Repetitive concussion in childhood, commonly characterized as more than two mild traumatic brain injuries (mTBIs) sustained within a short timeframe, has become an escalating recognised apprehension in paediatric neurology. Albeit most concussions in children resolve without protracted clinical sequalae, massing data indicate that repeated injuries throughout the critical phases of brain development can exert enduring neurobiological consequences [1,2]. The paediatric brain demonstrates heightened susceptibility to biomechanical and metabolic stress, and recurrent concussive episodes may impair neuronal connectivity and axonal integrity, in conjunction with disrupted neuroinflammatory pathways, arguable predisposing subjects to early neurodegenerative change [3].

Emerging studies have started to pinpoint early markers of these pathological processes, comprising pathological tau phosphorylation, amyloid-beta (Aβ) accumulation, glial activation and decrements in regional brain volume. These biomarkers – conventionally linked to adult-onset neurodegenerative conditions such as Alzheimer’s disease and chronic traumatic encephalopathy (CTE) - have been documented in experimental models and in certain young athletes with a background of repetitive head trauma [4,5]. For example, a 2025 NIH-funded study on young athletes (under 30) subjected to repetitive head impacts revealed early neuron loss, inflammation, and brain changes significantly prior to CTE symptoms emerge, with autopsy data showing CTE-like tau pathology in 63% of cases [46]. A further 2025 study in mice demonstrated that childhood concussions instigate subclinical brain alterations that re-emerge in adulthood, including impaired neural plasticity and increased sensitivity to neurodegeneration [47]. Furthermore, a 2023 study of over 150 brains from athletes under 30 uncovered early CTE signs correlated with repetitive impacts, highlighting the need for early intervention [48].

The mounting participation of children and adolescents in organised contact sports further reinforces the pertinence of this matter, as repetitive and commonly subclinical head impacts can trigger neuropathological pathways long before clinical symptoms manifest.

This review hence intends to integrate extant data on how repetitive concussions sustained during childhood may be associated with early markers of neurodegeneration, with a focus on structural, molecular and functional outcomes. The core premise is that cumulative concussive injuries in youth can modify neurodevelopmental trajectories, culminating in molecular and structural changes that simulate early Alzheimer-type and tau-related pathology.

The acute phase post localised brain injury notably ischemia, intracerebral haemorrhage, or traumatic brain injury (TBI) is defined by a prompt activation of the innate immune system [59]. This initial phase is a critical factor of both the magnitude of primary tissue loss and the trajectory of subsequent functional recovery. A notable earliest pathological event is disruption of the blood brain barrier (BBB) [59]. Under normal biological parameters, the BBB is formed by tightly connected endothelial cells, reinforced by astrocytic endfeet and pericytes, whereby together sustain strict modulation of molecular exchange between the peripheral circulation and the central nervous system [59]. Soon following injury, inflammatory mediators instigate structural and transcriptional changes in astrocytes, resulting in altered BBB continuity and augmented permeability to conceivably noxious circulating molecules [59]. This mechanism is inextricably linked to the Monro-Kellie doctrine, which postulates that the skull is a rigid, fixed-volume container holding three components brain tissue (80%), blood (10%), and cerebrospinal fluid (CSF) (10%) and any increase in one requires compensation by a decrease in another to uphold intracranial pressure (ICP) [49]. In TBI, the timeline conventionally manifests as follows: within minutes to hours post-injury, swelling (edema) or bleeding increases brain volume, shifting CSF and blood; if left unmitigated (e.g., due to severe injury), ICP rises exponentially, leading to herniation and secondary damage [50]. This doctrine elucidates the reason for acute interventions prioritizing on mitigating ICP to avert fatal outcomes, as observed in pediatric cases wherein developing brains possess reduced compensatory reserve [50].

A defining characteristic of the early inflammatory phase is reactive astrogliosis. Astrocytes undergo hypertrophy, proliferate, and redirect their secretory phenotype. Primarily, this reaction restricts lesion proliferation and supports metabolic and structural homeostasis of the surrounding tissue. Nevertheless, when astrocytic activation reaches pathological levels or chronic, astrocytes release pro-inflammatory cytokines and chemokines thereby further destabilize the BBB and participate in secondary neuronal injury [6].

Microglia, as the brain's resident immune cells, engage synchronously by transitioning from surveillance to activation and diverging into a spectrum from pro-inflammatory (M1) to reparative (M2) phenotypes. Acutely, a balanced or M2-dominant response encourages debris clearance, tissue remodelling, and resolution of inflammation, hence sustaining enhanced structural preservation and functional outcomes, while persistent M1 prevalence aggravates BBB breakdown, oxidative stress, and neurodegeneration [7].

Astrocytes and microglia collectively instigate the acute inflammatory propagate through release of cytokines (e.g., IL-1β, IL-6, TNF-α), reactive oxygen species (ROS), and nitric oxide (NO), which amplify endothelial adhesion molecules and permit peripheral immune cell infiltration. This mobilization, when properly modulated, is vital for necrotic tissue elimination and induction of repair mechanisms, specifically within the developing brain where acute inflammation can facilitate persistent neural maturation regardless of increased susceptibility to dysregulation [8].

Therapeutic interventions addressing acute neuroinflammation emphasize its protective potential. For example, early administration of minocycline within the first 24 hours post-TBI reduces microglial activation in the cortex and hippocampus, reduces acute neuronal loss, and maintain hippocampal synaptic density outcomes that appear pivotally contingent upon meticulous timing within the acute window. By inhibiting microglial proliferation and pro-inflammatory signaling, minocycline advances neuroprotective processes without comprehensively impairing beneficial acute immune functions [9]. For instance, a 2022 preclinical study in juvenile mice evidenced that minocycline administered at 1 and 24 hours post-TBI markedly diminished microglial activation and hippocampal neuronal loss at 7 days, with improved functional outcomes [59]. In clinical settings, a 2023 analysis of human trials suggested safety and potential for reducing acute inflammation, even so larger randomized trials are necessary to validate long-term cognitive benefits [51]. Empirical validation comes from reduced IL-6 and TNF-α levels in CSF samples from treated patients relative to controls.

Below, a comparative table summarizes key biomarkers of neuroinflammation after TBI. These markers may show differential elevation in recovering versus non-recovering patients and can therefore support clinical assessment and prognostication.

Table 1: Patterns of Neuroinflammatory Biomarkers in Paediatric TBI (Recovering vs. Non-Recovering Cohorts).

Following a traumatic brain injury (TBI), a transition to chronic inflammation and long-term complications frequently occurs because the initial injury precipitates an immune response in the brain that fails to reach resolution. This results in enduring inflammation that gradually damages neural pathways over extended periods.

Persistent neuroinflammation is considered a pivotal factor associating TBI to long-term cognitive decline. Ensuing from the initial lesion, microglia promptly activate to remove debris and support tissue repair. Nevertheless, in many subjects, this activation does not fully subside, eventuating in a persistent pro-inflammatory environment. Chronically engaged microglia persist in the secretion of cytokines and reactive oxygen species, catalysing redundant synaptic refinement, dendritic spine loss, and attenuated hippocampal neurogenesis, which collectively promote deficits in learning and memory. Preclinical TBI models illustrate that this persistent microglial activation, coupled with protracted neuronal loss and escalating hippocampal and cortical atrophy spanning several months ensuing the trauma, signified a transition from acute damage to neurodegenerative processes [14-17].

Extended neuroimaging investigations, for instance a 2014 prospective study group of 44 adults with severe TBI using diffusion tensor imaging (DTI) at 5 years post-injury, corroborate these enduring ramifications in human cohorts by uncovering ongoing white matter disconnection and decreased fractional anisotropy, albeit conventional MRI may manifest as unremarkable these alterations, comprising hippocampal volume diminution, strongly predict unfavourable cognitive results, notably memory impairments [19]. Peripheral inflammation, as evidenced by biomarkers like C-reactive protein (CRP), can remain augmented for month’s post-TBI and correlates with central nervous system derangements. The core premise of 'inflammaging' postulates that elevated inflammatory markers accelerate white matter injury and cognitive attrition, specifically in subjects with pre-existing vulnerabilities such as vascular or metabolic pathologies; by way of illustration, a 2023 synthesis emphasized how inflammaging in TBI aggravates age-related neurodegeneration, reinforced by increased CRP/IL-6 levels lingering 1–12 months post-insult in study groups [18,20].

Furthermore, accumulating insights reinforce a dose-response model wherein injury severity and host factors shape the developmental course from acute TBI to chronic deficits. Moderate-to-severe TBI induces more profound and persistent deficits in modalities such as attention, memory, and executive function relative to mild TBI, and bestow a higher risk of subsequent neurodegenerative conditions such as dementia, consistent with more pronounced cumulative inflammatory and structural burden. Even mild TBI is not invariably transient, as a non-negligible number of patients present with abiding cognitive and emotional sequelae years post-injury, notably couple with synergistic vulnerabilities. Sex and age are critical moderators of long-term outcomes. Women report more severe cognitive and somatic impairments than men from 12 months to 8 years post-TBI, despite similar early injury profiles [22,23]. Advance age at injury is linked with slower recovery, greater functional limitations, and more persistent cognitive complaints, mostly due to reduced brain resilience and elevated baseline inflammation as seen in a 2021 TRACK-TBI study of 2,700 patients showing worse symptoms in older children/females at 6-12 months [18,19,24-26].

These findings underscore that the progression to chronic inflammation and long-term deficits originate from a dynamic interaction between tenacious microglial activation, systemic inflammatory load, structural brain changes, and person-centric parameters such as injury severity, age, and gender.

Neuroinflammatory responses subsequent to pediatric traumatic brain injury (TBI) demonstrate considerable heterogeneity. Syntheses and prospective study groups disclose that cytokine profiles, glial mobilization, and derivative network reconfigurations fluctuate based on developmental stage at insult, trauma magnitude, and concomitant stressors. This implies a pivotal contribution of host-specific and environmental determinants in dictating whether inflammation reaches a homeostatic resolution or transitions to a protracted, dysfunctional state [27,28].

Among hereditary factors impinging upon TBI results, apolipoprotein E (APOE) has emerged as the most rigorously scrutinized. A comprehensive integration of pediatric TBI cohorts signified that youth possessing at least one APOE ε4 allele displayed over double the probability of unfavourable functional outcomes at 6 months relative to non-carriers, with the capacity for magnified ramifications across protracted epochs [29]. In a localized cohort of 82 pediatric subjects with acute TBI, ε4 presence was correlated with attenuated Glasgow Outcome Scale scores at 1-year post-insult, substantiating APOE genotype as a standalone predictive factor [30]. Nascent systems-biology evaluations in early-life TBI further posit that polymorphisms in genes linked to immunological cascades, apoptosis, and neuroontogeny may drive the disparity in permanent behavioral sequelae. Albeit these observations necessitate empirical validation, they justify integration into theoretical constructs [31].

The confluence of environmental and physiological modulators, particularly sleep, intersect with these biological susceptibilities. Systematic reviews of pediatric TBI underscore that sleep-wake cycle aberrations and fatigue are prevalent and often persistent, evolving into insomnia and increased daytime sleepiness months to years’ post-injury [32,33]. Diminished sleep quality depends on augmented symptom severity and reduced living quality, validating a bidirectional model where TBI-induced neuroinflammation impairs sleep regulation, while post-injury sleep disturbances exasperate sustained inflammation and symptoms [27,32,33]. Nevertheless, direct evidence correlating sleep disruption to uninterrupted inflammatory signalling in pediatric populations is presently negligible, mandating targeted research.

Therapeutic data in children are limited, but preclinical models offer insights into anti-inflammatory strategies. In rodent TBI models, omega-3 polyunsaturated fatty acid supplementation reduces microglial activation, pro-inflammatory cytokine levels, and white matter damage, while enhancing neurobehavioral recovery; for example, a 2013 study in juvenile rats showed improved neurologic recovery and attenuated axonal injury with post-injury dosing [34,53]. Given their favourable safety profile, these findings have spurred interest in pediatric clinical trials, though robust randomized data are lacking [53]. Conversely, systemic corticosteroids once viewed as broad anti-inflammatory agents were associated with increased mortality and no functional benefits in the large adult CRASH trial (2004, n=10,008, showing 18% mortality with steroids vs. 15% placebo) [35], prompting current guidelines to avoid their routine use for neuroprotection in TBI, including pediatric cases. Additional interventions like progesterone (failed Phase III trials in 2014 showing no benefit) and erythropoietin (mixed preclinical promise but limited pediatric data) highlight the need for targeted approaches [54,55].

Table 2: Therapeutic Interventions for Neuroinflammation in Pediatric TBI (Preclinical and Clinical Data).

Data synthesized from [34,35, 50-55].

Biomarkers such as serum or cerebrospinal fluid cytokines (e.g., IL-6, IL-8, IL-10, TNF-α) offer significant potential for risk stratification and refining clinical trials. Pediatric studies elucidate that cytokine profiles and ratios (e.g., IL-6/IL-10) align with TBI severity, even so data pertaining to chronic immune impairment after mild injuries is negligible and mandates additional analyses [28]. Clinical utility is impeded by temporal variability, absence of age-specific reference ranges, and inadequate selectivity for central nervous system processes. This accentuates the requirement for prospective pediatric cohorts that incorporates genetics, sleep metrics, and serial biomarker characterization to distinguish children who are optimal candidates for personalized anti-inflammatory strategies [27,28,31].

Table 3: Biomarkers in Pediatric TBI: Diagnostic and Prognostic Value.

Data synthesized from [13,48,56,57].

Great amount of knowledge gaps continues to exist in our grasp of neuroinflammation after pediatric traumatic brain injury (TBI). Primary domains comprise the dynamic contributions of microglia, inflammation-driven neurodegeneration, dysfunctional hippocampal neurogenesis, tenacious white matter modifications, interactions between systemic and central inflammation, and the modulating outcomes of age and sex on inflammatory responses and clinical trajectories.

Microglia act as central regulators of acute and chronic neuroinflammatory processes after TBI. While incipient microglial activation potentially induces neuroprotective effects through debris clearance and growth factor release, prolonged activation fosters neurodegeneration through the disruption neuronal homeostasis, impairing synaptic plasticity, and contributing to long-standing cognitive and behavioural impairments [36,37,14]. The molecular catalysts dictating the transition from beneficial to pathogenic microglial phenotypes continue to be inadequately explicated, specifically in the immature brain [37,38]. Furthermore, the cascades involving microglial priming, interferon signalling, and responses to secondary insults variable predicated upon developmental stage have received sparse attention in pediatric models [39].

Neuroinflammation is increasingly associated in chronic post-TBI sequelae, specifically progressive white matter degeneration, hippocampal atrophy, and heightened susceptibility of neurodegenerative disorders [14,40]. However, the exact transcriptomic profiles, cellular pathways, and cascades associating persistent inflammation to axonal damage and demyelination in the developing brain are under-characterized [40,41]. Likewise, whilst microglia-derived cytokines and chemokines inhibit hippocampal neurogenesis and undermine learning and memory, the underlying intracellular signalling mechanisms and their enduring functional consequences mandate additional analysis [42].

The bidirectional interplay between systemic inflammation and central neuroimmune activation constitutes another neglected domain. How peripheral immune signals impact brain recovery, neuroplasticity, and long-term outcomes in children are currently ambiguous [43,44]. Age at injury and sex are recognised modifiers of neuroinflammatory evolutionary courses and clinical outcomes, however most preclinical and clinical studies neglect to rigorously stratify by these variables or explicate fundamental pathways [39,41,45].

To resolve these gaps, future research should prioritize longitudinal pathway-specific analyses in varied pediatric cohorts, integrating advanced multimodal imaging, fluid-based biomarkers, and single-cell omics approaches. Favouring age- and sex-stratified designs, in conjunction with the development of targeted immunomodulatory interventions specifically calibrated for developmental stages, is vital for translating breakthroughs into efficacious therapies that alleviate long-term morbidity after pediatric TBI.

Pediatric traumatic brain injury (TBI) incites an intricate neuroinflammatory reaction that is intrinsically dichotomous. In the acute phase, this response functions as an indispensable function: immediate microglial activation and astrogliosis help isolate the lesion, eliminate necrotic debris, release growth factors, and recruit peripheral immune cells to facilitate early repair. Cytokine surges, including IL-1β, IL-6, and TNF-α, in tandem with controlled blood-brain barrier permeability, play a role in limiting the degree of initial damage and fostering short-term recovery. Nevertheless, when these processes persist beyond the temporal window in time a prevalent observation in the immature brain the identical pathway evolve into promoters of secondary injury, resulting in extended neuronal dysfunction and relentless tissue loss. Long-lasting neuroinflammation after pediatric TBI characterized by persisting pro-inflammatory microglia, oxidative stress, and high cytokine levels exacerbates long-term damage. This includes augmented synaptic pruning, hindered hippocampal neurogenesis, axonal damage, white matter loss, and hippocampal atrophy. These changes facilitate in explaining long-standing cognitive struggles (memory, attention, and executive function) and the emotional issues observed in survivors. Additionally, they may enhance the risk for later neurodegeneration, similar to patterns as observed in adult repetitive injury. Recovery is different greatly due to key factors: the APOE ε4 genotype persistently pointing to worse results; age at injury and gender oftentimes correlate to long-term symptoms and reduced clearing of inflammatory markers. Additionally, post-injury sleep problems attenuate inflammation in a feedback loop that hinders brain plasticity. Although animal studies offer encouraging data for early treatments like minocycline or omega-3 supplements to aid healing, few pediatric trials are present. By comparison, broad anti-inflammatory drugs (e.g., corticosteroids) have provided insight into having no benefit and can even cause harm. This lack of reliable, age-specific biomarkers makes it hard to time treatments correctly. Large gaps remain regarding what causes the switch from helpful to harmful inflammation, how microglia act at different ages, and the link between body and brain immune signals. Moving forward requires long-term pediatric studies using repeated biomarker testing, advanced imaging, genetic analysis, and sleep tracking, grouped by age, sex, severity, and genetic risk. Understanding the timing of inflammation could lead to targeted therapies that keep the early protective effects while stopping chronic damage. This would greatly lower long-term disability and improve life for children living with TBI.

1. McKee AC, Stein TD, Kiernan PT, Alvarez VE. The neuropathology of chronic traumatic encephalopathy. Brain Pathol. 2015; 25: 350-364.
2. Kooper CC, Van Houten MA, Niele N, Aarnoudse-Moens C, Roermund MV, Oosterlaan J, et al. Long-Term Neurodevelopmental Outcome of Children with Mild Traumatic Brain Injury. Pediatr Neurol. 2024; 160: 18-25.
3. Obenaus A, Noarbe BP, Lee JB, Panchenko PE, Tong F, Noarbe SD, et al. Progressive lifespan modifications in the corpus callosum following a single concussion in juvenile male mice monitored by diffusion MRI. Exp Neurol. 2025; 394: 115455.
4. Johnson VE, Stewart W, Smith DH. Axonal pathology in traumatic brain injury. Exp Neurol. 2013; 246: 35-43.
5. Mez J, Daneshvar DH, Abdolmohammadi B, Chua AS, Alosco ML, Kiernan PT, et al. Duration of American Football Play and Chronic Traumatic Encephalopathy. Ann Neurol. 2020; 87: 116-131.
6. Brandl S, Reindl M. Blood–Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models. National Library of Medicine. 2023; 24: 12699.
7. García-Domínguez M. Neuroinflammation: Mechanisms, Dual Roles, and Therapeutic Strategies in Neurological Disorders, National Library of medicine. 2025.
8. Patel A, Taksande A, Khandelwal R, Jain A. National Library of Medicine. 2024.
9. Celorrio M, Shumilov K, Payne C, Vadivelu S, Friess SH. Acute minocycline administration reduces brain injury and improves long-term functional outcomes after delayed hypoxemia following traumatic brain injury. Acta Neuropathologica Communications. National Library of Medicine. 2022; 10.
10. Huang H, Fu G, Lu S, Chen S, Huo J, Ran Y, et al. Plasma profiles of inflammatory cytokines in children with moderate to severe traumatic brain injury: a prospective cohort study. Eur J Pediatr. 2024; 183: 3359-3368.
11. Chiaretti A, Genovese O, Aloe L, Antonelli A, Piastra M, Polidori G, et al. Interleukin 1β and interleukin 6 relationship with paediatric head trauma severity and outcome. Childs Nerv Syst. 2005; 21: 185-193.
12. Munoz Pareja C, Mateo Chavez J, Bernal JA, Swaby K, Machado N, Pringle C, et al. Association of serum inflammasome proteins and pediatric traumatic brain injury severity. Pediatr Res. 2025.
13. Pryzmont M, Kosciuczuk U, Maciejczyk M. Biomarkers of traumatic brain injury: narrative review and future prospects in neurointensive care. Front Med. 2025; 12: 1539159.
14. Shao F, Wang X, Wu H, Wu Q, Zhang J. Microglia and neuroinflammation: crucial pathological mechanisms in Traumatic Brain Injury-Induced Neurodegeneration. Front Aging Neurosci. 2022; 14: 825086.
15. Loane DJ, Kumar A. Microglia in the TBI brain: The good, the bad, and the dysregulated. Exp Neurol. 2016; 275: 316-327.
16. Navabi SP, Badreh F, Shooshtari MK, Hajipour S, Vastegani SM, Khoshnam SE. Microglia-induced neuroinflammation in hippocampal neurogenesis following traumatic brain injury. Heliyon. 2024; 10: e35869.
17. Loane DJ, Kumar A, Stoica BA, Cabatbat R, Faden AI. Progressive Neurodegeneration after Experimental Brain Trauma. J Neuropathol Exp Neurol. 2014; 73: 14-29.
18. Lu Y, Jarrahi A, Moore N, Bartoli M, Brann DW, Baban B, et al. Inflammaging, cellular senescence, and cognitive aging after traumatic brain injury. Neurobiol Dis. 2023; 180: 106090.
19. Chaban V, Clarke GJB, Skandsen T, Islam R, Einarsen CE, Vik A, et al. Systemic Inflammation Persists the First Year after Mild Traumatic Brain Injury: Results from the Prospective Trondheim Mild Traumatic Brain Injury Study. J Neurotrauma. 2020; 37: 2120-2130.
20. Verhulst MMLH, Glimmerveen AB, Van Heugten CM, Helmich RCG, Hofmeijer J. MRI factors associated with cognitive functioning after acute onset brain injury: Systematic review and meta-analysis. Neuroimage Clin. 2023; 38: 103415.
21. Dinkel J, Drier A, Khalilzadeh O, Perlbarg V, Czernecki V, Gupta R, et al. Long-Term White Matter Changes after Severe Traumatic Brain Injury: A 5-Year Prospective Cohort. AJNR Am J Neuroradiol. 2014; 35: 23-29.
22. Wagberg S, Stalnacke BM, Magnusson BM. Gender and Age Differences in Outcomes after Mild Traumatic Brain Injury. J Clin Med. 2023; 12: 4883.
23. Levin HS, Temkin NR, Barber J, Nelson LD, Robertson C, Brennan J, et al. Association of Sex and Age with Mild Traumatic Brain Injury-Related Symptoms: A TRACK-TBI study. JAMA Netw Open. 2021; 4: e213046.
24. Starkey NJ, Duffy B, Jones K, Theadom A, Barker-Collo S, Feigin V. Sex differences in outcomes from mild traumatic brain injury eight years post-injury. PLoS One. 2022; 17: e0269101.
25. Vincent AS, Roebuck-Spencer TM, Cernich A. Cognitive changes and dementia risk after traumatic brain injury: Implications for aging military personnel. Alzheimers Dement. 2014; 10: S174-S187.
26. Rabinowitz AR, Levin HS. Cognitive sequelae of traumatic brain injury. Psychiatr Clin North Am. 2014; 37: 1-11.
27. Fraunberger E, Esser MJ. Neuro-Inflammation in Pediatric Traumatic Brain Injury from Mechanisms to Inflammatory Networks. Brain Sci. 2019; 9: 319.
28. Ryan E, Kelly L, Stacey C, Huggard D, Duff E, Mc Collum D, et al. Mild-to-severe traumatic brain injury in children: altered cytokines reflect severity. J Neuroinflammation. 2022; 19: 36.
29. Kassam I, Gagnon F, Cusimano MD. Association of the APOE-ε4 allele with outcome of traumatic brain injury in children and youth: a meta-analysis and meta-regression. J Neurol Neurosurg Psychiatry. 2016; 87: 433-440.
30. Brichtova E, Mackerle Z. Apolipoprotein E genotype as an independent prognostic factor for clinical outcome in traumatic brain injury in children and the adolescent population. Cesk Slov Neurol N. 2011; 74/107: 437-442.
31. Kurowski BG, Treble-Barna A, Pilipenko V, Wade SL, Yeates KO, Taylor HG, et al. Genetic influences on behavioral outcomes after childhood TBI: a novel systems biology-informed approach. Front Genet. 2019; 10: 481.
32. Luther M, Poppert Cordts KM, Williams CN. Sleep disturbances after pediatric traumatic brain injury: a systematic review of prevalence, risk factors, and association with recovery. Sleep. 2020; 43: zsaa083.
33. Gagner C, Landry-Roy C, Laine F, Beauchamp MH. Sleep-wake disturbances and fatigue after pediatric traumatic brain injury: a systematic review of the literature. J Neurotrauma. 2015; 32: 1539-1552.
34. Pu H, Guo Y, Zhang W, Huang L, Wang T, Tao G, et al. Omega-3 polyunsaturated fatty acid supplementation improves neurologic recovery and attenuates white matter injury after experimental traumatic brain injury. J Cereb Blood Flow Metab. 2013; 33: 1474-1484.
35. Roberts I, Yates D, Sandercock P, Farrell B, Wasserberg J, Lomas G, et al. CRASH Trial Collaborators. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet. 2004; 364: 1321-1328.
36. Witcher KG, Bray CE, Chunchai T, Zhao F, ONeil SM, Gordillo AJ, et al. Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. J Neuroscience: the official J Society for Neuroscience. 2021; 41: 1597-1616.
37. Obukohwo OM, Oreoluwa OA, Andrew UO, Williams UE. Microglia-mediated neuroinflammation in traumatic brain injury: a review. Molecular biology reports. 2024; 51: 1073.
38. Shah SS, Shetty AJ, Johnston DT, Hanan CL, OReilly BT, Skibber MA, et al. Implications and pathophysiology of neuroinflammation in pediatric patients with traumatic brain injury: an updated review. Frontiers in neuroscience. 2025; 19: 1587222.
39. Wangler LM, Godbout JP. Microglia moonlighting after traumatic brain injury: aging and interferons influence chronic microglia reactivity. Trends in Neurosciences. 2023; 46: 926-940.
40. Jacquens A, Csaba Z, Soleimanzad H, Bokobza C, Delmotte PR, Userovici C, et al. Deleterious effect of sustained neuroinflammation in pediatric traumatic brain injury. Brain, behavior, and immunity. 2024; 120: 99-116.
41. Grovola MR, Von Reyn C, Loane DJ, Cullen DK. Understanding microglial responses in large animal models of traumatic brain injury: an underutilized resource for preclinical and translational research. J Neuroinflammation. 2023; 20: 67.
42. Navabi SP, Badreh F, Khombi Shooshtari M, Hajipour S, Moradi Vastegani S, Khoshnam SE. Microglia-induced neuroinflammation in hippocampal neurogenesis following traumatic brain injury. Heliyon. 2024; 10: e35869.
43. Nasr IW, Chun Y, Kannan S. Neuroimmune responses in the developing brain following traumatic brain injury. Experimental Neurology. 2019; 320: 112957.
44. Zhao Q, Li H, Li H, Xie F, Zhang J. Research progress of neuroinflammation-related cells in traumatic brain injury: A review. Medicine. 2023; 102: e34009.
45. Morganti-Kossmann MC, Semple BD, Hellewell SC, Bye N, Ziebell JM. The complexity of neuroinflammation consequent to traumatic brain injury: from research evidence to potential treatments. Acta neuropathological. 2019; 137: 731-755.
46. Butler MLMD, Pervaiz N, Breen K, Calderazzo S, Ypsilantis P, Wang Y, et al. Repeated head trauma causes neuron loss and inflammation in young athletes. Nature. 2025; 647: 228-237.
47. Obenaus A, Noarbe BP, Lee JB, Panchenko PE, Noarbe SD, Lee YC, et al. Progressive lifespan modifications in the corpus callosum following a single juvenile concussion in male mice monitored by diffusion MRI. bioRxiv: The Preprint Server for Biology. 2023; 12: 572925.
48. McKee AC, Mez J, Abdolmohammadi B, Butler M, Huber BR, Uretsky M, et al. Neuropathologic and Clinical Findings in Young Contact Sport Athletes Exposed to Repetitive Head Impacts. JAMA Neurol. 2023; 80: 1037-1050.
49. Mokri B. The Monro-Kellie hypothesis: applications in CSF volume depletion. Neurology. 2001; 56: 1746-1748.
50. Wilson MH. Monro-Kellie 2.0: The dynamic vascular and venous pathophysiological components of intracranial pressure. J Cerebral blood flow and Metabolism: Official J International Society of Cerebral Blood Flow and Metabolism. 2016; 36: 1338-1350.
51. Bergold PJ, Furhang R, Lawless S. Treating Traumatic Brain Injury with Minocycline. Neurotherapeutics: The J American Society for Experimental Neuro Therapeutics. 2023; 20: 1546-1564.
52. Pu H, Guo Y, Zhang W, Huang L, Wang G, Liou AK, et al. Omega-3 polyunsaturated fatty acid supplementation improves neurologic recovery and attenuates white matter injury after experimental traumatic brain injury. J Cerebral blood flow and metabolism: Official J International Society of Cerebral Blood Flow and Metabolism. 2013; 33: 1474-1484.
53. University of Manitoba. Omega-3 Treatment for Concussion in Adolescents (CONCUSS). ClinicalTrials. 2023.
54. Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. The New England J Medicine. 2014; 371: 2457-2466.
55. Lee J, Cho Y, Choi KS, Kim W, Jang BH, Shin H, et al. Efficacy and safety of erythropoietin in patients with traumatic brain injury: A systematic review and meta-analysis. The American J Emergency Medicine. 2019; 37: 1101-1107.
56. Behforouz A, Arabfard M, Behzadnia MJ. Neuron-specific enolase: a potential biomarker in the prediction of pediatric head trauma outcomes: a systematic review and meta-analysis. International J Emergency Medicine. 2025; 18: 113.
57. Munoz Pareja JC, De Rivero Vaccari JP, Chavez MM, Kerrigan M, Pringle C, Guthrie K, et al. Prognostic and Diagnostic Utility of Serum Biomarkers in Pediatric Traumatic Brain Injury. J Neurotrauma. 2024; 41: 106-122.
58. Celorrio M, Shumilov K, Payne C, Vadivelu S, Friess SH. Acute minocycline administration reduces brain injury and improves long-term functional outcomes after delayed hypoxemia following traumatic brain injury. Acta Neuropathologica Communications. 2022; 10: 10.
59. Caceres E, Olivella JC, Di Napoli M, Raihane AS, Divani AA. Immune Response in Traumatic Brain Injury. Current neurology and neuroscience reports. 2024; 24: 593-609.