With the continued advancement in technology, such as increasingly sophisticated neuroimaging parameters, and the ongoing development of various scientific fields, like serum and blood biomarkers, genetics, and physiology, traumatic brain injury (TBI) research is a dynamic field of study. TBI remains a significant public health concern and research has continued to grow exponentially over the past decade. This review provides an overview of the frontiers of TBI research, from sports concussion to severe TBI, from acute and subacute injury to long-term/chronic outcomes, from assessment and management to prognosis, specifically examining recent neuroimaging, biomarkers, genetics, and physiologic studies.
Key points
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Traumatic brain injury (TBI) is a dynamic field of research that has benefited from continued advancement in technology and ongoing developments across various scientific fields.
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TBI assessment, management, and prognosis has been improved through neuroimaging, biomarkers, genetics, and physiology studies.
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TBI premorbid risk, pathophysiology, and clinical phenotype are important considerations that influence clinical outcomes.
Introduction
Traumatic brain injury (TBI) is a dynamic field of research that has exploded in the past decade. This increasing research interest has largely been associated with the continued advancement in technology (eg, neuroimaging) and ongoing developments across various scientific fields (eg, serum and blood biomarkers, genetics, and physiology), but also largely driven by the fact that TBI is a significant public health concern. It remains one of the leading causes of death among young adults and accounts for approximately one-half of all trauma-related fatalities globally. The World Health Organization estimates that between 150 and 300 individuals per 100,000 are affected by TBI worldwide, of which around 10 million TBI-related hospitalizations or deaths occur annually. In the United States alone, it is estimated that approximately 1.5 to 2 million Americans sustain a TBI annually. TBIs account for around 1.4 million emergency room visits, 275,000 hospital admissions, and 52,000 deaths in the United States each year. They contribute to approximately 30% of all deaths in the United States, annually. TBI also has an enormous social and financial cost, with estimates of the annual financial burden associated with TBI ranging between $9 and $10 billion. TBI often results in residual symptoms that affect an individual’s cognition, movement, sensation, and/or emotional functioning. Recovery and rehabilitation from TBI may require considerable resources and may take years.
Multidisciplinary approaches to TBI research have provided considerable insights into this injury, and epidemiologic studies have exposed the public health impact of TBI in relation to age, gender, and socioeconomic variables to incidence, prognosis, and outcome. In this special issue of Physical Medicine and Rehabilitation Clinics of North America on TBI, other articles have discussed fundamental issues such as the mechanism of injury, the biomechanics, pathophysiology, diagnosis, management, assessment/investigation(s), various postinjury sequelae, and potential long-term consequences. Therefore, the aim of this review is to provide an overview of the various new research approaches (“frontiers”) that have been adopted around the world examining TBI, to discuss advancements in clinical trials, and to provide an overview of possible directions for future research. This discussion includes an overview of a range of TBI research, from sports concussion to severe TBI, from acute and subacute injury to long-term and chronic outcomes, from assessment and management to prognosis, specifically examining recent neuroimaging, biomarkers, genetics, and physiologic studies. The current review is less focused on discussing the underpinnings and background of the various technologies discussed (see other articles in this special issue for specific details) and more focused on the research findings and advancements in the TBI field. We also do not review potential novel treatment paradigms.
Introduction
Traumatic brain injury (TBI) is a dynamic field of research that has exploded in the past decade. This increasing research interest has largely been associated with the continued advancement in technology (eg, neuroimaging) and ongoing developments across various scientific fields (eg, serum and blood biomarkers, genetics, and physiology), but also largely driven by the fact that TBI is a significant public health concern. It remains one of the leading causes of death among young adults and accounts for approximately one-half of all trauma-related fatalities globally. The World Health Organization estimates that between 150 and 300 individuals per 100,000 are affected by TBI worldwide, of which around 10 million TBI-related hospitalizations or deaths occur annually. In the United States alone, it is estimated that approximately 1.5 to 2 million Americans sustain a TBI annually. TBIs account for around 1.4 million emergency room visits, 275,000 hospital admissions, and 52,000 deaths in the United States each year. They contribute to approximately 30% of all deaths in the United States, annually. TBI also has an enormous social and financial cost, with estimates of the annual financial burden associated with TBI ranging between $9 and $10 billion. TBI often results in residual symptoms that affect an individual’s cognition, movement, sensation, and/or emotional functioning. Recovery and rehabilitation from TBI may require considerable resources and may take years.
Multidisciplinary approaches to TBI research have provided considerable insights into this injury, and epidemiologic studies have exposed the public health impact of TBI in relation to age, gender, and socioeconomic variables to incidence, prognosis, and outcome. In this special issue of Physical Medicine and Rehabilitation Clinics of North America on TBI, other articles have discussed fundamental issues such as the mechanism of injury, the biomechanics, pathophysiology, diagnosis, management, assessment/investigation(s), various postinjury sequelae, and potential long-term consequences. Therefore, the aim of this review is to provide an overview of the various new research approaches (“frontiers”) that have been adopted around the world examining TBI, to discuss advancements in clinical trials, and to provide an overview of possible directions for future research. This discussion includes an overview of a range of TBI research, from sports concussion to severe TBI, from acute and subacute injury to long-term and chronic outcomes, from assessment and management to prognosis, specifically examining recent neuroimaging, biomarkers, genetics, and physiologic studies. The current review is less focused on discussing the underpinnings and background of the various technologies discussed (see other articles in this special issue for specific details) and more focused on the research findings and advancements in the TBI field. We also do not review potential novel treatment paradigms.
Neuroimaging
Neuroimaging has been explored elsewhere in greater detail in this special issue (see Elisabeth Wilde ‘Neuroimaging’). The increasing sophistication of advanced neuroimaging techniques has provided researchers (and clinicians) with an incredible insight, not only into the structure of the brain, but also into various aspects of its function (eg, connectivity, metabolism, blood flow, perfusion, magnetization transfer effect, and local field inhomogeneities). Neuroimaging now has an increasingly important role in the clinical diagnosis and management of TBI. A number of advanced neuroimaging techniques that go beyond the capabilities of computed tomography (CT) and structural MRI have been increasingly used in TBI research. There are many variables that may affect the quality of data (the image resolution) that these techniques can acquire (ie, the magnetic field strength, the head coil specifications, improved filling of k-space), but also the processing of the data after acquisition. These processing techniques can sometimes rely on the manufacturer’s automated software, but others are operator dependent, which means that the data can vary depending on the expertise of the operator. A number of these techniques and their capabilities have been outlined in a previous review.
Neuroimaging research
Diffusion Tensor Imaging Traumatic Brain Injury Literature Summary
Diffusion tensor imaging (DTI) has become a frequently used technique in TBI research. There are 3 main approaches for DTI analysis ( Table 1 ).
| Technique | Capabilities |
|---|---|
| ROI | Predetermined regions in the brain are examined and the DTI metrics are calculated for these regions. This approach is appropriate where specific regions are expected to have been affected. |
| Tractography | Fiber tractography uses the collection of water molecules around fiber tracts to reconstruct the tracts. |
| VBA or TBSS | Enables a holistic approach without designating a specific anatomic location for analysis. |
Significant differences in the various DTI metrics (fractional anisotropy, mean diffusivity, and apparent diffusion coefficient) have been observed across all levels of TBI severity, in adults and children. The reported DTI changes have revealed a correlation with injury severity, functional outcome, neurologic function, and cognitive function. A recent systematic review of the DTI literature in sports concussion suggested that DTI may have potential for early identification of athletes with unresolved concussions who are at high risk for a poor outcome, which may assist in more specific and effective clinical management; however, consistency across methodology within the field would improve interpretation of the data across studies.
MR Spectroscopy Traumatic Brain Injury Literature Summary
MR spectroscopy MRS is an MR technique that calculates the biochemistry or neurometabolite alteration by observing the structure, dynamics, reaction state, and chemical environment of molecules. MRS has been used increasingly to investigate the presence of metabolite alteration after TBI, especially in tissue with no or little visible injury on conventional imaging. The various neurometabolites seen on MRS at 3T have been previously summarized elsewhere.
MRS has been touted as a reliable technique for providing early prognostic information in relation to clinical outcome in some patient groups. A recent systematic review of the MRS literature in sports concussion suggested that MRS may have potential as a tool for identifying altered neurophysiology and monitoring recovery in adult athletes, even beyond the resolution of postconcussive symptoms and other investigation techniques returning to normative levels.
Functional MRI Traumatic Brain Injury Literature Summary
Functional MRI (fMRI) has been used to examine functional activation in all levels of TBI severity in both adults and children. fMRI has demonstrated a dissociation between TBI and comparison groups in their allocation of cortical resources to the encoding, maintenance, and retrieval phases of working memory. In adolescent moderate to severe TBI, increased activation during encoding and retrieval of letters of a memory task was observed using event-related fMRI, whereas the healthy matched control group displayed increased activation during maintenance relative to encoding and retrieval. fMRI has also been effective in understanding and tracking recovery of mild TBI (mTBI), in addition to the effects of rehabilitation in more severe TBI, including understanding disorders of consciousness and arousal.
Resting State Functional MRI Traumatic Brain Injury Literature Summary
Examining what the brain does at rest (ie, resting state fMRI) has revealed altered activation patterns in veterans of the wars in Iraq and Afghanistan who had sustained 1 or more mTBIs, compared with veterans who had not been exposed to blasts and had not sustained a TBI during deployment.
Susceptibility Weighted Imaging Traumatic Brain Injury Literature Summary
The extent of hemorrhage as observed on susceptibility weighted imaging has been shown to correlate with injury severity as measured by the Glasgow Coma Scale, coma duration, and long-term outcome in children. The exact role of minor hemorrhage and its influence on prognosis is unclear.
Arterial Spin Labeling Traumatic Brain Injury Literature Summary
Arterial spin labeling has shown promise in characterizing regional brain function in more severe TBI where task-evoked responses are difficult to obtain, determining the relation between changes in regional cerebral blood flow and cognitive deficits for identification of potential pharmacologic or therapeutic targets, and as a biomarker for pharmaceutical trials. Perfusion parameters can be of interest both in acute mTBI as well as during the subacute and later phases of recovery from more moderate to severe TBI, to chronicle both transient and persistent TBI-related changes in cerebral perfusion.
Magnetoencephalography Traumatic Brain Injury Literature Summary
Magnetoencephalography possesses considerable potential for use in mTBI where traditional MR investigation is unrevealing. Magnetoencephalography seems to be sensitive to abnormal neuronal signals resulting from axonal injury, signified by focal or multifocal low-frequency neuronal magnetic signal (delta-band 1–4 Hz, or theta-band 5–7 Hz) that can be measured directly and localized. Such work may help to define preexisting patterns (ie, attention deficit hyperactivity disorder [ADHD] and those with TBI).
Serum and blood biomarkers
Discovering biomarkers or biological signals for specific diseases and/or injuries has become and increasing focus of many researchers and clinicians across a number of fields of study, including TBI. At present, the discovery of an accurate biochemical assessment for identifying objectively the extent of damage after TBI remains elusive. Four decades ago, a seminal paper on the evaluation of cerebrospinal fluid (CSF) levels of cyclic AMP as a potential biomarker of depth of coma was published. An increase in Glasgow Coma Scale score was associated with increased cyclic AMP in the CSF of individuals with severe TBI. Subsequently, the interest in elucidating and characterizing novel and selective TBI biomarkers has increased exponentially. Advancements in neuroproteomics have resulted in a number of candidates for serum and blood biomarkers of TBI. Indeed, some serum and blood TBI biomarker candidates have been studied for a number of years in this context. The various serum and blood biomarkers that have been investigated in the context of TBI are summarized in Table 2 .
S-100B Traumatic Brain Injury Literature Summary
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CSF and serum S-100B concentrations have been reported to be higher in TBI patients compared with subarachnoid hemorrhage.
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S-100B concentrations in CSF and serum were significantly higher in patients with an unfavorable outcome compared with patients with a good outcome.
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Serum S-100B concentrations on admission to hospital, and at 24 hours after injury, had among the greatest predictive value for poor status at 72 hours.
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Significant correlations in serum S-100B and Glasgow Outcome Scale score at 6 months.
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High initial S-100B levels (>0.7 μg/dL) in serum are associated with 100% mortality.
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Patients with intracerebral lesions on brain CT scan or with bad clinical evolution were identified using S-100B serum concentrations with a sensitivity of 100% and a specificity of 30%.
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In severe TBI, S-100B concentrations were significantly higher in patients who died compared with survivors.
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S-100B samples at 24, 48, 72, and 96 hours have been found to be useful tools for predicting mortality, with 72 hours providing the best prediction.
Tau Traumatic Brain Injury Literature Summary
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Microtubule-associated protein tau was increased at days 0, 30, and 90 in TBI cases compared with controls. Maximum tau levels were recorded at 24 hours.
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Day 0 tau was excellent at discriminating complicated mTBI from controls.
Neuron-Specific Enolase Traumatic Brain Injury Literature Summary
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In severe TBI patients, only the 48-hour neuron-specific enolase samples collected were found to be useful tools for predicting mortality, with neuron-specific enolase samples at 24, 72, and 96 hours not found to be predictive.
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Neuron-specific enolase has demonstrated a potential for determining outcomes at 6 months.
Glial Fibrillary Acidic Protein Traumatic Brain Injury Literature Summary
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Plasma glial fibrillary acidic protein (GFAP) was increased at days 0, 30, and 90 in TBI cases compared with controls. Maximum GFAP levels were recorded at 24 hours. Day 0 GFAP was excellent at discriminating complicated mTBI from controls. GFAP concentration was found to strongly predict outcome after pediatric TBI, and has been recommended as a candidate biomarker for pediatric TBI. Day 7 GFAP levels predicted a poorer Glasgow Outcome Scale score (1–3) at 1 year.
Ubiquitin Carboxy-Terminal Hydrolase L1 Traumatic Brain Injury Literature Summary
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The ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) concentration was found to strongly predict outcome after pediatric TBI, and has been recommended as a candidate biomarker for pediatric TBI. Higher serum levels of UCH-L1 were observed in brain-injured children compared with controls. A stepwise increase in UCH-L1 concentrations over the continuum of mild to severe TBI was observed. UCH-L1 holds the potential to detect acute intracranial lesions as assessed by CT. Serum UCH-L1 concentrations strongly predicted a poor outcome in this study. However, another study of UCH-L1 in pediatric mTBI did not find significant differences between pediatric mTBI compared with orthopedic injury controls, and UCH-L1 concentrations did not predict postconcussion symptom scale scores over the first month after injury.
Interleukin-1B Traumatic Brain Injury Literature Summary
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There is a paucity of studies that have examined circulating interleukin (IL)-1 changes after TBI, which may be a reflection of the challenges associated with measuring this protein in human TBI. Serum levels of IL-1B collected at 6 hours after severe TBI have been found to be associated with Glasgow Coma Scale, whereas increased serum IL-6 has been shown to be useful for the differential diagnosis of increased intracranial pressure after TBI. A favorable Glasgow Outcome Scale score (4–5) at 1 year was predicted by higher admission IL-6. Nonsurvivors at 1 year had day 7 IL-6 serum levels of greater than 71.26 pg/mL.
| Biomarkers | Description and Function |
|---|---|
| S-100B | A calcium-binding peptide produced mainly by astrocytes that exert paracrine and autocrine effects on neurons and glia. It is thought to be involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. |
| Tau | Proteins that stabilize microtubules. They are produced through alternative splicing of a single gene called MAPT (microtubule-associated protein tau). When tau proteins become defective and fail to adequately stabilize microtubules, pathologies of the nervous system can develop. |
| NSE | A specific serum marker for neuronal damage. It is a 78 kD gamma-homodimer and represents the dominant enolase-isoenzyme found in neuronal and neuroendocrine tissues. |
| GFAP | An intermediate-filament protein that is highly specific for cells of astroglial lineage. It is an intermediate filament protein that is expressed by numerous cell types of the CNS, including astrocytes, and ependymal cells. |
| UCH-L1 | A deubiquitinating enzyme found in nerve cells throughout the brain. It is thought to be involved in cell machinery that degrades extraneous proteins. |
| IL-1B | A proinflammatory cytokine thought to contribute to the development of posttraumatic astrogliosis. |
Genetics
There are currently a number of genes that are associated with TBI outcome that can be quite variable and unpredictable. The variability in post-TBI presentation of individuals with similar injury severity and preinjury intellect and educational background suggests that factors other than injury severity also have an important impact on TBI outcome. One such factor may be an individual’s genotype. Genetics influence the response to and recovery from TBI. It is a dynamic area and, as such, providing an exhaustive list of potential candidate genes and alleles here is not possible owing to space limitations. So, much like in the neuroimaging section, this section provides a brief overview of research in this field. An array of genetic responses are triggered by TBI both in the acute and subacute stages after injury.
Apolipoprotein E (ApoE) has historically been the most commonly studied gene, and it has been found to influence rehabilitation outcome, coma recovery, and risk of posttraumatic seizures, as well as cognitive and behavioral functions after injury. Other genes have been investigated to a lesser extent, such as catechol-o-methyltransferase (COMT) and DRD2, which may influence the degree of executive dysfunction by altering dopaminergic system function. IL genes have a role in post-TBI neuronal inflammation, and polymorphisms of the p53 gene may modulate post-TBI apoptosis. The angiotensin-converting enzyme gene may affect TBI outcome via mechanisms of cerebral blood flow and/or autoregulation, and the calcium channel, voltage-dependent, P/Q type, alpha-1A (CACNA1A) gene may exert influence via the calcium channel and its effect on delayed cerebral edema ( Table 3 ).
Apolipoprotein E Traumatic Brain Injury Literature Summary
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The ε4 allele is associated with poor outcomes after TBI.
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It is unlikely that ApoE genotype influences cognitive function in the initial recovery period after TBI, regardless of injury severity.
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The influence of ApoE ε4 allele on neuropsychological testing, functional outcome, and in pediatric populations has been found to be variable and complex, although a review found that the ApoE ε4 allele adversely influences recovery after TBI, particularly with respect to dementia-related outcomes and outcomes after severe TBI.
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A recent metaanalysis concluded that ApoEε4 allele is associated with the long-term functional outcome of patients with TBI.
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Another recent metaanalysis concluded that ApoEε4 allele does not have a detrimental effect on cognition after TBI.
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A further metaanalysis and metaregression concluded that the ApoEε4 allele is important to the prognosis of pediatric TBI, but not for adult TBI; this effect may be time dependent.
Angiotensin-Converting Enzyme Traumatic Brain Injury Literature Summary
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Significant effects on TBI outcome were found for 3 neighboring tag single nucleotide polymorphisms in the codominant (genotypic) model of inheritance.
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Genetic variations in a specific region of the angiotensin-converting enzyme gene possibly influences outcomes of TBI patients.
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The presence of 1 or more D alleles was associated with a mortality of 36.4% compared with 7.1% for 2 alleles.
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D allele carrier patients (insertion/deletion) performed worse than those with 1 allele homozygous (I/I) polymorphism on tests involving attention and processing speed.
Calcium Channel, Voltage-Dependent, P/Q Type, Alpha-1A Traumatic Brain Injury Literature Summary
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The CACNA1A gene may exert an influence via the calcium channel and its effect on delayed cerebral edema.
Catechol-o-Methyltransferase Traumatic Brain Injury Literature Summary
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The COMT Met (158) allele was associated with higher nonverbal processing speed compared with Val (158)/Val (158) homozygotes after controlling for demographics and injury severity.
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The COMT Val (158) Met polymorphism did not associate with mental flexibility or with verbal learning. The COMT genotypes have been suggested to play a role of in the long-term recovery of executive function after pediatric TBI. COMT polymorphism (3 COMT genotype groups; Val/Val, Val/Met, and Met/Met) did not differ in terms of neuropsychological performance or functional outcome after controlling for age, education, and severity of injury.
| Gene | Description and Function |
|---|---|
| ApoE | A complex glycolipoprotein that facilitates the uptake, transport, and distribution of lipids. A 4-exon gene codes for ApoE on chromosome 19 in humans. There are 3 major alleles: ε2, ε3, and ε4. |
| ACE | Plays a central role in regulation of blood pressure through the conversion of angiotensin I to angiotensin II. The ACE gene is located n chromosome 17 and has a common insertion/deletion mutation in intron 16. |
| CACNA 1 A | The CACNA 1 A gene codes for the α-1 subunit (pore-forming component) of the neuronal calcium channel. The functional polymorphisms in this gene might therefore alter the downstream effects of the influx of calcium into the neuron that is triggered at the time of TBI. |
| COMT | An enzyme that metabolizes catecholamine neurotransmitters (ie, dopamine, epinephrine, and norepinephrine). |
| BDNF | Initially manufactured as a precursor protein and then cleaved to BDNF and stored in and released from secretory vesicles in response to neural activity. It facilitates both early and late long-term potentiation, a process critical to the formation and maintenance of episodic and working memory. |
| NGB | A protein found in neurons of both the peripheral and central nervous system that appears to convey some resilience to hypoxic/ischemic insult, perhaps by facilitating oxygen transport across the blood–brain barrier or enhancing availability of oxygen to mitochondria. |
| DRD 2 | Located on chromosome 11, there are more than a dozen polymorphisms described for this gene, 3 that result in amino acid substitutions and 2 that reduce the expression of DRD 2 receptors. |
| IL | The IL-1 family consists of 2 proinflammatory interleukins (α and β) and an IL receptor antagonist (IL-1RA). IL-6 is a proinflammatory cytokine that has been associated with hippocampal neurogenesis. |
| TP53 | Considered a facilitator in orchestrating both cell growth arrest and the onset of apoptosis. |
Related posts:
Management of Medical Complications During the Rehabilitation of Moderate-Severe Traumatic Brain Injury
Diagnosis and Management of Acute Concussion
Rehabilitation of Persistent Symptoms After Concussion
Integrative Medicine in Traumatic Brain Injury
Educational and Vocational Issues in Traumatic Brain Injury
Toward a Postmodern Pragmatic Discourse Semioethics for Brain Injury Care
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