patients.

White matter microstructure of the neural emotion regulation circuitry in mild traumatic brain injury.

Emotion regulation is related to recovery after mild traumatic brain injury (mTBI). This longitudinal tractography study examined white matter tracts subserving emotion regulation across the spectrum of mTBI, with a focus on persistent symptoms. Four groups were examined: (a) symptomatic (n = 33) and (b) asymptomatic (n = 20) patients with uncomplicated mTBI (i.e., no lesions on computed tomography [CT]), (c) patients with CT-lesions in the frontal areas (n = 14), and (d) healthy controls (HC) (n = 20). Diffusion and conventional MRI were performed approximately 1- and 3-months post-injury. Whole-brain deterministic tractography followed by region of interest analyses was used to identify forceps minor (FM), uncinate fasciculus (UF), and cingulum bundle as tracts of interest. An adjusted version of the ExploreDTI Atlas Based Tractography method was used to obtain reliable tracts for every subject. Mean fractional anisotropy (FA), mean, radial and axial diffusivity (MD, RD, AD), and number of streamlines were studied per tract. Linear mixed models showed lower FA, and higher MD, and RD of the right UF in asymptomatic patients with uncomplicated mTBI relative to symptomatic patients and HC. Diffusion alterations were most pronounced in the group with frontal lesions on CT, particularly in the FM and UF; these effects increased over time. Within the group of patients with uncomplicated mTBI, there were no associations of diffusion measures with the number of symptoms nor with lesions on conventional MRI. In conclusion, mTBI can cause microstructural changes in emotion regulation tracts, however, no explanation was found for the presence of symptoms.

Drugs with anti-inflammatory effects to improve outcome of traumatic brain injury: a meta-analysis.

Outcome after traumatic brain injury (TBI) varies largely and degree of immune activation is an important determinant factor. This meta-analysis evaluates the efficacy of drugs with anti-inflammatory properties in improving neurological and functional outcome. The systematic search following PRISMA guidelines resulted in 15 randomized placebo-controlled trials (3734 patients), evaluating progesterone, erythropoietin and cyclosporine. The meta-analysis (15 studies) showed that TBI patients receiving a drug with anti-inflammatory effects had a higher chance of a favorable outcome compared to those receiving placebo (RR = 1.15; 95% CI 1.01-1.32, p = 0.041). However, publication bias was indicated together with heterogeneity (I2 = 76.59%). Stratified analysis showed that positive effects were mainly observed in patients receiving this treatment within 8 h after injury. Subanalyses by drug type showed efficacy for progesterone (8 studies, RR 1.22; 95% CI 1.01-1.47, p = 0.040), again heterogeneity was high (I2 = 62.92%) and publication bias could not be ruled out. The positive effect of progesterone covaried with younger age and was mainly observed when administered intramuscularly and not intravenously. Erythropoietin (4 studies, RR 1.20; p = 0.110; I2 = 76.59%) and cyclosporine (3 studies, RR 0.75; p = 0.189, I2 = 0%) did not show favorable significant effects. While negative findings for erythropoietin may reflect insufficient power, cyclosporine did not show better outcome at all. Current results do not allow firm conclusions on the efficacy of drugs with anti-inflammatory properties in TBI patients. Included trials showed heterogeneity in methodological and sample parameters. At present, only progesterone showed positive results and early administration via intramuscular administration may be most effective, especially in young people. The anti-inflammatory component of progesterone is relatively weak and other mechanisms than mitigating overall immune response may be more important.

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.

Altered Wiring of the Human Structural Connectome in Adults with Mild Traumatic Brain Injury.

In this study, structural connectivity after mild traumatic brain injury (mTBI) was examined from a network perspective, with a particular focus on post-traumatic complaints. Fifty-three patients with and without self-reported complaints at 2 weeks after uncomplicated mTBI were included, in addition to 20 matched healthy controls. Diffusion weighted imaging was performed at 4 weeks post-injury, and neuropsychological tests measuring processing speed and verbal memory were administered at 3 months post-injury to determine cognitive outcome. Structural connectivity was investigated using whole brain tractography and subsequent graph theory analysis. In patients with mTBI, eigenvector centrality within the left temporal pole was lower than in healthy controls. In patients without complaints, global and mean local efficiency were lower than in patients with complaints, although no differences were found between either subgroup and the group of healthy controls. Neuropsychological test scores were similar for patients with mTBI and healthy controls. However, patients with complaints showed higher processing speed than patients without complaints. Within the total mTBI group, a trend was found toward a correlation between lower network clustering and higher processing speed. Additionally, significant correlations were found between higher betweenness centrality values of language areas and lower verbal memory scores in patients with mTBI. In conclusion, our findings may indicate that global graph measures of the structural connectome are associated with pre- and/or non-injury-related factors that determine the susceptibility to developing (persistent) complaints after mTBI. Further, correlations between graph measures and neuropsychological test scores could suggest early compensatory mechanisms to maintain adequate cognitive performance.