Structural brain connectivity predicts acute pain after mild traumatic brain injury

Mild traumatic brain injury, mTBI, is a leading cause of disability worldwide, with acute pain manifesting as one of its most debilitating symptoms. Understanding acute post-injury pain is important since it is a strong predictor of long-term outcomes. In this study, we imaged the brains of 172 patients with mTBI, following a motorized vehicle collision and used a machine learning approach to extract white matter structural and resting state fMRI functional connectivity measures to predict acute pain. Stronger white matter tracts within the sensorimotor, thalamic-cortical, and default-mode systems predicted 20% of the variance in pain severity within 72 hours of the injury. This result generalized in two independent groups: 39 mTBI patients and 13 mTBI patients without whiplash symptoms. White matter measures collected at 6-months after the collision still predicted mTBI pain at that timepoint (n = 36). These white-matter connections were associated with two nociceptive psychophysical outcomes tested at a remote body site – namely conditioned pain modulation and magnitude of suprathreshold pain–, and with pain sensitivity questionnaire scores. Our validated findings demonstrate a stable white-matter network, the properties of which determine a significant amount of pain experienced after acute injury, pinpointing a circuitry engaged in the transformation and amplification of nociceptive inputs to pain perception.

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Diffusion Tensor Imaging of the Evolving Response to Mild Traumatic Brain Injury in Rats

Journal of Experimental Neuroscience ◽

10.1177/1179069519858627 ◽

2019 ◽

Vol 13 ◽

pp. 117906951985862 ◽

Cited By ~ 5

Author(s):

Wouter S Hoogenboom ◽

Todd G Rubin ◽

Kenny Ye ◽

Min-Hui Cui ◽

Kelsey C Branch ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Diffusion Tensor Imaging ◽

Brain Injury ◽

White Matter ◽

Mild Traumatic Brain Injury ◽

Diffusion Tensor ◽

Axonal Injury ◽

Mean Diffusivity ◽

Multiple Time ◽

Post Injury

Mild traumatic brain injury (mTBI), also known as concussion, is a serious public health challenge. Although most patients recover, a substantial minority suffers chronic disability. The mechanisms underlying mTBI-related detrimental effects remain poorly understood. Although animal models contribute valuable preclinical information and improve our understanding of the underlying mechanisms following mTBI, only few studies have used diffusion tensor imaging (DTI) to study the evolution of axonal injury following mTBI in rodents. It is known that DTI shows changes after human concussion and the role of delineating imaging findings in animals is therefore to facilitate understanding of related mechanisms. In this work, we used a rodent model of mTBI to investigate longitudinal indices of axonal injury. We present the results of 45 animals that received magnetic resonance imaging (MRI) at multiple time points over a 2-week period following concussive or sham injury yielding 109 serial observations. Overall, the evolution of DTI metrics following concussive or sham injury differed by group. Diffusion tensor imaging changes within the white matter were most noticeable 1 week following injury and returned to baseline values after 2 weeks. More specifically, we observed increased fractional anisotropy in combination with decreased radial diffusivity and mean diffusivity, in the absence of changes in axial diffusivity, within the white matter of the genu corpus callosum at 1 week post-injury. Our study shows that DTI can detect microstructural white matter changes in the absence of gross abnormalities as indicated by visual screening of anatomical MRI and hematoxylin and eosin (H&E)-stained sections in a clinically relevant animal model of mTBI. Whereas additional histopathologic characterization is required to better understand the neurobiological correlates of DTI measures, our findings highlight the evolving nature of the brain’s response to injury following concussion.

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Diverse Changes in Microglia Morphology and Axonal Pathology Over One Year after Mild Traumatic Brain Injury in Pigs

10.1101/2020.10.16.343103 ◽

2020 ◽

Author(s):

Michael R. Grovola ◽

Nicholas Paleologos ◽

Daniel P. Brown ◽

Nathan Tran ◽

Kathryn L. Wofford ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

White Matter ◽

Mild Traumatic Brain Injury ◽

Periventricular White Matter ◽

Post Injury ◽

Mild Tbi ◽

Time Points ◽

Axonal Pathology ◽

The Brain

AbstractOver 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long-term neurological dysfunction. The mechanical forces that occur due to TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1 year post injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1 year post injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.

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Minocycline plus N-acteylcysteine induces remyelination, synergistically protects oligodendrocytes and modifies neuroinflammation in a rat model of mild traumatic brain injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17718106 ◽

2017 ◽

Vol 38 (8) ◽

pp. 1312-1326 ◽

Cited By ~ 16

Author(s):

Margalit Haber ◽

Jessica James ◽

Justine Kim ◽

Michael Sangobowale ◽

Rachel Irizarry ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

White Matter ◽

Mild Traumatic Brain Injury ◽

Drug Combination ◽

Molecular Mechanisms ◽

Post Injury ◽

White Matter Damage ◽

Drug Treatments ◽

Approved Drugs

Mild traumatic brain injury afflicts over 2 million people annually and little can be done for the underlying injury. The Food and Drug Administration-approved drugs Minocycline plus N-acetylcysteine (MINO plus NAC) synergistically improved cognition and memory in a rat mild controlled cortical impact (mCCI) model of traumatic brain injury.3 The underlying cellular and molecular mechanisms of the drug combination are unknown. This study addressed the effect of the drug combination on white matter damage and neuroinflammation after mCCI. Brain tissue from mCCI rats given either sham-injury, saline, MINO alone, NAC alone, or MINO plus NAC was investigated via histology and qPCR at four time points (2, 4, 7, and 14 days post-injury) for markers of white matter damage and neuroinflammation. MINO plus NAC synergistically protected resident oligodendrocytes and decreased the number of oligodendrocyte precursor cells. Activation of microglia/macrophages (MP/MG) was synergistically increased in white matter two days post-injury after MINO plus NAC treatment. Patterns of M1 and M2 MP/MG were also altered after treatment. The modulation of neuroinflammation is a potential mechanism to promote remyelination and improve cognition and memory. These data also provide new and important insights into how drug treatments can induce repair after traumatic brain injury.

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Severity of Ongoing Post-Concussive Symptoms as a Predictor of Cognitive Performance Following a Pediatric Mild Traumatic Brain Injury

Journal of the International Neuropsychological Society ◽

10.1017/s1355617720001228 ◽

2020 ◽

pp. 1-11

Author(s):

Veronik Sicard ◽

Danielle C. Hergert ◽

Sharvani Pabbathi Reddy ◽

Cidney R. Robertson-Benta ◽

Andrew B. Dodd ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Performance ◽

Mild Traumatic Brain Injury ◽

Parental Education ◽

Visual Learning ◽

Learning Task ◽

Risk Scores ◽

Group Differences ◽

Post Injury

Abstract Objective: This study aimed to examine the predictors of cognitive performance in patients with pediatric mild traumatic brain injury (pmTBI) and to determine whether group differences in cognitive performance on a computerized test battery could be observed between pmTBI patients and healthy controls (HC) in the sub-acute (SA) and the early chronic (EC) phases of injury. Method: 203 pmTBI patients recruited from emergency settings and 159 age- and sex-matched HC aged 8–18 rated their ongoing post-concussive symptoms (PCS) on the Post-Concussion Symptom Inventory and completed the Cogstate brief battery in the SA (1–11 days) phase of injury. A subset (156 pmTBI patients; 144 HC) completed testing in the EC (∼4 months) phase. Results: Within the SA phase, a group difference was only observed for the visual learning task (One-Card Learning), with pmTBI patients being less accurate relative to HC. Follow-up analyses indicated higher ongoing PCS and higher 5P clinical risk scores were significant predictors of lower One-Card Learning accuracy within SA phase, while premorbid variables (estimates of intellectual functioning, parental education, and presence of learning disabilities or attention-deficit/hyperactivity disorder) were not. Conclusions: The absence of group differences at EC phase is supportive of cognitive recovery by 4 months post-injury. While the severity of ongoing PCS and the 5P score were better overall predictors of cognitive performance on the Cogstate at SA relative to premorbid variables, the full regression model explained only 4.1% of the variance, highlighting the need for future work on predictors of cognitive outcomes.

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Rapid EEG Activity during Sleep Dominates in Mild Traumatic Brain Injury Patients with Acute Pain

Journal of Neurotrauma ◽

10.1089/neu.2012.2519 ◽

2013 ◽

Vol 30 (8) ◽

pp. 633-641 ◽

Cited By ~ 49

Author(s):

Samar Khoury ◽

Florian Chouchou ◽

Florin Amzica ◽

Jean-François Giguère ◽

Ronald Denis ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Acute Pain ◽

Eeg Activity

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Language function in a child following mild traumatic brain injury: Evidence from pre- and post-injury language testing

Developmental Neurorehabilitation ◽

10.3109/17518423.2011.620576 ◽

2011 ◽

Vol 14 (6) ◽

pp. 348-354 ◽

Cited By ~ 3

Author(s):

Fiona M. Lewis ◽

Bruce E. Murdoch

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Language Testing ◽

Language Function ◽

Post Injury

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Longitudinal Volumetric Changes following Traumatic Brain Injury: A Tensor-Based Morphometry Study

Journal of the International Neuropsychological Society ◽

10.1017/s1355617712000835 ◽

2012 ◽

Vol 18 (6) ◽

pp. 1006-1018 ◽

Cited By ~ 55

Author(s):

Kimberly D.M. Farbota ◽

Aparna Sodhi ◽

Barbara B. Bendlin ◽

Donald G. McLaren ◽

Guofan Xu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

White Matter ◽

Degenerative Change ◽

Extended Period ◽

Spatiotemporal Pattern ◽

Volume Loss ◽

Post Injury ◽

Cognitive Changes ◽

Brain White Matter

AbstractAfter traumatic injury, the brain undergoes a prolonged period of degenerative change that is paradoxically accompanied by cognitive recovery. The spatiotemporal pattern of atrophy and the specific relationships of atrophy to cognitive changes are ill understood. The present study used tensor-based morphometry and neuropsychological testing to examine brain volume loss in 17 traumatic brain injury (TBI) patients and 13 controls over a 4-year period. Patients were scanned at 2 months, 1 year, and 4 years post-injury. High-dimensional warping procedures were used to create change maps of each subject's brain for each of the two intervals. TBI patients experienced volume loss in both cortical areas and white matter regions during the first interval. We also observed continuing volume loss in extensive regions of white matter during the second interval. Neuropsychological correlations indicated that cognitive tasks were associated with subsequent volume loss in task-relevant regions. The extensive volume loss in brain white matter observed well beyond the first year post-injury suggests that the injured brain remains malleable for an extended period, and the neuropsychological relationships suggest that this volume loss may be associated with subtle cognitive improvements. (JINS, 2012,18, 1–13)

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