Long-term Effects Of Traumatic Brain Injury Research Articles

Transcranial Doppler Ultrasound Role for Patients with Traumatic Brain Injury

Neurologists, neurosurgeons, and neurointensivists, including military, have a large armamentarium of diagnostic and monitoring devices available to detect primary and secondary brain injury and guide therapy in patients with acute traumatic brain injury (TBI) to avoid cerebral ischemia due to the posttraumatic vasospasm (PTV) and intracranial hypertension (ICH). This review summarizes the advantages and the specific roles of transcranial Doppler (TCD) ultrasonography for patients with acute and longterm effects of TBI. In critical care setting numerous publications showed that TCD is predictive of angiographic PTV and onset of ICH. The post TBI status of cerebrovascular reactivity and cerebral hemodynamics also has important implications with regard to the treatment of long-term effects of mild TBI (mTBI). Today it is abundant evidence that TCD is an important tool for monitoring the natural course of acute moderate and severe TBI, for evaluating the effect of medical treatment or intervention, for forecasting, and for identifying high-risk patients for onset of cerebral ischemia after TBI. TCD makes good clinical and economic sense as it is a reliable, quantitative, non-invasive and non-expensive “biomarker” to the acute clinical manifestations of TBI. TCD clinical utilization holds promise for better detection, characterization, and monitoring of objective cerebral hemodynamics changes in symptomatic patients with TBI not readily apparent by standard CT or conventional MRI techniques. TCD utilization will improve the sensitivity of neuroimaging to subtle brain perturbations and combining these objective measures with careful clinical characterization of patients may facilitate better understanding of the neural bases and treatment of the signs and symptoms of TBI. This review summarizes the advantages and the specific roles of TCD ultrasonography for patients with acute and long-term effects of TBI.

Assessment of the individual and compounding effects of marginalization factors on injury severity, discharge location, recovery, and employment outcomes at 1 year after traumatic brain injury.

ObjectiveThe aim of this study is to examine the effect of eight distinct marginalized group memberships and explore their compounding effect on injury severity, recovery, discharge location, and employment outcomes 1-year after traumatic brain injury (TBI).MethodsIndividuals with medically confirmed, complicated mild-severe TBI (N = 300) requiring inpatient rehabilitation care between the ages of 18 and 65 were recruited at two urban (public and private) health systems between 2013 and 2019. Data were collected from self-report and medical record abstraction. Marginalized group membership (MGM) includes racial and ethnic minority status, less than a high school diploma/GED, limited English proficiency, substance abuse, homelessness, psychiatric hospitalizations, psychiatric disorders, and incarceration history. Membership in four or more of these groups signifies high MGM. In addition, these factors were explored individually. Unadjusted and adjusted linear and logistic regressions and Kruskal–Wallis tests were used to assess the associations of interest in RStudio.ResultsAfter adjusting for age, sex, and cause of injury, compared to TBI patients with low MGM, those with high MGM experience significantly longer post-traumatic amnesia (95% CI = 2.70, 16.50; p = 0.007) and are significantly more likely to have a severe TBI (per the Glasgow-Coma Scale) (95% CI = 1.70, 6.10; p ≤ 0.001) than a complicated mild-moderate injury. Individuals with high MGM also are significantly less likely to be engaged in competitive paid employment 1 year after injury (95% CI = 2.40, 23.40; p = 0.001). Patients with high MGM are less likely to be discharged to the community compared to patients with low MGM, but this association was not significant (95% CI = 0.36, 1.16; p = 0.141). However, when assessing MGMs in isolation, certain associations were not significant in unadjusted or adjusted models.ConclusionThis exploratory study's findings reveal that when four or more marginalization factors intersect, there is a compounding negative association with TBI severity, recovery, and employment outcomes. No significant association was found between high MGM and discharge location. When studied separately, individual MGMs had varying effects. Studying marginalization factors affecting individuals with TBI has critical clinical and social implications. These findings underline the importance of addressing multidimensional factors concurrent with TBI recovery, as the long-term effects of TBI can place additional burdens on individuals and their economic stability.

Simulation of the Strain Amplification in Sulci Due to Blunt Impact to the Head

Traumatic brain injury (TBI) has become a concern in sports, automobile accidents and combat operations. A better understanding of the mechanics leading to a TBI is required to cope with both the short-term life-threatening effects and long-term effects of TBIs, such as the development chronic traumatic encephalopathy (CTE). Kornguth et al. (1) proposed that an inflammatory and autoimmune process initiated by a water hammer effect at the bases of the sulci of the brain is a mechanism of TBI leading to CTE. A major objective of this study is to investigate whether the water hammer effect is present due to blunt impacts through the use of computational models. Frontal blunt impacts were simulated with 2D finite element models developed to capture the biofidelic geometry of a human head. The models utilized the Arbitrary Lagrangian Eulerian (ALE) method to model a layer of cerebrospinal fluid (CSF) as a deforming fluid allowing for CSF to move in and out of sulci. During the simulated impacts, CSF was not observed to be driven into the sulci during the transient response. However, elevated shear strain levels near the base of the sulci were exhibited. Further, increased shear strain was present when differentiation between white and gray matter was taken into account. Both of the results support clinical observations of (1).

Traumatic Brain Injury by Weight-Drop Method Causes Transient Amyloid-β Deposition and Acute Cognitive Deficits in Mice.

There has been growing awareness of the correlation between an episode of traumatic brain injury (TBI) and the development of Alzheimer's disease (AD) later in life. It has been reported that TBI accelerated amyloid-β (Aβ) pathology and cognitive decline in the several lines of AD model mice. However, the short-term and long-term effects of TBI by the weight-drop method on amyloid-β pathology and cognitive performance are unclear in wild-type (WT) mice. Hence, we examined AD-related histopathological changes and cognitive impairment after TBI in wild-type C57BL6J mice. Five- to seven-month-old WT mice were subjected to either TBI by the weight-drop method or a sham treatment. Seven days after TBI, the WT mice exhibited significantly lower spatial learning than the sham-treated WT mice. However, 28 days after TBI, the cognitive impairment in the TBI-treated WT mice recovered. Correspondingly, while significant amyloid-β (Aβ) plaques and amyloid precursor protein (APP) accumulation were observed in the TBI-treated mouse hippocampus 7 days after TBI, the Aβ deposition was no longer apparent 28 days after TBI. Thus, TBI induced transient amyloid-β deposition and acute cognitive impairments in the WT mice. The present study suggests that the TBI could be a risk factor for acute cognitive impairment even when genetic and hereditary predispositions are not involved. The system might be useful for evaluating and developing a pharmacological treatment for the acute cognitive deficits.

Reduced Neuroinflammation and Improved Functional Recovery after Traumatic Brain Injury by Prophylactic Diet Supplementation in Mice

Currently, there are no approved therapeutic drugs for the treatment of traumatic brain injury (TBI), and new targets and approaches are needed to provide relief from the long-term effects of TBI. Recent studies suggest that nutrition plays a critical role in improving the outcome from TBI in both civilians and military personnel. We have previously shown that GrandFusion® (GF) diets improved recovery from cerebral ischemia and enhanced physical activity and endurance in rodent models. We, therefore, sought to determine the impact of a prophylactic diet enriched in fruits and vegetables on recovery from TBI in the controlled cortical impact rodent model. Results demonstrated that mice fed the diets had improved neuromotor function, reduced lesion volume, increased neuronal density in the hippocampus and reduced inflammation. As previously shown, TBI increases cathepsin B as part of the inflammasome complex resulting in elevated inflammatory markers like interleukin-1β (IL-1β). Consumption of the GF diets attenuated the increase in cathepsin B levels and prevented the increase in the proapoptotic factor Bax following TBI. These data suggest that prior consumption of diets enriched in fruits and vegetables either naturally or through powdered form can provide protection from the detrimental effects of TBI.

Probability of New-Onset Cancer Between Patients with Traumatic Brain Injury and a Comparison General Population Cohort

Traumatic brain injury (TBI) has been reported as a risk factor for the development of brain tumors. However, whether TBI affects systemic cancer remains to be determined. We investigated the incidence and factors associated with cancer development in patients with TBI. A propensity score (age, gender, and comorbidity)-matched longitudinal cohort study of 34,556 patients with pre-existing TBI and 69,112 patients without TBI from January 2000 to December 2015 was presented using the Taiwan's National Health Insurance Research Database. The Cox proportional hazard regression model was used to estimate the hazard ratio of developing cancer adjusted by the potential confounding factors. The stratified analysis of age, gender, and comorbidities for each cancer type was evaluated using forest plot analysis. The cancer incidence rate in the patients with TBI (4.38%) was greater than that in patients without TBI (3.88%). The interval to cancer development in those with TBI (5.65 ± 3.58 years) was shorter than that in those without TBI (6.02 ± 3.65 years). The cancer risk in those with TBI was increased 1.27-fold compared with that in the general population. Of the patients with TBI, age <55 years and male gender indicated a greater incidence of cancer than that of the general population. The patients with TBI had greater cancer frequencies in the head and neck structures compared with those in the general population. TBI is a risk factor for cancer development, especially in males and those aged <55 years. We hope this information will remind physicians to consider the long-term effects of TBI on cancer development.

Ten-year outcome of early childhood traumatic brain injury: Diffusion tensor imaging of the ventral striatum in relation to executive functioning

Primary objective: The long-term effects of TBI on verbal fluency and related structures, as well as the relation between cognition and structural integrity, were evaluated. It was hypothesized that the group with TBI would evidence poorer performance on cognitive measures and a decrease in structural integrity.Research design: Between a paediatric group with TBI and a group of typically-developing children, the long-term effects of traumatic brain injury were investigated in relation to both structural integrity and cognition. Common metrics for diffusion tensor imaging (DTI) were used as indicators of white matter integrity.Methods and procedures: Using DTI, this study examined ventral striatum (VS) integrity in 21 patients aged 10–18 years sustaining moderate-to-severe traumatic brain injury (TBI) 5–15 years earlier and 16 demographically comparable subjects. All participants completed Delis-Kaplan Executive Functioning System (D-KEFS) sub-tests.Main outcomes and results: The group with TBI exhibited lower fractional anisotropy (FA) and executive functioning performance and higher apparent diffusion coefficient (ADC). DTI metrics correlated with D-KEFS performance (right VS FA with Inhibition errors, right VS ADC with Letter Fluency, left VS FA and ADC with Category Switching).Conclusions: TBI affects VS integrity, even in a chronic phase, and may contribute to executive functioning deficits.

A Large-Scale Informatics Database to Advance Research and Discovery of the Effects of Mild Traumatic Brain Injury.

Clinical research advances in traumatic brain injury (TBI) and behavioral health have always been restricted by the quantity and quality of the data as well as the difficulty of collecting standardized clinical elements. Those barriers, together with the complexity of evaluating TBI, have resulted in serious challenges for clinicians, researchers, and organizations interested in analyzing the short- and long-term effects of TBI. In an effort to raise awareness about existing and cost-effective ways to collect clinical data within the Department of Defense, this article describes some of the steps taken to quickly build a large-scale informatics database to facilitate collection of standardized clinical data and obtain trends of the longitudinal outcomes of service members diagnosed with mild TBI. The database was built following the Defense of Health Agency guidelines and currently has millions of longitudinal clinical data points, Department of Defense-wide clinical data for service members diagnosed with mild TBI to support population studies, and multiple built-in analytical applications to enable interactive data exploration and analysis.

Post-traumatic neurodegeneration and chronic traumatic encephalopathy.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity around the world. Concussive and subconcussive forms of closed-head injury due to impact or blast neurotrauma represent the most common types of TBI in civilian and military settings. It is becoming increasingly evident that TBI can lead to persistent, long-term debilitating effects, and in some cases, progressive neurodegeneration and chronic traumatic encephalopathy (CTE). The epidemiological literature suggests that a single moderate-to-severe TBI may be associated with accelerated neurodegeneration and increased risk of Alzheimer's disease, Parkinson's disease, or motor neuron disease. However, the pathologic phenotype of these post-traumatic neurodegenerations is largely unknown and there may be pathobiological differences between post-traumatic disease and the corresponding sporadic disorder. By contrast, the pathology of CTE is increasingly well known and is characterized by a distinctive pattern of progressive brain atrophy and accumulation of hyperphosphorylated tau neurofibrillary and glial tangles, dystrophic neurites, 43 kDa TAR DNA-binding protein (TDP-43) neuronal and glial aggregates, microvasculopathy, myelinated axonopathy, neuroinflammation, and white matter degeneration. Clinically, CTE is associated with behavioral changes, executive dysfunction, memory deficits, and cognitive impairments that begin insidiously and most often progress slowly over decades. Although research on the long-term effects of TBI is advancing quickly, the incidence and prevalence of post-traumatic neurodegeneration and CTE are unknown. Critical knowledge gaps include elucidation of pathogenic mechanisms, identification of genetic risk factors, and clarification of relevant variables-including age at exposure to trauma, history of prior and subsequent head trauma, substance use, gender, stress, and comorbidities-all of which may contribute to risk profiles and the development of post-traumatic neurodegeneration and CTE. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.

Aging, neurodegenerative disease, and traumatic brain injury: the role of neuroimaging.

Traumatic brain injury (TBI) is a highly prevalent condition with significant effects on cognition and behavior. While the acute and sub-acute effects of TBI recover over time, relatively little is known about the long-term effects of TBI in relation to neurodegenerative disease. This issue has recently garnered a great deal of attention due to publicity surrounding chronic traumatic encephalopathy (CTE) in professional athletes, although CTE is but one of several neurodegenerative disorders associated with a history of TBI. Here, we review the literative on neurodegenerative disorders linked to remote TBI. We also review the evidence for neuroimaging changes associated with unhealthy brain aging in the context of remote TBI. We conclude that neuroimaging biomarkers have significant potential to increase understanding of the mechanisms of unhealthy brain aging and neurodegeneration following TBI, with potential for identifying those at risk for unhealthy brain aging prior to the clinical manifestation of neurodegenerative disease.

Controlled cortical impact model for traumatic brain injury.

Every year over a million Americans suffer a traumatic brain injury (TBI). Combined with the incidence of TBIs worldwide, the physical, emotional, social, and economical effects are staggering. Therefore, further research into the effects of TBI and effective treatments is necessary. The controlled cortical impact (CCI) model induces traumatic brain injuries ranging from mild to severe. This method uses a rigid impactor to deliver mechanical energy to an intact dura exposed following a craniectomy. Impact is made under precise parameters at a set velocity to achieve a pre-determined deformation depth. Although other TBI models, such as weight drop and fluid percussion, exist, CCI is more accurate, easier to control, and most importantly, produces traumatic brain injuries similar to those seen in humans. However, no TBI model is currently able to reproduce pathological changes identical to those seen in human patients. The CCI model allows investigation into the short-term and long-term effects of TBI, such as neuronal death, memory deficits, and cerebral edema, as well as potential therapeutic treatments for TBI.

Traumatic brain injury and risk of dementia in older veterans

Traumatic brain injury (TBI) is common in military personnel, and there is growing concern about the long-term effects of TBI on the brain; however, few studies have examined the association between TBI and risk of dementia in veterans. We performed a retrospective cohort study of 188,764 US veterans aged 55 years or older who had at least one inpatient or outpatient visit during both the baseline (2000-2003) and follow-up (2003-2012) periods and did not have a dementia diagnosis at baseline. TBI and dementia diagnoses were determined using ICD-9 codes in electronic medical records. Fine-Gray proportional hazards models were used to determine whether TBI was associated with greater risk of incident dementia, accounting for the competing risk of death and adjusting for demographics, medical comorbidities, and psychiatric disorders. Veterans were a mean age of 68 years at baseline. During the 9-year follow-up period, 16% of those with TBI developed dementia compared with 10% of those without TBI (adjusted hazard ratio, 1.57; 95% confidence interval: 1.35-1.83). There was evidence of an additive association between TBI and other conditions on risk of dementia. TBI in older veterans was associated with a 60% increase in the risk of developing dementia over 9 years after accounting for competing risks and potential confounders. Our results suggest that TBI in older veterans may predispose toward development of symptomatic dementia and raise concern about the potential long-term consequences of TBI in younger veterans and civilians.

Emotion Labeling and Socio-Emotional Outcomes 18 Months after Early Childhood Traumatic Brain Injury

A growing body of literature has documented evidence for emotion labeling (EL) deficits after traumatic brain injury (TBI); however, long-term effects of TBI on EL abilities, particularly among young children, are unclear. We investigated EL abilities and socio-emotional outcomes in 32 children with moderate-severe TBI, 23 with complicated-mild TBI, and 82 children with orthopedic injuries (OI), shortly after injury and at 18 months post-injury. All children were between 3:0 and 6:11 years of age at the time of injury. Repeated measures analyses indicated that all groups showed improved EL performance between acute and 18-month assessments, but that the moderate-severe TBI group improved at a slower rate than the OI group, so that the two groups showed significantly different performance at 18 months. Emotion labeling ability did not significantly contribute to the prediction of socio-emotional outcomes after controlling for pre-injury functioning. These results provide preliminary evidence of emerging EL deficits after early childhood TBI that are related to injury severity but that do not predict social and behavioral outcomes.

Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk.

Pediatric Traumatic Brain Injury

Pediatric Traumatic Brain Injury

Rejecting familiar distracters during recognition in young adults with traumatic brain injury and in healthy older adults

The most common cognitive complaint reported by healthy older adults and young adults with traumatic brain injury (TBI) is memory difficulties. We investigated the effects of normal aging and the long-term effects of TBI in young adults on the susceptibility to incorrectly endorse distracter information on a memory test. Prior to a study phase, participants viewed a "pre-exposure" list containing distracter words, presented once or three times, and half of the target study words. Subsequently, during the study phase, all target words were presented such that, across lists, study words were viewed either once or three times. On the recognition test, TBI and older adult participants were more likely to falsely endorse "pre-exposed" distracter words viewed three times as being from the target study list, compared to non-head-injured young controls. Normal aging and head injury in young may similarly compromise one's ability to reject highly familiar, but distracting, information during recognition. Older adult and TBI participants were also slower to complete the Trail Making task and had poorer output on a Digit Span task, suggesting these two populations share a deficit in executive function and working memory. Similar changes in frontal lobe function may underlie these shared cognitive deficits.

Implications of Reduced Callosal Area for Social Skills after Severe Traumatic Brain Injury in Children

The corpus callosum has been shown to be particularly vulnerable to the effects of traumatic brain injury (TBI) in childhood, and severe injury frequently results in a smaller corpus callosum post-injury. However, the long-term effects of TBI on the integrity of the callosum, as well as the potential functional significance of callosal injury are poorly understood. Some studies suggest the corpus callosum may be involved in social skills, which are often reduced following TBI. In this study, callosal size was investigated in 37 individuals 10 years post-childhood TBI, and its relationship with social competence was examined. The results indicate that individuals who sustain severe TBI in childhood display reduced callosal size 10 years post-injury. In addition, callosal size correlated significantly with social skills, suggesting that callosal atrophy may be related to poorer social skills after TBI. These findings highlight the persistence of callosal abnormalities, which may be a result of interrupted neural development after childhood TBI. The results further underscore the potential importance of the corpus callosum for social competence after TBI.

Cerebral blood flow at one year after controlled cortical impact in rats: assessment by magnetic resonance imaging.

Progressive tissue loss and delayed cognitive deficits are seen in rats during the initial year after experimental traumatic brain injury (TBI). As much as 10% of parenchymal volume is lost even in the contralateral hemisphere by 1 year after controlled cortical impact (CCI) in rats. Progressive declines in cerebral blood flow (CBF) are also associated with advanced age and neurodegenerative diseases. Surprisingly, the long-term effects of TBI on CBF remain undefined. CBF was quantified by continuous arterial spin-labeled magnetic resonance imaging (MRI) and measurements of spin-lattice relaxation time in a slice through the plane of injury at 1 year after experimental TBI produced by CCI (n = 4) or sham surgery (n = 4) in rats. CBF was quantified in six regions of interest (ROIs) that were anatomically identified on the control images in each hemisphere and included a medial cortical segment (contusion-enriched, beneath the impact site, on the ipsilateral side) cortex, hippocampus, thalamus, amygdala/pyriform cortex, and hemisphere. At 1 year after injury, CBF was dramatically (96%) reduced in structures within the large cystic lesion that was seen in three of four rats and variably included cortex and hippocampus. Overall, there was an 80% reduction in CBF in the ipsilateral medial cortical segment comparing CCI and sham groups. Similarly, 52% and 67% reductions were seen in CBF in the cortical and hippocampal ROIs ipsilateral to impact (CCI vs. sham), respectively. These are regions both with marked CBF disturbances early after injury and that ultimately suffer considerable tissue loss over the 1-year interval. However, at 1 year after CCI, CBF was not different from sham in other ROIs, including ipsilateral thalamus, or either contralateral hippocampus or hemisphere. We conclude that, at 1 year after CCI, CBF is reduced in anatomic structures at or near the impact site, including injured cortex and hippocampus, and this translates into a reduction in hemispheric CBF. However, despite both significant occult tissue loss ipsilateral and contralateral to the injury and delayed cognitive deficits, widespread reductions in CBF are not observed. This suggests the possibility of remodeling or repackaging of the brain that preserves CBF outside of the cystic lesion.