Open access peer-reviewed chapter

Age-Dependent Responses Following Traumatic Brain Injury

Written By

Thomas Brickler, Paul Morton, Amanda Hazy and Michelle H. Theus

Submitted: April 18th, 2017 Reviewed: September 28th, 2017 Published: December 20th, 2017

DOI: 10.5772/intechopen.71344

Chapter metrics overview

1,437 Chapter Downloads

View Full Metrics


Traumatic brain injury (TBI) is a growing health concern worldwide that affects a broad range of the population. As TBI is the leading cause of disability and mortality in children, several preclinical models have been developed using rodents at a variety of different ages; however, key brain maturation events are overlooked that leave some age groups more or less vulnerable to injury. Thus, there has been a large emphasis on producing relevant animal models to elucidate molecular pathways that could be of therapeutic potential to help limit neuronal injury and improve behavioral outcome. TBI involves a host of different biochemical events, including disruption of the cerebral vasculature and breakdown of the blood-brain barrier (BBB) that exacerbates secondary injuries. A better understanding of age-related mechanism(s) underlying brain injury will aid in establishing more effective treatment strategies aimed at improving restoration and preventing further neuronal loss. This review looks at studies that focus on modeling the adolescent population and highlights the importance of individualized aged therapeutics to TBI.


  • childhood
  • juvenile
  • traumatic brain injury
  • brain development
  • functional outcome
  • age dependence

1. Introduction

Traumatic brain injury (TBI) is a leading cause of long-term disability among all age groups with the adolescent population having a higher incidence of TBI [1]. Males sustain TBI at a much higher rate compared to females [1], and functional outcomes vary across patient’s age and severity of injury [2, 3]. Studies have shown that younger patients are more likely to demonstrate continued improvements, while older patients are more likely to decline [24]. On the other hand, childhood TBI (<6 years of age) presents poorer recovery of function compared to early adolescent or adolescent-aged patients [5, 6], with severe TBI in early childhood resulting in long-term impairment. Although better neuroplasticity or adaptation to brain injury in children has once been attributed to better recovery, the effect of age on outcome depends upon the function under study and the stage of development at the time of injury. In fact, the effects of childhood TBI may take years to “grow into deficit” as the developing brain hits milestones of maturation [7, 8]. Multiple regression analyses has also identified that age-at-injury onset is a major contributor to post-injury IQ [6]. While there are distinct periods of vulnerability in the developing brain, evidence from animal models also show that metabolic and physiological alterations specific to the juvenile or early adolescent brain may induce acute protection compared to adults [911]. These potentially distinct age-related responses are currently understudied and require a more accurate correlation of disease outcome with the maturation stage of the brain. Moreover, both small and large animal models need to be interpreted with caution since developmental milestones are distinct between swine, mice, and rat species as well as across different strains during the postnatal stages of growth. These differences make age comparisons to human infancy, childhood, early adolescence, adolescence, and adulthood challenging. To that end, correlating age-specific TBI outcomes from rodent to human thus requires consideration of key neurobiological maturation events, rather than chronological age, to predict differential responses to TBI which may eventually help guide effective diagnostic and treatment strategies. Here, we will review key events that accompany brain development in both humans and rodents to identify temporal “benchmarks” that may positively or negatively influence age-at-injury outcome. We will also provide an overview of research findings from clinical and preclinical age-related TBI studies.

1.1. Human brain structure and development

The human brain is a remarkably complex organ which we still do not fully understand. Representing 2% of the entire body weight in adulthood, the brain requires 20% of the body’s oxygen supply to accommodate its extreme metabolic demands. Human brain development is a highly dynamic process which can be broken down into orchestrated cellular and molecular epochs. The neocortex is the newest and arguably most sophisticated structure in the human brain and accounts for most of the brain size. By adulthood, the neocortex will have amassed approximately 20 billion neurons each capable of forming an average of 7000 connections with other neurons [12, 13]. The brain is considered to be immune privileged as it is isolated from the bloodstream by the blood-brain barrier (BBB). Cerebral spinal fluid (CSF) flows through the ventricles located in the center of the brain also provides a cushion. The cerebrum is described as having four lobes: frontal, parietal, temporal, and occipital. The frontal lobe is involved in higher-order executive functions such as planning, reasoning, abstract thinking, decision-making, attention, and personality. Gray and white matters represent the two broad components of the brain. Gray matter is heavily populated with neuronal cell bodies which are essential for transmitting/communicating information throughout the brain. White matter accounts for 50% of the human brain volume and is white in appearance because it is highly composed of myelin [14], a specialized membrane, densely enriched with lipids, which can accelerate neuronal communication throughout the brain.

Human brain development commences during the third week of gestation and continues through adolescence [15]. Within the first year of life, the brain doubles in volume and will grow another 15% over the following year [16]. By the age of 6, the brain will have increased in size by fourfold which is roughly 90% of the size achieved in adulthood [15]. At the beginning of the fetal period of development, the brain is smooth, and later becomes convoluted with folds and ridges. This drastic increase in cortical volume is primarily through an increase in surface area, as opposed to an increase in thickness, which is how the cortex constitutes up to 80% of the total brain mass [17]. Higher-order cognitive function requires precise connections and communication throughout the brain. For example, cortical neurons can form connections with neighboring and distant cells to enable communication and integration of sensory, cognitive, and motor modalities. The corpus callosum is the largest white matter tract in the brain and serves as a major highway of axons connecting the left and right cerebral hemispheres. These axons are wrapped in myelin to foster rapid interhemispheric communication of information. Myelination is a process that begins around the middle of the second trimester, is most appreciably robust up to the second year of life, and continues throughout adolescence, though to a much lesser degree during adulthood [18, 19]. White matter development in the human brain is an asynchronous process, commencing earlier and more rapidly in sensory than motor pathways, and is later highly prominent in the frontal and temporal lobes at 6–8 months of age [19]. The left and right cerebral hemispheres serve different functions and do not develop in a completely symmetric manner [19]. One explanation for such spatial and temporal asymmetries is a hierarchy of connections formed in an experience-dependent order, such that brain regions involved with lower-level processes need to be established earlier in life before higher-order integrative regions are required. For example, the somatosensory cortex—important for tactile information—matures earlier in development than the prefrontal cortex which is involved in higher-level executive functions such as planning [20].

Our knowledge of human brain development has primarily been gathered from noninvasive neuroimaging measurements and their functional correlates to neurological outcomes, in addition to cellular associations with histopathology. It has become increasingly clear that the brain is extremely vulnerable during key developmental epochs. During these sensitive maturation-dependent time windows, childhood TBI may increase the risk of brain dysmaturation and atypical development depending on the severity and location of the injury [2123]. For example, generalized (frontal/extrafrontal) or extrafrontal lesion severity but not frontal lesion alone was predictive of poor performance in children who sustained a moderate to severe TBI at ages 1–9 years of age [23]. Mechanistic insights into the etiologies of the neurological deficits and age-specific regions of vulnerability are vital to the understanding and treatment of pediatric TBI. However, rodent models of childhood and adolescent TBI in the postnatal growth stage may be difficult to translate into chronological age in humans. A better understanding of the major developmental processes in the brain across species and strains at the time of injury may be more instrumental for interpreting key findings. A few of these major milestones in neurodevelopment are noted below in Table 1.

Embryonic day (E), postnatal day (P),
months (M), years (Y)
Sexual maturation#F: P23
M: P42
F: P32-34
M: P45-48
F: 10-17Y
M: 11-17Y
[1, 24]
Peak brain volume (MRI)P20P60F: 10.5Y
M: 14.5Y
[8, 25, 26]
Developmental processes/milestones
Neurogenesis completed by*,P16.5P157.5 M[8]
Astrocytogenesis peakAt birthAt birthAt birth[8, 27]
Prefrontal cortex peak synaptic density*P27.5P2512.4 M[28]
Corpus callosum body myelination onset*P15.5P142.6 M[28]
Corpus callosum body myelination end*P35.5P3220.4 M[28]
Internal capsule myelination onset*P13.5P121.4 M[28]
Functional blood-brain barrierE15.5E1410w gestation[29]

Table 1.

Developmental processes and milestones across mammals.

Estimates determined across species with, based on Workman et al. [28].

Estimate based off of neurogenesis completion in rat by postnatal day 15 [8]. F, female; M, male; P, postnatal days; Y, years; M, months; E, embryonic days; na, not applicable.

Sexual maturation is strain dependent.

1.2. Age-at-injury response to clinical TBI

The widespread conception that the young brain is more resilient in its response to TBI has been challenged as there is considerable evidence that childhood TBI results in poorer outcomes. The developing brain may actually fair much worse compared to adults in cognitive and motor functions [3032]. Levin and colleaguesutilized the Glasgow Coma Scale (GCS), the primary measure of functional impairment, in children at 0–4 years of age and 5–10 years of age following TBI. The 0–4-year-olds were found to suffer the worst clinical outcome, comparatively. These and other findings analyzed the long-term behavioral outcomes in children who sustained a moderate to severe head injury [33]. Moreover, given the longevity of white matter development and maturation, TBI negatively impacts white matter integrity in the chronic (13–19 post-injury) but not acute (1–5 months) phase of injury which was linked to cognitive impairments in patients at 8–19 years of age [34, 35]. Patients with a history of neurological illness, brain tumor, seizures, psychosis, ADHD, Tourette’s disorder, and other developmental disabilities were excluded from the study. This study also showed that the GCS was not significantly associated with white matter tract changes, as measured by diffuse tensor imaging (DTI), suggesting that advanced imaging modalities are vital to clinical tracking of disease progression and may be a more sensitive measure of outcome compared to GCS alone. Indeed, DTI coupled with functional MRI and perhaps other imaging strategies would greatly advance our understanding of the age-related mechanisms of repair and plasticity following TBI [3639]. White matter dysregulation after childhood TBI may also affect motor recovery and social cognitive skills which are realized once the skills reach maturity [4043]. Therefore, given the lengthy developmental course of myelination and synaptogenesis, TBI may disrupt the maturation of functions that support higher-order cognitive outcomes later in life [39, 44, 45]. The expression of glutamate receptors NMDA and AMPA greatly changes during development [46, 47]. Typically, there is an imbalance between excitatory and inhibitory neurotransmission in the developing brain, which could heighten the sensitivity of the young brain to glutamatergic excitotoxicity after trauma that may not be amplified in a mature brain [48]. Interestingly, the younger brain has less antioxidant capacity compared to the more matured brain, which during TBI increases the amount of reactive oxygen species (ROS) that could exacerbate the injury in the younger brain [49]. Inflammation also plays a critical role in brain tissue recovery after TBI [50]. In early childhood TBI, microglial cells that have infiltrated the brain may become overactive exacerbating secondary tissue damage [51]. Taken together, improving our understanding of developmentally related differences will be vital for predicting differential, age-specific outcomes and treatment responses to TBI .

Since the adolescent population sees a disproportionate percentage of hospitalizations and deaths compared to other age groups, this population should have its own outcome category tailoring research findings and treatment outcomes [52]. While adolescents fall between the childhood and adult age groups, how to appropriately treat these patients has been particularly challenging in the hospital setting [53]. Over a 13-year study, Gross and colleagues analyzed the adolescent TBI population (15–17 years of age) treated at pediatric or adult trauma centers. Although this study found no significant differences in outcomes between the centers, it raised an important question regarding how to treat adolescent brain injury, where differences in developmental vulnerability may exist compared to early childhood [53]. While early childhood TBI is associated with deficits in memory [54, 55], attention [56], intellectual functioning [57], and language acquisition [58], few studies have compared the outcomes of adolescent aged or young adults to older adults. A multiple regression model has demonstrated that increased age negatively influences outcome, as measured by the Disability Rating Scale (DRS) [4]. This study found a greater decline in older patients (≥40 years) over 5 years post-TBI but also demonstrated that the greatest amount of improvement in disability in young adults (16–26 years) compared to adults (27–39 years) and aged (≥40 years) patients. The mechanism(s) underlying this age-specific difference may be due, in part, to a reduction in the capacity to recover or decreased synaptic plasticity and cortical volume as we age or yet undetermined protective factors present during the late adolescence. Although TBI incidence has a bimodal age distribution peaking in adolescence and again in the elderly, few age-related studies have compared acute and chronic effects across the spectrum of age ranges including early childhood, adolescence, adulthood, and elderly. One prospective study of 330 severe TBI patients showed that younger patients (0–19 years of age) had a significantly higher percentage of good outcomes, lower mortality rates, and a reduced incidence of surgical mass lesions compared to adults (20–80 years of age) [11]. Although poorer recovery of function is known to exist in early childhood compared to adolescent-aged TBI patients, it should be noted that the mean age for the abovementioned study was 15–19 years and 39 years, respectively. Taken together, these findings suggest that the greatest vulnerability in age-specific responses lies in early childhood and advanced ages. Interestingly, there may be a narrow time window during which adolescence may confer protection, the mechanism(s) of which may be fully elucidated using animal models of brain injury, discussed below.

1.3. Age-at-injury response to preclinical TBI

Rodents are the most commonly used animal models in TBI research and are therefore well characterized and cross-validated [5962]. The following sections will comprehensively review the acute and long-term TBI responses in both mice and rats at pre-weanling (P17), post-weanling/juvenile (P21), and adult (P60-90) ages. The commonly used models of TBI are the controlled cortical impact (CCI) injury and lateral fluid percussion injuries (LFPI) which have been adapted and scaled to younger rodent animals to account for differences in animal weight and brain size. However, the initial mechanical forces to the brain depend on an array of factors that are independently determined. These factors include location, severity, focal, or diffuse injury. Similar to clinical findings, there are a spectrum of outcomes following preclinical TBI that are not only age dependent but species and strain specific which must be interpreted with caution. Although the importance of gyrification of the human brain, which is fully formed at birth but increases in complexity postnatally, is still under debate [63], this cross species differences should be kept in mind. Nonetheless, animal models of TBI have been instrumental in assessing the vulnerability of the developing brain to mechanical forces applied following CCI or LFP injury models.

Neurogenesis, gliogenesis, synaptogenesis, and myelination are key developmental events that may impact age-at-injury outcomes after TBI [6466]. While neurogenesis peaks during gestational periods, by adulthood the generation of neurons is restricted to the dentate gyrus (DG) of the hippocampus and the lateral wall of the subventricular zone (SVZ) [64, 67]. Induction of post-injury neurogenesis has been suggested to play a critical role in learning and memory recovery as well as providing neurotrophic factor secretion as neuroprotective cues. While selectively ablating adult neurogenesis can dampen functional recovery [68, 69], the effects on early childhood or adolescence are unclear. Sun and colleagues analyzed the morphological changes within the subgranular zone of the DG and the SVZ following LFPI using P28 juvenile and P90 adult rats [70]. The LFPI model mimics both focal and diffuse mechanical injuries and results in histopathological changes similar to those seen in humans [60]. The study determined that LFPI enhanced proliferation within the DG of both adult and juvenile rats. However, the juvenile response in the SVZ was greater compared to adults. Furthermore, they identified twice as many neurons that were born from the juvenile SVZ compared to adults. Similarly, juvenile mice at P21 subjected to CCI injury show an increased presence of doublecortin-positive neuroblasts in the DG at 2 weeks post-injury [71]. However, a significant decline in these cells was seen at 3 months post-injury suggesting that an acute protective response may be subdued by long-term activation of yet unknown cellular programs. No comparisons to adult CCI injury were made. Unfortunately, data regarding age effects on neurogenesis are still lacking since numerous studies in mice or rats either have not performed adult comparisons [72] or have not used relevant TBI models [67, 73]. Of note, while naïve P9 mice display increased proliferation in the DG compared to P21, hypoxic-ischemic injury adversely affected neurogenesis in P9 but greatly enhanced it in P21 suggesting that early adolescence may display a critical window of regenerative potential that may be lost in adulthood. These findings would need to be confirmed using an appropriately controlled, longitudinal investigation (days, weeks, months) of neurogenesis with the inclusion of adult mice. Likewise, suitably comparable ages of rats subjected to TBI could support this hypothesis and help demonstrate a cross species phenomenon.

Synaptogenesis peaks at 2 years of age in humans and in 3 weeks in both rats and mice [65]. The number of synapses at these time points is greater, and pruning events follow to decrease the number of synapses [7476]. In addition, myelination is an ongoing process that continues well into adulthood [66]; atypical development of these processes as a result of TBI may significantly impact synaptic reorganization and long-term neurobehavioral development [7779]. Ajao and colleagues found that TBI in rats at P17 resulted in measurable deficits in motor performance on the rotarod and foot faults at 60 days post-injury well into adulthood [77]. Anxiety-like behaviors were also increased compared to noninjured sham controls. Sensorimotor tasks and anxiety-like behaviors are often linked to histological changes such as cell death in the brain as a consequence of childhood TBI. Neuronal loss due to focal impact can impair major electrical signaling pathways by disconnecting circuits, increasing calcium in dying cells, triggering inflammation, and blunting key trophic support. The immature rat brain is particularly sensitive to excitotoxicity in the neonatal period [80, 81]. This is regulated, in part, by developmental changes in expression of the NR2A and NR2B subunits of the NMDA receptor [82, 83] and/or GABAergic neurotransmission impairments through, for example, cortical loss of GABAergic interneurons [84, 85]. In the second and third postnatal weeks, however, this effect is reduced. In fact, minimal neuronal loss is seen following weight drop and LFPI in juvenile (P15–P19) rats [81, 86, 87] suggesting that long-term behavioral deficits following TBI are due in greater part to neuronal dysfunction rather than neuronal loss. On the other hand, a significant delay in loss of neural tissue is observed in juvenile (P21) mice after CCI injury [71, 88, 89] which correlates with progressive dysfunction. Differences in injury model, rodent species, or time of histopathological assessment after injury may account for these differences. Indeed, a gyrencephalic model of cortical impact delivered at different maturation stages to the piglet brain demonstrated increased vulnerability with age to cortical trauma, with the smallest lesions seen at 7 days post-injury in 5-day-old pigs, modest injury in 1-month-old piglets, and largest lesion volume in 4-month-olds [90, 91]. Progressive histopathological or behavioral changes over time were not evaluated.

While the maturation-dependent response of the resident neuroimmune system (microglial and astrocytes) remains under investigation, a notable difference in peripheral immune activation following TBI has been demonstrated. Bidirectional neural-immune communication exists to clear the brain of dead cellular debris from necrotic spillover of intracellular components. However, when overactivated, the immune system can mediate neurotoxicity and exacerbate secondary injury including free radical formation and oxidative damage as well as activation of microglia [92]. Although TBI increases the presence of leukocytes both in neural tissue, due to BBB disruption, and in the peripheral blood [93], the destructive phenotype of activated immune cell subpopulations is not well understood. Recent findings suggest that progressive injury in P21 mice observed months following CCI injury compared to adult may result from an age-dependent temporal patterns in leukocyte infiltration [88]. While no differences were noted for the CD4+ and CD8+ populations, CD45+ cells and GR-1+ granulocytes remained elevated for weeks in P21 mice compared to 3 days in adult. This effect may be regulated, in part, by IL-1β. Injection of IL-1β into the P21 rat brain exacerbates rapid neutrophil recruitment, CXC chemokine production, and BBB disruption compared to adult rats [9496]. While the juvenile immune system may display increased sensitivity to neutrophil chemoattractants (CXCL1, CXCL2, CXC8) [97], extension of neutrophil life span may also translate into increased numbers [98, 99]. Indeed, adult neutrophil depletion studies appear to reduce edema, cell death, and macrophage/microglia activation while having no effect on BBB and functional outcome suggesting that neutrophils may negatively impact TBI outcome and their long-lived nature may cause progressive injury and contribute to other age-related responses [100, 101]. Findings from our laboratory have shown significant neuroprotection in P21 mice subjected to moderate CCI injury compared to adults (unpublished findings). Interestingly, we have identified numerous genes in the whole cell fractions of peripheral blood from P21 mice that are differentially regulated compared to adults (unpublished findings). Next-generation RNA sequencing and ontology analysis identified several pathways that are differentially regulated including (1) metabolic, (2) apoptotic, and (3) inflammatory processes (Figure 1). Peripheral blood cells isolated from P21 mice display reduced expression of several Toll-like receptors (Tlr1, Tlr6, Tlr4, Tlr2), TNF receptor (TNFRSF1A), MMP9, and upregulation of the antioxidant superoxide dismutase 2 (SOD2), autophagy-elated ATG4A, antiapoptotic Bag1, and a number of other genes that may influence their response once recruited after TBI. Enhanced survival of immune-derived cells in the brain may have long-lasting effects on tissue repair and recovery. There may be beneficial effects of early recruitment and survival in the damaged neural tissue that may be outweighed in the long run if their transient presence is extended. Differences in immune cell-type survival, gene expression, and function need to be further explored.

Figure 1.

GO analysis of differentially expressed genes between juvenile and adult mouse peripheral blood cells. Six hundred and ten genes showed differential expression (q < 0.05) between juvenile and adults. Ontology analysis using GeneCodis (biological process) was performed using this gene list to identify differentially regulated pathways [13].

Lastly, subtype-specific recruitment of monocytes/macrophages (M1 vs. M2) has also been shown to play a critical role in outcome following CNS injury [102, 103]. However, age-dependent effects of these cell types in both acute and chronic TBI outcome have yet to be investigated. Further examination into the temporal–spatial recruitment of immune cell subtypes and the employment of depletion and cell-type-specific knockout studies will help address the important emerging role of the peripheral-derived immune system in responding to brain trauma across the life span.

The BBB is established during embryogenesis in rodents and humans [104, 105]; however, postnatal coverage with astrocytic end feet, which aids in the maturation and maintenance of the BBB, occurs in the first few postnatal weeks [104, 106, 107]. This maturation stage is critical with regard to changes in permeability as a result of insult. For example, systemic inflammation increases BBB permeability in P0 and P8 rats while having no effect at P20 [108, 109]. TBI induces endothelial cell dysfunction that increases the permeability of the BBB including disruption of astrocytic end feet, transporters/channels, and tight junction proteins claudin-5 and occludin-1 causing widespread vasogenic edema [110, 111]. The temporal changes in BBB permeability likely depend on the model of TBI, age-at-injury, and severity of impact. Interestingly, monocarboxylate transporter 2 (MCT2) is substantially increased in the microvessels of juvenile P35 rats following CCI injury compared to P75 adult rats [112]. This increase correlated with improved behavioral outcome and reduced cortical lesion volume in P35 rats receiving a ketogenic diet post-TBI compared to adults [113]. Pop and colleagues observed BBB disruption following CCI injury in P17 rats through high amounts of IgG staining, which is consistent with what is seen after CCI injury [114]. At 1-week after injury, a substantial reduction in BBB permeability correlated with an increase expression of tight junction protein (claudin-5). This was maintained as far out as 2 months post-injury, suggesting that tight junction proteins may modulate early disruption and subsequent repair. Likewise, administration of DHA and EPA, the main sources found in fish oil, after CCI injury in P17 juvenile rats reduces BBB permeability, behavioral deficits, and MMP9 expression [115]. The relevance of these studies to the adult response was not evaluated, and further work needs to be conducted in order to improve our understanding of the age-dependent mechanism(s) regulating the BBB following TBI.


2. Conclusions

There has been intense investigation into the brain’s maturation-dependent response to TBI using numerous early childhood and juvenile rodent models. Over recent years, studies have revealed age-specific differences in the regulation of metabolism, oxidative stress, neurogenesis, innate immunity, and BBB function following acute and/or chronic injury. Further exploration into the age-specific elements of vascular function, neuroimmune regulation, and the neurovascular niche would help improve our understanding, not only of typical but also atypical developmental trajectories as a consequence of childhood TBI. The insurgence of these animal models, however, must be met with caution as key maturation stages of the brain vary considerably between murine and rat species. Studies of immature or juvenile injury must also be accompanied by appropriate comparisons to adult-aged animals, which thus far has been inadequate. The need for larger animal models that more accurately recapitulate human brain structure and maturational age is also warranted. Although predicting the age-specific response to TBI in childhood, adolescence, and young adulthood is limited based on current available animal model data, it is clear that “a window of susceptibility” exists that may deter normal growth and development. On the other hand, it is important not to underestimate the early neuroprotective findings observed in a number of studies, which may yield valuable mechanistic insight into pathways that could be utilized for neuroprotection in the adult brain.


  1. 1. Dewan MC, Mummareddy N, Wellons JC, 3rd CM. Bonfield, epidemiology of global pediatric traumatic brain injury: Qualitative review. World Neurosurgery. 2016;91:497-509 e491
  2. 2. Mosenthal AC et al. The effect of age on functional outcome in mild traumatic brain injury: 6-month report of a prospective multicenter trial. The Journal of Trauma. 2004;56:1042-1048
  3. 3. van der Naalt J et al. Early predictors of outcome after mild traumatic brain injury (UPFRONT): An observational cohort study. Lancet Neurology. 2017;16:532-540
  4. 4. Marquez de la Plata CD et al. Impact of age on long-term recovery from traumatic brain injury. Archives of Physical Medicine and Rehabilitation. 2008;89:896-903
  5. 5. Catroppa C, Anderson VA, Morse SA, Haritou F, Rosenfeld JV. Outcome and predictors of functional recovery 5 years following pediatric traumatic brain injury (TBI). Journal of Pediatric Psychology. 2008;33:707-718
  6. 6. Duval J et al. Brain lesions and IQ: Recovery versus decline depends on age of onset. Journal of Child Neurology. 2008;23:663-668
  7. 7. Giza CC, Prins ML. Is being plastic fantastic? Mechanisms of altered plasticity after developmental traumatic brain injury. Developmental Neuroscience. 2006;28:364-379
  8. 8. Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Progress in Neurobiology. 2013;106-107:1-16
  9. 9. Prins ML, Hovda DA. The effects of age and ketogenic diet on local cerebral metabolic rates of glucose after controlled cortical impact injury in rats. Journal of Neurotrauma. 2009;26:1083-1093
  10. 10. Babikian T et al. Molecular and physiological responses to juvenile traumatic brain injury: Focus on growth and metabolism. Developmental Neuroscience. 2010;32:431-441
  11. 11. Alberico AM, Ward JD, Choi SC, Marmarou A, Young HF. Outcome after severe head injury. Relationship to mass lesions, diffuse injury, and ICP course in pediatric and adult patients. Journal of Neurosurgery. 1987;67:648-656
  12. 12. Herculano-Houzel S. The human brain in numbers: A linearly scaled-up primate brain. Frontiers in Human Neuroscience. 2009;3:31
  13. 13. Pakkenberg B et al. Aging and the human neocortex. Experimental Gerontology. 2003;38:95-99
  14. 14. Filley CM. White matter dementia. Therapeutic Advances in Neurological Disorders. 2012;5:267-277
  15. 15. Stiles J, Jernigan TL. The basics of brain development. Neuropsychology Review. 2010;20:327-348
  16. 16. Knickmeyer RC et al. A structural MRI study of human brain development from birth to 2 years. The Journal of Neuroscience. 2008;28:12176-12182
  17. 17. Geschwind DH, Rakic P. Cortical evolution: Judge the brain by its cover. Neuron. 2013;80:633-647
  18. 18. Geng X et al. Quantitative tract-based white matter development from birth to age 2years. NeuroImage. 2012;61:542-557
  19. 19. Qiu A, Mori S, Miller MI. Diffusion tensor imaging for understanding brain development in early life. Annual Review of Psychology. 2015;66:853-876
  20. 20. Guillery RW. Is postnatal neocortical maturation hierarchical? Trends in Neurosciences. 2005;28:512-517
  21. 21. Popernack ML, Gray N, Reuter-Rice K. Moderate-to-severe traumatic brain injury in children: Complications and rehabilitation strategies. Journal of Pediatric Health Care. 2015;29:e1-e7
  22. 22. Vaewpanich J, Reuter-Rice K. Continuous electroencephalography in pediatric traumatic brain injury: Seizure characteristics and outcomes. Epilepsy & Behavior. 2016;62:225-230
  23. 23. Power T, Catroppa C, Coleman L, Ditchfield M, Anderson V. Do lesion site and severity predict deficits in attentional control after preschool traumatic brain injury (TBI)? Brain Injury. 2007;21:279-292
  24. 24. Sengupta P. The laboratory rat: Relating its age with Human's. International Journal of Preventive Medicine. 2013;4:624-630
  25. 25. Chuang N et al. An MRI-based atlas and database of the developing mouse brain. NeuroImage. 2011;54:80-89
  26. 26. Mengler L et al. Brain maturation of the adolescent rat cortex and striatum: Changes in volume and myelination. NeuroImage. 2014;84:35-44
  27. 27. Sauvageot CM, Stiles CD. Molecular mechanisms controlling cortical gliogenesis. Current Opinion in Neurobiology. 2002;12:244-249
  28. 28. Workman AD, Charvet CJ, Clancy B, Darlington RB, Finlay BL. Modeling transformations of neurodevelopmental sequences across mammalian species. The Journal of Neuroscience. 2013;33:7368-7383
  29. 29. Ben-Zvi A et al. Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature. 2014;509:507-511
  30. 30. Anderson VA et al. Understanding predictors of functional recovery and outcome 30 months following early childhood head injury. Neuropsychology. 2006;20:42-57
  31. 31. Bruce DA, Schut L, Bruno LA, Wood JH, Sutton LN. Outcome following severe head injuries in children. Journal of Neurosurgery. 1978;48:679-688
  32. 32. Taylor HG et al. Influences on first-year recovery from traumatic brain injury in children. Neuropsychology. 1999;13:76-89
  33. 33. Treble-Barna A et al. Long-term neuropsychological profiles and their role as mediators of adaptive functioning after traumatic brain injury in early childhood. Journal of Neurotrauma. 2017;34:353-362
  34. 34. Dennis EL et al. White matter disruption in moderate/severe pediatric traumatic brain injury: Advanced tract-based analyses. Neuroimage: Clinical. 2015;7:493-505
  35. 35. Dennis EL et al. Callosal function in Pediatric traumatic brain injury linked to disrupted white matter integrity. The Journal of Neuroscience. 2015;35:10202-10211
  36. 36. Mechtler LL, Shastri KK, Crutchfield KE. Advanced neuroimaging of mild traumatic brain injury. Neurologic Clinics. 2014;32:31-58
  37. 37. Edlow BL, Wu O. Advanced neuroimaging in traumatic brain injury. Seminars in Neurology. 2012;32:374-400
  38. 38. Ashwal S, Holshouser BA, Tong KA. Use of advanced neuroimaging techniques in the evaluation of pediatric traumatic brain injury. Developmental Neuroscience. 2006;28:309-326
  39. 39. Levin HS. Neuroplasticity following non-penetrating traumatic brain injury. Brain Injury. 2003;17:665-674
  40. 40. Stephens J, Salorio C, Denckla M, Mostofsky S, Suskauer S. Subtle motor findings during recovery from Pediatric traumatic brain injury: A preliminary report. Journal of Motor Behavior. 2017;49:20-26
  41. 41. Ryan NP et al. Longitudinal outcome and recovery of social problems after pediatric traumatic brain injury (TBI): Contribution of brain insult and family environment. International Journal of Developmental Neuroscience. 2016;49:23-30
  42. 42. Ryan NP et al. The emergence of age-dependent social cognitive deficits after generalized insult to the developing brain: A longitudinal prospective analysis using susceptibility-weighted imaging. Human Brain Mapping. 2015;36:1677-1691
  43. 43. Li L, Liu J. The effect of pediatric traumatic brain injury on behavioral outcomes: A systematic review. Developmental Medicine and Child Neurology. 2013;55:37-45
  44. 44. Chapman SB, McKinnon L. Discussion of developmental plasticity: Factors affecting cognitive outcome after pediatric traumatic brain injury. Journal of Communication Disorders. 2000;33:333-344
  45. 45. Cook LG, Chapman SB, Elliott AC, Evenson NN, Vinton K. Cognitive gains from gist reasoning training in adolescents with chronic-stage traumatic brain injury. Frontiers in Neurology. 2014;5:87
  46. 46. Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL. GABAA, NMDA and AMPA receptors: A developmentally regulated 'menage a trois'. Trends in Neurosciences. 1997;20:523-529
  47. 47. Nunez JL, McCarthy MM. Evidence for an extended duration of GABA-mediated excitation in the developing male versus female hippocampus. Developmental Neurobiology. 2007;67:1879-1890
  48. 48. McDonald JW, Trescher WH, Johnston MV. Susceptibility of brain to AMPA induced excitotoxicity transiently peaks during early postnatal development. Brain Research. 1992;583:54-70
  49. 49. Bayir H, Kochanek PM, Kagan VE. Oxidative stress in immature brain after traumatic brain injury. Developmental Neuroscience. 2006;28:420-431
  50. 50. Das M, Mohapatra S, Mohapatra SS. New perspectives on central and peripheral immune responses to acute traumatic brain injury. Journal of Neuroinflammation. 2012;9:236
  51. 51. Hagberg H, Gressens P, Mallard C. Inflammation during fetal and neonatal life: Implications for neurologic and neuropsychiatric disease in children and adults. Annals of Neurology. 2012;71:444-457
  52. 52. Coronado VG et al. Surveillance for traumatic brain injury-related deaths--United States, 1997-2007. MMWR Surveillance Summaries. 2011;60:1-32
  53. 53. Gross BW et al. Big children or little adults? A statewide analysis of adolescent isolated severe traumatic brain injury outcomes at pediatric versus adult trauma centers. Journal of Trauma and Acute Care Surgery. 2017;82:368-373
  54. 54. Anderson VA, Catroppa C, Morse SA, Haritou F. Functional memory skills following traumatic brain injury in young children. Pediatric Rehabilitation. 1999;3:159-166
  55. 55. Anderson VA, Catroppa C, Rosenfeld J, Haritou F, Morse SA. Recovery of memory function following traumatic brain injury in pre-school children. Brain Injury. 2000;14:679-692
  56. 56. Bakker K, Anderson V. Assessment of attention following pre-school traumatic brain injury: A behavioural attention measure. Pediatric Rehabilitation. 1999;3:149-157
  57. 57. Anderson V, Catroppa C, Morse S, Haritou F, Rosenfeld J. Recovery of intellectual ability following traumatic brain injury in childhood: Impact of injury severity and age at injury. Pediatric Neurosurgery. 2000;32:282-290
  58. 58. Morse S et al. Early effects of traumatic brain injury on young children's language performance: A preliminary linguistic analysis. Pediatric Rehabilitation. 1999;3:139-148
  59. 59. Johnson VE, Meaney DF, Cullen DK, Smith DH. Animal models of traumatic brain injury. Handbook of Clinical Neurology. 2015;127:115-128
  60. 60. Xiong Y, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nature Reviews. Neuroscience. 2013;14:128-142
  61. 61. Adelson PD. Animal models of traumatic brain injury in the immature: A review. Experimental and Toxicologic Pathology. 1999;51:130-136
  62. 62. Morganti-Kossmann MC, Yan E, Bye N. Animal models of traumatic brain injury: Is there an optimal model to reproduce human brain injury in the laboratory? Injury. 2010;41(Suppl 1):S10-S13
  63. 63. White T, Su S, Schmidt M, Kao CY, Sapiro G. The development of gyrification in childhood and adolescence. Brain and Cognition. 2010;72:36-45
  64. 64. Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models. Environmental Health Perspectives. 2000;108(Suppl 3):511-533
  65. 65. Low LK, Cheng HJ. Axon pruning: An essential step underlying the developmental plasticity of neuronal connections. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2006;361:1531-1544
  66. 66. Giedd JN et al. Brain development during childhood and adolescence: A longitudinal MRI study. Nature Neuroscience. 1999;2:861-863
  67. 67. Covey MV, Jiang Y, Alli VV, Yang Z, Levison SW. Defining the critical period for neocortical neurogenesis after pediatric brain injury. Developmental Neuroscience. 2010;32:488-498
  68. 68. Dixon KJ et al. Endogenous neural stem/progenitor cells stabilize the cortical microenvironment after traumatic brain injury. Journal of Neurotrauma. 2015;32:753-764
  69. 69. Blaiss CA et al. Temporally specified genetic ablation of neurogenesis impairs cognitive recovery after traumatic brain injury. The Journal of Neuroscience. 2011;31:4906-4916
  70. 70. Sun D et al. Cell proliferation and neuronal differentiation in the dentate gyrus in juvenile and adult rats following traumatic brain injury. Journal of Neurotrauma. 2005;22:95-105
  71. 71. Pullela R et al. Traumatic injury to the immature brain results in progressive neuronal loss, hyperactivity and delayed cognitive impairments. Developmental Neuroscience. 2006;28:396-409
  72. 72. Potts MB et al. Glutathione peroxidase overexpression does not rescue impaired neurogenesis in the injured immature brain. Journal of Neuroscience Research. 2009;87:1848-1857
  73. 73. Qiu L et al. Less neurogenesis and inflammation in the immature than in the juvenile brain after cerebral hypoxia-ischemia. Journal of Cerebral Blood Flow and Metabolism. 2007;27:785-794
  74. 74. Herschkowitz N, Kagan J, Zilles K. Neurobiological bases of behavioral development in the first year. Neuropediatrics. 1997;28:296-306
  75. 75. Huttenlocher PR. Synaptic density in human frontal cortex - developmental changes and effects of aging. Brain Research. 1979;163:195-205
  76. 76. Crain B, Cotman C, Taylor D, Lynch G. A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat. Brain Research. 1973;63:195-204
  77. 77. Ajao DO et al. Traumatic brain injury in young rats leads to progressive behavioral deficits coincident with altered tissue properties in adulthood. Journal of Neurotrauma. 2012;29:2060-2074
  78. 78. Jullienne A et al. Juvenile traumatic brain injury induces long-term perivascular matrix changes alongside amyloid-beta accumulation. Journal of Cerebral Blood Flow and Metabolism. 2014;34:1637-1645
  79. 79. Kamper JE et al. Juvenile traumatic brain injury evolves into a chronic brain disorder: Behavioral and histological changes over 6months. Experimental Neurology. 2013;250:8-19
  80. 80. Ikonomidou C, Qin Y, Labruyere J, Kirby C, Olney JW. Prevention of trauma-induced neurodegeneration in infant rat brain. Pediatric Research. 1996;39:1020-1027
  81. 81. Bittigau P et al. Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain. Annals of Neurology. 1999;45:724-735
  82. 82. Giza CC, Maria NS, Hovda DA. N-methyl-D-aspartate receptor subunit changes after traumatic injury to the developing brain. Journal of Neurotrauma. 2006;23:950-961
  83. 83. Jantzie LL et al. Developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in human white and gray matter: Potential mechanism of increased vulnerability in the immature brain. Cerebral Cortex. 2015;25:482-495
  84. 84. Wu C, Sun D. GABA receptors in brain development, function, and injury. Metabolic Brain Disease. 2015;30:367-379
  85. 85. Robinson S, Li Q, Dechant A, Cohen ML. Neonatal loss of gamma-aminobutyric acid pathway expression after human perinatal brain injury. Journal of Neurosurgery. 2006;104:396-408
  86. 86. Adelson PD et al. Histopathologic response of the immature rat to diffuse traumatic brain injury. Journal of Neurotrauma. 2001;18:967-976
  87. 87. Gurkoff GG, Giza CC, Hovda DA. Lateral fluid percussion injury in the developing rat causes an acute, mild behavioral dysfunction in the absence of significant cell death. Brain Research. 2006;1077:24-36
  88. 88. Claus CP et al. Age is a determinant of leukocyte infiltration and loss of cortical volume after traumatic brain injury. Developmental Neuroscience. 2010;32:454-465
  89. 89. Tong W, Igarashi T, Ferriero DM, Noble LJ. Traumatic brain injury in the immature mouse brain: Characterization of regional vulnerability. Experimental Neurology. 2002;176:105-116
  90. 90. Duhaime AC et al. Maturation-dependent response of the piglet brain to scaled cortical impact. Journal of Neurosurgery. 2000;93:455-462
  91. 91. Grate LL, Golden JA, Hoopes PJ, Hunter JV, Duhaime AC. Traumatic brain injury in piglets of different ages: Techniques for lesion analysis using histology and magnetic resonance imaging. Journal of Neuroscience Methods. 2003;123:201-206
  92. 92. Clark RS, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM. Neutrophil accumulation after traumatic brain injury in rats: Comparison of weight drop and controlled cortical impact models. Journal of Neurotrauma. 1994;11:499-506
  93. 93. Furlan JC, Krassioukov AV, Fehlings MG. Hematologic abnormalities within the first week after acute isolated traumatic cervical spinal cord injury: A case-control cohort study. Spine (Phila Pa 1976). 2006;31:2674-2683
  94. 94. Anthony DC, Bolton SJ, Fearn S, Perry VH. Age-related effects of interleukin-1 beta on polymorphonuclear neutrophil-dependent increases in blood-brain barrier permeability in rats. Brain. 1997;120(Pt 3):435-444
  95. 95. Anthony D et al. CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier breakdown. Current Biology. 1998;8:923-926
  96. 96. Campbell SJ, Carare-Nnadi RO, Losey PH, Anthony DC. Loss of the atypical inflammatory response in juvenile and aged rats. Neuropathology and Applied Neurobiology. 2007;33:108-120
  97. 97. Semple BD, Kossmann T, Morganti-Kossmann MC. Role of chemokines in CNS health and pathology: A focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. Journal of Cerebral Blood Flow and Metabolism. 2010;30:459-473
  98. 98. Kigerl KA, McGaughy VM, Popovich PG. Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. The Journal of Comparative Neurology. 2006;494:578-594
  99. 99. Hazeldine J, Lord JM, Belli A. Traumatic brain injury and peripheral immune suppression: Primer and prospectus. Frontiers in Neurology. 2015;6:235
  100. 100. Kenne E, Erlandsson A, Lindbom L, Hillered L, Clausen F. Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice. Journal of Neuroinflammation. 2012;9:17
  101. 101. Semple BD, Bye N, Ziebell JM, Morganti-Kossmann MC. Deficiency of the chemokine receptor CXCR2 attenuates neutrophil infiltration and cortical damage following closed head injury. Neurobiology of Disease. 2010;40:394-403
  102. 102. Kigerl KA et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. The Journal of Neuroscience. 2009;29:13435-13444
  103. 103. Kumar A, Alvarez-Croda DM, Stoica BA, Faden AI, Loane DJ. Microglial/macrophage polarization dynamics following traumatic brain injury. Journal of Neurotrauma. 2016;33:1732-1750
  104. 104. Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature. 2010;468:562-566
  105. 105. Saunders NR, Liddelow SA, Dziegielewska KM. Barrier mechanisms in the developing brain. Frontiers in Pharmacology. 2012;3:46
  106. 106. Cornford EM, Cornford ME. Nutrient transport and the blood-brain barrier in developing animals. Federation Proceedings. 1986;45:2065-2072
  107. 107. Engelhardt B. Development of the blood-brain barrier. Cell and Tissue Research. 2003;314:119-129
  108. 108. Stolp HB, Dziegielewska KM, Ek CJ, Potter AM, Saunders NR. Long-term changes in blood-brain barrier permeability and white matter following prolonged systemic inflammation in early development in the rat. The European Journal of Neuroscience. 2005;22:2805-2816
  109. 109. Stolp HB et al. Breakdown of the blood-brain barrier to proteins in white matter of the developing brain following systemic inflammation. Cell and Tissue Research. 2005;320:369-378
  110. 110. Price L, Wilson CG. Grant. In: Laskowitz D, Grant G, editors. Translational Research in Traumatic Brain Injury. CRC Press/Taylor and Francis Group: Boca Raton (FL); 2016
  111. 111. Chodobski A, Zink BJ, Szmydynger-Chodobska J. Blood-brain barrier pathophysiology in traumatic brain injury. Translational Stroke Research. 2011;2:492-516
  112. 112. Prins ML, Giza CC. Induction of monocarboxylate transporter 2 expression and ketone transport following traumatic brain injury in juvenile and adult rats. Developmental Neuroscience. 2006;28:447-456
  113. 113. Appelberg KS, Hovda DA, Prins ML. The effects of a ketogenic diet on behavioral outcome after controlled cortical impact injury in the juvenile and adult rat. Journal of Neurotrauma. 2009;26:497-506
  114. 114. Pop V, Badaut J. A neurovascular perspective for long-term changes after brain trauma. Translational Stroke Research. 2011;2:533-545
  115. 115. Russell KL, Berman NE, Gregg PR, Levant B. Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2014;90:5-11

Written By

Thomas Brickler, Paul Morton, Amanda Hazy and Michelle H. Theus

Submitted: April 18th, 2017 Reviewed: September 28th, 2017 Published: December 20th, 2017