Increased Cholinergic Activity in Mild Traumatic Brain Injury: Preliminary Evidence from [18F]FEOBV PET Study.

Balance and mobility issues are common non-resolving symptoms following mild traumatic brain injury (mTBI). Current approaches for evaluating balance and mobility following an mTBI can be subjective and sub-optimal as they may not be sensitive to subtle deficits, particularly in those with chronic mTBI. Wearable inertial measurement units (IMU) allow objective quantification of continuous mobility outcomes in natural free-living environments. This study aimed to explore free-living mobility (physical activity and turning) of healthy and chronic mild traumatic brain injury (mTBI) participants using a single IMU.Free-living mobility was examined in twenty-three healthy control (48.56±23.07years) and twenty-nine symptomatic mTBI (40.2±12.1years) participants (average 419days post-injury, persistent balance complaints) over one week, using a single IMU placed at the waist. Free-living mobility was characterized in terms of Macro (physical activity volume, pattern and variability) and Micro-level (discrete measures of turning) features.Macro-level outcomes showed those with chronic mTBI had similar quantities of mobility compared to controls. Micro-level outcomes within walking bouts showed that chronic mTBI participants had impaired quality of mobility. Specifically, people with chronic mTBI made larger turns, had longer turning durations, slower average and peak velocities (all p<.001) and greater turn variability compared to controls. Results highlighted that the quality, rather than quantity of mobility differentiated chronic mTBI from controls.Our findings support the use of free-living IMU continuous monitoring to enhance understanding of specific chronic mTBI-related mobility deficits. Future work is required to develop an optimal battery of free-living measures across the mTBI spectrum to aid application within clinical practice.

Vesicular acetylcholine transporter (VAChT) is a rate-limiting factor for synaptic acetylcholine transport. Our study focused on whether [18 F] VAT, a novel positron emission tomography (PET) tracer, could be used in detecting cognitive deficits in epilepsy. Morris water maze test was used to evaluate learning and memory deficits in pilocarpine-induced chronic epilepsy rats 12 weeks after status epilepticus. Interictal [18 F] VAT PET was performed 13 weeks after status epilepticus to evaluate the level of VAChT in cholinergic pathways compared with [18 F] fluorodeoxyglucose PET. The association between VAChT levels and memory measures was analyzed. Neuropathological tests were performed. Epileptic rats exhibited significant memory deficits in Morris water maze test. [18 F] VAT uptake decreased in septum, hippocampus, thalamus, and basal forebrain, and correlated to memory function. Of note, the level of VAChT in basal forebrain significantly decreased, yet no glucose hypometabolism was detected. Immunofluorescence and Western blot demonstrated decreased expression of VAChT in hippocampus and basal forebrain in the epilepsy group, but no change of expression of acetyltransferase or activity of acetylcholinesterase was detected. [18 F] VAT PET is a promising method to test the level of VAChT as a valuable biomarker for memory deficits in pilocarpine-induced chronic epileptic rats.

Recent Neuroimaging Techniques in Mild Traumatic Brain Injury

Objective:To examine neurocognitive correlates of oculomotor performance among U.S. military personnel with history of mild traumatic brain injury (mTBI).Participants and Methods:A series of studies (total n=356) were conducted to examine saccadic eye movements and manual button presses collected in response to attention stimuli, and to compare these findings to the results of standardized neuropsychological tests. Study 1 included n=27 with remote mTBI and n=54 controls who completed the Bethesda Eye and Attention Measure (BEAM), an eye tracking task that was designed to measure visual attention and executive function. In Study 2, n=51 with chronic mTBI and n=33 controls completed the Fusion n-Back task, an eye tracking task that was designed to assess the impact of working memory load on visual attention performance. Study 3 examined psychometric characteristics of BEAM among n=191 military personnel with remote mTBI. In all studies, participants completed eye tracking tasks, a structured TBI diagnostic interview, and a brief battery of standardized neuropsychological tests.Results:In Study 1, BEAM saccadic and manual metrics demonstrated strong reliability and high sensitivity to multiple cognitive cues designed to elicit spatial orienting, temporal alerting, executive interference, perceptual release (gap) and inhibition (n2p=.76, p&lt;.001). However, corresponding saccadic and manual measurements were weakly related to each other, and only manual (not saccadic) measurements were related to estimated verbal intelligence or years of education. Standardized neuropsychological measures did not differ between groups, but mTBI participants were more likely to be impaired on saccadic metrics than controls.In Study 2, Standardized cognitive measures and estimated premorbid intelligence were positively associated with all manual metrics from the Fusion n-Back test, but were not associated with mTBI history or with saccadic metrics. Fusion n-Back saccadic and manual metrics had strong reliability and complementary sensitivity to chronic mTBI, with combined predictive power of PPV=.78, NPV=.72, r2=.44 for classification of remote mild TBI vs. controls on the more cognitively-challenging 1-back task condition.In Study 3, BEAM metrics including manual RT latency and consistency, saccadic RT consistency, and saccadic inhibition errors showed consistent correlations with standardized measures of visual attention, processing speed, task switching, working memory, and executive functions. Hierarchical regressions showed that BEAM saccadic and manual metrics were independently predictive of cognitive test performance, above and beyond effects of demographic factors and clinical characteristics.Conclusions:Results demonstrated some surprising findings related to neurocognitive influences on oculomotor performance. While both saccadic and manual performance were strongly and similarly influenced by attention cues, these two modalities were only weakly correlated to one another. Additionally, manual metrics were more strongly and consistently related to standardized cognitive test performance and premorbid intelligence than saccadic metrics. However, saccadic metrics demonstrated superior sensitivity to remote/chronic mTBI relative to manual metrics and standardized neuropsychological measures. Overall, these results suggest that saccadic eye tracking measures may provide unique value in assessment of mTBI and neurocognitive functions that is complementary with more common forms of assessment relying upon somatomotor response modalities.

Ocular motor control (OMC) and cognitive dysfunction are common persistent sequelae in persons with mild traumatic brain injury (mTBI). Combat and training operations frequently expose military Service Members to biomechanical and blast events that render them susceptible to mTBI, and problems such as OMC disturbances and cognitive dysfunction are frequent long after injury. However, these problems can be difficult to detect, often only becoming clinically evident with physical or psychological stress. Knowledge of the relationship between OMC and cognitive dysfunction in chronic mTBI, and of clinical tools to assess this issue, is limited. Setting: Academic laboratory; Marcus Institute for Brain Health, University of Colorado; Design: 2-arm, examiner-blinded cross-sectional observational study. Participants: Military Veterans with chronic mTBI (experimental; n = 38) whose most recent mTBI was more than 3 months before enrolment, and Veterans without a history of TBI (control; n = 40); Measures: The computerized King-Devick (K-D) test assessed rapid number naming tasks; the Right Eye computerized eye tracker system measured antisaccade tasks; the Conners' Continuous Performance Test (CPT) tested aspects of selective and sustained attention and impulsivity; the FAS test measured the ability to name as many common nouns that start with "F," "A," and "S" as a method to assess phonemic verbal fluency, attention, and initiation; and the Posttraumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5) was used as a self-report of posttraumatic stress-related symptoms. Veterans in the experimental group had a median of 2 mTBIs, and these occurred approximately 11 years before the study. On the K-D Test, the experimental group had significantly more errors and took significantly more time (51.32 seconds) compared with the control group (43.00 seconds). Significantly greater antisaccade latencies were found in the experimental group for target only, on target distractor, and ipsilateral proximal distractor paradigms, and antisaccade error rates were significantly greater in the experimental group for the contralateral proximal distractor paradigm. Significantly greater PCL-5, and worse FAS test scores and CPT commissions and omissions scores were found in the experimental group. For the experimental group, time since most recent TBI correlated with antisaccade on target distractor error rates. Regression modeling showed that FAS test scores were a significant determinant of K-D test performance. Separate regression modeling for each of the antisaccade task paradigms indicated that group status was significantly associated with antisaccade latency scores for the ipsilateral proximal distractor paradigm. PCL-5 was a significant factor for the on target distractor paradigm, and age and cognitive function denoted by FAS test and CPT scores were significant factors contributing to error rates in multiple specified antisaccade paradigm task performances. Results support the conclusion that OMC and cognitive performance are persistent co-occurring problems in Veterans with chronic mTBI. Notably, these deficits can be detected even after as few as 2 mTBIs that occurred 11 years earlier, indicating that an OMC-cognition axis of sequelae may exist in the chronic stage of mTBI. The results also identify cognitive correlates of the OMC task paradigms, aiding in the clinical application and interpretation of these tests in chronic mTBI.

This pilot study explores the metabolic changes associated with persistent postconcussion syndrome (PCS) after mild traumatic brain injury (mTBI; >12 months after injury) using magnetic resonance spectroscopy. We hypothesized that those mTBI participants with PCS will have larger metabolic differences than those without. Data were collected from mTBI participants with PCS, mTBI participants without PCS and non-head-injured participants (all groups: n=8). Magnetic resonance spectroscopy metabolite profiles within the dorsolateral prefrontal cortex showed a reduced creatine/choline ratio in mTBI patients compared with control participants. This data provides initial evidence for residual metabolic changes in chronic mTBI patients, but there was no conclusive relationship between these metabolic changes and PCS symptom report. Creatine is involved in maintaining energy levels in cells with high or fluctuating energy demand, suggesting that there may be some residual energy impairment in chronic mTBI.

Background: Elevations of inflammatory cytokine levels occur immediately after mild traumatic brain injury (mTBI) and can persist for years. These elevations have been associated with neuropsychological outcomes, including depression and PTSD symptoms. Sleep disorders, another common sequelae of mTBI, are independently associated with inflammation in otherwise healthy individuals. However, whether sleep and inflammation are linked in chronic mTBI has not been reported.Methods: A retrospective cross-sectional cohort of warfighters was used to investigate the hypothesis that inflammation may be linked to sleep quality in chronic mTBI. Clinical history, peripheral blood samples, and sleep quality scores were collected from 182 warfighters (n = 138 mTBI; n = 44 controls) during enrollment in the Chronic Effects of Neurotrauma Consortium study. Biomarkers of inflammation (IL-6, IL-10, TNFα cytokines) from plasma and plasma-derived extracellular vesicles (EVs) were quantified using single molecule array. Relationships between sleep quality and cytokine levels were assessed, controlling for age, sex, and BMI. Using clinical cutoff scores for sleep quality, mTBI patients were then divided into “good” and “poor” sleepers and cytokine levels compared between groups.Results: In mTBI participants, sleep quality was significantly associated with EV levels of IL-10 [ß (SE) = 0.11 (0.04), p = 0.01] and TNFα [ß (SE) = 0.07 (0.03), p < 0.01]. When divided according to “good” versus “poor” sleepers, those reporting poor sleep had significantly elevated EV IL-10 compared to those reporting good sleep [ß (SE) = 0.12 (0.04), p < 0.01]. Plasma-derived associations were not significant. No associations were found between sleep quality and cytokine levels in controls.Conclusion: These results suggest a significant relationship between sleep quality and chronic inflammation in mTBI patients. Clinically, mTBI patients with a high likelihood of sleep disorders demonstrate elevated levels of inflammatory cytokines. Signal from EVs, though smaller in magnitude, may have stronger clinical associations than from plasma. Sleep-focused interventions may also serve to regulate chronic inflammatory processes in these patients. Larger prospective studies are needed to investigate the mechanisms and therapeutic implications of the likely bi-directional relationship between sleep and inflammation following mTBI.

Turning is common in daily activity and requires rapid, coordinated reorientation of the head, trunk, and pelvis toward the new direction of travel. Yet, turning gait has not been well explored in populations with mild traumatic brain injury (mTBI) who may alter their turning behavior according to self-perceived symptoms or motor dysfunction. The purpose of this study was to examine turning velocities and coordination in adults with chronic mTBI (>3 months post-injury and still reporting balance complaints) during a task simulating everyday ambulation. We hypothesized that individuals with chronic mTBI would reduce their angular velocity when turning and increase the variability of head-pelvis coordination compared with controls, and that the reduction in velocity and increased variability would be associated with their self-reported symptom score. Forty-two adults (14 chronic mTBI, 28 controls) completed the Neurobehavioral Symptom Inventory before walking 12 laps around a marked course containing two 45-degree turns, four 90-degree turns, and two 135-degree turns. Inertial sensors collected angular velocities of the head and pelvis. After adjusting for covariates, participants with chronic mTBI had significantly slower lap times and peak angular velocities of the pelvis (p < 0.01) compared with the control group. The peak velocity timing (PVT) between peak velocities of the head and pelvis, and the variability of that timing was significantly greater in participants with chronic mTBI (p < 0.01). Within the chronic mTBI group, somatosensory symptoms were associated with slower angular velocities of the head and pelvis (p = 0.03) and increased PVT variability (p < 0.01). The results suggest individuals with chronic mTBI with worse somatic symptoms have impaired head stabilization during turning in situations similar to everyday life. These results encourage future research on turning gait to examine the causal relationship between symptoms and daily locomotor function in adults with chronic mTBI.

Mild traumatic brain injury (mTBI) accounts for more than 80% of people experiencing brain injuries. Symptoms of mTBI include short-term and long-term adverse clinical outcomes. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) was conducted to measure voxel-based indices including fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) in patients suffering from chronic mTBI; 64 patients with chronic mTBI at least 3 months post injury and 40 healthy controls underwent rs-fMRI scanning. Partial correlation analysis controlling for age and gender was performed within mTBI cohort to explore the association between rs-fMRI metrics and neuropsychological scores. Compared with controls, chronic mTBI patients showed increased fALFF in the left middle occipital cortex (MOC), right middle temporal cortex (MTC), and right angular gyrus (AG), and increased ReHo in the left MOC and left posterior cingulate cortex (PCC). Enhanced FC was observed from left MOC to right precuneus; from right MTC to right superior temporal cortex (STC), right supramarginal, and left inferior parietal cortex (IPC); and from the seed located at right AG to left precuneus, left superior medial frontal cortex (SMFC), left MTC, left superior temporal cortex (STC), and left MOC. Furthermore, the correlation analysis revealed a significant correlation between neuropsychological scores and fALFF, ReHo, and seed-based FC measured from the regions with significant group differences. Our results demonstrated that alterations of low-frequency oscillations in chronic mTBI could be representative of disruption in emotional circuits, cognitive performance, and recovery in this cohort.

Neuron-derived exosomes (NDEs) were enriched by anti-L1CAM antibody immunoabsorption from plasmas of subjects ages 18-26 yr within 1 wk after a sports-related mild traumatic brain injury (acute mTBI) ( n = 18), 3 mo or longer after the last of 2-4 mTBIs (chronic mTBI) ( n = 14) and with no recent history of TBI (controls) ( n = 21). Plasma concentrations of NDEs, assessed by counts and levels of extracted exosome marker CD81, were significantly depressed by a mean of 45% in acute mTBI ( P < 0.0001), but not chronic mTBI, compared with controls. Mean CD81-normalized NDE levels of a range of functional brain proteins were significantly abnormal relative to those of controls in acute but not chronic mTBI, including ras-related small GTPase 10, 73% decrease; annexin VII, 8.8-fold increase; ubiquitin C-terminal hydrolase L1, 2.5-fold increase; AII spectrin fragments, 1.9-fold increase; claudin-5, 2.7-fold increase; sodium-potassium-chloride cotransporter-1, 2.8-fold increase; aquaporin 4, 8.9-fold increase (3.6-fold increase in chronic mTBI); and synaptogyrin-3, 3.1-fold increase (1.3-fold increase in chronic mTBI) (all acute mTBI proteins P < 0.0001). In chronic mTBI, there were elevated CD81-normalized NDE levels of usually pathologic β-amyloid peptide 1-42 (1.6-fold, P < 0.0001), P-T181-tau (2.2-fold, P < 0.0001), P-S396-tau (1.6-fold, P < 0.01), IL-6 (16-fold, P < 0.0001), and prion cellular protein (PRPc) (5.1-fold, P < 0.0001) with lesser or greater (IL-6, PRPc) increases in acute mTBI. Increases in NDE levels of most neurofunctional proteins in acute, but not chronic, mTBI, and elevations of most NDE neuropathological proteins in chronic and acute mTBI delineated phase-specificity. Longitudinal studies of more mTBI subjects may identify biomarkers predictive of and etiologically involved in mTBI-induced neurodegeneration.-Goetzl, E. J., Elahi, F. M., Mustapic, M., Kapogiannis, D., Pryhoda, M., Gilmore, A., Gorgens, K. A., Davidson, B., Granholm, A.-C., Ledreux, A. Altered levels of plasma neuron-derived exosomes and their cargo proteins characterize acute and chronic mild traumatic brain injury.

ABSTRACTPrimary Objective: Risk for mental health disturbances (e.g., depression and anxiety), is elevated following a mild traumatic brain injury (mTBI), even in the chronic stages of injury. In our previous work, we found individuals with chronic mTBI have decreased emotion habituation. The objective of the current study was to test whether reduced habituation is a mechanism underlying increased risk for mental health disturbances following mTBI.Research Design: We used a cross-sectional assessment of emotion habituation in a sample of young adults at least 1 year after an mTBI.Methods and Procedures: We repeatedly showed mTBI and control participants the same set of highly arousing, negative images and positive images. Participants rated each image for arousal and valence.Main Outcomes and Results: Unexpectedly, we found individuals with mTBI habituated faster to emotional images than controls. However, enhanced habituation was not linkd with emotional outcomes. Participants with mTBI did not differ from controls for reactivity, but blunted reactivity in all participants was associated with higher depressive symptoms.Conclusions: Although there are subtle differences in emotion responses in chronic mTBI, the differences were not associated with mental health disturbances. Nevertheless, this difference in emotional processing may increase risk for untested mental health issues.

Aerobic exercise training engages cholinergic signaling to improve emphysema induced by cigarette smoke exposure in mice

Complaints of non-resolving imbalance are common in individuals with chronic mild traumatic brain injury (mTBI). Vestibular rehabilitation therapy may be beneficial for this population. Additionally, wearable sensors can enable biofeedback, specifically audio biofeedback (ABF), and aid in retraining balance control mechanisms in people with balance impairments. In this study, we described the effectiveness of vestibular rehabilitation therapy with and without ABF to improve balance in people with chronic mTBI. Participants (n = 31; females = 22; mean age = 40.9 ± 11 y) with chronic (>3 months) mTBI symptoms of self-reported imbalance were randomized into vestibular rehabilitation with ABF (n = 16) or without ABF (n = 15). The intervention was a standard vestibular rehabilitation, with or without ABF, for 45 min biweekly for 6 weeks. The ABF intervention involved a smartphone that provided auditory feedback when postural sway was outside of predetermined equilibrium parameters. Participant's completed the Post-Concussion Symptom Scale (PCSS). Balance was assessed with the sensory organization test (SOT) and the Central Sensorimotor Integration test which measured sensory weighting, motor activation, and time delay with sway evoked by surface and/or visual surround tilts. Effect sizes (Hedge's G) were calculated on the change between pre-and post-rehabilitation scores. Both groups demonstrated similar medium effect-sized decreases in PCSS and large increases in SOT composite scores after rehabilitation. Effect sizes were minimal for increasing sensory weighting for both groups. The with ABF group showed a trend of larger effect sizes in increasing motor activation (with ABF = 0.75, without ABF = 0.22) and in decreasing time delay (with ABF = −0.77, without ABF = −0.52) relative to the without ABF group. Current clinical practice focuses primarily on sensory weighting. However, the evaluation and utilization of motor activation factors in vestibular rehabilitation, potentially with ABF, may provide a more complete assessment of recovery and improve outcomes.

Mild traumatic brain injury (mTBI) is a major health concern among active duty service members and Veterans returning from combat operations, and it can result in variable clinical and cognitive outcomes. Identifying biomarkers that can improve diagnosis and prognostication has been at the forefront of recent research efforts. The purpose of this study was to compare the sensitivity and specificity of abnormalities identified using more traditional magnetic resonance imaging (MRI) sequences such as fluid attenuation inversion recovery (FLAIR) to more advanced MRI sequences such as susceptibility weighted imaging (SWI) among a cohort of active duty service members experiencing persistent cognitive symptoms after mTBI. One-hundred and fifty-two active duty service members (77 mTBI, 58 orthopedically injured [OI] only, 17 post-traumatic stress disorder [PTSD] only) underwent MRI and neuropsychological evaluation at a large military treatment facility. Results demonstrated that FLAIR white matter hyperintensities (WMHs) were present in all three groups at statistically similar rates (41% mTBI, 49% OI, and 29% PTSD). With the exception of a single OI participant showing a small discrete SWI lesion, SWI abnormalities were overwhelmingly present in mTBI patients (22% mTBI, 1% OI, and 0% PTSD). Functionally, mTBI participants with and without SWI abnormalities did not differ in demographics, symptom reporting, or cognitive performance. However, mTBI participants with and without WMH did differ for on measures of working memory with the mTBI participants with WMH having worse cognitive performance. No other significant differences were noted for those participants with and without imaging abnormalities for either the OI or PTSD only cohorts. These results appear to illustrate the sensitivity and specificity of SWI findings though these results did not have any significant functional impact in this cohort. In contrast, WMHs noted on FLAIR imaging were not sensitive or specific findings, but functionally relevant among mTBI participants. These findings emphasize the complexity of injury and functional outcome in mTBI patients that requires additional examination.

Symptoms of post-traumatic stress disorder (PTSD) are common in military populations, and frequently associated with a history of combat-related mild traumatic brain injury (mTBI). In this study, we examined relationships between severity of PTSD symptoms and levels of extracellular vesicle (EV) proteins and miRNAs measured in the peripheral blood in a cohort of military service members and Veterans (SMs/Vs) with chronic mTBI(s). Participants (n = 144) were divided into groups according to mTBI history and severity of PTSD symptoms on the PTSD Checklist for DSM-5 (PCL-5). We analyzed EV levels of 798 miRNAs (miRNAs) as well as EV and plasma levels of neurofilament light chain (NfL), Tau, Amyloid beta (Aβ) 42, Aβ40, interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF). We observed that EV levels of neurofilament light chain (NfL) were elevated in participants with more severe PTSD symptoms (PCL-5 ≥ 38) and positive mTBI history, when compared to TBI negative controls (p = 0.024) and mTBI participants with less severe PTSD symptoms (p = 0.006). Levels of EV NfL, plasma NfL, and hsa-miR-139–5p were linked to PCL-5 scores in regression models. Our results suggest that levels of NfL, a marker of axonal damage, are associated with PTSD symptom severity in participants with remote mTBI. Specific miRNAs previously linked to neurodegenerative and inflammatory processes, and glucocorticoid receptor signaling pathways, among others, were also associated with the severity of PTSD symptoms. Our findings provide insights into possible signaling pathways linked to the development of persistent PTSD symptoms after TBI and biological mechanisms underlying susceptibility to PTSD.