Neuroplasticity after Traumatic Brain Injury

YouRong Sophie Su; Anand Veeravagu; Gerald Grant

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Laskowitz D, Grant G, editors. Translational Research in Traumatic Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016.

Translational Research in Traumatic Brain Injury.

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Chapter 8Neuroplasticity after Traumatic Brain Injury

YouRong Sophie Su, Anand Veeravagu, and Gerald Grant.

Traumatic brain injury (TBI) is a challenging disease process, both to treat and investigate. Broadly speaking, TBI consists of structural injuries or physiologic changes in brain function secondary to external forces.¹ Such injuries may result in cell death, gliotic scar formation, and/or damage from reactive oxygen species and inflammation.¹

Prior TBI population studies revealed that the prevalence of TBI in adults over 18 was 8.5%.² In 2010, 2.5 million emergency department visits, hospitalizations, and deaths were associated with TBI with data from the Centers for Disease Control and Prevention³ suggesting that TBI was related to 30% of mortalities. Pediatric TBI, while largely understudied, is also an important concern, as it can reach an annual incidence of 100,000–200,000 with children between the ages of 0 and 4 years having the highest percentage of incidence and mortality.⁴^,⁵ The economic impact of brain injury is difficult to determine when considering compensation for work loss, quality of life, rehabilitation, and home services in addition to medical costs. Nonetheless, estimates of total lifetime costs range from $147 billion for fatal TBI to $18 billion for nonhospitalized TBI.²

Although brain injuries are a significant portion of trauma, the severity of TBI ranges from mild, defined as a momentary change in consciousness, to severe, which involves sustained periods of unconsciousness and/or amnesia. Fortunately, more than 85% of TBI that is medically treated is considered mild and most patients are able to recover from their injuries.²

NEUROPLASTICITY

The central nervous system (CNS) retains an innovative ability to recover and adapt secondary compensatory mechanisms to injury. The basis of recovery stems from neuroplasticity, defined as the ability for neuronal circuits to make adaptive changes on both a structural and functional level, ranging from molecular, synaptic, and cellular changes to more global network changes. The adult brain was traditionally thought to be stagnant, with neuroplasticity confined to cortical development.

Now, however, neuronal plasticity occurs after an injury in a sequence of three phases.⁶ Immediately after injury, cell death occurs along with decrease in cortical inhibitory pathways for 1 to 2 days that is thought to recruit or unmask new and secondary neuronal networks.⁷ Eventually, the activity of cortical pathways shift from inhibitory to excitatory followed by neuronal proliferation and synaptogenesis. Both neuronal and nonneuronal cells (i.e., endothelial progenitors, glial cells, and inflammatory cells) are recruited to replace the damaged cells, facilitate gliotic scar tissue, and revascularize.⁶ Weeks after injury, new synaptic markers and axonal sprouting are upregulated,⁸ allowing for remodeling and cortical changes for recovery. Chronic changes have been studied in several mouse injury models, although outcomes vary and are affected by the age of the mouse at time of injury.⁴ Preliminary work does suggest that long-lasting morphologic changes occur in the hippocampus after TBI, including growth of cell soma and recruitment of neurons to the hippocampus.⁴^,⁹

Direct evidence for neurogenesis and plasticity have existed for decades, since the discovery of labeling agents such as BrdU, ³H-thymidine, and 14C,¹⁰^–¹² allowing for the direct visualization of cell division and turnover. Mapping studies, using these same agents on nonhuman primates after injury, demonstrated that the original injured cortical region in monkeys after behavioral recovery would localize to an adjacent territory.¹³ Studies in the somatosensory and motor cortex, in particular, have implicated these regions to be capable and receptive to neuroplasticity, although little work has looked at the entire cortical circuitry. Early evidence for neuroplasticity was determined in the healthy brain in the somatosensory and motor cortex. Both somatosensory and motor maps of the body surface could be retrained so that adjacent body parts come to represent a larger cortical region.¹⁴^,¹⁵ Clark et al.¹⁶ sutured two adjacent digits together in primates and found that, over time, the receptive fields of certain neurons, especially at the junction of the two fingers, would span across both digits. Nudo¹⁴ trained primates to move multiple joints in a reach-and-retrieval task that similarly increased cortical representations of adjacent muscles. In the injured brain, with work focusing on stroke-related injuries, researchers have found that the outcome of neuroplasticity ultimately depends on postinjury behaviors. Furthermore, imaging studies using diffusion tensor imaging have found that plasticity can occur in areas that were initially spared from stroke-related damage, such as changes in the arcuate fasciculus that occur secondary to chronic Broca’s aphasia.¹⁷ Plasticity furthermore correlates with changes in the functional performance of patients. Fraser et al.,¹⁵ in looking at corticobulbar excitability in stroke patients suffering from dysphagia, found that stimulus to the corticobulbar nucleus prompted reorganization of the cortex, as gauged by functional MRI (fMRI), and yielded improvements in swallowing. Evidence for whether neuroplasticity occurs on a more global, cortical level is limited as most studies have focused on either the somatosensory or motor cortex through electrophysiology or fMRI. Nonetheless, work by Schlaug et al.¹⁷ in patients with dysphagia raises the possibility that the entire cortex may be indirectly shaped by neuroplastic changes, although more imaging studies will be needed. These studies set the groundwork that neuroplasticity exists for certain regions of the cortex and occurs throughout life and that injuries, such as stroke or trauma, serve as stimuli to prompt further regenerative events.

Studies on the response of the pediatric brain to injury have yielded interesting findings and differing views on the effect of age on recovery after injury and its functional effect. One view, first proposed by Margaret Kennard, later to be named the Kennard principle, proposed that the developing brain is capable of more significant reorganization and recovery after injury.¹⁸ Furthermore, the younger brain, in contrast to the elderly brain, is less likely to develop progressive cognitive decline, and the ongoing development may in actuality promote recovery.¹⁹ The opposing perspective, however, sees the developing brain as more vulnerable to damage given that it is undergoing significant growth and circuitry formation during critical periods, which may lead to more severe or more permanent physiologic changes in the presence of injury. Animal work by Casella et al.⁴ in juvenile (postnatal day 17) and immature (postnatal day 7) rats who underwent focal TBI with contusion revealed that the age of the mice at time of injury affects the plasticity and recovery of the brain postinjury. In their work, the researchers find that juvenile rats have both memory and learning deficits in the Morris water maze that last until postinjury day 17 (PID 17). Juvenile mice have longer-lasting somatic and emotional dysfunction, up until PID 60, as tested by behaviors displaying anxiety and sensorimotor function.⁴ The poor functional outcomes in juvenile mice were found to correlate with anatomical changes specifically in the hippocampus, including increases in the soma size, dendritic length and branching points in cells of the dentate gyrus after injury. Soma size of cells in CA3 also increased, whereas the dendritic length and branch points of cells in CA1 decreased after injury. Interestingly, immature mice were found to have no morphological changes in cells of the dentate gyrus, CA1, or CA3 after injury.⁴ Casella reports his work as evidence for dependency on not only age, but also the region of the brain in regards to response after injury. Unfortunately, his work does not correlate the morphological findings in PND7 mice with any cognitive, motor, or sensorimotor outcomes. Other work in mice report that outcomes after age-related injuries is associated more with the particular stage of cortical development at a certain age rather than the age itself.¹⁸

In human studies, contradictory evidence exists regarding the effect of age on the response of children after injury. The consistency across the studies, however, suggests that the type of injury plays a large factor in the final response. Several studies support the theory that younger age is a protective factor. Berger et al.²⁰ reviewed their series of 37 children under 17 years of age with traumatic brain injury and found that the children had better functional recovery than adults. Another group shows that patients injured at a younger age (less than 26 years) were less disabled compared to older patients (greater than 40 years) despite having more severe injuries.¹⁹ In contrast, other studies report that children less than 4 years old have a worse motor and cognitive outcome compared with older children who suffer from TBI.²¹ More recent work found that younger age had more adverse impacts on language in work done by Levin et al.²² who tested word generation, repetition, receptive vocabulary, narration, and recall in both young and older children with varying degrees of close head injuries (CHI). Young children with severe CHI took longer to recover word fluency when compared to same-aged children with mild CHI and older children with any degree of head injury. This finding is thought to be explained by the disruption of white matter development and tracks by the diffuse axonal injury that typically occurs secondary to severe trauma.²² Furthermore, it is thought that older age allows for not only more neuronal tracks to be incorporated into the appropriate circuitry, but also normal brain development, thus improving overall functions.²² Still other studies seem to suggest that age is not a critical factor in determining functional outcomes and capacity for recovery, as was the case for Schuett and Zihl²³ in their study of age-related effects on visual field disorders. Both older and younger patients had no difference in the severity of impairments, functional outcomes, and response to treatments. Although studies have yielded varying results, they did establish the use of neuroimaging in tracking and investigating neuroplasticity.

FUNCTIONAL IMAGING OF TRAUMATIC BRAIN INJURY AND NEUROPLASTICITY

Until very recently, noninvasive neuroimaging had limited power to detect white matter structural changes. The development of techniques such as positron emission tomography (PET), functional MRI (fMRI), diffusion tensor imaging (DTI), and transcranial magnetic stimulation (TMS) have changed the detection of response after brain injury (see Table 8.1).

TABLE 8.1

Comparison of Various Imaging Modalities for Neuroplasticity

Positron Emission Tomography and Functional MRI

PET and fMRI are two techniques that do not assess neuronal activity directly; rather, they use vascular and metabolic changes, respectively, as indications of neuronal activity. PET is a more invasive imaging technique that involves either inhalation or injection of radioactive tracers that accumulate in activated brain regions. PET relies on the premise that cerebral blood flow increases to regions of neuronal activity. Signal changes are then mapped onto a standard MRI scan of the brain to allow for anatomical correlation. While PET offers high spatial resolution up to 5–10 mm, it has poor temporal resolution given the time needed to record blood flow.²⁴

Similarly, fMRI operates on the assumption that neuronal activity increases oxygen consumption and glucose metabolism. A particular sequence called blood oxygenation level dependent (BOLD) is sensitive to the presence of deoxyhemoglobin in the blood, which distorts the magnetic fields and uses the ratio of deoxy- to oxyhemoglobin to create signals. BOLD fMRI allows for multiple acquisitions that offer useful temporal resolution to detect differences between brain regions.²⁴^,²⁵ Preliminary fMRI studies in patients with TBI show differential activation patterns; for example, in a patient with right temporoparietal contusion now experiencing dyscalculia and reading disability, fMRI reveals considerable left hemisphere activation and minimal right hemisphere activation in contrast to the bilateral activation detected in neurologically intact patients.²⁶ Unfortunately, given that PET and fMRI depend on blood flow and metabolic activities, the readout can be affected by age and cerebrovascular diseases such as atherosclerosis.

Diffusion Tensor Imaging

Diffusion tensor imaging (DTI) has high sensitivity for microscopic injury and is increasingly used to detect earlier signs of injury. DTI analyzes the microstructure of white matter based on vector maps created from diffusion patterns of water molecules. Algorithms that analyze properties of water diffusion can determine fiber tracts²⁷ and can confer information on fiber orientation and damage that are not detectable through conventional MRI.²⁸^,²⁹ Preliminary work indicates that DTI can detect microscopic injury in moderate to severe TBI, whereas imaging on patients with mild TBI have thus far not shown any significant difference compared to neurologically intact patients.²⁹^,³⁰ Unfortunately, there are limited studies on patients with mild TBI, making it difficult to determine the effect of time lapse after injury on the lack of changes. Nonetheless, DTI does provide information on the amount and severity of brain injury with promising findings on the structural disorganization associated with diffuse axonal injury.²⁶^,³⁰ Diffuse axonal injury has never been directly detected but rather inferred at a later time point when white matter injury leads to degenerative changes contributing to ventriculomegaly.²⁶ As such, there is interest in using DTI to not only quantify the degree of white matter injury, but also prognosticate severity based on the abnormalities discovered. Future work will also focus on the effects of interventions on the trajectories and connections of white matter tracts.²⁶

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) uses magnetic fields and electrical currents to stimulate cortical regions of the brain in a noninvasive manner. Primarily used to trigger brain plasticity in the motor system, TMS involves applying a current over the scalp corresponding to a motor region that then triggers an electrographic response in its target muscles called motor evoked potentials (MEP).³¹ Comparing MEPs before and after injury or across injured and uninjured hemispheres determines residual and changing cortical function. Preliminary work thus far demonstrates that cortical maps change in response to injury through two mechanisms: (1) the region of excitation for a cortical map will either enlarge or shrink and (2) the region corresponding to a cortical map may migrate to adjacent regions.³²^,³³ The applicability of TMS in studying plasticity was shown by Liepert et al., who imaged patients trained in new fine motor skills using both hands and feet and found shifts in cortical representations for the muscle groups. The shifts in cortical representations detected by TMS recapitulated the early mapping studies done by Glees and Cole and was thought to be secondary to cortical modulations. TMS can also detect asymmetry between hemispheres in motor map stimulation after a hemispheric stroke that is likely related to disuse on the injured side and compensatory changes on the uninjured side.

Imaging modalities such as fMRI, PET, and DTI are exciting for their potential use in monitoring ongoing neuroplasticity. DTI, however, is limited to monitoring only single white matter tracks as its sensitivity is decreased with the presence of multiple white matter tracks intersecting or degenerating in complex or injured regions. While long-term neuroplasticity and improvement has not been fully monitored after injury, stimulation and training seems to promote neural changes that are long lasting, suggesting that neuroplasticity should generally be a chronic process. One group reviewed fMRI across multiple studies to determine that poststroke treatment promoted cortical changes in the motor region beyond the recovery plateau typically seen after stroke.³⁴ Limited longitudinal studies are available on the presence of chronic neuroplasticity in other domains, such as the sensory cortex or language.

PROMISING THERAPEUTICS AFTER TBI

Traumatic brain injury causes both direct damage, through shear injury of neurons and blood vessels, and indirect damage from secondary ischemia, edema, or inflammation. Through destruction of the blood-brain barrier (BBB), TBI allows immune cells to enter the injured region to activate inflammatory responses. TBI also activates microglia and astrocytes to release inflammatory cytokines, chemokines, and prostaglandins that further increase the permeability of the BBB.³⁵

Acute treatment algorithms for TBI include minimizing intracranial pressure and optimizing cerebral perfusion pressure to limit secondary damage. Long-term therapies focus on improving motor, cognitive, and behavioral outcomes. However, therapies for TBI and intrinsic repair mechanisms in the brain are often constrained by the extent and severity of injury, age of the patient, prior or polytrauma, and time lapse to medical management. Thus, newer therapies target prevention of secondary sequelae to enhance neuroprotection. In particular, mounting evidence for neuroplasticity and neural regeneration in the adult CNS has encouraged the development of pharmacologic therapies to enhance the regenerative process. Many of the pharmacological therapies described below are still in their early stages of investigation, but target processes such as neurogenesis, inflammation, angiogenesis, and synaptic remodeling and formation (see Table 8.2).

TABLE 8.2

Summary of Promising New Therapies

Stem Cells

Animal studies have shown promising results in the use of stem cells to ameliorate the sequelae of TBI. Because stem cells are capable of self-renewal and differentiation into multiple cell types, exogenous stem cell transplantation into injured brain can counteract multiple damaging mechanisms, from direct neuronal loss to secondary inflammatory sequelae and even provide trophic factors for a nurturing microenvironment.³⁶ By compensating for many aspects of recovery, stem cells are protective even for chronic phases of recovery. Types of stem cells under investigation for TBI include neural stem cells (NSCs), bone-marrow-derived mesenchymal stem cells (BM-MSCs), and umbilical cord-derived mesenchymal stem cells (UC-MSCs).

The existence of NSCs were first discovered from adult mice striatal tissue,³⁷ but have since been isolated from diverse parts of the adult brain, including the cortex, subventricular zone, and ventricular zone.¹²^,³⁸ NSCs can differentiate into functional neurons, astrocytes, and oligodendrocytes and integrate into existing neuronal circuitry.³⁹ The argument for using adult neural stem cells rather than embryonic and other multipotent stem cells is related to possible tumorigenicity with the latter cells. In contrast, others argue that NSCs is limited in that it provides only the neural cells and trophic factors, while ignoring the role of the surrounding microenvironment, vasculature, and immune system on repair. However, perhaps because of their ability to respond to and secrete trophic factors, NSCs have an advantage over other types of stem cells in migrating to regions of injury. NSCs express cell adhesion proteins, integrins, and chemokine receptors that hone onto inflammatory regions of the brain.³⁸ Once at the site of injury, NSCs can confer certain functional benefits. In mice subjected to controlled cortical impact (CCI) injuries, transplanted NSCs can return motor but not cognitive function.⁴⁰^,⁴¹ The benefits of NSCs are likely derived from increased expression of neurotrophic factors and release of chemokines. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and fibroblast growth factor (FGF) promote cell survival, growth, and differentiation through activation of signaling pathways, whereas chemokines help to modulate the inflammatory response.³⁸ The utility of NSCs unfortunately may be limited by the severity of TBI, improving function only in cases of mild TBI⁴² and for younger populations experiencing TBI.⁴³ In mice subjected to CCI, Shindo et al.⁴² found that transplanted NSCs survived in mild TBI injuries in contrast to severe TBI thought to be due to differences in the surrounding microenvironment prompting differential expression of neurotrophic factors. Furthermore, intrinsic NSCs, detectable in TBI-injured brain, is present in higher quantities and have increased survival rates in younger mice compared to older mice, and also thought to be related to increased expression of neurotrophic factors and decreased expression of proinflammatory cytokines such as tumor necrosis factor a (TNF-α) and interleukins (IL)-1/β.⁴³

Mesenchymal stem cells (MSCs) are multipotent nonhematopoietic cells that have been shown to have a protective role in TBI. While the exact protective mechanism of transplanted MSCs still needs to be elucidated and likely multifactorial, initial work suggests that the promise of MSCs lies with modulating the immune system and altering the inflammatory responses commonly triggered by TBI. As part of the immune response to TBI, astrocytes become reactive and trigger a glial scar response surrounding the brain injury. The glial scar serves to limit the excitotoxicity that occurs with neuronal death and will also recruit microglia and macrophages to digest dead neurons. However, the presence of the glial scar itself often inhibits synaptic reformation and repair. Transplanted MSCs modulate this response by migrating to sites of injury and decreasing the thickness of the glial scar, allowing for enhanced regeneration and improved functional recovery.⁴⁴ Furthermore, MSCs differentiate into neurons, glial cells, and vascular endothelial cells, and secrete factors and cytokines to promote neurogenesis and angiogenesis.³⁶^,⁴⁵ The ability of MSCs to influence the surrounding microenvironment and their low immunogenicity when allogenic also confer advantages over other types of stem cells.³⁵^,⁴⁵ In addition, MSCs are easily obtained and will rapidly proliferate ex vivo. MSCs derived from bone marrow (BM-MSCs) and umbilical cord blood (UCB-MSCs) have both been investigated. Functional recovery improves with either intravenous or intraarterial infusion of BM-MSCs as does intracisternal MSCs.⁴⁶^,⁴⁷ Tian et al.⁴⁸ also found that a subpopulation of patients with TBI had functional improvements after transplantation with BM-MSCs through lumbar puncture. Outcomes, however, can be confounded by a number of factors, such as age of patients, time after injury, mode of delivery, and MSC isolation and culture techniques. Nonetheless, the benefits of MSCs are conferred through BDNF and NGF⁴⁹ as well as differential expressions of pro-inflammatory cytokines depending on the time period after TBI. MSCs initially decrease levels of IL-6 in the acute period, but subsequently upregulate IL-6 levels to promote revascularization and scar formation.³⁵

Despite the success with cells from the bone marrow, umbilical cord blood (UCB) is desirable for multiple reasons: (1) UCB offers a rich source of multiple types of stem cells, from hematopoietic and mesenchymal stem cells to embryonic stem cells; (2) is easily and readily obtained compared to bone marrow aspiration, and (3) ethically accepted.⁴⁹ UC-MSCs also have more proliferative activity than BM-MSCs when initially cultured, which may confer greater benefits in transplantation to an injured brain.⁵⁰^,⁵¹ UC-MSCs have been investigated in both ischemic and traumatic brain injuries. Zanier et al.⁴⁴ show that that UC-MSCs behave similarly to BM-MSCs; when placed intracerebroventricularly, UC-MSCs survive at a high rate, migrate to the injury site, and secrete BDNF, which then alters the response of microglia and macrophages to inflammation to decrease the size of the brain scar. In mice with CCI injuries, UC-MSCs were able to clinically improve sensorimotor functions.⁵² Limited studies with UC-MSCs exist in humans, but in patients with distant TBI, UC-MSCs improved motor scores and functional independence measures.⁵¹

Antioxidant Therapy

Reactive oxygen species (ROS) are a common source of damage secondary to ischemic-related injury. Ischemia induces excitotoxicity when neurons release glutamate that then sets off cascades for free radical production. Free radical production after TBI has been shown to induce NSC degeneration and death,⁵³^,⁵⁴ preventing the neuronal regeneration needed for ultimate repair. ROS also interfere with autoregulatory mechanisms in the vasculature and induce lipid peroxidation, which damages neuronal membranes. As such, antioxidant therapies seek to inhibit the formation of ROS, neutralize the ROS, or antagonize the enzymes that act upon the ROS. As such, antioxidant therapies seek to inhibit the formation of ROS, neutralize the ROS, or antagonize the enzymes that act upon the ROS. The presence of antioxidative enzymes decrease with age, leading to more radical-induced damage and cell death when TBI occurs among the elderly. This gives antioxidative agents a special niche in functional recovery for the elderly.⁵⁵ Examples of ROS scavenging compounds include polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), the 2-methylamino-chroman compound, U-83836E, and edaravone. PEG-SOD prevents post-traumatic microvascular dysfunction by isolating the Image O2bull.jpg radicals responsible for the damage.⁵⁶ Although phase II trials studying PEG-SOD showed initial promise, subsequent phase III studies did not produce any significant clinical benefit, related to either poor penetration through the blood-brain barrier or degree of TBI studied.⁵⁷ U-83836E, considered to be the most effective lipid peroxidation inhibitor due to high affinity for membrane phospholipids, has reduced lipid peroxidation and protein nitration and preserved mitochondrial function in mouse injury models.⁵⁶ Clinical trials on U-83836E, however, are still needed to demonstrate clinical efficacy. Edavarone, also known as 3-methyl-1-phenyl-pyrazoline-5-one, has the ability to penetrate through the BBB and has already shown remarkable neuroprotective effects in ischemic mouse models and patients with stroke. In TBI, edavarone attenuates ischemic damage through interactions with Image O2minus.jpg and ^•OH, which reduce brain edema. Edavarone also has the ability to block apoptotic pathways through inhibition of cytochrome c and caspase-3 and upregulation of phosphatidylinositol 3-kinase-Akt pathway. Combined, these effects prevent neuronal and glial death and allow for NSCs to appear and survive at the site of TBI.⁵⁴ Functionally, edavarone administration allowed mice with TBI to perform the Morris water maze faster than control mice, suggesting its potential in ameliorating TBI.⁵⁸

Cyclosporin A (CsA) preserves mitochondrial function by inhibiting permeability of the transition pore and reducing the amount of reactive oxygen species.⁵⁹ Combined with its ability to inhibit calcineurin, CsA reduces the amount of axonal injury and size of lesion after TBI.⁶⁰ Functionally, CsA improves motor outcomes as gauged by the Morris water maze when tested in mice after lateral fluid percussion injuries (FPI).⁶¹ However, depending on the type of mouse injury model studied, CsA can yield conflicting results. In the CCI injury model, CsA had no effect on cognitive outcomes.⁶² In humans, initial clinical trials comparing CsA to a placebo in adults with severe TBI have been promising; CsA both improves Glasgow Coma Scores (GCS) at 6 months and increases mean arterial pressure (MAP) and cerebral perfusion pressure (CPP).⁶³ Unfortunately, many studies with CsA have small sample sizes and lack long-term follow-up for evaluation of toxicity.

Pharmacologic Treatment

Erythropoietin (EPO) is a cytokine, known for its role in erythropoiesis, but also capable of counteracting a multitude of apoptotic, oxidative, and inflammatory reactions.⁶⁴ EPO came under study when mice without EPO receptor were found to have worse outcomes after CCI compared to wild-type mice.⁶⁵ EPO confers benefits across multiple mouse injury models, such as CCI, FPI, impact acceleration, and combined injuries.⁶⁴ For example, carbamylated EPO, which does not affect hematocrit, reduces lesion size in CCI and promotes both neurogenesis and angiogenesis.⁶⁶ Work with EPO in human TBI has mostly focused on determining timing and dosing, but preliminary data reveals that EPO decreases hospital mortality.⁶⁷^,⁶⁸

The steroid progesterone, enriched in the brain, is another agent with multiple mechanisms for neuroprotection. Its metabolic derivatives and action on GABA_A receptors produce an anti-inflammatory state by reducing brain edema, apoptosis, and neuronal cell death.⁶⁹^–⁷¹ Limited randomized controlled trials currently exist on the effects of progesterone in TBI, but reveal that progesterone decreases the mortality rate, compared to placebo, following acute TBI and also increases scores measuring functional outcomes (Wright et al., 2007).⁷²

As part of the mechanical damage to brain tissue and the ensuing inflammatory response, the blood-brain barrier often becomes disrupted. Prior work demonstrated that a nonhistone chromatin DNA-binding protein, called high mobility group box-1 (HMGB1), is released from damaged cells particularly in ischemic regions, which sets off the inflammatory events responsible for BBB disruption.⁷³ As such, therapies such as a neutralizing monoclonal antibody against HMGB1 (mAB-HMGB1) have been investigated, discovering that mAB-HMGB1 is able to reduce the extent of brain injury and edema from fluid percussion by reducing the extent of BBB permeability.⁷⁴^,⁷⁵ Furthermore, anti-HMGB1 reduces the amount of inflammatory proteins expressed, thus limiting the degree of secondary insults.⁷⁴

CONCLUSION

The recovery process after traumatic brain injury is long, but with emerging evidence for neuroplasticity, the prospects for recovery are no longer so grim. The exact mechanism remains unknown, however, many hypotheses are currently being investigated. Many potential therapeutic opportunities are being explored to target known changes with neuroplasticity, from differential gene expression and cellular proliferation, to the upregulation of synaptic proteins and junctions for new network connections, to the modulation of inflammatory reactions and the recruitment of immune cells to limit the size and volume of damage. Future therapies may find benefit in targeting multiple mechanisms of recovery and as such, stem cell therapies or a combination of different pharmacologic therapies are of utmost interest and currently under heavy investigation.

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Sophie Su YR, Veeravagu A, Grant G. Neuroplasticity after Traumatic Brain Injury. In: Laskowitz D, Grant G, editors. Translational Research in Traumatic Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016. Chapter 8.

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NEUROPLASTICITY
FUNCTIONAL IMAGING OF TRAUMATIC BRAIN INJURY AND NEUROPLASTICITY
PROMISING THERAPEUTICS AFTER TBI
CONCLUSION
REFERENCES

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Neuroplasticity after Traumatic Brain Injury - Translational Research in Traumat...
Neuroplasticity after Traumatic Brain Injury - Translational Research in Traumatic Brain Injury
PREDICTED: Egretta garzetta keratinocyte associated protein 2 (KRTCAP2), mRNA
PREDICTED: Egretta garzetta keratinocyte associated protein 2 (KRTCAP2), mRNA
gi|1894682289|ref|XM_009648440.2|
Nucleotide
PREDICTED: Meriones unguiculatus U6 spliceosomal RNA (LOC132650317), ncRNA
PREDICTED: Meriones unguiculatus U6 spliceosomal RNA (LOC132650317), ncRNA
gi|2599597310|ref|XR_009588684.1|
Nucleotide
Tolpis succulenta maturase K-like (matK) gene, partial sequence; chloroplast
Tolpis succulenta maturase K-like (matK) gene, partial sequence; chloroplast
gi|268628077|gb|GU046668.1|
Nucleotide
Klebsiella pneumoniae strain FDAARGOS_1076 plasmid unnamed1, complete sequence
Klebsiella pneumoniae strain FDAARGOS_1076 plasmid unnamed1, complete sequence
gi|1958359326|gb|CP068140.1|
Nucleotide

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