Temporal Window of Vulnerability to Repetitive Experimental Concussive Brain Injury

Longhi, Luca; Saatman, Kathryn E.; Fujimoto, S.; Raghupathi, Ramesh; Meaney, David F.; Davis, Jason; McMillan, Asenia; Conte, V.; Laurer, Helmut; Stein, Sherman C.; Stocchetti, Nino; McIntosh, Tracy K.

doi:10.1227/01.neu.0000149008.73513.44

Cited by 278 publications

(243 citation statements)

References 59 publications

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“…Therefore, as previously reported, 26,27 the present research offers a real time course of NAA, Cr, and Cho following mTBI, demonstrating transient cerebral hypometabolism (decrease in NAA and Cr) corresponding to the window of metabolic brain vulnerability. [1][2][3][5][6][7][8]10,11,35 In light of the data questioning the validity of neuropsychological tests to determine the safe return of athletes to play, 48,49 the present results, besides confirming that recovery of brain metabolism occurs much later than disappearance of postconcussive symptoms, once again indicate that 1 H MRS is a potent, unique tool with which to monitor the closure of the window of metabolic brain vulnerability following mTBI that may involve important brain metabolites such as NAA and Cr. Furthermore, the very recent report carried out in a cohort of 24 symptomfree athletes with concussive head injury (as assessed by clinical self-reported symptom resolution, cognitive and clinical balance testing (SCAT2 and Balance Error Scoring System), and clearance from a medical professional for the first stage of aerobic activity) showing significant alterations in brain metabolism (decrease in NAA in the genu but not in the splenium of the corpus callosum) strongly support the concept that clinical resolution is not coincident with normalization of brain metabolism.…”

Section: Discussionsupporting

confidence: 61%

“…31,32 To explain their results, these authors concluded that an increase in total Cr (Cr and CrP) levels in the white matter may support a larger pool of high-energy phosphates (CrP and ATP), helping to restore mTBI-induced alteration of cell homeostasis through upregulation of membrane pumps and other processes of cellular repair. 28,29 Notwithstanding, these conclusions are in contrast with the notion of brain vulnerability, [1][2][3][5][6][7][8]10,11,35 which is characterized by a period of metabolic depression (hypometabolism), mainly due to mitochondrial malfunctioning, [36][37][38] particularly affecting NAA homeostasis 39 and ATP supply, [8][9][10][11]31,39 and also causing significant depletion in the total Cr pool. 31,32 Furthermore, given the relative CrP/ATP ratio in the brain tissue, ranging from about 0.8 (from Bryant et al) 32 to about 0.33 (from Signoretti et al), 31 it seems implausible that CrP may efficiently buffer ATP stores in the case of impaired ATP homeostasis.…”

Section: Discussionmentioning

confidence: 84%

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Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

Vagnozzi¹,

Signoretti²,

Floris³

et al. 2013

Journal of Head Trauma Rehabilitation

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Objectives:To assess the time course changes in N-acetylaspartate (NAA) and creatine (Cr) levels in the brain of athletes who suffered a sport-related concussion. Participants: Eleven nonconsecutive athletes with concussive head injury and 11 sex-and age-matched control volunteers Main outcome measures: At 3, 15, 30, and 45 days postinjury, athletes were examined by proton magnetic resonance spectroscopy for the determination of NAA, Cr, and choline (Cho) levels. Proton magnetic resonance spectroscopic data recorded for the control group were used for comparison. Results: Compared with controls (2.18 ± 0.19), athletes showed an increase in the NAA/Cr ratio at 3 (2.71 ± 0.16; P < .01) and 15 (2.54 ± 0.21; P < .01) days postconcussion, followed by a decrease and subsequent normalization at 30 (1.95 ± 0.16, P < .05) and 45 (2.17 ± 0.20; P < .05) days postconcussion. The NAA/Cho ratio decreased at 3, 15, and 30 days postinjury (P < .01 compared with controls), with no differences observed in controls at 45 days postconcussion. Compared with controls, significant increase in the Cho/Cr ratio after 3 (+33%, P < .01) and 15 (+31.5%, P < .01) days postinjury was observed whereas no differences were recorded at 30 and 45 days postinjury. Conclusions: This cohort of athletes indicates that concussion may cause concomitant decrease in cerebral NAA and Cr levels. This provokes longer time for normalization of metabolism, as well as longer time for resolution of concussion-associated clinical symptoms. Geology and Environmental Sciences, Viale A. Doria 6, 95125 Catania, Italy (lazzarig@unict.it). DOI: 10.1097/HTR.0b013e3182795045C ONCUSSION is defined as a biomechanically induced brain injury characterized by the absence of gross anatomic damages. Supported by the absence of structural lesions on traditional neuroimaging, a general and broadly accepted view is that mild traumatic brain injury (mTBI) is indeed a very frequent entity but is not a very serious injury, leading only to transient disturbances, and that no intervention other than observation is typically required. However, mTBI triggers molecular changes in neuronal cells involving a complex cascade of neurometabolic alterations 1-3 that reversibly modify the concentrations of several low-molecular-weight compounds actively involved in functions crucial for cell homeostasis and survival. 3,4 Such a cascade of molecular events is considered as the determinant of the so-called state of metabolic brain vulnerability, 5,6 which transiently exposes cerebral tissue to the cumulative effect of a second mTBI occurring during this particular period. 7,8 High-energy phosphates, 9,10 coenzyme A metabolites, 11 ATP catabolites, 11 and neurotransmitters, 12,13 are some of the substances whose concentrations are temporarily affected as a result of a traumatic insult. Of

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 84%

Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

Vagnozzi¹,

Signoretti²,

Floris³

et al. 2013

Journal of Head Trauma Rehabilitation

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show abstract

“…Moreover, our interinjury interval was 48 h, which is similar to our previous work,13, 19 a temporal window during which the mouse brain is known to be vulnerable to subsequent injuries21 in order to mimic human situations (combat or sports) in which additional injuries are sustained prior to full recovery from the previous injury. At the end of the procedure, each animal was removed from the stereotaxic table and allowed to recover on a heating pad and, upon becoming ambulatory, was returned to its home cage.…”

Section: Methodsmentioning

confidence: 87%

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Mouzon

Bachmeier

Ojo

et al. 2017

Ann Clin Transl Neurol

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ObjectiveExposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long‐term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late survival.MethodsMale C57BL/6J mice (aged 2–3 months) were exposed to either single or repetitive mild TBI or sham procedure. Thereafter, animals were monitored and assessed at 24 months post last injury for measures of motor coordination, learning deficits, cognitive function, and anxiety‐like behavior prior to euthanasia and preparation of the brains for detailed neuropathological and protein biochemical studies.ResultsAt 24 months survival animals exposed to r‐mTBI showed clear evidence of learning and working memory impairment with a lack of spatial memory and vestibule‐motor vestibulomotor deficits compared to sham animals. Associated with these late behavioral deficits there was evidence of ongoing axonal degeneration and neuroinflammation in subcortical white matter tracts. Notably, these changes were also observed after a single mTBI, albeit to a lesser degree than repetitive mTBI.InterpretationIn this context, our current data demonstrate, for the first time, that rather than an acute, time limited event, mild TBI can precipitate a lifelong degenerative process. These data therefore suggest that successful treatment strategies should consider both the acute and chronic nature of mTBI.

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“…Moreover, confirmation of the likely residual pathology from concussion is clearly demonstrated in the secondinjury circumstance, where a prior concussion increases the likelihood of a second concussion and greater morbidity of the second concussion in both human and animal studies (Huh et al, 2007;Longhi et al, 2005;Manville et Wall et al, 2006). The most straight forward explanation of the pathology of the second injury concussion is that the first concussion is simply not benign, but that the brain adapts quickly to the injury in most cases.…”

Section: Pathophysiology Of Concussionmentioning

confidence: 96%

Neuropsychology and clinical neuroscience of persistent post-concussive syndrome

Bigler

2007

J Int Neuropsychol Soc

363

248

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On the mild end of the acquired brain injury spectrum, the terms concussion and mild traumatic brain injury (mTBI) have been used interchangeably, where persistent post-concussive syndrome (PPCS) has been a label given when symptoms persist for more than three months post-concussion. Whereas a brief history of concussion research is overviewed, the focus of this review is on the current status of PPCS as a clinical entity from the perspective of recent advances in the biomechanical modeling of concussion in human and animal studies, particularly directed at a better understanding of the neuropathology associated with concussion. These studies implicate common regions of injury, including the upper brainstem, base of the frontal lobe, hypothalamic-pituitary axis, medial temporal lobe, fornix, and corpus callosum. Limitations of current neuropsychological techniques for the clinical assessment of memory and executive function are explored and recommendations for improved research designs offered, that may enhance the study of long-term neuropsychological sequelae of concussion. (JINS, 2008, 14, 1-22.)

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Temporal Window of Vulnerability to Repetitive Experimental Concussive Brain Injury

Cited by 278 publications

References 59 publications

Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Neuropsychology and clinical neuroscience of persistent post-concussive syndrome

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