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1.  Predicting Outcome after Traumatic Brain Injury: Development and International Validation of Prognostic Scores Based on Admission Characteristics 
PLoS Medicine  2008;5(8):e165.
Traumatic brain injury (TBI) is a leading cause of death and disability. A reliable prediction of outcome on admission is of great clinical relevance. We aimed to develop prognostic models with readily available traditional and novel predictors.
Methods and Findings
Prospectively collected individual patient data were analyzed from 11 studies. We considered predictors available at admission in logistic regression models to predict mortality and unfavorable outcome according to the Glasgow Outcome Scale at 6 mo after injury. Prognostic models were developed in 8,509 patients with severe or moderate TBI, with cross-validation by omission of each of the 11 studies in turn. External validation was on 6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial. We found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and CT characteristics, including the presence of traumatic subarachnoid hemorrhage. A prognostic model that combined age, motor score, and pupillary reactivity had an area under the receiver operating characteristic curve (AUC) between 0.66 and 0.84 at cross-validation. This performance could be improved (AUC increased by approximately 0.05) by considering CT characteristics, secondary insults (hypotension and hypoxia), and laboratory parameters (glucose and hemoglobin). External validation confirmed that the discriminative ability of the model was adequate (AUC 0.80). Outcomes were systematically worse than predicted, but less so in 1,588 patients who were from high-income countries in the CRASH trial.
Prognostic models using baseline characteristics provide adequate discrimination between patients with good and poor 6 mo outcomes after TBI, especially if CT and laboratory findings are considered in addition to traditional predictors. The model predictions may support clinical practice and research, including the design and analysis of randomized controlled trials.
Ewout Steyerberg and colleagues describe a prognostic model for the prediction of outcome of traumatic brain injury using data available on admission.
Editors' Summary
Traumatic brain injury (TBI) causes a large amount of morbidity and mortality worldwide. According to the Centers for Disease Control, for example, about 1.4 million Americans will sustain a TBI—a head injury—each year. Of these, 1.1 million will be treated and released from an emergency department, 235,000 will be hospitalized, and 50,000 will die. The burden of disease is much higher in the developing world, where the causes of TBI such as traffic accidents occur at higher rates and treatment may be less available.
Why Was This Study Done?
Given the resources required to treat TBI, a very useful research tool would be the ability to accurately predict on admission to hospital what the outcome of a given injury might be. Currently, scores such as the Glasgow Coma Scale are useful to predict outcome 24 h after the injury but not before.
Prognostic models are useful for several reasons. Clinically, they help doctors and patients make decisions about treatment. They are also useful in research studies that compare outcomes in different groups of patients and when planning randomized controlled trials. The study presented here is one of a number of analyses done by the IMPACT research group over the past several years using a large database that includes data from eight randomized controlled trials and three observational studies conducted between 1984 and 1997. There are other ongoing studies that also seek to develop new prognostic models; one such recent study was published in BMJ by a group involving the lead author of the PLoS Medicine paper described here.
What Did the Researchers Do and Find?
The authors analyzed data that had been collected prospectively on individual patients from the 11 studies included in the database and derived models to predict mortality and unfavorable outcome at 6 mo after injury for the 8,509 patients with severe or moderate TBI. They found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and characteristics on the CT scan, including the presence of traumatic subarachnoid hemorrhage. A core prognostic model could be derived from the combination of age, motor score, and pupillary reactivity. A better score could be obtained by adding CT characteristics, secondary problems (hypotension and hypoxia), and laboratory measurements of glucose and hemoglobin. The scores were then tested to see how well they predicted outcome in a different group of patients—6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial.
What Do These Findings Mean?
In this paper the authors show that it is possible to produce prognostic models using characteristics collected on admission as part of routine care that can discriminate between patients with good and poor outcomes 6 mo after TBI, especially if the results from CT scans and laboratory findings are added to basic models. This paper has to be considered together with other studies, especially the paper mentioned above, which was recently published in the BMJ (MRC CRASH Trial Collaborators [2008] Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ 336: 425–429.). The BMJ study presented a set of similar, but subtly different models, with specific focus on patients in developing countries; in that case, the patients in the CRASH trial were used to produce the models, and the patients in the IMPACT database were used to verify one variant of the models. Unfortunately this related paper was not disclosed to us during the initial review process; however, during PLoS Medicine's subsequent consideration of this manuscript we learned of it. After discussion with the reviewers, we took the decision that the models described in the PLoS Medicine paper are sufficiently different from those reported in the other paper and as such proceeded with publication of the paper. Ideally, however, these two sets of models would have been reviewed and published side by side, so that readers could easily evaluate the respective merits and value of the two different sets of models in the light of each other. The two sets of models are, however, discussed in a Perspective article also published in PLoS Medicine (see below).
Additional Information.
Please access these Web sites via the online version of this summary at
This paper and the BMJ paper mentioned above are discussed further in a PLoS Medicine Perspective article by Andrews and Young
The TBI Impact site provides a tool to calculate the scores described in this paper
The CRASH trial, which is used to validate the scores mentioned here, has a Web site explaining the trial and its results
The R software, which was used for the prognostic analyses, is freely available
The MedlinePlus encyclopedia has information on head injury
The WHO site on neurotrauma discusses head injury from a global perspective
The CDC's National Center for Injury Prevention and Control gives statistics on head injury in the US and advice on prevention
PMCID: PMC2494563  PMID: 18684008
2.  Direct cost associated with acquired brain injury in Ontario 
BMC Neurology  2012;12:76.
Acquired Brain Injury (ABI) from traumatic and non traumatic causes is a leading cause of disability worldwide yet there is limited research summarizing the health system economic burden associated with ABI. The objective of this study was to determine the direct cost of publicly funded health care services from the initial hospitalization to three years post-injury for individuals with traumatic (TBI) and non-traumatic brain injury (nTBI) in Ontario Canada.
A population-based cohort of patients discharged from acute hospital with an ABI code in any diagnosis position in 2004 through 2007 in Ontario was identified from administrative data. Publicly funded health care utilization was obtained from several Ontario administrative healthcare databases. Patients were stratified according to traumatic and non-traumatic causes of brain injury and whether or not they were discharged to an inpatient rehabilitation center. Health system costs were calculated across a continuum of institutional and community settings for up to three years after initial discharge. The continuum of settings included acute care emergency departments inpatient rehabilitation (IR) complex continuing care home care services and physician visits. All costs were calculated retrospectively assuming the government payer’s perspective.
Direct medical costs in an ABI population are substantial with mean cost in the first year post-injury per TBI and nTBI patient being $32132 and $38018 respectively. Among both TBI and nTBI patients those discharged to IR had significantly higher treatment costs than those not discharged to IR across all institutional and community settings. This tendency remained during the entire three-year follow-up period. Annual medical costs of patients hospitalized with a brain injury in Ontario in the first follow-up year were approximately $120.7 million for TBI and $368.7 million for nTBI. Acute care cost accounted for 46-65% of the total treatment cost in the first year overwhelming all other cost components.
The main finding of this study is that direct medical costs in ABI population are substantial and vary considerably by the injury cause. Although most expenses occur in the first follow-up year ABI patients continue to use variety of medical services in the second and third year with emphasis shifting over time from acute care and inpatient rehabilitation towards homecare physician services and long-term institutional care. More research is needed to capture economic costs for ABI patients not admitted to acute care.
PMCID: PMC3518141  PMID: 22901094
3.  A Review of Magnetic Resonance Imaging and Diffusion Tensor Imaging Findings in Mild Traumatic Brain Injury 
Brain imaging and behavior  2012;6(2):137-192.
Mild traumatic brain injury (mTBI), also referred to as concussion, remains a controversial diagnosis because the brain often appears quite normal on conventional computed tomography (CT) and magnetic resonance imaging (MRI) scans. Such conventional tools, however, do not adequately depict brain injury in mTBI because they are not sensitive to detecting diffuse axonal injuries (DAI), also described as traumatic axonal injuries (TAI), the major brain injuries in mTBI. Furthermore, for the 15 to 30% of those diagnosed with mTBI on the basis of cognitive and clinical symptoms, i.e., the “miserable minority,” the cognitive and physical symptoms do not resolve following the first three months post-injury. Instead, they persist, and in some cases lead to long-term disability. The explanation given for these chronic symptoms, i.e., postconcussive syndrome, particularly in cases where there is no discernible radiological evidence for brain injury, has led some to posit a psychogenic origin. Such attributions are made all the easier since both post-traumatic stress disorder (PTSD) and depression are frequently co-morbid with mTBI. The challenge is thus to use neuroimaging tools that are sensitive to DAI/TAI, such as diffusion tensor imaging (DTI), in order to detect brain injuries in mTBI. Of note here, recent advances in neuroimaging techniques, such as DTI, make it possible to characterize better extant brain abnormalities in mTBI. These advances may lead to the development of biomarkers of injury, as well as to staging of reorganization and reversal of white matter changes following injury, and to the ability to track and to characterize changes in brain injury over time. Such tools will likely be used in future research to evaluate treatment efficacy, given their enhanced sensitivity to alterations in the brain. In this article we review the incidence of mTBI and the importance of characterizing this patient population using objective radiological measures. Evidence is presented for detecting brain abnormalities in mTBI based on studies that use advanced neuroimaging techniques. Taken together, these findings suggest that more sensitive neuroimaging tools improve the detection of brain abnormalities (i.e., diagnosis) in mTBI. These tools will likely also provide important information relevant to outcome (prognosis), as well as play an important role in longitudinal studies that are needed to understand the dynamic nature of brain injury in mTBI. Additionally, summary tables of MRI and DTI findings are included. We believe that the enhanced sensitivity of newer and more advanced neuroimaging techniques for identifying areas of brain damage in mTBI will be important for documenting the biological basis of postconcussive symptoms, which are likely associated with subtle brain alterations, alterations that have heretofore gone undetected due to the lack of sensitivity of earlier neuroimaging techniques. Nonetheless, it is noteworthy to point out that detecting brain abnormalities in mTBI does not mean that other disorders of a more psychogenic origin are not co-morbid with mTBI and equally important to treat. They arguably are. The controversy of psychogenic versus physiogenic, however, is not productive because the psychogenic view does not carefully consider the limitations of conventional neuroimaging techniques in detecting subtle brain injuries in mTBI, and the physiogenic view does not carefully consider the fact that PTSD and depression, and other co-morbid conditions, may be present in those suffering from mTBI. Finally, we end with a discussion of future directions in research that will lead to the improved care of patients diagnosed with mTBI.
PMCID: PMC3803157  PMID: 22438191
Mild Traumatic Brain Injury; mTBI; TBI; Diffusion Tensor Imaging; DTI; Magnetic Resonance Imaging; MRI; Diffusion-Weighted Imaging; DWI; Susceptibility-Weighted Imaging; SWI; Signature Injury of War; Concussion; Postconcussive syndrome; Postconcussive Symptoms; Complicated mTBI; Uncomplicated mTBI; Physiogenesis; Psychogenesis; Miserable Minority
4.  Older adults with acquired brain injury: a population based study 
BMC Geriatrics  2013;13:97.
Acquired brain injury (ABI), which includes traumatic (TBI) and non-traumatic brain injury (nTBI), is a leading cause of death and disability worldwide. The objective of this study was to examine the trends, characteristics, cause of brain injury, and discharge destination of hospitalized older adults aged 65 years and older with an ABI diagnosis in a population with universal access to hospital care. The profile of characteristics of patients with TBI and nTBI causes of injury was also compared.
A population based retrospective cohort study design with healthcare administrative databases was used. Data on acute care admissions were obtained from the Discharge Abstract Database and patients were identified using the International Classification of Diseases – Version 10 codes for Ontario, Canada from April 1, 2003 to March 31, 2010. Older adults were examined in three age groups – 65 to 74, 75 to 84, and 85+ years.
From 2003/04 to 2009/10, there were 14,518 episodes of acute care associated with a TBI code and 51, 233 episodes with a nTBI code. Overall, the rate of hospitalized TBI and nTBI episodes increased with older age groups. From 2007/08 to 2009/10, the percentage of patients that stayed in acute care for 12 days or more and the percentage of patients with delayed discharge from acute care increased with age. The most common cause of TBI was falls while the most common type of nTBI was brain tumours. The percentage of patients discharged to long term care and complex continuing care increased with age and the percentage discharged home decreased with age. In-hospital mortality also increased with age. Older adults with TBI and nTBI differed significantly in demographic and clinical characteristics and discharge destination from acute care.
This study showed an increased rate of acute care admissions for both TBI and nTBI with age. It also provided additional support for falls prevention strategies to prevent injury leading to cognitive disability with costly human and economic consequences. Implications for increased numbers of people with ABI are discussed.
PMCID: PMC3849645  PMID: 24060144
Brain injury; Epidemiology; Outcomes
5.  Current pre-hospital traumatic brain injury management in China 
Traumatic brain injury (TBI) is associated with most trauma-related deaths. Secondary brain injury is the leading cause of in-hospital deaths after traumatic brain injury. By early prevention and slowing of the initial pathophysiological mechanism of secondary brain injury, pre-hospital service can significantly reduce case-fatality rates of TBI. In China, the incidence of TBI is increasing and the proportion of severe TBI is much higher than that in other countries. The objective of this paper is to review the pre-hospital management of TBI in China.
A literature search was conducted in January 2014 using the China National Knowledge Infrastructure (CNKI). Articles on the assessment and treatment of TBI in pre-hospital settings practiced by Chinese doctors were identified. The information on the assessment and treatment of hypoxemia, hypotension, and brain herniation was extracted from the identified articles.
Of the 471 articles identified, 65 met the selection criteria. The existing literature indicated that current practices of pre-hospital TBI management in China were sub-optimal and varied considerably across different regions.
Since pre-hospital care is the weakest part of Chinese emergency care, appropriate training programs on pre-hospital TBI management are urgently needed in China.
PMCID: PMC4272926  PMID: 25548596
Traumatic brain injury; Pre-hospital; China; Emergency medicine
6.  Aggregated n-of-1 trials of central nervous system stimulants versus placebo for paediatric traumatic brain injury – a pilot study 
Trials  2014;15:54.
In 2006 there were 432,700 people in Australia who had acquired brain injury (ABI) with some limitation of activities; 90% of these were traumatic brain injuries (TBIs) and nearly a third sustained injury below age 15 years. One to four years post injury, 20% to 46% of children with traumatic brain injury (TBI) have clinically significant disorders of attention. There is controversy as to whether central nervous system (CNS) stimulants can be an effective method of treating these.
Objectives were to determine the efficacy of CNS stimulants for children with TBI, and to calculate the sample size for a larger trial using the Conners’ 3 Parent Rating Scales Score as the primary endpoint.
Pilot series of aggregated prospective randomised, double-blind, n-of-1 trials of stimulant versus placebo within individual patients. Setting: tertiary children’s public hospital. Participants: ten children aged 6 to 16 years more than 12 months post TBI with attention, concentration and behavioral difficulties on stimulants. Interventions: Three cycles of methylphenidate or dexamphetamine orally at doses titrated by physician compared to placebo. Main Outcome Measures: Conners 3 Parent (Conners 3-P) and Teacher (Conners 3-T) Rating Scales (Global Index), Behaviour Rating Inventory of Executive Function (BRIEF) and Eyberg Child Behaviour Inventory (ECBI).
Five of ten patients completed the study. Data from 18 completed cycles from seven patients were analysed. The posterior mean difference between stimulant and placebo scores for the Conners 3-PS (Global Index) was 2.3 (SD 6.2; 95% credible region -1.0 to 6.1; posterior probability that this mean difference was greater than zero was 0.92), and for the Conners 3-T (Global Index) the posterior mean difference was 5.9 (SD 4.5; 95% credible region -3.1 to 14.9; posterior probability 0.93). Posterior mean differences suggest improvement in behaviour and executive function and a decrease in number and intensity of child behaviour problems when taking stimulants compared to placebo. Taken together these data are suggestive of a small benefit at group level.
In this pilot study, there was sufficient evidence that stimulants may be useful in management of behavioral and cognitive sequelae following TBI, to warrant a larger trial.
Trial registration
he trial was registered with the Australian and New Zealand Clinical Trials Registry: registration number ACTRN12609000873224.
PMCID: PMC3925439  PMID: 24524676
Traumatic brain injury; Children; Methylphenidate; Dexamphetamine; n-of-1 trials
7.  Change in Inpatient Rehabilitation Admissions for Individuals With Traumatic Brain Injury After Implementation of the Medicare Inpatient Rehabilitation Facility Prospective Payment System 
To evaluate the impact of Medicare’s inpatient rehabilitation facility (IRF) prospective payment system (PPS) on use of inpatient rehabilitation for individuals with traumatic brain injury (TBI).
Retrospective cohort study of patients with TBI.
One hundred twenty-three level I and II trauma centers across the U.S. who contributed data to the National Trauma Data Bank.
Patients (N = 135,842) with TBI and an Abbreviated Injury Score of the head of 2 or greater admitted to trauma centers between 1995 and 2004.
Main Outcome Measure
Discharge location: IRF, skilled nursing facility, home, and other hospitals.
Compared with inpatient rehabilitation admissions before IRF PPS came into effect, demographic characteristics of admitted patients changed. Those admitted to acute care trauma centers after PPS was enacted (January 2002) were older and nonwhite. No differences were found in rates of injury between men and women. Over time, there was a significant drop in the percent of patients being discharged to inpatient rehabilitation, which varied by region, but was found across all insurance types. In a logistic regression, after controlling for patient characteristics (age, sex, race), injury characteristics (cause, severity), insurance type, and facility, the odds of being discharged to an IRF after a TBI decreased 16% after Medicare’s IRF PPS system was enacted.
The enactment of the Medicare PPS appears to be associated with a reduction in the chance that patients receive inpatient rehabilitation treatment after a TBI. The impact of these changes on the cost, quality of care, and patient outcome is unknown and should be addressed in future studies.
PMCID: PMC4207214  PMID: 22840827
Brain injuries; Medicare; Rehabilitation
8.  Risk of Violent Crime in Individuals with Epilepsy and Traumatic Brain Injury: A 35-Year Swedish Population Study 
PLoS Medicine  2011;8(12):e1001150.
Seena Fazel and colleagues report findings from a longitudinal follow-up study in Sweden that evaluated the risks of violent crime subsequent to hospitalization for epilepsy, or traumatic brain injury. The researchers control for familial confounding with sibling controls. The analyses call into question an association between epilepsy and violent crime, although they do suggest that there may be a relationship between traumatic brain injury and violent crime.
Epilepsy and traumatic brain injury are common neurological conditions, with general population prevalence estimates around 0.5% and 0.3%, respectively. Although both illnesses are associated with various adverse outcomes, and expert opinion has suggested increased criminality, links with violent behaviour remain uncertain.
Methods and Findings
We combined Swedish population registers from 1973 to 2009, and examined associations of epilepsy (n = 22,947) and traumatic brain injury (n = 22,914) with subsequent violent crime (defined as convictions for homicide, assault, robbery, arson, any sexual offense, or illegal threats or intimidation). Each case was age and gender matched with ten general population controls, and analysed using conditional logistic regression with adjustment for socio-demographic factors. In addition, we compared cases with unaffected siblings.
Among the traumatic brain injury cases, 2,011 individuals (8.8%) committed violent crime after diagnosis, which, compared with population controls (n = 229,118), corresponded to a substantially increased risk (adjusted odds ratio [aOR] = 3.3, 95% CI: 3.1–3.5); this risk was attenuated when cases were compared with unaffected siblings (aOR = 2.0, 1.8–2.3). Among individuals with epilepsy, 973 (4.2%) committed a violent offense after diagnosis, corresponding to a significantly increased odds of violent crime compared with 224,006 population controls (aOR = 1.5, 1.4–1.7). However, this association disappeared when individuals with epilepsy were compared with their unaffected siblings (aOR = 1.1, 0.9–1.2). We found heterogeneity in violence risk by age of disease onset, severity, comorbidity with substance abuse, and clinical subgroups. Case ascertainment was restricted to patient registers.
In this longitudinal population-based study, we found that, after adjustment for familial confounding, epilepsy was not associated with increased risk of violent crime, questioning expert opinion that has suggested a causal relationship. In contrast, although there was some attenuation in risk estimates after adjustment for familial factors and substance abuse in individuals with traumatic brain injury, we found a significantly increased risk of violent crime. The implications of these findings will vary for clinical services, the criminal justice system, and patient charities.
Please see later in the article for the Editors' Summary
Editors' Summary
News stories linking mental illness (diseases that appear primarily as abnormalities of thought, feeling or behavior) with violence frequently hit the headlines. But what about neurological conditions—disorders of the brain, spinal cord, and nerves? People with these disorders, which include dementia, Parkinson's disease, and brain tumors, often experience stigmatization and discrimination, a situation that is made worse by the media and by some experts suggesting that some neurological conditions increase the risk of violence. For example, many modern textbooks assert that epilepsy—a neurological condition that causes repeated seizures or fits—is associated with increased criminality and violence. Similarly, various case studies have linked traumatic brain injury—damage to the brain caused by a sudden blow to the head—with an increased risk of violence.
Why Was This Study Done?
Despite public and expert perceptions, very little is actually known about the relationship between epilepsy and traumatic brain injury and violence. In particular, few if any population-based, longitudinal studies have investigated whether there is an association between the onset of either of these two neurological conditions and violence at a later date. This information might make it easier to address the stigma that is associated with these conditions. Moreover, it might help scientists understand the neurobiological basis of violence, and it could help health professionals appropriately manage individuals with these two disorders. In this longitudinal study, the researchers begin to remedy the lack of hard information about links between neurological conditions and violence by investigating the risk of violent crime associated with epilepsy and with traumatic brain injury in the Swedish population.
What Did the Researchers Do and Find?
The researchers used the National Patient Register to identify all the cases of epilepsy and traumatic brain injury that occurred in Sweden between 1973 and 2009. They matched each case (nearly 23,000 for each condition) with ten members of the general population and retrieved data on all convictions for violent crime over the same period from the Crime Register. They then linked these data together using the personal identification numbers that identify Swedish residents in national registries. 4.2% of individuals with epilepsy had at least one conviction for violence after their diagnosis, but only 2.5% of the general population controls did. That is, epilepsy increased the absolute risk of a conviction for violence by 1.7%. Using a regression analysis that adjusted for age, gender, and various socio-demographic factors, the researchers calculated that the odds of individuals with epilepsy committing a violent crime were 1.5 times higher than for general population controls (an adjusted odds ratio [aOR] of 1.5). The strength of this association was reduced when further adjustment was made for substance abuse, and disappeared when individuals with epilepsy were compared with their unaffected siblings (a sibling control study). Similarly, 8.8% of individuals with traumatic brain injury were convicted of a violent crime after their diagnosis compared to only 3% of controls, giving an aOR of 3.3. Again, the strength of this association was reduced when affected individuals were compared to their unaffected siblings (aOR = 2.0) and when adjustment was made for substance abuse (aOR = 2.3).
What Do These Findings Mean?
Although some aspects of this study may have affected the accuracy of its findings, these results nevertheless challenge the idea that there are strong direct links between epilepsy and violent crime. The low absolute rate of violent crime and the lack of any association between epilepsy and violent crime in the sibling control study argue against a strong link, a potentially important finding given the stigmatization of epilepsy. For traumatic brain injury, the reduced association with violent crime in the sibling control study compared with the general population control study suggests that shared familial features may be responsible for some of the association between brain injury and violence. As with epilepsy, this finding should help patient charities who are trying to reduce the stigma associated with traumatic brain injury. Importantly, however, these findings also suggest that some groups of patients with these conditions (for example, patients with head injuries who abuse illegal drugs and alcohol) would benefit from being assessed for their risk of behaving violently and from appropriate management.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Jan Volavka
The US National Institute of Neurological Disorders and Stroke provides detailed information about traumatic brain injury and about epilepsy (in English and Spanish)
The UK National Health Service Choices website provides information about severe head injury, including a personal story about a head injury sustained in a motor vehicle accident, and information about epilepsy, including personal stories about living with epilepsy
Healthtalkonline has information on epilepsy, including patient perspectives
MedlinePlus provide links to further resources on traumatic brain injury and on epilepsy (available in English and Spanish)
PMCID: PMC3246446  PMID: 22215988
9.  Investigations on Alterations of Hippocampal Circuit Function Following Mild Traumatic Brain Injury 
Short Abstract
A multi-faceted approach to investigating functional changes to hippocampal circuitry is explained. Electrophysiological techniques are described along with the injury protocol, behavioral testing and regional dissection method. The combination of these techniques can be applied in similar fashion for other brain regions and scientific questions.
Long Abstract
Traumatic Brain Injury (TBI) afflicts more than 1.7 million people in the United States each year and even mild TBI can lead to persistent neurological impairments (1). Two pervasive and disabling symptoms experienced by TBI survivors, memory deficits and a reduction in seizure threshold, are thought to be mediated by TBI-induced hippocampal dysfunction (2,3). In order to demonstrate how altered hippocampal circuit function adversely affects behavior after TBI in mice, we employ lateral fluid percussion injury, a commonly used animal model of TBI that recreates many features of human TBI including neuronal cell loss, gliosis, and ionic perturbation (4–6).
Here we demonstrate a combinatorial method for investigating TBI-induced hippocampal dysfunction. Our approach incorporates multiple ex vivo physiological techniques together with animal behavior and biochemical analysis, in order to analyze post-TBI changes in the hippocampus. We begin with the experimental injury paradigm along with behavioral analysis to assess cognitive disability following TBI. Next, we feature three distinct ex vivo recording techniques: extracellular field potential recording, visualized whole-cell patch-clamping, and voltage sensitive dye recording. Finally, we demonstrate a method for regionally dissecting subregions of the hippocampus that can be useful for detailed analysis of neurochemical and metabolic alterations post-TBI.
These methods have been used to examine the alterations in hippocampal circuitry following TBI and to probe the opposing changes in network circuit function that occur in the dentate gyrus and CA1 subregions of the hippocampus (see Figure 1). The ability to analyze the post-TBI changes in each subregion is essential to understanding the underlying mechanisms contributing to TBI-induced behavioral and cognitive deficits.
The multi-faceted system outlined here allows investigators to push past characterization of phenomenology induced by a disease state (in this case TBI) and determine the mechanisms responsible for the observed pathology associated with TBI.
PMCID: PMC3523419  PMID: 23183856
hippocampus; traumatic brain injury; electrophysiology; patch clamp; voltage sensitive dye; extracellular recording; high-performance liquid chromatography; gas chromatography-mass spectrometry
10.  Post traumatic brain perfusion SPECT analysis using reconstructed ROI maps of radioactive microsphere derived cerebral blood flow and statistical parametric mapping 
Assessment of cerebral blood flow (CBF) by SPECT could be important in the management of patients with severe traumatic brain injury (TBI) because changes in regional CBF can affect outcome by promoting edema formation and intracranial pressure elevation (with cerebral hyperemia), or by causing secondary ischemic injury including post-traumatic stroke. The purpose of this study was to establish an improved method for evaluating regional CBF changes after TBI in piglets.
The focal effects of moderate traumatic brain injury (TBI) on cerebral blood flow (CBF) by SPECT cerebral blood perfusion (CBP) imaging in an animal model were investigated by parallelized statistical techniques. Regional CBF was measured by radioactive microspheres and by SPECT 2 hours after injury in sham-operated piglets versus those receiving severe TBI by fluid-percussion injury to the left parietal lobe. Qualitative SPECT CBP accuracy was assessed against reference radioactive microsphere regional CBF measurements by map reconstruction, registration and smoothing. Cerebral hypoperfusion in the test group was identified at the voxel level using statistical parametric mapping (SPM).
A significant area of hypoperfusion (P < 0.01) was found as a response to the TBI. Statistical mapping of the reference microsphere CBF data confirms a focal decrease found with SPECT and SPM.
The suitability of SPM for application to the experimental model and ability to provide insight into CBF changes in response to traumatic injury was validated by the SPECT SPM result of a decrease in CBP at the left parietal region injury area of the test group. Further study and correlation of this characteristic lesion with long-term outcomes and auxiliary diagnostic modalities is critical to developing more effective critical care treatment guidelines and automated medical imaging processing techniques.
PMCID: PMC2311288  PMID: 18312639
11.  Comparison of SNOMED CT versus Medcin Terminology Concept Coverage for Mild Traumatic Brain Injury 
Traumatic Brain Injury (TBI) is a “signature” injury of the current wars in Iraq and Afghanistan. Structured electronic data regarding TBI findings is important for research, population health and other secondary uses but requires appropriate underlying standard terminologies to ensure interoperability and reuse. Currently the U.S. Department of Veterans Affairs (VA) uses the terminology SNOMED CT and the Department of Defense (DOD) uses Medcin.
We developed a comprehensive case definition of mild TBI composed of 68 clinical terms. Using automated and manual techniques, we evaluated how well the mild TBI case definition terms could be represented by SNOMED CT and Medcin, and compared the results. We performed additional analysis stratified by whether the concepts were rated by a TBI expert panel as having High, Medium, or Low importance to the definition of mild TBI.
SNOMED CT sensitivity (recall) was 90% overall for coverage of mild TBI concepts, and Medcin sensitivity was 49%, p < 0.001 (using McNemar’s chi square). Positive predictive value (precision) for each was 100%. SNOMED CT outperformed Medcin for concept coverage independent of import rating by our TBI experts.
SNOMED CT was significantly better able to represent mild TBI concepts than Medcin. This finding may inform data gathering, management and sharing, and data exchange strategies between the VA and DOD for active duty soldiers and veterans with mild TBI. Since mild TBI is an important condition in the civilian population as well, the current study results may be useful also for the general medical setting.
PMCID: PMC3243122  PMID: 22195156
12.  Intracranial pressure monitoring and outcomes after traumatic brain injury 
Canadian Journal of Surgery  2000;43(6):442-448.
Uncontrolled intracranial hypertension after traumatic brain injury (TBI) contributes significantly to the death rate and to poor functional outcome. There is no evidence that intracranial pressure (ICP) monitoring alters the outcome of TBI. The objective of this study was to test the hypothesis that insertion of ICP monitors in patients who have TBI is not associated with a decrease in the death rate.
Study of case records.
The data files from the Ontario Trauma Registry from 1989 to 1995 were examined. Included were all cases with an Injury Severity Score (ISS) greater than 12 from the 14 trauma centres in Ontario. Cases identifying a Maximum Abbreviated Injury Scale score in the head region (MAIS head) greater than 3 were selected for further analysis. Logistic regression analyses were conducted to investigate the relationship between ICP and death.
Of 9001 registered cases of TBI, an MAIS head greater than 3 was recorded in 5507. Of these patients, 541 (66.8% male, mean age 34.1 years) had an ICP monitor inserted. Their average ISS was 33.4 and 71.7% survived. There was wide variation among the institutions in the rate of insertion of ICP monitors in these patients (ranging from 0.4% to over 20%). Univariate logistic regression indicated that increased MAIS head, ISS, penetrating trauma and the insertion of an ICP monitor were each associated with an increased death rate. However, multivariate analyses controlling for MAIS head, ISS and injury mechanism indicated that ICP monitoring was associated with significantly improved survival (p < 0.015).
ICP monitor insertion rates vary widely in Ontario’s trauma hospitals. The insertion of an ICP monitor is associated with a statistically significant decrease in death rate among patients with severe TBI. This finding strongly supports the need for a prospective randomized trial of management protocols, including ICP monitoring, in patients with severe TBI.
PMCID: PMC3695200  PMID: 11129833
13.  Epidemiology and clinical characteristics of traumatic brain injuries in a rural setting in Maharashtra, India. 2007–2009 
Though some studies have described traumatic brain injuries in tertiary care, urban hospitals in India, very limited information is available from rural settings.
To evaluate and describe the epidemiological and clinical characteristics of patients with traumatic brain injury and their clinical outcomes following admission to a rural, tertiary care teaching hospital in India.
Settings and Design:
Retrospective, cross-sectional, hospital-based study from January 2007 to December 2009.
Materials and Methods:
Epidemiological and clinical data from all patients with traumatic brain injury (TBI) admitted to the neurosurgery service of a rural hospital in district Wardha, Maharashtra, India, from 2007 to 2009 were analyzed. The medical records of all eligible patients were reviewed and data collected on age, sex, place of residence, Glasgow Coma Scale (GCS) score, mechanism of injury, severity of injury, concurrent injuries, length of hospital stay, computed tomography (CT) scan results, type of management, indication and type of surgical intervention, and outcome.
Statistical Analysis:
Data analysis was performed using STATA version 11.0.
The medical records of 1,926 eligible patients with TBI were analyzed. The median age of the study population was 31 years (range <1 year to 98 years). The majority of TBI cases occurred in persons aged 21 - 30 years (535 or 27.7%), and in males (1,363 or 70.76%). Most patients resided in nearby rural areas and the most frequent external cause of injury was motor vehicle crash (56.3%). The overall TBI-related mortality during the study period was 6.4%. From 2007 to 2009, TBI-related mortality significantly decreased (P < 0.01) during each year (2007: 8.9%, 2008: 8.5%, and 2009: 4.9%). This decrease in mortality could be due to access and availability of better health care facilities.
Road traffic crashes are the leading cause of TBI in rural Maharashtra ffecting mainly young adult males. At least 10% of survivors had moderate or more severe TBI-related disabilities. Future research should include prospective, population based studies to better elucidate the incidence, prevalence, and economic impact of TBI in rural India.
PMCID: PMC3500010  PMID: 23181212
Head injury; India; rural; traumatic brain injury
14.  Association Between Treatment or Usual Care Region and Hospitalization for Fall-Related Traumatic Brain Injury in the Connecticut Collaboration for Fall Prevention 
Most traumatic brain injuries among older persons in the U.S. are attributed to falls. Efforts to prevent falls may also plausibly reduce the incidence of TBIs and resultant costs.
To evaluate the association between the treatment or usual care region of the Connecticut Collaboration for Fall Prevention (CCFP), a clinical intervention for prevention of falls, and the rate of hospitalization for fall-related traumatic brain injury (FR-TBI) among persons ≥ 70 years. The Medicare charges of FR-TBI hospitalizations are also described.
Using a quasi-experimental design, rates of hospitalization for FR-TBI were recorded over an eight year period (2000–2007) in two distinct geographic regions (treatment and usual care) chosen for their similarity in characteristics associated with occurrence of falls.
Over 200,000 persons, 70 years and older, residing in two geographical regions in Connecticut.
Clinicians in the treatment region translated research protocols from Yale FICSIT, a successful fall prevention randomized clinical trial, into discipline- and site-specific fall prevention procedures for integration into their clinical practices.
The rate of hospitalization for fall-related traumatic brain injury among persons 70 years and older
Relative to the usual care region, CCFP’s treatment region exhibited lower rates of hospitalization for FR-TBI; RR= 0.84 with 95% credible interval (0.72 – 0.99).
The significantly lower rate of hospitalization for FR-TBI in CCFP’s treatment region suggests that the engagement of practicing clinicians in the implementation of evidence-based fall-prevention practices may reduce hospitalizations for FR-TBI.
PMCID: PMC3801219  PMID: 24083593
Connecticut Collaboration for Fall Prevention; fall-related traumatic brain injury; hospitalization; Bayesian; spatial model
15.  Risk for late-life re-injury, dementia and death among individuals with traumatic brain injury: a population-based study 
To determine the association of self-reported traumatic brain injury (TBI) with loss of consciousness (LOC) with late-life re-injury, dementia diagnosis and mortality.
Ongoing longitudinal population-based prospective cohort study.
Seattle-area integrated health system.
4225 dementia-free individuals age 65 and older were randomly selected and enrolled between 1994 and 2010. Participants were seen every 2 years, with mean (range) follow-up of 7.4 (0–16) years. 606 (14%) participants reported a lifetime history of TBI with LOC at enrolment. 3466 participants provided information regarding lifetime history of TBI and completed at least one follow-up visit.
Main outcome measures
Self-reported TBI with LOC after study entry, incident all-cause dementia and Alzheimer’s disease (AD), and all-cause mortality.
There were 25 567 person-years of follow-up. History of TBI with LOC reported at study enrolment was associated with increased risk for TBI with LOC during follow-up, with adjusted HRs ranging from 2.54 (95% CI 1.42 to 4.52) for those reporting first injury before age 25 to 3.79 (95% CI 1.89 to 7.61) for those with first injury after age 55. History of TBI with LOC was not associated with elevated risk for developing dementia or AD. There was no association between baseline history of TBI with LOC and mortality, though TBI with LOC since the previous study visit (‘recent TBI’) was associated with increased mortality (HR 2.12, 95% CI 1.62 to 2.78).
Individuals aged 65 or older who reported a history of TBI with LOC at any time in their lives were at elevated risk of subsequent re-injury. Recent TBI with LOC sustained in older adulthood was associated with increased risk for mortality. Findings support the need for close clinical monitoring of older adults who sustain a TBI with LOC.
PMCID: PMC3752841  PMID: 23172868
16.  Postinjury employment as a surrogate for functional outcomes: a quality indicator for trauma systems 
Return to work may be easily monitored as a surrogate of long-term functional outcome for benchmarking and performance improvement of trauma systems. We hypothesized that employment rates among survivors of traumatic brain injury (TBI) decrease following injury and remain depressed for an extended period of time. Data were obtained from a statewide surveillance system of 3522 TBI patients (aged >15 years) who were discharged alive from acute care hospitals and followed yearly using telephone interviews (1996–1999). The study population consisted of patients with severe TBI (head abbreviated injury score 3, 4, or 5) and complete follow-up for 3 years postinjury (n = 572). Patients were mostly young males (43 ± 19 years, 65% male) with blunt TBI (92%). The preinjury employment rate was 67%, which declined to 52% (P < 0.001) in the first year and slowly rose in subsequent years but never reached the preinjury level (54% in year 2, P < 0.001; 57% in year 3, P = 0.001). Increasing severity of TBI was associated with a lower employment rate. Patients who remained employed worked the same number of hours as they did before the injury (47.8 ± 10.5 hours). Female employment rates rose similar to rates for males. However, women who were employed full-time before TBI were more likely to work part-time after TBI than men (50% vs 24%, P < 0.001). In conclusion, survivors of severe injury do not attain preinjury employment levels for several years. Once validated in other studies, postinjury employment may be used as an indicator to monitor functional outcomes in trauma registries.
PMCID: PMC2943447  PMID: 20944755
17.  Factors associated with discharge destination from acute care after acquired brain injury in Ontario, Canada 
BMC Neurology  2012;12:16.
The aim of this paper is to examine factors associated with discharge destination after acquired brain injury in a publicly insured population using the Anderson Behavioral Model as a framework.
We utilized a retrospective cohort design. Inpatient data from provincial acute care records from fiscal years 2003/4 to 2006/7 with a diagnostic code of traumatic brain injury (TBI) and non-traumatic brain injury (nTBI) in Ontario, Canada were obtained for the study. Using multinomial logistic regression models, we examined predisposing, need and enabling factors from inpatient records in relation to major discharge outcomes such as discharge to home, inpatient rehabilitation and other institutionalized care.
Multinomial logistic regression revealed that need factors were strongly correlated with discharge destinations overall. Higher scores on the Charlson Comorbidity Index were associated with discharge to other institutionalized care in the nTBI population. Length of stay and special care days were identified as markers for severity and were both strongly positively correlated with discharge to other institutionalized care and inpatient rehabilitation, compared to discharge home, in both nTBI and TBI populations. Injury by motor vehicle collisions was found to be positively correlated with discharge to inpatient rehabilitation and other institutionalized care for patients with TBI. Controlling for need factors, rural location was associated with discharge to home versus inpatient rehabilitation.
These findings show that need factors (Charlson Comorbidity Index, length of stay, and number of special care days) are most significant in terms of discharge destination. However, there is evidence that other factors such as rural location and access to supplemental insurance (e.g., through motor vehicle insurance) may influence discharge destination outcomes as well. These findings should be considered in creating more equitable access to healthcare services across the continuum of care.
PMCID: PMC3402989  PMID: 22443681
18.  Traumatic Brain Injury Detection Using Electrophysiological Methods 
Measuring neuronal activity with electrophysiological methods may be useful in detecting neurological dysfunctions, such as mild traumatic brain injury (mTBI). This approach may be particularly valuable for rapid detection in at-risk populations including military service members and athletes. Electrophysiological methods, such as quantitative electroencephalography (qEEG) and recording event-related potentials (ERPs) may be promising; however, the field is nascent and significant controversy exists on the efficacy and accuracy of the approaches as diagnostic tools. For example, the specific measures derived from an electroencephalogram (EEG) that are most suitable as markers of dysfunction have not been clearly established. A study was conducted to summarize and evaluate the statistical rigor of evidence on the overall utility of qEEG as an mTBI detection tool. The analysis evaluated qEEG measures/parameters that may be most suitable as fieldable diagnostic tools, identified other types of EEG measures and analysis methods of promise, recommended specific measures and analysis methods for further development as mTBI detection tools, identified research gaps in the field, and recommended future research and development thrust areas. The qEEG study group formed the following conclusions: (1) Individual qEEG measures provide limited diagnostic utility for mTBI. However, many measures can be important features of qEEG discriminant functions, which do show significant promise as mTBI detection tools. (2) ERPs offer utility in mTBI detection. In fact, evidence indicates that ERPs can identify abnormalities in cases where EEGs alone are non-disclosing. (3) The standard mathematical procedures used in the characterization of mTBI EEGs should be expanded to incorporate newer methods of analysis including non-linear dynamical analysis, complexity measures, analysis of causal interactions, graph theory, and information dynamics. (4) Reports of high specificity in qEEG evaluations of TBI must be interpreted with care. High specificities have been reported in carefully constructed clinical studies in which healthy controls were compared against a carefully selected TBI population. The published literature indicates, however, that similar abnormalities in qEEG measures are observed in other neuropsychiatric disorders. While it may be possible to distinguish a clinical patient from a healthy control participant with this technology, these measures are unlikely to discriminate between, for example, major depressive disorder, bipolar disorder, or TBI. The specificities observed in these clinical studies may well be lost in real world clinical practice. (5) The absence of specificity does not preclude clinical utility. The possibility of use as a longitudinal measure of treatment response remains. However, efficacy as a longitudinal clinical measure does require acceptable test–retest reliability. To date, very few test–retest reliability studies have been published with qEEG data obtained from TBI patients or from healthy controls. This is a particular concern because high variability is a known characteristic of the injured central nervous system.
PMCID: PMC4316720
event-related potentials; EEG; traumatic brain injury; qEEG; non-linear dynamical analysis
Shock (Augusta, Ga.)  2013;40(6):471-475.
Traumatic brain injury (TBI) is a leading cause of mortality and disability. Acute postinjury insults after TBI, such as hypoxia, contribute to secondary brain injury and worse clinical outcomes. The functional and neuroinflammatory effects of brief episodes of hypoxia experienced following TBI have not been evaluated. Our previous studies have identified interleukin 6 (IL-6) as a potential mediator of mild TBI–induced pathology. In the present study, we sought to determine the effects of brief hypoxia on mild TBI and whether IL-6 played a role in the neuroinflammatory and functional deficits after injury. A murine model of mild TBI was induced by a weight drop (500 g from 1.5 cm). After injury, mice were exposed to immediate hypoxia (Fio2 = 15.1%) or normoxia (Fio2 = 21%) for 30 min. Serum and brain samples were analyzed for inflammatory cytokines 24 h after TBI. Neuron-specific enolase was measured as a serum biomarker of brain injury. Evaluation of motor coordination was performed for 5 days after TBI using a rotarod device. In some animals, anti–IL-6 was administered following TBI and hypoxia to neutralize systemic IL-6. Mice undergoing TBI had significant increases in brain injury. Exposure to brief hypoxia after TBI resulted in a more than 5-fold increase in serum neuron-specific enolase. This increase was associated with increases in serum and brain cytokine expression, suggesting that brief hypoxia exacerbates systemic and brain inflammation. Neutralization of IL-6 suppressed postinjury neuroinflammation and neuronal injury. In addition, TBI and hypoxia induced significant motor coordination deficits that were completely abrogated by IL-6 blockade. Exposure to hypoxia after TBI induces neuroinflammation and brain injury. These changes can be mitigated by neutralization of systemic IL-6. Interleukin 6 blockade also corrected the TBI-induced deficit in motor coordination. These data suggest that systemic IL-6 modulates the degree of neuroinflammation and contributes to reduced motor coordination after mild TBI.
PMCID: PMC4218737  PMID: 24088994
Traumatic brain injury; neuroinflammation; motor coordination; hypoxia; trauma; inflammation
20.  Traumatic Brain Injury among Older Adults at Level I and II Trauma Centers 
Journal of Neurotrauma  2013;30(24):2001-2013.
Individuals 65 years of age and over have the highest rates of traumatic brain injury (TBI)-related hospitalizations and deaths, and older adults (defined variably across studies) have particularly poor outcomes after TBI. The factors predicting these outcomes remain poorly understood, and age-specific care guidelines for TBI do not exist. This study provides an overview of TBI in older adults using data from the National Trauma Data Bank (NTDB) gathered between 2007 and 2010, evaluates age group-specific trends in rates of TBI over time using U.S. Census data, and examines whether routinely collected information is able to predict hospital discharge status among older adults with TBI in the NTDB. Results showed a 20–25% increase in trauma center admissions for TBI among the oldest age groups (those >=75 years), relative to the general population, between 2007 and 2010. Older adults (>=65 years) with TBI tended to be white females who have incurred an injury from a fall resulting in a “severe” Abbreviated Injury Scale (AIS) score of the head. Older adults had more in-hospital procedures, such as neuroimaging and neurosurgery, tended to experience longer hospital stays, and were more likely to require continued medical care than younger adults. Older age, injury severity, and hypotension increased the odds of in-hospital death. The public health burden of TBI among older adults will likely increase as the Baby Boom generation ages. Improved primary and secondary prevention of TBI in this cohort is needed.
PMCID: PMC3868380  PMID: 23962046
adult brain injury; epidemiology; geriatric brain injury; traumatic brain injury
21.  The epidemiology of hospital treated traumatic brain injury in Scotland 
BMC Neurology  2014;14:2.
Traumatic Brain Injury (TBI) is an important global public health problem made all the more important by the increased likelihood of disability following a hospital admission for TBI. Understanding those groups most at risk will help inform interventions designed to prevent causes of TBI, such as falls prevention measures. This study identifies the rate of hospitalisation episodes of TBI in Scotland, explores causes of TBI admissions, and trends in hospitalisation episodes by age and gender over a twelve year period using routinely collected hospital data.
A retrospective analysis of routine hospital episode data identified records relating to TBI for the twelve years between 1998 and 2009. Descriptive and joinpoint regression analysis were used, average annual percentage changes (AAPC) and annual percentage change (APC) in rates were calculated.
Between 1998 and 2009 there were 208,195 recorded episodes of continuous hospital care in Scotland as a result of TBI. Almost half (47%) of all TBIs were the result of falls, with marked peaks observed in the very young and the oldest groups. The AAPC of hospitalization episode rates over the study period for boys and girls aged 0-14 were -4.9% (95% CI -3.5 to-6.3) and -4.7% (95% CI -2.6 to -6.8) respectively. This reduction was not observed in older age groups. In women aged 65 and over there was an APC of 3.9% (95% CI 1.2 to 6.6) between 2004 and 2009.
Hospitalisation for TBI is relatively common in Scotland. The rise in the age-adjusted rate of hospitalisation episodes observed in older people indicates that reduction of TBI should be a public health priority in countries with an ageing population. Public health interventions such as falls prevention measures are well advised and evaluations of such interventions should consider including TBI hospitalisation as an alternative or supplementary outcome measure to fractured neck of femur. Further research is needed to advance understanding of the associations of risk factors with increased incidence of TBI hospital episodes in the elderly population.
PMCID: PMC3893436  PMID: 24386897
Traumatic brain injury; Accidental falls; Patient admissions; Epidemiology; Scotland; Trends
22.  Disrupted modular organization of resting-state cortical functional connectivity in U.S. military personnel following concussive ‘mild’ blast-related traumatic brain injury† 
NeuroImage  2013;84:10.1016/j.neuroimage.2013.08.017.
Blast-related traumatic brain injury (TBI) has been one of the “signature injuries” of the wars in Iraq and Afghanistan. However, neuroimaging studies in concussive ‘mild’ blast-related TBI have been challenging due to the absence of abnormalities in computed tomography or conventional magnetic resonance imaging (MRI) and the heterogeneity of the blast-related injury mechanisms. The goal of this study was to address these challenges utilizing single-subject, module-based graph theoretic analysis of resting-state functional MRI (fMRI) data. We acquired 20 minutes of resting-state fMRI in 63 U.S. military personnel clinically diagnosed with concussive blast-related TBI and 21 U.S. military controls who had blast exposures but no diagnosis of TBI. All subjects underwent an initial scan within 90 days post-injury and 65 subjects underwent a follow-up scan 6 to 12 months later. A second independent cohort of 40 U.S. military personnel with concussive blast-related TBI patients served as a validation dataset. The second independent cohort underwent an initial scan within 30 days post-injury. 75% of scans were of good quality, with exclusions primarily due to excessive subject motion. Network analysis of the subset of these subjects in the first cohort with good quality scans revealed spatially localized reductions in participation coefficient, a measure of between-module connectivity, in the TBI patients relative to the controls at the time of the initial scan. These group differences were less prominent on the follow-up scans. The 15 brain areas with the most prominent reductions in participation coefficient were next used as regions of interest (ROIs) for single-subject analyses. In the first TBI cohort, more subjects than would be expected by chance (27/47 versus 2/47 expected, p < 0.0001) had 3 or more brain regions with abnormally low between-module connectivity relative to the controls on the initial scans. On the follow-up scans, more subjects than expected by chance (5/37, p = 0.044) but fewer subjects than on the initial scans had 3 or more brain regions with abnormally low between-module connectivity. Analysis of the second TBI cohort validation dataset with no free parameters provided a partial replication; again more subjects than expected by chance (8/31, p = 0.006) had 3 or more brain regions with abnormally low between-module connectivity on the initial scans, but the numbers were not significant (2/27, p = 0.276) on the follow-up scans. A single-subject, multivariate analysis by probabilistic principal component analysis of the between-module connectivity in the 15 identified ROIs, showed that 31/47 subjects in the first TBI cohort were found to be abnormal relative to the controls on the initial scans. In the second TBI cohort, 9/31 patients were found to be abnormal in identical multivariate analysis with no free parameters. Again, there were not substantial differences on the follow-up scans. Taken together, these results indicate that single-subject, module-based graph theoretic analysis of resting-state fMRI provides potentially useful information for concussive blast-related TBI if high quality scans can be obtained. The underlying biological mechanisms and consequences of disrupted between-module connectivity are unknown, thus further studies are required.
PMCID: PMC3849319  PMID: 23968735
functional connectivity; traumatic brain injury; graph theory; modularity; functional magnetic resonance imaging (fMRI); blast injury
23.  Traumatic Brain Injury Related Hospitalization and Mortality in California 
BioMed Research International  2013;2013:143092.
Objective. The aim of this study is to describe the traumatic brain injury (TBI) population and causes and identify factors associated with TBI hospitalizations and mortality in California. Methods. This is a cross-sectional study of 61,188 patients with TBI from the California Hospital Discharge Data 2001 to 2009. We used descriptive, bivariate, and multivariate analyses in SAS version 9.3. Results. TBI-related hospitalizations decreased by 14% and mortality increased by 19% from 2001 to 2009. The highest percentages of TBI hospitalizations were due to other causes (38.4%), falls (31.2%), being of age ≥75 years old (37.2%), being a males (58.9%), and being of Medicare patients (44%). TBIs due to falls were found in those age ≤4 years old (53.5%), ≥75 years old (44.0%), and females (37.2%). TBIs due to assaults were more frequent in Blacks (29.0%). TBIs due to motor vehicle accidents were more frequent in 15–19 and 20–24 age groups (48.7% and 48.6%, resp.) and among Hispanics (27.8%). Higher odds of mortality were found among motor vehicle accident category (adjusted odds ratio (AOR): 1.27, 95% CI: 1.14–1.41); males (AOR: 1.36, 95% CI: 1.27–1.46); and the ≥75-year-old group (AOR: 6.4, 95% CI: 4.9–8.4). Conclusions. Our findings suggest a decrease in TBI-related hospitalizations but an increase in TBI-related mortality during the study period. The majority of TBI-related hospitalizations was due to other causes and falls and was more frequent in the older, male, and Medicare populations. The higher likelihood of TBI-related mortalities was found among elderly male ≥75 years old who had motor vehicle accidents. Our data can inform practitioners, prevention planners, educators, service sectors, and policy makers who aim to reduce the burden of TBI in the community. Implications for interventions are discussed.
PMCID: PMC3845866  PMID: 24324953
24.  Epidemiological Trends of Spine Trauma: An Australian Level 1 Trauma Centre Study 
Global Spine Journal  2013;3(2):75-84.
Knowledge of current epidemiology and spine trauma trends assists in public resource allocation, fine-tuning of primary prevention methods, and benchmarking purposes. Data on all patients with traumatic spine injuries admitted to the Alfred Hospital, Melbourne between May 1, 2009, and January 1, 2011, were collected from the Alfred Trauma Registry, Alfred Health medical database, and Victorian Orthopaedic Trauma Outcomes Registry. Epidemiological trends were analyzed as a general cohort, with comparison cohorts of nonsurvivors versus survivors and elderly versus nonelderly. Linear regression analysis was utilized to demonstrate trends with statistical significance. There were 965 patients with traumatic spine injuries with 2,333 spine trauma levels. The general cohort showed a trimodal age distribution, male-to-female ratio of 2:2, motor vehicle accidents as the primary spine trauma mechanism, 47.7% patients with severe polytrauma as graded using the Injury Severity Score (ISS), 17.3% with traumatic brain injury (TBI), the majority of patients with one spine injury level, 7% neurological deficit rate, 12.8% spine trauma operative rate, and 5.2% mortality rate. Variables with statistical significance trending toward mortality were the elderly, motor vehicle occupants, severe ISS, TBI, C1–2 dissociations, and American Spinal Injury Association (ASIA) A, B, and C neurological grades. Variables with statistical significance trending toward the elderly were females; low falls; one spine injury level; type 2 odontoid fractures; subaxial cervical spine distraction injuries; ASIA A, B, and C neurological grades; and patients without neurological deficits. Of the general cohort, 50.3% of spine trauma survivors were discharged home, and 48.1% were discharged to rehabilitation facilities. This study provides baseline spine trauma epidemiological data. The trimodal age distribution of patients with traumatic spine injuries calls for further studies and intervention targeted toward the 46- to 55-year age group as this group represents the main providers of financial and social security. The study's unique feature of delineating variables with statistical significance trending toward both mortality and the elderly also provides useful data to guide future research studies, benchmarking, public health policy, and efficient resource allocation for the management of spine trauma.
PMCID: PMC3854579  PMID: 24436855
spine trauma; epidemiology; demographics; spinal injury characteristics; neurological status; registry; prevention
25.  The Moderating Effects of Sex and Age on the Association between Traumatic Brain Injury and Harmful Psychological Correlates among Adolescents 
PLoS ONE  2014;9(9):e108167.
Although it is well established that sex is a risk factor in acquiring a traumatic brain injury (TBI) among adolescents, it has not been established whether it also moderates the influence of other TBI psychological health correlates.
Methods and Findings
Data were derived from a 2011 population-based cross-sectional school survey, which included 9,288 Ontario 7th–12th graders who completed anonymous self-administered questionnaires in classrooms. Response rate was 62%. Preliminary analyses found no evidence of nonresponse bias in the reporting of TBI. TBI was defined as a hit or blow to the head that resulted in a 5 minutes loss of consciousness or at least one overnight hospitalization due to symptoms associated with it. Reports of lifetime TBI were more common among males than females (23.1%, 95% CI: 20.5, 25.8 vs. 17.1%, 95% CI: 14.7, 19.8). Thirteen correlates were examined and included cigarette smoking, elevated psychological distress, suicide ideation, bully victimization (at school, as well as cyber bullying), bullying others, cannabis use, cannabis dependence and drug use problems, physical injuries, daily smoking, drinking alcohol, binge drinking, use of cannabis, and poor academic performance. Among the outcomes examined, sex moderated the relationship between lifetime TBI and cigarette smoking. In addition, sex and age jointly moderated the relationship between lifetime TBI and daily smoking, alcohol use and physical injuries. Late adolescent males who reported lifetime TBI, relative to females, displayed elevated daily smoking and injuries, whereas their females counterparts displayed elevated past year drinking. Possible bias related to self-report procedures and the preclusion of causal inferences due to the cross-sectional nature of the data are limitations of this study.
TBI differences in outcomes need to be assessed for potential moderating effects of sex and age. Results have important implications for more tailored injury prevention efforts.
PMCID: PMC4182663  PMID: 25268238

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