Symptomatic mTBI Research Articles

P.091 Multi-modal analysis of outcomes in pediatric mild traumatic brain injury (mTBI)

Background: mTBI is the most common type of head injury among children but diagnosing and managing symptoms are challenging due to heterogeneity. This study used multi-modal analysis to examine how acute mTBI symptoms transition to chronic deficits. Methods: Subjects included a cohort with mild TBI (n=40, 8-18 years old) and age/sex-matched controls (n=27). All participants received symptom assessment, neuropsychological evaluation, ERP assessment, neuroimaging, and serum cytokine analysis. Results were analyzed individually and in multi-modal models to identify important outcome predictors. Results: mTBI resulted in higher symptom burdens compared to controls. There were no group differences in measures of balance, ERP, FA, or MD. Female mTBI participants had lower CNSVS Neurocognition Index scores (p=0.0401) and faster reaction times (p=0.0385) than controls. Repetitive mTBI males had faster psychomotor speed than symptomatic mTBI males (p=0.0260). CTACK levels were higher in female mTBI groups (p= 0.0043), SCGF- levels were lower in male mTBI groups (p=0.0486), and MDC levels were lower in female mTBI groups (p=0.0377) compared to controls. Multi-modal models revealed key predictors from all modalities, despite most measures producing non-statistically significant results in individual analyses. Conclusions: Multi-modal analysis may afford the opportunity to delineate complex mTBI pathology and provide better identification of biomarkers than unimodal analysis.

0625 Characterization of Obstructive Sleep Apnea in Active-Duty US Military Personnel Receiving Interdisciplinary Care at the National Intrepid Center of Excellence

Abstract Introduction Among active-duty service members (ADSMs), obstructive sleep apnea (OSA) is associated with decreased quality of life and military readiness/retention. Limited evidence suggests mild traumatic brain injury (mTBI) patients have increased OSA incidence, but little is known about the underlying physiology. This study aims to characterize OSA in treatment-seeking ADSMs with a history of remote mTBI and/or persistent neurobehavioral symptoms to improve detection and early intervention. Methods This is a retrospective analysis of data collected from ADSMs attending the National Intrepid Center of Excellence Intensive Outpatient Program for persistent symptoms associated with mTBI. Sleep assessment included overnight polysomnography and self-report assessments of sleep quality, somatic and mood symptoms. OSA severity was determined by apnea-hypopnea index (negative: <5, mild: 5-15, moderate/severe: ≥15). Group differences were assessed using analysis of covariance and pairwise least squares regression, controlling for age and body mass index, and corrected for multiple comparisons. Results Analyses included 574 ADSMs, mostly male (99%), with a mean age of 39.7. The majority (n=288; 50.2%) were OSA negative (OSA-neg); a third had mild OSA (m-OSA) (n=216; 38%); and a tenth were diagnosed with moderate/severe OSA (mod/s-OSA) (n=70; 12%). Mod/s-OSA patients had increased arousal index (p<0.01), hypoxia time (p<0.001), reduced total sleep time (p<0.01) and sleep efficiency (p<0.001) compared to m-OSA and OSA-neg patients. M-OSA patients had an increased arousal index compared to OSA-neg patients (p<0.01). Patient groups did not significantly differ on subjective measures of sleep (i.e., quality, sleepiness), post-concussive, or behavioral health symptoms (anxiety, depression, post-traumatic stress symptoms, alcohol misuse). Conclusion In our sample of treatment-seeking ADSMs, nearly half presented with OSA according to cut-scores derived for AHI, greater than that expected in the general population. As reported in civilian populations, mod/s-OSA patients demonstrated worse objective sleep measures compared to m-OSA and OSA-neg patients, yet in our sample their self-reported symptom severity did not differ. These findings suggest a low threshold for OSA screening is needed in the symptomatic mTBI population and that multiple factors other than OSA likely contribute to perceived sleep disturbances and neurobehavioral symptoms. Support (If Any) None.

Learning and Attention Deficit/Hyperactivity Disorders as Risk Factors for Prolonged Concussion Recovery in Children and Adolescents.

Examine pre-existing learning disorders (LD) and attention deficit/hyperactivity disorders (ADHD) as risk factors for prolonged recovery and increased symptomology following pediatric mild traumatic brain injury (mTBI). We conducted a retrospective cohort study of children/adolescents (5-17 years) with mTBI who presented to a Children's Minnesota Concussion Clinic between April 2018 and March 2019. Differences across strata of pre-existing conditions (present vs. absent) in time to recovery measures were estimated via Kaplan-Meier and Cox proportional hazards analyses and differences in symptom trajectories were examined via linear mixed-effects regression models. Regression models were adjusted for age, sex and other confounders. In our cohort of 680 mTBI patients, those with LD (n = 70) or ADHD (n = 107) experienced significantly longer median durations of symptoms (58 and 68 days, respectively) than those without (43 days). Accordingly, LD was significantly associated with delayed symptom recovery (adjusted hazard ratio (aHR) = 1.63, 95% CI: 1.16-2.29), return to school (1.47, 1.08-2.00), and return to physical activity (1.50, 1.10-2.04). Likewise, ADHD was associated with delayed recovery (1.69, 1.28-2.23), return to school (1.52, 1.17-1.97) and physical activity (1.55, 1.19-2.01). Further, patients with LD or ADHD reported, on average, significantly more concussion symptoms and higher vision symptom scores throughout recovery versus those without. There was no evidence that concussion or vision symptom recovery trajectories varied over time between those with/without LD or ADHD (joint P-interactions > 0.05). Pre-existing LD and ADHD are risk factors for prolonged and more symptomatic mTBI recovery in youth. These results can inform clinical concussion management and recovery expectations.

Persistent impairment based symptoms post mild traumatic brain injury: Does a standard symptom scale detect them?

AimTo further explore symptoms in patients beyond the expected recovery period post mild Traumatic Brain Injury (mTBI) that are potentially indicative of impairment. MethodsNinety-four individuals (62 diagnosed with mTBI within the previous 4–24 weeks and 32 healthy controls) participated in the study. Participants in the mTBI group were further grouped as symptomatic (n = 33) or asymptomatic (n = 29) based on their spontaneous report of symptoms at the time of screening. Measures included a demographic questionnaire, 8 impairment specific self-report clinical tools, and a standard post-mTBI self-report symptom scale (Head Injury Scale (HIS)). ResultsCompared to the control group, scores for all instruments (including the HIS) were higher in the symptomatic mTBI group (P < 0.05), and higher for the neck disability and hyperarousal measures in the asymptomatic mTBI group (p < 0.035), but not the HIS (p > 0.093). Overall 94% of the symptomatic and 62% of the asymptomatic participants post-mTBI, recorded scores considered to be clinically relevant on at least one impairment screening tool. In contrast, only 28% of the asymptomatic mTBI group recorded a clinically relevant score for the HIS. ConclusionSymptoms indicative of persisting impairments beyond the expected recovery period were apparent in a substantial proportion of individuals post mTBI. Furthermore, a high percentage of individuals initially reporting as symptom free demonstrated clinically relevant scores on at least one impairment screening tool. Findings also suggest that a standard post-mTBI self-report symptom scale may often not detect the presence of persisting symptoms.

Relationships Between Subcortical Shape Measures and Subjective Symptom Reporting in US Service Members With Mild Traumatic Brain Injury.

To assess interactions of subcortical structure with subjective symptom reporting associated with mild traumatic brain injury (mTBI), using advanced shape analysis derived from volumetric MRI. Seventy-six cognitively symptomatic individuals with mTBI and 59 service members sustaining only orthopedic injury. Descriptive cross-sectional study. Self-report symptom measures included the PTSD Checklist-Military, Neurobehavioral Symptom Inventory, and Symptom Checklist-90-Revised. High-dimensional measures of shape characteristics were generated from volumetric MRI for 7 subcortical structures in addition to standard volume measures. Several significant interactions between group status and symptom measures were observed across the various shape measures. These interactions were revealed in the right thalamus and globus pallidus for each of the shape measures, indicating differences in structure thickness and expansion/contraction for these regions. No relationships with volume were observed. Results provide evidence for the sensitivity of shape measures in differentiating symptomatic mTBI individuals from controls, while volumetric measures did not exhibit this same sensitivity. Disruptions to thalamic nuclei identified here highlight the role of the thalamus in the spectrum of symptoms associated with mTBI. Additional work is needed to prospectively, and longitudinally, assess these measures along with cognitive performance and advanced multimodal imaging methods to extend the utility of shape analysis in relation to functional outcomes in this population.

Functional Magnetic Resonance Imaging of Cognitive Control following Traumatic Brain Injury.

Novel and non-routine tasks often require information processing and behavior to adapt from moment to moment depending on task requirements and current performance. This ability to adapt is an executive function that is referred to as cognitive control. Patients with moderate-to-severe traumatic brain injury (TBI) have been reported to exhibit impairments in cognitive control and functional magnetic resonance imaging (fMRI) has provided evidence for TBI-related alterations in brain activation using various fMRI cognitive control paradigms. There is some support for greater and more extensive cognitive control-related brain activation in patients with moderate-to-severe TBI, relative to comparison subjects without TBI. In addition, some studies have reported a correlation between these activation increases and measures of injury severity. Explanations that have been proposed for increased activation within structures that are thought to be directly involved in cognitive control, as well as the extension of this over-activation into other brain structures, have included compensatory mechanisms, increased demand upon normal processes required to maintain adequate performance, less efficient utilization of neural resources, and greater vulnerability to cognitive fatigue. Recent findings are also consistent with the possibility that activation increases within some structures, such as the posterior cingulate gyrus, may reflect a failure to deactivate components of the default mode network (DMN) and that some cognitive control impairment may result from ineffective coordination between the DMN and components of the salience network. Functional neuroimaging studies examining cognitive control-related activation following mild TBI (mTBI) have yielded more variable results, with reports of increases, decreases, and no significant change. These discrepancies may reflect differences among the various mTBI samples under study, recovery of function in some patients, different task characteristics, and the presence of comorbid conditions such as depression and posttraumatic stress disorder that also alter brain activation. There may be mTBI populations with activation changes that overlap with those found following more severe injuries, including symptomatic mTBI patients and those with acute injuries, but future research to address such dysfunction will require well-defined samples with adequate controls for injury characteristics, comorbid disorders, and severity of post-concussive symptoms.

The impact of symptomatic mild traumatic brain injury on complex everyday activities and the link with alterations in cerebral functioning: Exploratory case studies

ABSTRACTThe objective of the study was to explore the neurophysiological correlates of altered functional independence using functional magnetic resonance imaging (fMRI) and event-related potentials (ERP) after a mild traumatic brain injury (mTBI). The participants consisted of three individuals with symptomatic mTBI (3.9 ± 3.6 months post-mTBI) and 12 healthy controls. The main measures used were the Instrumental Activities of Daily Living (IADL) Profile observation-based assessment; a visual externally ordered working memory task combined to event-related potentials (ERP) and fMRI recordings; neuropsychological tests; post-concussion symptoms questionnaires; and the Activities of Daily Living (ADL) Profile interview. Compared to normal controls, all three patients had difficulty with a real-world complex budgeting activity due to deficits in planning, ineffective strategy use and/or a prolonged time to detect and correct errors. Reduced activations in the right mid-dorsolateral prefrontal cortex on fMRI as well as abnormal frontal or parietal components of the ERP occurred alongside these deficits. Results of this exploratory study suggest that reduced independence in complex everyday activities in symptomatic mTBI may be at least partly explained by a decrease in brain activation in the prefrontal cortex, abnormal ERP, or slower reaction times on working memory tasks. The study presents an initial attempt at combining research in neuroscience with ecological real-world evaluation research to further our understanding of the difficulties in complex everyday activities experienced by individuals with mTBI.

Altered cognitive processes in the acute phase of mTBI: an analysis of independent components of event-related potentials.

Mild traumatic brain injuries (mTBI) generate acute disruptions of brain function and a subset of patients shows persisting cognitive, affective, and somatic symptoms. Deficits in the executive function domain are among the more frequent cognitive impairments reported by mTBI patients. By means of independent component analysis, event-related potential components from a visual cued go/nogo task, namely contingent negative variation (CNV) and NoGo-P3, were decomposed into distinct independent components that have been shown to be associated with the executive processes of energization, monitoring, and task setting. A group of symptomatic mTBI patients was compared with a group of controls matched for sex, age, and education. Patients showed reduced amplitudes in the late CNV as well as in the early NoGo-P3 subcomponents. Whereas the decreased CNVlate component indicates an impaired ability to generate representations of stimulus-response associations and to energize the maintenance of response patterns, the reduced P3NOGOearly component suggests a deficient ability to invest attentional effort in the initiation of response patterns in mTBI patients. Besides indicating the effects of mTBI on cognitive brain processing, the results may open up the possibility for assessing individual mTBI profiles and facilitate personalized rehabilitative measures.

Cognitive Improvement after Mild Traumatic Brain Injury Measured with Functional Neuroimaging during the Acute Period.

Functional neuroimaging studies in mild traumatic brain injury (mTBI) have been largely limited to patients with persistent post-concussive symptoms, utilizing images obtained months to years after the actual head trauma. We sought to distinguish acute and delayed effects of mild traumatic brain injury on working memory functional brain activation patterns < 72 hours after mild traumatic brain injury (mTBI) and again one-week later. We hypothesized that clinical and fMRI measures of working memory would be abnormal in symptomatic mTBI patients assessed < 72 hours after injury, with most patients showing clinical recovery (i.e., improvement in these measures) within 1 week after the initial assessment. We also hypothesized that increased memory workload at 1 week following injury would expose different cortical activation patterns in mTBI patients with persistent post-concussive symptoms, compared to those with full clinical recovery. We performed a prospective, cohort study of working memory in emergency department patients with isolated head injury and clinical diagnosis of concussion, compared to control subjects (both uninjured volunteers and emergency department patients with extremity injuries and no head trauma). The primary outcome of cognitive recovery was defined as resolution of reported cognitive impairment and quantified by scoring the subject’s reported cognitive post-concussive symptoms at 1 week. Secondary outcomes included additional post-concussive symptoms and neurocognitive testing results. We enrolled 46 subjects: 27 with mild TBI and 19 controls. The time of initial neuroimaging was 48 (+22 S.D.) hours after injury (time 1). At follow up (8.7, + 1.2 S.D., days after injury, time 2), 18 of mTBI subjects (64%) reported moderate to complete cognitive recovery, 8 of whom fully recovered between initial and follow-up imaging. fMRI changes from time 1 to time 2 showed an increase in posterior cingulate activation in the mTBI subjects compared to controls. Increases in activation were greater in those mTBI subjects without cognitive recovery. As workload increased in mTBI subjects, activation increased in cortical regions in the right hemisphere. In summary, we found neuroimaging evidence for working memory deficits during the first week following mild traumatic brain injury. Subjects with persistent cognitive symptoms after mTBI had increased requirement for posterior cingulate activation to complete memory tasks at 1 week following a brain injury. These results provide insight into functional activation patterns during initial recovery from mTBI and expose the regional activation networks that may be involved in working memory deficits.

Differential Eye Movements in Mild Traumatic Brain Injury Versus Normal Controls

Objective measures to diagnose and to monitor improvement of symptoms following mild traumatic brain injury (mTBI) are lacking. Computerized eye tracking has been advocated as a rapid, user friendly, and field-ready technique to meet this need. Eye-tracking data collected via a head-mounted, video-based binocular eye tracker was used to examine saccades, fixations, and smooth pursuit movement in military Service Members with postconcussive syndrome (PCS) and asymptomatic control subjects in an effort to determine if eye movement differences could be found and quantified. Sixty Military Service Members with PCS and 26 asymptomatic controls. The diagnosis of mTBI was confirmed by the study physiatrist's history, physical examination, and a review of any medical records. Various features of saccades, fixation and smooth pursuit eye movements were analyzed. Subjects with symptomatic mTBI had statistically larger position errors, smaller saccadic amplitudes, smaller predicted peak velocities, smaller peak accelerations, and longer durations. Subjects with symptomatic mTBI were also less likely to follow a target movement (less primary saccades). In general, symptomatic mTBI tracked the stepwise moving targets less accurately, revealing possible brain dysfunction. A reliable, standardized protocol that appears to differentiate mTBI from normals was developed for use in future research. This investigation represents a step toward objective identification of those with PCS. Future studies focused on increasing the specificity of eye movement differences in those with PCS are needed.

Enhanced attention capture by emotional stimuli in mild traumatic brain injury.

Mild traumatic brain injury (mTBI) may be associated with compromised executive functioning and altered emotional reactivity. Despite frequent affective and cognitive symptoms in mTBI, objective evidence for brain dysfunction is often lacking. Previously we have reported compromised performance in symptomatic mTBI patients in an executive reaction time (RT) test, a computer-based RT test engaging several executive functions simultaneously. Here, we investigated the cognitive control processes in mTBI in context of threat-related stimuli. We used behavioral measures and event-related potentials (ERP) to investigate attentional capture by task-relevant and task-irrelevant emotional stimuli during a Go-NoGo task requiring cognitive control. We also assessed subjective cognitive, somatic, and emotional symptoms with questionnaires. Twenty-seven subjects with previous mTBI and 17 controls with previous ankle injury participated in the study over 9 months post-injury. Electroencephalogram (EEG) was recorded while patients performed a modified executive RT-test. N2-P3 ERP component was used as a general measure of allocated attentional and executive processing resources. Although at the time of the testing, the mTBI and the control groups did not differ in symptom endorsement, mTBI patients reported having had more emotional symptoms overall since the injury than controls. The overall RT-test performance levels did not differ between groups. However, when threat-related emotional stimuli were used as Go-signals, the mTBI group was faster than the control group. In comparison to neutral stimuli, threat-related stimuli were associated with increased N2-P3 amplitude in all conditions. This threat-related enhancement of the N2-P3 complex was greater in mTBI patients than in controls in response to Go signals and NoGo signals, independent of relevance. We conclude that mTBI may be associated with enhanced attentional and executive resource allocation to threat-related stimuli. Along with behavioral evidence for enhanced attention allocation to threat stimuli, increased brain responses to threat were observed in mTBI. Enhanced attention capture by threat-related emotional stimuli may reflect inefficient top-down control of bottom-up influences of emotion, and might contribute to affective symptoms in mTBI.

Optimization of the pattern visual evoked potential (VEP) in the visually-normal and mild traumatic brain injury (mTBI) populations

Primary objective: The purpose of this study was to assess the effect of check size (CS) and contrast (C) on VEP amplitude and latency in visually-normal (VN) and in mild traumatic brain injury (mTBI) adults to develop an optimized test protocol in each group.Research design and methods: Subjects were comprised of VN (n = 19) and individuals with mTBI (n = 16). Full-field, pattern VEP testing was employed with three different CSs (10, 20 and 40 min arc) and at two C levels (20 and 85%).Results: There was a significant effect of CS and C on the VEP amplitude and latency in both groups. The 20 min arc CS at both contrast levels produced the largest VEP amplitude, in conjunction with normative latency values, in both populations. There was a significant differential effect of CS and C on VEP responses in the visually symptomatic vs. asymptomatic mTBI sub-groups. A significant correlation was found between time since their most recent brain injury and VEP amplitude for the 20 min arc CS at low contrast.Conclusions: Use of the 20 min arc CS at both contrast levels represents an optimized clinical VEP test protocol in both the VN and mTBI groups. This protocol is rapid, high yield, and targeted for each diagnostic group.

Functional Magnetic Resonance Imaging of Working Memory and Response Inhibition in Children with Mild Traumatic Brain Injury

The current pilot study examined functional magnetic resonance imaging (fMRI) activation in children with mild traumatic brain injury (mTBI) during tasks of working memory and inhibitory control, both of which are vulnerable to impairment following mTBI. Thirteen children with symptomatic mTBI and a group of controls completed a version of the Tasks of Executive Control (TEC) during fMRI scanning. Both groups showed greater prefrontal activation in response to increased working memory load. Activation patterns did not differ between groups on the working memory aspects of the task, but children with mTBI showed greater activation in the posterior cerebellum with the addition of a demand for inhibitory control. Children with mTBI showed greater impairment on symptom report and "real world" measures of executive functioning, but not on traditional "paper and pencil" tasks. Likewise, cognitive testing did not correlate significantly with imaging results, whereas increased report of post-concussive symptoms were correlated with increased cerebellar activation. Overall, results provide some evidence for the utility of symptom report as an indicator of recovery and the hypothesis that children with mTBI may experience disrupted neural circuitry during recovery. Limitations of the study included a small sample size, wide age range, and lack of in-scanner accuracy data.

Deficits in complex visual information processing after mild TBI: Electrophysiological markers and vocational outcome prognosis

Primary objective: To evaluate low-level to complex information processing using visual electrophysiology and to examine the latter's prognostic value in regards to vocational outcome in persons having sustained a mild traumatic brain injury (mTBI).Research design/methods: Event-related potentials (ERPs) were recorded to pattern-reversal, simple motion, texture segregation and cognitive oddballparadigms from 17 participants with symptomatic mTBI at onset of specialized clinical intervention and from 15 normal controls. The relationship between abnormal electrophysiology and post-intervention return to work status was also examined.Main outcomes and results: Participants with mTBI showed a statistically significant (p< 0.05) amplitude reduction for cognitive ERPs and delayed latencies for texture (p< 0.05) and cognitive paradigms (p< 0.005) compared to controls. Furthermore, participants with mTBI presenting texture or cognitive ERP latency delays upon admission were at significantly (p< 0.01) greater risk of negative vocational outcome than mTBI participants with normal electrophysiology.Conclusions: The findings suggest that individuals with symptomatic mTBI can present selective deficits in complex visual information processing that could interfere with vocational outcome. ERP paradigms such as those employed in this study thus show potential for evaluating outcome prognosis and merit further study.

Vocational outcome indicators in atypically recovering mild TBI: A post-intervention study

Beyond issues of MTBI etiology, a key question remains the characterization and early identification of those individuals at risk of poor functional outcome. Using a retrospective analysis, the current study aimed at identifying the specific indicators related to return to work in adults with both symptomatic MTBI and functional impacts, having completed a specialized intervention program. In terms of outcome, 59.1% of the cohort (n=110) returned to some form of work-related activity by the end of intervention whereas the rest had not. Three of the sixteen variables studied were retained (logistic regression) as providing unique and significant (p<0.05) contributions to the prediction outcome model, namely age, number of subjective symptoms and the presence of a public insurance provider. There was also an interaction between the presence of a public insurance provider and referral delay. Overall percentage of cases correctly classified by the model was 70%, positive predictive accuracy was 72.9%, whereas negative predictive accuracy was 65%. Our findings suggest that any studies attempting to assess functional outcome need to take account of the multifactorial nature of MTBI, including not only more objective psychological/physiological variables related to the injury, but also subjective complaints and environmental factors.

WAIS-III and WMS-III Profiles of Mildly to Severely Brain-Injured Patients

Wechsler Adult Intelligence Scale-III (WAIS-III) and Wechsler Memory Scale-III (WMS-III; The Psychological Corporation, 1997) scores of patients with mild traumatic brain injury (MTBI, n = 23) to moderate-severe traumatic brain injury (M-S TBI, n = 22) were compared to those of 45 matched normal control patients. WAIS-III results revealed that IQ and index scores of MTBI patients did not significantly differ from those of controls, whereas M-S TBI patients received significantly lower mean scores on all measures. All M-S TBI patients' WMS-III index scores also revealed significantly lower scores in comparison to those of control participants, with the exception of Delayed Auditory Recognition. MTBI patients showed significantly lower mean index scores compared to normal controls on measures of immediate and delayed auditory memory, immediate memory, visual delayed memory, and general memory. Eta-squared analyses revealed that WMS-III visual indexes and WAIS-III processing speed showed particularly large effect sizes. These results suggest that symptomatic MTBI patients obtain some low WMS-III test scores comparable to those of more severely injured patients.