mTBI Group Research Articles

EEG Oscillatory Activity and Resting-State Networks Associated with Neurocognitive Function in Mild Traumatic Brain Injury.

This study aimed to investigate the characteristics of resting-state electroencephalography (EEG) activity and brain networks in patients with mild traumatic brain injury (mTBI) and their association with neurocognitive function (NCF). We analyzed 26 patients with subacute mTBI and 21 healthy controls. The subacute mTBI group (9 females, 17 males) had a mean age of 29.9 ± 9.9 years, and the healthy controls (11 females, 10 males) had a mean age of 29.7 ± 11.5 years. Current source density, lagged phase synchronization, and resting-state network activity were analyzed using exact low-resolution electromagnetic tomography (eLORETA) with 60 s resting-state EEG data. In addition, a correlation analysis was performed between these EEG parameters and NCF in patients with mTBI. We used the statistical nonparametric mapping method in eLORETA to correct for multiple comparisons. There were no significant differences in EEG parameters between the patients with mTBI and healthy controls. However, in patients with mTBI, correlation analysis revealed negative correlations between theta activity in the anterior cingulate cortex and verbal short-term memory and between activity in the memory perception network and verbal memory. Our findings suggest that resting-state EEG may be clinically useful in investigating the mechanism of NCF decline in patients with mTBI.

The Role of Hearing Difficulty: Cognitive-Communication and Speech-in-Noise Deficits in Adults Following Mild Traumatic Brain Injury

Purpose: Mild traumatic brain injury (TBI) has a high rate of occurrence across the lifespan. Following mild TBI (mTBI), perceived deficits in cognitive communication and hearing may be noted. This study aimed to determine if adults with a history of mTBI and hearing difficulty perceived greater degrees of cognitive-communication difficulty and performed poorer on a speech-in-noise task when compared to participants with mTBI and controls without reported hearing difficulty. Method: Adults aged 19–77 years with and without a history of mTBI were analyzed. Participants were divided into three groups: control ( n = 49), mTBI ( n = 22), and mTBI with hearing difficulty (mTBI-HD, n = 26). Perception of hearing difficulty was based on a score of ≥ 20 on the Hearing Handicap Inventory or a score ≥ 2 on the Adult Auditory Performance Scale. Self-perceived cognitive communication was measured using the Cognitive Difficulties Scale (CDS) and the La Trobe Communication Questionnaire (LCQ). Speech-in-noise performance was measured using the low-cue speech recognition threshold (SRT) from the Listening in Spatialized Noise–Sentences (LiSN-S) test. Results: Adults in the mTBI-HD group reported significantly greater degrees of cognitive-communication difficulties (higher CDS and LCQ scores) and exhibited significantly poorer speech-in-noise performance on the low-cue LiSN-S condition when compared to the control and mTBI groups. Results also revealed significant correlations between the LiSN-S low-cue SRT and perceived cognitive communication on the CDS. Conclusions: Results of the current study indicate that adults with a history of mTBI and hearing difficulty experience greater subjective cognitive-communication difficulties and perform more poorly on difficult speech-in-noise tasks than adults who do not experience self-perceived hearing difficulties. The results of this study support the consideration of hearing and cognitive-communication difficulties when determining appropriate speech, language, and hearing assessment, treatment, and intervention strategies for individuals following mTBI.

Cervical Spine Vibration Modifies Oculomotor Function in Young Adults with Traumatic Brain Injury

ObjectiveThe purpose of this study was to investigate if vibrational interference of spinal proprioception affects oculomotor function, visual attention and processing, and selective attention in individuals with mild traumatic brain injury (mTBI) compared to healthy age-matched controls. MethodsThis study was a parallel design, single-session intervention with 20 young adults with mTBI and 20 age-matched controls. Each completed a battery of computerized eye-tracking assessments (CEAs), including egocentric localization, fixational stability, smooth pursuit, saccades, Stroop, and the vestibulo-ocular reflex (VOR), and then had their cervical spine function (flexion-relaxation ratio) recorded at baseline. Spinal vibration (100 Hz) was applied to the cervical spine and the CEA battery was repeated. CEA outcomes were compared to baseline and between mTBI and control groups. ResultsFollowing cervical vibration, significant pre to post-differences were seen in both the mTBI and control group for egocentric localization, fixation stability, pursuit, saccades, Stroop, and VOR. At baseline, there was a significant difference between the mTBI and control groups across many CEA measures, with the mTBI group performing more poorly in egocentric localization, pursuit, saccades, Stroop, and VOR. The mTBI group also had a poorer flexion-relaxation ratio than the control group. ConclusionCervical spine vibration improved cognitive and oculomotor performance in the mTBI group for VOR, Stroop, and pursuit, but had mixed effects on the control group. These findings suggest that some optometric mTBI symptoms may result from spinal or proprioceptive dysfunction, as altering proprioceptive input appears to positively impact visual outcomes.

Comparative Performance of Three Eye-Tracking Devices in Detection of Mild Traumatic Brain Injury in Acute Versus Chronic Subject Populations.

Presently, traumatic brain injury (TBI) triage in field settings relies on symptom-based screening tools such as the updated Military Acute Concussion Evaluation. Objective eye-tracking may provide an alternative means of neurotrauma screening due to sensitivity to neurotrauma brain-health changes. Previously, the US Army Medical Research and Development Command Non-Invasive NeuroAssessment Devices (NINAD) Integrated Product Team identified 3 commercially available eye-tracking devices (SyncThink EYE-SYNC, Oculogica EyeBOX, NeuroKinetics IPAS) as meeting criteria toward being operationally effective in the detection of TBI in service members. We compared these devices to assess their relative performance in the classification of mild traumatic brain injury (mTBI) subjects versus normal healthy controls. Participants 18 to 45 years of age were assigned to Acute mTBI, Chronic mTBI, or Control group per study criteria. Each completed a TBI assessment protocol with all 3 devices counterbalanced across participants. Acute mTBI participants were tested within 72 hours following injury whereas time since last injury for the Chronic mTBI group ranged from months to years. Discriminant analysis was undertaken to determine device classification performance in separating TBI subjects from controls. Area Under the Curves (AUCs) were calculated and used to compare the accuracy of device performance. Device-related factors including data quality, the need to repeat tests, and technical issues experienced were aggregated for reporting. A total of 63 participants were recruited as Acute mTBI subjects, 34 as Chronic mTBI subjects, and 119 participants without history of TBI as controls. To maximize outcomes, poorer quality data were excluded from analysis using specific criteria where possible. Final analysis utilized 49 (43 male/6 female, mean [x̅] age = 24.3 years, SD [s] = 5.1) Acute mTBI subjects, and 34 (33 male/1 female, x̅ age = 38.8 years, s = 3.9) Chronic mTBI subjects were age- and gender-matched as closely as possible with Control subjects. AUCs obtained with 80% of total dataset ranged from 0.690 to 0.950 for the Acute Group and from 0.753 to 0.811 for the Chronic mTBI group. Validation with the remaining 20% of dataset produced AUCs ranging from 0.600 to 0.750 for Acute mTBI group and 0.490 to 0.571 for the Chronic mTBI group. Potential eye-tracking detection of mTBI, per training model outcomes, ranged from acceptable to excellent for the Acute mTBI group; however, it was less consistent for the Chronic mTBI group. The self-imposed targeted performance (AUC of 0.850) appears achievable, but further device improvements and research are necessary. Discriminant analysis models differed for the Acute versus Chronic mTBI groups, suggesting performance differences in eye-tracking. Although eye-tracking demonstrated sensitivity in the Chronic group, a more rigorous and/or longitudinal study design is required to evaluate this observation. mTBI injuries were not controlled for this study, potentially reducing eye-tracking assessment sensitivity. Overall, these findings indicate that while eye-tracking remains a viable means of mTBI screening, device-specific variability in data quality, length of testing, and ease of use must be addressed to achieve NINAD objectives and DoD implementation.

Cognitive Symptoms Are Not Associated with Cognitive Performance in Post-Acute mTBI.

Subjective cognitive symptoms are commonly reported after mild traumatic brain injury (mTBI) but are often not associated with objective cognitive performance. This may be due to limitations in traditional cognitive performance measures, which may not be sensitive to subtle variations in cognition in post-acute mTBI. This study explored associations between objective and subjective cognition using computer-based tasks of increasing cognitive load, proposed to be more sensitive to subtle differences in performance. Individuals with mTBI (n = 68) and trauma controls (n = 40) were prospectively recruited and assessed approximately 8weeks post-injury. Participants completed measures of subjective symptom reporting, objective cognitive performance (including two computer-based tasks of increasing cognitive load), and psychological distress. There were no significant associations between subjective and objective cognition reporting in the mTBI group, both in bivariate correlations (|r| = 0.01-0.20, p> .05) and when controlling for psychological distress (|r| = 0.00-0.17, p> .05). A similar pattern of results was observed in trauma controls, suggesting that the limited relationships between objective and subjective cognition in mTBI may not be specific to this population. Despite employing measures of cognitive performance proposed to be more sensitive than traditional tasks, no significant relationships were observed between objective and subjective cognition in post-acute mTBI, and estimated effect sizes were small to negligible. This provides further evidence that at a group level 8weeks after mTBI subjective cognitive symptoms primarily reflect factors aside from objective cognition.

White matter microstructural changes in post-traumatic headache: A diffusion tensor imaging (DTI) study.

Post-traumatic headache (PTH) is a common consequence of mild traumatic brain injury (mTBI) that can severely impact an individual's quality of life and rehabilitation. However, the underlying neuropathogenesis mechanisms contributing to PTH are still poorly understood. This study utilized diffusion tensor imaging (DTI) to detect microstructural alterations in the brains of mTBI participants with or at risk of developing PTH. This study investigated associations between DTI metrics 1-month postinjury and pain sensitivity, as well as psychological assessments 6-months postinjury to identify differences between mTBI (n = 12) and healthy controls (HC; n = 10). MRI scans, including T1-weighted anatomical imaging and DTI were acquired at 1-month postinjury. Pain sensitivity assays included quantitative sensory testing and psychological assessment questionnaires at 1-month and 6-months postinjury. Significant aberrations of mean axial diffusivity in the forceps major were observed in mTBI relative to HCs at 1-month postinjury (p =0.02). Within the mTBI group, DTI metrics at 1-month postinjury were significantly associated (p's < 0.05) with pain-related measures and psychological outcomes at 6-month postinjury in several white matter tracts (right sagittal stratum, left anterior thalamic radiation, left corticospinal tract, left insula, left superior longitudinal fasciculus). Notably, the associations between DTI metrics at 1-month postinjury and pain-related measures at 6-month postinjury showed significant group differences in the right sagittal stratum (p's < 0.01), white matter tract in left insula (p < 0.04), and left superior longitudinal fasciculus (p's < 0.05). This study suggests that "Post-Traumatic Stress Disorder for DSM-5" and "Center for Epidemiological Studies-Depression Scale" are the most sensitive psychological measures to early microstructural changes after mTBI, and that the DTI metrics are predictive of pain and psychological measures in mTBI. Together, these results suggest that white matter microstructure plays an important role in the PTH following mTBI.

Poor sleep and decreased cortical thickness in veterans with mild traumatic brain injury and post-traumatic stress disorder

BackgroundPoor sleep quality has been associated with changes in brain volume among veterans, particularly those who have experienced mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). This study sought to investigate (1) whether poor sleep quality is associated with decreased cortical thickness in Iraq and Afghanistan war veterans, and (2) whether these associations differ topographically depending on the presence or absence of mTBI and PTSD.MethodsA sample of 440 post-9/11 era U.S. veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders study at VA Boston, MA from 2010 to 2022 was included in the study. We examined the relationship between sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), and cortical thickness in veterans with mTBI (n = 57), PTSD (n = 110), comorbid mTBI and PTSD (n = 129), and neither PTSD nor mTBI (n = 144). To determine the topographical relationship between subjective sleep quality and cortical thickness in each diagnostic group, we employed a General Linear Model (GLM) at each vertex on the cortical mantle. The extent of topographical overlap between the resulting statistical maps was assessed using Dice coefficients.ResultsThere were no significant associations between PSQI and cortical thickness in the group without PTSD or mTBI (n = 144) or in the PTSD-only group (n = 110). In the mTBI-only group (n = 57), lower sleep quality was significantly associated with reduced thickness bilaterally in frontal, cingulate, and precuneus regions, as well as in the right parietal and temporal regions (β = −0.0137, P < 0.0005). In the comorbid mTBI and PTSD group (n = 129), significant associations were observed bilaterally in frontal, precentral, and precuneus regions, in the left cingulate and the right parietal regions (β = −0.0094, P < 0.0005). Interaction analysis revealed that there was a stronger relationship between poor sleep quality and decreased cortical thickness in individuals with mTBI (n = 186) compared to those without mTBI (n = 254) specifically in the frontal and cingulate regions (β = −0.0077, P < 0.0005).ConclusionsThis study demonstrates a significant relationship between poor sleep quality and lower cortical thickness primarily within frontal regions among individuals with both isolated mTBI or comorbid diagnoses of mTBI and PTSD. Thus, if directionality is established in longitudinal and interventional studies, it may be crucial to consider addressing sleep in the treatment of veterans who have sustained mTBI.

Long-term cognitive and affective consequences of mild traumatic brain injury: comparison with older adults

ABSTRACT Objective Memory and affective processing were compared in young adults with a remote mild traumatic brain injury (mTBI), to healthy younger and older adults. We evaluated memory performance when encoding was done under multi-tasking (divided attention) conditions, likely to exacerbate cognitive and psychological symptoms in mTBI. Methods Participants studied pairs of unrelated words under either full or divided attention conditions. Memory for single words (item memory) and for pairs of words (associative memory) was then assessed in sequential independent recognition tests, under full attention. Results Associative memory was poorer than item memory, and worse when encoding was done under divided than full attention. The decline in recognition accuracy from full to divided attention conditions on the associative memory test was significantly greater in mTBI compared to young adults and was similar in magnitude to that observed in older adults under full attention. Self-reported mental and total fatigue increased significantly as performance on the memory tests, following the divided attention condition, decreased, but only in the mTBI group. Conclusions Results show lingering memory deficits, and suggest that cognitive tasks may be experienced as psychologically more demanding in those with a mTBI, even months or years after injury.

White Matter Hyperintensities and Mild TBI in Post-9/11 Veterans and Service Members.

The neurobehavioral significance of white matter hyperintensities (WMHs) seen on magnetic resonance imaging after traumatic brain injury (TBI) remains unclear, especially in Veterans and Service Members with a history of mild TBI (mTBI). In this study, we investigate the relation between WMH, mTBI, age, and cognitive performance in a large multisite cohort from the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. The neuroimaging and neurobehavioral assessments for 1,011 combat-exposed, post-9/11 Veterans and Service Members (age range 22-69 years), including those with a history of at least 1 mTBI (n = 813; median postinjury interval of 8 years) or negative mTBI history (n = 198), were examined. White matter hyperintensities were present in both mTBI and comparison groups at similar rates (39% and 37%, respectively). There was an age-by-diagnostic group interaction, such that older Veterans and Service Members with a history of mTBI demonstrated a significant increase in the number of WMHs present compared to those without a history of mTBI. Additional associations between an increase in the number of WMHs and service-connected disability, insulin-like growth factor-1 levels, and worse performance on tests of episodic memory and executive functioning-processing speed were found. Subtle but important clinical relationships are identified when larger samples of mTBI participants are used to examine the relationship between history of head injury and radiological findings. Future studies should use follow-up magnetic resonance imaging and longitudinal neurobehavioral assessments to evaluate the long-term implications of WMHs following mTBI.

Service needs and neurobehavioral functioning following traumatic brain injury in U.S. military personnel.

The purpose of this study was to (a) identify the prevalence and barriers of self-reported service needs in a military sample with and without traumatic brain injury (TBI), (b) evaluate the influence of the number of service needs on overall neurobehavioral functioning, and (c) examine the longitudinal trajectories of service needs over time. Participants were 941 U.S. service members and veterans (SMVs) prospectively enrolled into four groups: uncomplicated mild TBI (MTBI; n = 455); complicated mild, moderate, severe, and penetrating TBI combined (STBI; n = 164); injured controls (IC, n = 138); and noninjured controls (NIC, n = 184). Participants completed a battery of neurobehavioral measures, as well as a self-reported service need interview, 12 or more month's postinjury. In addition, a longitudinal cohort (n = 553) was included using a subset of participants who had completed two or more evaluations. When examining the total number of self-reported service needs, there was a greater proportion of the MTBI and STBI groups that had a higher number of service needs compared to the NIC and IC groups (p < .001). In the MTBI and STBI groups, as the number of service needs increased, worse scores were found on all neurobehavioral measures. In the longitudinal cohort, the STBI group reported the highest number of service needs that persisted or developed over time (six needs), followed by the MTBI (three needs), IC (one need), and NIC (zero need) groups. These findings call for the need to enhance the provision of information given to service members and veterans following TBI regarding available services. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

Gender Disparities in Neurobehavioral Symptoms and the Role of Post-Traumatic Symptoms in US Service Members Following Mild Traumatic Brain Injury.

Women are more directly involved in combat operations today than ever before, currently making up 18.6% of officers and 16.8% of enlisted personnel in the United States military. However, women continue to be under-represented in military research. Studies that do consider gender differences in traumatic brain injury (TBI) outcomes have shown that women report significantly more post-concussive symptoms than men. Conclusions for true gender differences related to TBI are hard to make without controlling for non-TBI factors. The effects previously identified in the literature may be an artifact of how men and women differ in their response to injury, unrelated to the neurological recovery process associated with TBI. The objective of this study was to examine the effects of gender specifics on mild TBI (mTBI) sequelae on injured and uninjured control groups, and to investigate the role of post-traumatic stress disorder (PTSD) on symptom reporting. It should be noted that the terms "gender" and "men/women" are used in this article in place of "sex" or "males/females" given that we are not discussing biological attributes. A total of 966 United States military service members and veterans were included in the study. Of the total sample, 455 men and 46 women were in the mTBI group, 285 men and 31 women were in the injured controls group (IC), and 111 men and 38 women in the non-injured controls group (NIC). Post-concussive and quality of life symptoms were compared for men and women while controlling for combat exposure. MTBI and IC groups were also stratified by PTSD presentation. Measures used included the Neurobehavioral Symptom Inventory (NSI), PTSD Checklist (PCL-C), Traumatic Brain Injury Quality of Life (TBI-QOL), and Combat Exposure Scale. In the mTBI group, women had worse scores on NSI total, NSI Somatosensory and Affective clusters, and the TBI-QOL Anxiety, Fatigue, and Headache scales (n2 = 0.018-0.032, small to small-medium effect sizes). When PTSD was present, women had worse scores on the NSI Somatosensory cluster only (n2 = 0.029, small-medium effect size). In contrast, when PTSD was absent, women had worse scores than men on the NSI Somatosensory and Affective clusters, and the TBI-QOL Anxiety and Headache scales (n2 = 0.032-0.063, small to medium effect sizes). In the IC group, women had worse scores on the NSI Cognitive cluster and the TBI-QOL Fatigue and Pain Interference scales (n2 = 0.024-0.042, small to small-medium effect sizes). However, group differences were no longer found when stratified by PTSD sub-groups. In the NIC group, there were no significant group differences for any analyses. We were able to identify symptoms unique to women recovering from mTBI that were not present following other forms of physical injury or in healthy controls. However, the impact of PTSD exacerbates the symptom profile and its comorbidity with mTBI equates to most of the noted gender differences.

Graph Analysis of the Visual Cortical Network during Naturalistic Movie Viewing Reveals Increased Integration and Decreased Segregation Following Mild TBI.

Traditional neuroimaging methods have identified alterations in brain activity patterns following mild traumatic brain injury (mTBI), particularly during rest, complex tasks, and normal vision. However, studies using graph theory to examine brain network changes in mTBI have produced varied results, influenced by the specific networks and task demands analyzed. In our study, we employed functional MRI to observe 17 mTBI patients and 54 healthy individuals as they viewed a simple, non-narrative underwater film, simulating everyday visual tasks. This approach revealed significant mTBI-related changes in network connectivity, efficiency, and organization. Specifically, the mTBI group exhibited higher overall connectivity and local network specialization, suggesting enhanced information integration without overwhelming the brain's processing capabilities. Conversely, these patients showed reduced network segregation, indicating a less compartmentalized brain function compared to healthy controls. These patterns were consistent across various visual cortex subnetworks, except in primary visual areas. Our findings highlight the potential of using naturalistic stimuli in graph-based neuroimaging to understand brain network alterations in mTBI and possibly other conditions affecting brain integration.

Clinical relevance of subthreshold PTSD versus full criteria PTSD following traumatic brain injury in U.S. service members and veterans

BackgroundThe purpose of this cross-sectional study was to examine the influence of subthreshold posttraumatic stress disorder (PTSD) and full PTSD on quality of life following mild traumatic brain injury (mTBI). MethodsParticipants were 734 service members and veterans (SMV) classified into two injury groups: uncomplicated mild TBI (MTBI; n = 596) and injured controls (IC, n = 139). Participants completed a battery of neurobehavioral measures, 12-or-more months post-injury, that included the PTSD Checklist Civilian version, Neurobehavioral Symptom Inventory, and select scales from the TBI-QOL and MPAI. The MTBI group was divided into three PTSD subgroups: No-PTSD (n = 266), Subthreshold PTSD (n = 139), and Full-PTSD (n = 190). ResultsThere was a linear relationship between PTSD severity and neurobehavioral functioning/quality of life in the MTBI sample. As PTSD severity increased, significantly worse scores were found on 11 of the 12 measures (i.e., MTBI: Full-PTSD > Sub-PTSD > No-PTSD). When considering the number of clinically elevated scores, a linear relationship between PTSD severity and neurobehavioral functioning/quality of life was again observed in the MTBI sample (e.g., 3-or-more elevated scores: Full-PTSD = 92.1 %, Sub-PTSD = 61.9 %, No-PTSD = 19.9 %). LimitationsLimitations included the use of a self-report measure to determine diagnostic status that may under/overcount or mischaracterize individuals. ConclusionPTSD symptoms, whether at the level of diagnosable PTSD, or falling short of that because of the intensity or characterization of symptoms, have a significant negative impact on one's quality of life following MTBI. Clinicians' treatment targets should focus on the symptoms that are most troubling for an individual and the individual's perception of quality of life, regardless of the diagnosis itself.

Prospective memory performance in veterans with and without histories of mild traumatic brain injury: effect of the apolipoprotein E (APOE) ε4 genotype

ABSTRACT Objective Identifying factors that moderate cognitive outcomes following mild traumatic brain injury (mTBI) is crucial. Prospective memory (PM) is a cognitive domain of interest in mTBI recovery as it may be especially sensitive to TBI-related changes. Since studies show that genetic status – particularly possession of the apolipoprotein E (APOE) ε4 allele – can modify PM performance, we investigated associations between mTBI status and APOE-ε4 genotype on PM performance in a well-characterized sample of Veterans with neurotrauma histories. Methods 59 Veterans (mTBI = 33, Military Controls [MCs] = 26; age range: 24–50; average years post-injury = 10.41) underwent a structured clinical interview, neuropsychological assessment, and genotyping. The Memory for Intentions Test (MIST) measured PM across multiple subscales. ANCOVAs, adjusting for age and posttraumatic stress symptoms, tested the effects of mTBI status (mTBI vs. MC) and ε4 status (ε4+ vs. ε4−) on MIST scores. Results Veterans with mTBI history performed more poorly compared to MCs on the MIST 15-min delay (p=.002, ηp 2 =.160), Time Cue (p = .003, ηp 2 =.157), and PM Total (p = .016, ηp 2 =.102). Those with at least one copy of the ε4 allele performed more poorly compared to ε4- Veterans on the MIST 15-min delay (p = .011, ηp 2 =.113) and PM Total (p = .048, ηp 2 = .071). No significant interactions were observed between mTBI and APOE-ε4 status on MIST outcomes (ps>.25). Within the mTBI group, APOE-ε4+ Veterans performed worse than APOE-ε4− Veterans on the MIST 15-min delay subscale (p = .031, ηp 2 = .150). Conclusions mTBI history and APOE-ε4 genotype status were independently associated with worse PM performance compared to those without head injury histories or possession of the APOE-e4 genotype. Performance on the MIST 15-min delay was worse in Veterans with both risk factors (mTBI history and APOE-ε4 positivity). Findings suggest that genetic status may modify outcomes even in relatively young Veterans with mTBI histories. Future research examining longitudinal associations and links to neuroimaging and biomarker data are needed.

CSF β-Amyloid and Tau Biomarker Changes in Veterans With Mild Traumatic Brain Injury.

Moderate-to-severe traumatic brain injuries (TBI) have been reported to increase the risk of Alzheimer disease (AD). Whether mild TBI (mTBI) in veterans confers a similar increased risk of AD is less known. This study investigated early AD changes using CSF biomarkers in veterans with blast mTBI. This was a cross-sectional case-control study of veterans with mTBI and non-mTBI veterans and civilians from 2 study sources. Blast-mTBI veterans had at least 1 war zone blast or combined blast/impact mTBI meeting Veterans Affairs (VA) and Department of Defense (DoD) criteria for mTBI. Non-mTBI participants had no lifetime history of TBI. All participants underwent standardized clinical and neuropsychological assessments and lumbar puncture for collection of the CSF. CSF biomarkers were measured using MesoScale Discovery assays for Aβ40 and Aβ42 and INNOTEST ELISAs for phosphorylated tau181 (p-tau181) and total tau (t-tau). Our sample comprised 51 participants with mTBI and 85 non-mTBI participants with mean (SD) ages 34.0 (10.1) and 33.5 years (8.9), respectively. All participants but 1 (99%) were male. Differences in CSF AD biomarkers between mTBI and non-mTBI groups were age dependent and most pronounced at older ages (omnibus test p ≤ 0.08). At age 50 years, the mTBI group had lower mean [95% CI] CSF Aβ42 and Aβ40 than the non-mTBI group by 154 [-12 to 319] and 1864 [610-3,118] pg/mL, respectively. By contrast, CSF p-tau181 and t-tau mean levels remained relatively constant with age in participants with mTBI, while tending to be higher at older ages for the non-mTBI group. The mTBI group also demonstrated poorer cognitive performance at older ages (omnibus p < 0.08): at age 50 years, the mean TMT-B time was higher by 34 seconds [10-58] and the mean CVLT-II short-delay recall was lower by 4.2 points [1.9-6.6]. Poorer verbal memory and verbal fluency performance were associated with lower CSF Aβ42 (p ≤ 0.05) in older participants. CSF Aβ levels decreased in middle-aged veterans with blast-related mTBI. These data suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes known to portend AD onset, thus raising concern that veterans with blast-related mTBI may develop a dementing disorder later in life.

White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is the signature injury experienced by military service members and is associated with poor neuropsychiatric outcomes. Yet, there is a lack of reliable clinical tools for mTBI diagnosis and prognosis. To examine the white matter microstructure and neuropsychiatric outcomes of service members with a remote history of mTBI (ie, mTBI that occurred over 2 years ago) using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). This case-control study examined 98 male service members enrolled in a study at the National Intrepid Center of Excellence. Eligible participants were active duty status or able to enroll in the Defense Enrollment Eligibility Reporting system, ages 18 to 60 years, and had a remote history of mTBI; controls were matched by age. Remote history of mTBI. White matter microstructure was assessed using a region-of-interest approach of skeletonized diffusion images, including DTI (fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity) and NODDI (orientation dispersion index [ODI], isotropic volume fraction, intra-cellular volume fraction). Neuropsychiatric outcomes associated with posttraumatic stress disorder (PTSD) and postconcussion syndrome were assessed. A total of 65 male patients with a remote history of mTBI (mean [SD] age, 40.5 [5.0] years) and 33 age-matched male controls (mean [SD] age, 38.9 [5.6] years) were included in analysis. Compared with the control cohort, the 65 service members with mTBI presented with significantly more severe PTSD-like symptoms (mean [SD] PTSD CheckList-Civilian [PCL-C] version scores: control, 19.0 [3.8] vs mTBI, 41.2 [11.6]; P < .001). DTI and NODDI metrics were altered in the mTBI group compared with the control, including intra-cellular volume fraction of the right cortico-spinal tract (β = -0.029, Cohen d = 0.66; P < .001), ODI of the left posterior thalamic radiation (β = -0.006, Cohen d = 0.55; P < .001), and ODI of the left uncinate fasciculus (β = 0.013, Cohen d = 0.61; P < .001). In service members with mTBI, fractional anisotropy of the left uncinate fasciculus was associated with postconcussion syndrome (β = 5.4 × 10-3; P = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (β = 4.3 × 10-4; P = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (β = 1.2 × 10-3; P = .02). In this case-control study of military-related mTBI, the results suggest that advanced magnetic resonance imaging techniques using NODDI can reveal white matter microstructural alterations associated with neuropsychiatric symptoms in the chronic phase of mTBI. Diffusion trends observed throughout widespread white matter regions-of-interest may reflect mechanisms of neurodegeneration as well as postinjury tissue scarring and reorganization.

Quality of Life in Youth Soccer Players After Mild Traumatic Brain Injury.

Pediatric mild traumatic brain injuries (mTBIs) represent an evolving field of interest in youth athletics. Although most players recover within 4 weeks, some have symptoms that last longer. Little is known about youth health-related quality of life (HRQoL) after mTBI. To characterize youth HRQoL after soccer-related mTBI and to identify predictors of individual differences in HRQoL recovery. Prospective cohort study. Youth soccer. Soccer players, aged 8 to 17 years, who sustained an mTBI (n = 23) or orthopaedic injury (OI, n = 24) or remained uninjured (n = 23) during a single season. We assessed HRQoL via the Pediatric Quality of Life Inventory, version 4.0, and postconcussive symptoms via the Health and Behavior Index. Serial assessments occurred at 24 to 48 hours, 7 days, 30 days, and 90 days postinjury via telephone interview. At 7 days postinjury, the mTBI and OI groups had poorer total HRQoL (F2,67 = 11.35, P < .001) than the uninjured control group. At 7 days, the mTBI group had the poorest psychosocial HRQoL, whereas the OI group had the poorest physical HRQoL. Differences between the mTBI and uninjured control groups resolved by 30 days. Within the mTBI group, players with significant postconcussive symptoms at 7 days had poorer total (F1,21 = 23.071, P ≤ .001; F1,21 = 5.798, P = .028), psychosocial (F1,21 = 16.488, P = < .001; F1,21 = 5.050, P = .039), and physical (F1,21 = 21.671, P = < .001; F1,21 = 5.119, P = .038) HRQoL at 7 and 30 days, respectively, than players with minimal symptoms; these differences resolved by 90 days. As a group, youth soccer players who sustained mTBI had transient impairments in HRQoL that resolved by 30 days. A subset of players with significant postconcussive symptoms at 7 days postinjury had poorer HRQoL for at least 30 days postinjury than those whose postconcussive symptoms had resolved within a week of injury. This suggests ongoing recovery in this subset at 30 days and the potential utility of HRQoL as a measure of recovery.

Serum GFAP, NfL, and tau concentrations are associated with worse neurobehavioral functioning following mild, moderate, and severe TBI: a cross-sectional multiple-cohort study.

The purpose of this study was to examine whether blood-based biomarkers associate with neurobehavioral functioning at three time points following traumatic brain injury (TBI). Participants were 328 United States service members and veterans (SMVs) prospectively enrolled in the Defense and Veterans Brain Injury Center-Traumatic Brain Injury Center of Excellence (DVBIC-TBICoE) 15-Year Longitudinal TBI Study, recruited into three groups: uncomplicated mild TBI (MTBI, n = 155); complicated mild, moderate, severe TBI combined (STBI, n = 97); non-injured controls (NIC, n = 76). Participants were further divided into three cohorts based on time since injury (≤12 months, 3-5 years, and 8-10 years). Participants completed the Minnesota Multiphasic Personality Inventory-2-Restructured Format (MMPI-2-RF) and underwent blood draw to measure serum concentrations of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau. A total of 11 MMPI-2-RF scales were examined (e.g., depression, anxiety, anger, somatic, cognitive symptoms). Stepwise hierarchical regression models were conducted within each group. Significant associations were found between biomarkers and MMPI-2-RF scales (all p < 0.05; R2Δ > 0.10). GFAP was inversely related to (a) neurological complaints in the MTBI group at ≤12 months, (b) demoralization, anger proneness in the STBI group at ≤12 months, and (c) head pain complaints in the STBI group at 8-10 years. NfL was (a) related to low positive emotions in the NIC group; and inversely related to (b) demoralization, somatic complaints, neurological complaints, cognitive complaints in the MTBI group at ≤12 months, (c) demoralization in the STBI group at ≤12 months, and (d) demoralization, head pain complaints, stress/worry in the STBI group at 3-5 years. In the STBI group, there were meaningful findings (R2Δ > 0.10) for tau, NFL, and GFAP that did not reach statistical significance. Results indicate worse scores on some MMPI-2-RF scales (e.g., depression, stress/worry, neurological and head pain complaints) were associated with lower concentrations of serum GFAP, NfL, and tau in the sub-acute and chronic phase of the recovery trajectory up to 5 years post-injury, with a reverse trend observed at 8-10 years. Longitudinal studies are needed to help elucidate any patterns of association between blood-based biomarkers and neurobehavioral outcome over the recovery trajectory following TBI.

Does pain influence cognitive performance in patients with mild traumatic brain injury?

Pain is still a neglected problem in mild traumatic brain injury (mTBI). In this cross-sectional study, we examined the frequency of musculoskeletal pain in a sample of adult patients with persistent cognitive symptoms after mTBI and whether pain level affected cognition. The participants were 23 adult patients aged 18-50 referred to brain injury rehabilitation clinics for neuropsychological assessment after having sustained an mTBI. A non-injured control group (n = 29) was recruited through advertisements. The patients were, on average, assessed 22 months after trauma. All participants completed a comprehensive neuropsychological test battery and completed the Örebro Musculoskeletal Pain Screening Questionnaire, The Rivermead Post-Concussion Symptoms Questionnaire, and the State-Trait Anxiety Inventory. Patients reported high levels of current pain and significantly more frequent neck and shoulder pain than the non-injured controls. Patients also reported high post-concussive symptoms and anxiety levels and performed less well on several neuropsychological tests. Pain level was associated with slower processing speed among the controls but not related to performance in the mTBI group. We conclude that musculoskeletal pain is frequent in mTBI patients referred to rehabilitation settings. Furthermore, the results indicate that the interaction between pain and cognitive functioning differs in mTBI compared to controls. Our results implicate that pain screening should be an integrated part of neuropsychological rehabilitation after mTBI to identify conditions that run the risk of becoming chronic. The study was approved by the Regional Ethical Board in Stockholm, Sweden (04-415/2).