APOE ε4 allele status modulates the spatial patterns of progressive atrophy in the temporal lobes after mild traumatic brain injury.

INTRODUCTION: We evaluated how the apolipoprotein E (APOE) ε4 allele modulated the spatial patterns of longitudinal atrophy in the Alzheimer's disease-vulnerable brain areas of patients with mild traumatic brain injury (mTBI) from the acute to chronic phase post injury. METHODS: Fifty-nine adult patients with acute mTBI and 48 healthy controls with APOE ε4 allele testing underwent T1-weighted magnetic resonance imaging and neuropsychological assessments with 6 to 12 months of follow-up. Progressive brain volume loss was compared voxel-wise in the temporal lobes. RESULTS: Patients with the APOE ε4 allele presented significant longitudinal atrophy in the left superior and middle temporal gyri, where the progressive gray matter volume loss predicted longitudinal impairment in language fluency, whereas mTBI APOE ε4 allele noncarriers showed mainly significant longitudinal atrophy in the medial temporal lobes, without significant neuropsychological relevance. DISCUSSION: The atrophy progression observed in mTBI patients with the APOE ε4 allele may increase the possibility of developing a specific phenotype of Alzheimer's disease with language dysfunction. Highlights: The apolipoprotein E (APOE) ε4 allele and mild traumatic brain injury (mTBI) are risk factors for Alzheimer's disease (AD) progression.It is unclear how the interaction of mTBI with the APOE ε4 allele impacts the progressive atrophy topography in AD-vulnerable brain regions.In this study, patients with the APOE ε4 allele showed progressive atrophy patterns similar to the early stage of logopenic variant of primary progressive aphasia (lvPPA) phenotype of AD. APOE ε4 allele carriers with mTBI history may be at the risk of developing a given AD phenotype with language dysfunction.

Reorganized Hubs of Brain Functional Networks after Acute Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI)-associated damage to hub regions can lead to disrupted modular structures of functional brain networks and may result in widespread cognitive and behavioral deficits. The spatial layout of brain connections and modules is essential for understanding the reorganization of brain networks to trauma. We investigated the roles of hubs in inter-subnetwork information coordination and integration using participation coefficients (PCs) in 74 patients with acute mTBI and 51 matched healthy controls. In some brain networks, such as default mode network (DMN) and frontoparietal network (FPN), mild TBI patients had decreased PC levels, while this measure was saliently increased in patients in other networks, such as the visual network. The hub disruption index was defined as the gradient of a straight line fitted to scatterplots of individual mTBI in participation coefficient versus mean participation coefficient of healthy groups. There was a trend of radical reorganization of some efficient "hub" nodes in patients (κ = -0.15), compared with controls (κ close to 0). The PC of brain hubs can also differentiate mTBI patients from controls with an 88% accuracy, and decreased PC levels in FPN can predict patient' s worse cognitive information processing speed (r = 0.36, p < 0.002) and working memory performance (r = 0.35, p < 0.002). Reduced PC within the DMN was associated with patients' complaints of post-concussion symptoms (r = -0.35, p < 0.002). This evidence suggests a trend of spatial transition of hub profiles in acute mTBI, and graph metrics of PC measures can be used as potential diagnostic biomarkers.

Cerebral Hemodynamic Correlates of Transcutaneous Auricular Vagal Nerve Stimulation in Consciousness Restoration: An Open-Label Pilot Study.

This study aimed to preliminarily illustrate the cerebral hemodynamic correlates of transcutaneous auricular vagal nerve stimulation (taVNS) in consciousness restoration. Arterial spin labeling (ASL) was adopted with functional magnetic resonance imaging (fMRI) to measure cerebral blood flow (CBF) changes before and after taVNS in 10 qualified patients with disorders of consciousness (DOC). Before taVNS, five patients responded to auditory stimuli (RtAS), and five did not respond to auditory stimuli (nRtAS). The RtAS DOC patients obtained favorable prognoses after the 4-week taVNS treatment, whereas the nRtAS ones did not. Simultaneously, taVNS increased CBF of multiple brain regions in the RtAS DOC patients, but hardly in the nRtAS ones. In conclusion, the preserved auditory function might be the prior key factor of the taVNS responders in DOC patients, and taVNS might alleviate RtAS DOC by activating the salience network, the limbic system, and the interoceptive system.

Accelerated Brain Aging in Mild Traumatic Brain Injury: Longitudinal Pattern Recognition with White Matter Integrity.

Mild traumatic brain injury (mTBI) initiating long-term effects on white matter integrity resembles brain-aging changes, implying an aging process accelerated by mTBI. This longitudinal study aims to investigate the mTBI-induced acceleration of the brain-aging process by developing a neuroimaging model to predict brain age. The brain-age prediction model was defined using relevance vector regression based on fractional anisotropy from diffusion tensor imaging of 523 healthy individuals. The model was used to estimate the brain-predicted age difference (brain-PAD) between the chronological and estimated brain age in 116 acute mTBI patients and 63 healthy controls. Fifty patients were followed for 6 ∼ 12 months to evaluate the longitudinal changes in brain-PAD. We investigated whether brain-PAD was greater in patients of older age, post-concussion complaints, and apolipoprotein E (APOE) ɛ4 genotype, and whether it had the potential to predict neuropsychological outcomes. The brain-age prediction model predicted brain age accurately (r = 0.96). The brains of mTBI patients in the acute phase were estimated to be "older," with greater brain-PAD (2.59 ± 5.97 years) than the healthy controls (0.12 ± 3.19 years) (p < 0.05), and remained stable 6-12 month post-injury (2.50 ± 4.54 years). Patients who were older or who had post-concussion complaints, rather than APOE ɛ4 genotype, had greater brain-PADs (p < 0.001, p = 0.024). Additionally, brain-PAD in the acute phase predicted information processing speed at the 6 ∼ 12 month follow-up (r = -0.36, p = 0.01). In conclusion, mTBI accelerates the brain-aging process, and brain-PAD may be capable of evaluating aging-associated issues post-injury, such as increased risks of neurodegeneration.

A Longitudinal Study of White Matter Functional Network in Mild Traumatic Brain Injury.

Some patients after mild traumatic brain injury (mTBI) experience microstructural damages in the long-distance white matter (WM) connections, which disrupts the functional connectome of large-scale brain networks that support cognitive function. Patterns of WM structural damage following mTBI were well documented using diffusion tensor imaging (DTI). However, the functional organization of WM and its association with gray matter functional networks (GM-FNs) and its DTI metrics remain unknown. The present study adopted resting-state functional magnetic resonance imaging to explore WM functional properties in mTBI patients (108 acute patients, 48 chronic patients, 46 healthy controls [HCs]). Eleven large-scale WM functional networks (WM-FNs) were constructed by the k-means clustering algorithm of voxel-wise WM functional connectivity (FC). Compared with HCs, acute mTBI patients observed enhanced FC between inferior fronto-occipital fasciculus (IFOF) WM-FN and primary sensorimotor WM-FNs, and cortical primary sensorimotor GM-FNs. Further, acute mTBI patients showed increased DTI metrics (mean diffusivity, axial diffusivity, and radial diffusivity) in deep WM-FNs and higher-order cognitive WM-FNs. Moreover, mTBI patients demonstrated full recovery of FC and partial recovery of DTI metrics in the chronic stage. Additionally, enhanced FC between IFOF WM-FN and anterior cerebellar GM-FN was correlated with impaired information processing speed. Our findings provide novel evidence for functional and structural alteration of WM-FNs in mTBI patients. Importantly, the convergent damage of the IFOF network might imply its crucial role in our understanding of the pathophysiology mechanism of mTBI patients.

Serum Neuron-Specific Enolase Levels Associated with Connectivity Alterations in Anterior Default Mode Network after Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) is the most prevalent neurological insult and leads to long-lasting cognitive impairment. Neuroimaging studies have discovered abnormalities in brain network connectivity following mTBI as the underlying neural basis of cognitive deficits. However, the pathophysiologic mechanisms involved in imaging alterations remain elusive. Proteins neuron-specific enolase (NSE) and ubiquitin C terminal hydrolase 1 are reliable markers for neuronal cell-body damage, both of which have been demonstrated to be increased in serum following mTBI. Therefore, we conducted a longitudinal study to examine relationships between abnormal brain network connectivity and serum neuronal biomarkers and their associations with cognitive recovery following mTBI. Sixty patients were followed-up at 1 week and 3 months post-injury and 41 controls were recruited. Resting-state functional magnetic resonance imaging was used to build a functional connectivity matrix within large-scale intrinsic networks, and their topological properties were analyzed using graph theory measures. We found that, compared with controls, mTBI patients showed significant decreases in a number of nodal characteristics in default mode network (DMN), salience network, and executive network (p < 0.05, false discovery rate corrected) at 3 months post-injury. Linear regression analysis found elevated serum NSE in acute phase could predict lower efficiency and degree centrality of anterior DMN at 3 months post-injury. In addition, efficiency and degree centrality of anterior DMN were negatively associated with working memory. Our study showed neuronal injury was associated with alterations in brain network connectivity after mTBI. These findings can facilitate capability to predict the brain functional outcomes and cognitive recovery in mTBI.

Decoupling of Structural and Functional Connectivity in Hubs and Cognitive Impairment After Mild Traumatic Brain Injury.

Introduction: Mild traumatic brain injury (mild TBI) exhibited abnormal brain network topologies associated with cognitive dysfunction. However, it was still unclear which aspects of network organization were critical underlying the key pathology of mild TBI. Here, a multi-imaging strategy was applied to capture dynamic topological features of both structural and functional connectivity networks (SCNs and FCNs), to provide more sensitive detection of altered FCN from its anatomical backbone and identify novel biomarkers of mild TBI outcomes. Methods: A total of 62 mild TBI patients (30 subjects as an original sample with 3-12 months of follow-up, 32 subjects as independent replicated sample) and 37 healthy controls were recruited. Both diffusion tensor imaging and resting-state functional magnetic resonance imaging were used to create global connectivity matrices in the same individuals. Global and regional network analyses were applied to identify group differences and correlations with clinical assessments. Results: Most global network properties were conserved in both SCNs and FCNs in subacute mild TBI, whereas SCNs presented decreased global efficiency and characteristic path length at follow-up. Specifically, some hubs in healthy brain networks typically became nonhubs in patients and vice versa, such as the medial prefrontal cortex, superior temporal gyrus, and middle frontal gyrus. The relationship between structural and functional connectivity (SC and FC) in patients also showed salient decoupling as a function of time, primarily located in the hubs. Conclusions: These results suggested mild TBI influences the relationship between SCN and FCN, and the SC-FC coupling strength may be used as a potential biomarker to predict long-term outcomes after injury. Impact statement The current study was the first study to explore the coupling of structural-functional connectivity (SC-FC) from large-scale whole-brain networks in patients with mild traumatic brain injury. The results showed that the global properties homeostatically conserved in functional connectivity networks while altered in structural connectivity networks. The SC-FC coupling strength showed salient decoupling as a function of time and primarily occurred in hub regions.

Single Mild Traumatic Brain Injury Deteriorates Progressive Interhemispheric Functional and Structural Connectivity.

The present study examined dynamic interhemispheric structural and functional connectivity in mild traumatic brain injury (mTBI) patients with longitudinal observations from early subacute to chronic stages within 1 year of injury. Forty-two mTBI patients and 42 matched healthy controls underwent clinical and neuropsychological evaluations, diffusion tensor imaging, and resting-state functional magnetic resonance imaging. All mTBI patients were initially evaluated within 14 d post-injury (T-1) and at 3 months (T-2) and 6-12 months (T-3) follow-ups. Separate transcallosal fiber tracts in the corpus callosum (CC) with respect to their specific interhemispheric cortical projections were derived with fiber tracking and voxel-mirrored homotopic connectivity analyses. With diffusion tensor imaging-based tractography, five vertical segments of the CC (I-V) were distinguished. Correlation analyses were performed to evaluate relationships between structural and functional imaging measures as well as imaging indices and neuropsychological measures. The loss of integrity in the CC demonstrated saliently persistent and time-dependent regional specificity after mTBI. The impairment spanned multiple segments from CC II at T-1 and CC I, II, VI, and V at T-2 to all subregions at T-3. Moreover, loss of interhemispheric structural connectivity through the CC corresponded well to regions presenting altered interhemispheric functional connectivity. Decreased functional connectivity in the dorsolateral prefrontal cortex thereafter contributed to poor executive function in mTBI patients. The current study provides further evidence that the CC is a sign to interhemispheric highways underpinning the widespread cerebral pathology typifying mTBI syndrome.

Neuroimaging-based brain-age prediction of first-episode schizophrenia and the alteration of brain age after early medication.

BACKGROUND: Neuroimaging- and machine-learning-based brain-age prediction of schizophrenia is well established. However, the diagnostic significance and the effect of early medication on first-episode schizophrenia remains unclear. AIMS: To explore whether predicted brain age can be used as a biomarker for schizophrenia diagnosis, and the relationship between clinical characteristics and brain-predicted age difference (PAD), and the effects of early medication on predicted brain age. METHOD: The predicted model was built on 523 diffusion tensor imaging magnetic resonance imaging scans from healthy controls. First, the brain-PAD of 60 patients with first-episode schizophrenia, 60 healthy controls and 21 follow-up patients from the principal data-set and 40 pairs of individuals in the replication data-set were calculated. Next, the brain-PAD between groups were compared and the correlations between brain-PAD and clinical measurements were analysed. RESULTS: The patients showed a significant increase in brain-PAD compared with healthy controls. After early medication, the brain-PAD of patients decreased significantly compared with baseline (P < 0.001). The fractional anisotropy value of 31/33 white matter tract features, which related to the brain-PAD scores, had significantly statistical differences before and after measurements (P < 0.05, false discovery rate corrected). Correlation analysis showed that the age gap was negatively associated with the positive score on the Positive and Negative Syndrome Scale in the principal data-set (r = -0.326, P = 0.014). CONCLUSIONS: The brain age of patients with first-episode schizophrenia may be older than their chronological age. Early medication holds promise for improving the patient's brain ageing. Neuroimaging-based brain-age prediction can provide novel insights into the understanding of schizophrenia.

Mild traumatic brain injury is associated with effect of inflammation on structural changes of default mode network in those developing chronic pain.

BACKGROUND: Mild traumatic brain injury (mTBI) has a higher prevalence (more than 50%) of developing chronic posttraumatic headache (CPTH) compared with moderate or severe TBI. However, the underlying neural mechanism for CPTH remains unclear. This study aimed to investigate the inflammation level and cortical volume changes in patients with acute PTH (APTH) and further examine their potential in identifying patients who finally developed CPTH at follow-up. METHODS: Seventy-seven mTBI patients initially underwent neuropsychological measurements, 9-plex panel of serum cytokines and MRI scans within 7 days post-injury (T-1) and 54 (70.1%) of patients completed the same protocol at a 3-month follow-up (T-2). Forty-two matched healthy controls completed the same protocol at T-1 once. RESULTS: At baseline, mTBI patients with APTH presented significantly increased GM volume mainly in the right dorsal anterior cingulate cortex (dACC) and dorsal posterior cingulate cortex (dPCC), of which the dPCC volume can predict much worse impact of headache on patients' lives by HIT-6 (ß = 0.389, P = 0.007) in acute stage. Serum levels of C-C motif chemokine ligand 2 (CCL2) were also elevated in these patients, and its effect on the impact of headache on quality of life was partially mediated by the dPCC volume (mean [SE] indirect effect, 0.088 [0.0462], 95% CI, 0.01-0.164). Longitudinal analysis showed that the dACC and dPCC volumes as well as CCL2 levels had persistently increased in patients developing CPTH 3 months postinjury. CONCLUSION: The findings suggested that structural remodelling of DMN brain regions were involved in the progression from acute to chronic PTH following mTBI, which also mediated the effect of inflammation processes on pain modulation. TRIAL REGISTRATION: ClinicalTrial.gov ID: NCT02868684 ; registered 16 August 2016.

Strategic white matter injury associated with long-term information processing speed deficits in mild traumatic brain injury.

Deficits in information processing speed (IPS) are among the earliest and most prominent cognitive manifestations in mild traumatic brain injury (mTBI). We investigated the impact of white matter fiber location on IPS outcome in an individual basis assessment. A total of 112 acute mild TBI with all CT negative underwent brain DTI and blood sampling for inflammation cytokines within 7 days postinjury and 72 age- and sex matched healthy controls with same assessments were enrolled. IPS outcome was assessed by the trail making test at 6-12 month postinjury in mild TBI. Fractional anisotropy (FA) features were extracted using a novel lesion-load analytical strategy to capture spatially heterogeneous white matter injuries and minimize implicit assumptions of uniform injury across diverse clinical presentations. Acute mild TBI exhibited a general pattern of increased and decreased FA in specific white matter tracts. The power of acute FA measures to identify patients developing IPS deficits with 92% accuracy and further improved to 96% accuracy by adding inflammation cytokines. The classifiers predicted individual's IPS and working memory ratings (r = .74 and .80, respectively, p < .001). The thalamo-cortical circuits and commissural tracts projecting or connecting frontal regions became important predictors. This prognostic model was also verified by an independent replicate sample. Our findings highlighted damage to frontal interhemispheric and thalamic projection fiber tracts harboring frontal-subcortical neuronal circuits as a predictor for processing speed performance in mild TBI.

Elevated Serum Levels of Inflammation-Related Cytokines in Mild Traumatic Brain Injury Are Associated With Cognitive Performance.

Mild traumatic brain injury (mTBI) is the most common neurological insult and leads to long-lasting cognitive impairments. The immune system modulates brain functions and plays a key role in cognitive deficits, however, the relationship between TBI-induced changes in inflammation-related cytokine levels and cognitive consequences is unclear. This was investigated in the present study in two cohorts of individuals within 1 week of mTBI (n = 52, n = 43) and 54 matched healthy control subjects. Patients with mTBI were also followed up at 1 and 3 months post-injury. Measures included cognitive assessments and a 9-plex panel of serum cytokines including interleukin (IL)-1ß, IL-4, IL-6, IL-8, IL-10, IL-12, chemokine ligand 2 (CCL2), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). The contribution of cytokine levels to cognitive function was evaluated by multivariate linear regression analysis. The results showed that serum levels of IL-1ß, IL-6, and CCL2 were acutely elevated in mTBI patients relative to controls; CCL2 level was remained high over 3 months whereas IL-1ß and IL-6 levels were declined by 3 months post-injury. A high level of CCL2 was associated with greater severity of post-concussion symptoms (which survived in the multiple testing correction); elevated IL-1ß was associated with worse working memory in acute phase (which failed in correction); and acute high CCL2 level predicted higher information processing speed at 3 months post-injury (which failed in correction). Thus, acute serum cytokine levels are useful for evaluating post-concussion symptoms and predicting cognitive outcome in participants with mTBI.

The reliability of estimating visual working memory capacity.

The reliability of estimations of working memory capacity has not been thoroughly examined. The present study examined the test-retest reliability for working memory capacity as estimated in a lateralized change detection task, which is frequently used in studies involving electroencephalography. The test-retest correlations between K values for each set size in the two tests varied from 0.502 to 0.757, with test-retest correlations rising as set size increased. The results indicate that individual visual working memory capacity can be reliably estimated in a change detection task. Furthermore, test-retest reliability was higher when the two tests occurred at the same time of day than at different times of day.

Sex differences in cerebral perfusion changes after mild traumatic brain injury: Longitudinal investigation and correlation with outcome.

Cerebral blood flow (CBF) is known to have marked developmental sex differences. We investigated whether gender differences exert modulatory effect on mild traumatic brain injury (mTBI) from both neuropsychological testing and brain CBF changes using a longitudinal design from acute stage to subacute 1 month post-injury. Our results supported that cognitive information processing speed (IPS), as one of core cognitive impairments following mTBI, were at least partially independent from other self-reported syndromes, such as post concussive symptom and posttraumatic stress disorder, and that it can be selectively impaired in specific male mTBI individuals. The gender difference of this cognitive domain in healthy control attenuated following mTBI and only male patients showed impaired language fluency accompanying with increased CBF changes compared with male controls. The increased CBF in the posterior parietal cortex (PPC) can predict much worse cognitive IPS performance in male patients. In contrast, female patients with mTBI displayed no impairments on any neuropsychological performance, and female sex may be a protective factor against neuropsychological impairments. Moreover, the significant interaction effect of time and gender exhibited in the left inferior frontal cortex (Broca's area). Simple effect test suggested gender differences in this area was mainly derived from the patients group at later subacute but not acute phase, for the reduced CBF at subacute mainly in the male patients. Thus, the current findings suggest that regional CBF may provide an objective biomarker for tracking gender modulatory effect on mTBI and its potentially pathological recovery process.

Disruption of periaqueductal grey-default mode network functional connectivity predicts persistent post-traumatic headache in mild traumatic brain injury.

OBJECTIVE: Post-traumatic headache (PTH) is one of the most frequent and persistent physical symptoms following mild traumatic brain injury (mTBI) and develop in more than 50% of this population. This study aimed to investigate the periaqueductal grey (PAG)-seeded functional connectivity (FC) in patients with mTBI with acute post-traumatic headache (APTH) and further examine whether the FC can be used as a neural biomarker to identify patients developing chronic pain 3 months postinjury. METHODS: 70 patients with mTBI underwent neuropsychological measurements and MRI scans within 7 days postinjury and 56 (80%) of patients were followed up at 3 months. 46 healthy controls completed the same protocol on recruitment to the study. PAG-seeded resting-state FC analysis was measured in 54 patients with mTBI with APTH, in comparison with 46 healthy volunteers. RESULTS: The mTBI+APTH group presented significantly reduced PAG-seeded FC within the default mode network (DMN), compared with healthy volunteers group. The connectivity strength can also predict patients' complaints on the impact of headache on their lives. Crucially, the initial FC strength between the PAG-right precuneus as well as the PAG-right inferior parietal lobule became the important predictor to identify patients with mTBI developing persistent PTH 3 months postinjury. CONCLUSIONS: Patients with mTBI+APTH exhibited significant PAG-related FC differences mainly within the DMN. These regions extended beyond traditional pain processing areas and may reflect the diminished top-down attention regulation of pain perception through antinociceptive descending modulation network. The disrupted PAG-DMN FC may be used as an early imaging biomarker to identify patients at risk of developing persistent PTH.

Sex Differences in Abnormal Intrinsic Functional Connectivity After Acute Mild Traumatic Brain Injury.

Mild traumatic brain injury (TBI) is considered to induce abnormal intrinsic functional connectivity within resting-state networks (RSNs). The objective of this study was to estimate the role of sex in intrinsic functional connectivity after acute mild TBI. We recruited a cohort of 54 patients (27 males and 27 females with mild TBI within 7 days post-injury) from the emergency department (ED) and 34 age-, education-matched healthy controls (HCs; 17 males and 17 females). On the clinical scales, there were no statistically significant differences between males and females in either control group or mild TBI group. To detect whether there was abnormal sex difference on functional connectivity in RSNs, we performed independent component analysis (ICA) and a dual regression approach to investigate the between-subject voxel-wise comparisons of functional connectivity within seven selected RSNs. Compared to female patients, male patients showed increased intrinsic functional connectivity in motor network, ventral stream network, executive function network, cerebellum network and decreased connectivity in visual network. Further analysis demonstrated a positive correlation between the functional connectivity in executive function network and insomnia severity index (ISI) scores in male patients (r = 0.515, P = 0.006). The abnormality of the functional connectivity of RSNs in acute mild TBI showed the possibility of brain recombination after trauma, mainly concerning male-specific.

Preliminary Evidence of Sex Differences in Cortical Thickness Following Acute Mild Traumatic Brain Injury.

The main objective of this study was to evaluate sex differences in cortical thickness after acute mild traumatic brain injury (mTBI) and its associations with clinical outcomes. Thirty-two patients with mTBI at acute phase (2.4 ± 1.3 days post-injury) and 30 healthy controls were enrolled. All the participants underwent comprehensive neurocognitive assessments and MRI to assess cortical thickness. Significant sex differences were determined by using variance analysis of factorial design. Relations between the cortical thickness and clinical assessments were measured with the Spearman Correlation. Results revealed that patients with mTBI had significantly reduced cortical thickness in the left entorhinal cortex while increased cortical thickness in the left precuneus cortex and right lateral occipital cortex, compared with healthy controls. The interaction effect of the group × sex on cortical thickness was significant. Female patients had significant thicker cortical thickness in the left caudal anterior cingulate cortex (ACC) than male patients and had higher scores on Posttraumatic stress disorder Checklist-Civilian Version (PCL-C). Spearman correlational analysis showed a significantly positive correlations between the cortical thickness of the left caudal ACC and PCL-C ratings in female patients. Sex differences in cortical thickness support its potential as a neuroimaging phenotype for investigating the differences in clinical profiles of mild TBI between women and men.