Repetitive Mild Traumatic Brain Injury in the Developing Brain: Effects on Long-Term Functional Outcome and Neuropathology

Fidan, Emin; Lewis, Jesse; Kline, Anthony E.; Garman, Robert H.; Alexander, Henry; Cheng, Jeffrey P.; Bondi, Corina O.; Clark, Robert S. B.; Dezfulian, Cameron; Kochanek, Patrick M.; Kagan, Valerian E.; Bayır, Hülya

doi:10.1089/neu.2015.3958

Cited by 59 publications

(51 citation statements)

References 90 publications

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“…Research on sports‐related head injury suggests that history of “multiple” or “recurrent” TBI may be associated with greater postconcussive symptoms and delayed recovery (Covassin, Stearne, & Elbin, ; Guskiewicz et al., ; Iverson et al., ; Matser, Kessels, Lezak, Jordan, & Troost, ; Morgan et al., ; Ponsford et al., ; Wall et al., ; Zuckerman et al., ). Preclinical research also suggests that recurrent TBI may increase risk for negative neurocognitive outcomes through white matter and microvascular disruption, increased neuroinflammation, astrogliosis, and p‐Tau immunoreactivity (Donovan et al., ; Fidan et al., ; Fujita, Wei, & Povlishock, ; Luo et al., ; Mannix et al., ; Mouzon et al., ), although numerous questions related to the pathophysiology of recurrent head injury remain unanswered (Brody et al., ). Future study of peripheral immune markers within the MRS‐II sample may help identify immune pathways associated with TBI‐related increases in fear conditioning.…”

Section: Discussionmentioning

confidence: 99%

Fear learning alterations after traumatic brain injury and their role in development of posttraumatic stress symptoms

et al. 2017

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Background: It is unknown how traumatic brain injury (TBI) increases risk for posttraumatic stress disorder (PTSD). One potential mechanism is via alteration of fear-learning processes that could affect responses to trauma memories and cues. We utilized a prospective, longitudinal design to determine if TBI is associated with altered fear learning and extinction, and if fear processing mediates effects of TBI on PTSD symptom change. Methods:Eight hundred fifty two active-duty Marines and Navy Corpsmen were assessed before and after deployment. Assessments included TBI history, PTSD symptoms, combat trauma and deployment stress, and a fear-potentiated startle task of fear acquisition and extinction. Startle response and self-reported expectancy and anxiety served as measures of fear conditioning, and PTSD symptoms were measured with the Clinician-Administered PTSD Scale.Results: Individuals endorsing "multiple hit" exposure (both deployment TBI and a prior TBI) showed the strongest fear acquisition and highest fear expression compared to groups without multiple hits. Extinction did not differ across groups. Endorsing a deployment TBI was associated with higher anxiety to the fear cue compared to those without deployment TBI. The association of deployment TBI with increased postdeployment PTSD symptoms was mediated by postdeployment fear expression when recent prior-TBI exposure was included as a moderator. TBI associations with increased response to threat cues and PTSD symptoms remained when controlling for deployment trauma and postdeployment PTSD diagnosis.Conclusions: Deployment TBI, and multiple-hit TBI in particular, are associated with increases in conditioned fear learning and expression that may contribute to risk for developing PTSD symptoms.

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Section: Discussionmentioning

confidence: 99%

Fear learning alterations after traumatic brain injury and their role in development of posttraumatic stress symptoms

et al. 2017

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“…In general, to model pediatric TBI, rodents 11–21 days of age (post-natal day [PND] 11–21) have been used to model the injury response in humans ranging from a term infant (using PND 7–11) to a toddler (using PND 17–21) [4–17]. This contrasts work in the area of neonatal brain injury where PND 7 rats are generally studied, predominantly using the Rice-Vanucci model of hypoxic-ischemic injury.…”

Section: Unique Facets Of the Developing Brain—relevance To Pediatricmentioning

confidence: 99%

“…The most commonly used models to produce mTBI or repetitive mTBI in pediatric applications have been variants of the CCI model using a closed head approach [15, 17, 32, 33, 68]. In these studies PND 11 rats have been used to model AHT, PND 18 rats to model toddlers, and PND 35 have been used to model sports concussion in adolescent athletes.…”

Section: Mild Tbi and Repetitive Tbimentioning

confidence: 99%

Pre-clinical models in pediatric traumatic brain injury—challenges and lessons learned

et al. 2017

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PURPOSE Despite the enormity of the problem and the lack of new therapies, research in the pre-clinical arena specifically using pediatric traumatic brain injury (TBI) models is limited. In this review, some of the key models addressing both the age spectrum of pediatric TBI and its unique injury mechanisms will be highlighted. Four topics will be addressed, namely, 1) unique facets of the developing brain important to TBI model development, 2) a description of some of the most commonly used pre-clinical models of severe pediatric TBI including work in both rodents and large animals, 3) a description of the pediatric models of mild TBI and repetitive mild TBI that are relatively new, and finally 4) a discussion of challenges, gaps and potential future directions to further advance work in pediatric TBI models. METHODS This narrative review on the topic of pediatric TBI models was based on review of PUBMED/Medline along with a synthesis of information on key factors in pre-clinical and clinical developmental brain injury that influence TBI modeling. RESULTS In the contemporary literature, six types of models have been used in rats including weight drop, fluid percussion injury (FPI), impact acceleration, controlled cortical impact (CCI), mechanical shaking, and closed head modifications of CCI. In mice, studies are largely restricted to CCI. In large animals, FPI and rotational injury have been used in piglets and shake injury has also been used in lambs. Most of the studies have been in severe injury models, although more recently studies have begun to explore mild and repetitive mild injuries to study concussion. CONCLUSIONS Given the emerging importance of TBI in infants and children, the morbidity and mortality that is produced, along with its purported link to the development of chronic neurodegenerative diseases, studies in these models merit greater systematic investigations along with consortium type approaches and long-term follow-up to translate new therapies to the bedside.

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“…By contrast, pre-clinical studies of TBI and anxiety-like behaviors have generally treated the injured population as a homogenous group, and compared the aggregate physiological and molecular sequelae in injured animals against those in control animals that experience sham surgery. These studies report a wide range of (conflicting) effects: from (i) a decrease in anxiety-like behaviors following a controlled cortical impact injury (Washington et al, 2012) and weight-drop injury (Pandey et al, 2009) at 20 to 30 days post-TBI, to (ii) an increase in anxiety-like behaviors following weight-drop (Meyer et al, 2012), lateral fluid percussion (Johnstone et al, 2015), and blast overpressure (Awwad et al, 2015), up to 3 months after later, as well as (iii) no change in anxiety-like behaviors in animals exposed to controlled cortical impact injury (CCI) (Sierra-Mercado et al, 2015), repeated weight-drop (Fidan et al, 2016) and lateral fluid percussion injury (Ferreira et al, 2014), up to 3 months after injury. Indeed, even when the injury model is fixed, the specific behavioral assay used to measure anxiety, the metric used to quantify it, as well as the time points of measurement, can all play a role in the results regarding anxiety outcomes following injury (Popovitz et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Neural markers of vulnerability to anxiety outcomes following traumatic brain injury

Popovitz

Mysore

Adwanikar³

2020

Preprint

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11Anxiety outcomes following traumatic brain injury (TBI) are complex, and the underlying neural 12 mechanisms are poorly understood. Here, we developed a multidimensional behavioral profiling 13 approach to investigate anxiety-like outcomes in mice that takes into account individual variability. 14 Departing from the tradition of comparing outcomes in TBI versus sham groups, we identified animals 15 within the TBI group that are vulnerable to anxiety dysfunction by applying dimensionality reduction, 16 clustering and post-hoc validation to behavioral data obtained from multiple assays for anxiety at 17 several post-injury timepoints. These vulnerable animals expressed distinct molecular profiles in the 18 corticolimbic network, with downregulation in GABA and glutamate, and upregulation in NPY 19 markers. Indeed, among vulnerable animals, not resilient or sham controls, severity of anxiety 20 outcomes correlated strongly with expression of molecular markers. Our results establish a 21 foundational approach, with predictive power, for reliably identifying maladaptive anxiety outcomes 22 following TBI and uncovering neural signatures of vulnerability to anxiety.23 24 101 sections (Methods).102 103 Figure 1. Multidimensional behavioral clustering with validation (MBCV) for identifying animals 104 vulnerable to anxiety after TBI 105 (A) Experimental timeline and protocol for measuring anxiety-like behaviors before and after injury. EZM 106 -elevated zero maze; OFT -open field test; EPM -elevated zero maze; all standard assays for 107 5 measuring anxiety-like behaviors in rodents. CCI -Controlled cortical impact injury model. IHC -108 immunohistochemistry. 109 (B) Anxiety behavioral 'profile' of a mouse: A 11-dimensional vector which combines behavioral data on 110 the EZM, OFT and EPM across time points. Each element in the vector is the proportion of time spent by 111 the mouse in the anxiogenic zones of one of the assays (ex. EZM) at one of the post-injury time points 112 (ex. Week 7), normalized to the animal's pre-injury baseline value in that assay (Methods). 113(C) Multidimensional behavioral clustering with validation approach: Behavioral profiles of mice exposed 114 TBI are first subject to principal components analysis (PCA), and then to k-means clustering (with k=2) to 115 identify two clusters in principal component (PC) space. The final validation step determines (i) whether 116 animals in the two clusters exhibit distinct anxiety phenotypes after TBI, and if so, (ii) whether (and 117 which) cluster consists of animals vulnerable to anxiety outcomes after TBI. This involves plotting and 118 comparing between the clusters, anxiety metrics from each assay. 120We asked if, based on their multidimensional anxiety behavioral profiles, mice that underwent TBI could 121 be separated into two distinct groups such that one exhibited severe affective behavioral consequences 122 of injury, and the other was largely resistant to effects of injury. To address this question, we developed 123 a data-driven approach. W...

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Repetitive Mild Traumatic Brain Injury in the Developing Brain: Effects on Long-Term Functional Outcome and Neuropathology

Cited by 59 publications

References 90 publications

Fear learning alterations after traumatic brain injury and their role in development of posttraumatic stress symptoms

Fear learning alterations after traumatic brain injury and their role in development of posttraumatic stress symptoms

Pre-clinical models in pediatric traumatic brain injury—challenges and lessons learned

Neural markers of vulnerability to anxiety outcomes following traumatic brain injury

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