Metabolic and Structural Imaging at 7 Tesla After Repetitive Mild Traumatic Brain Injury in Immature Rats

Abstract

Mild traumatic brain injury (mTBI) in children is a common and serious public health problem. Traditional neuroimaging findings in children who sustain mTBI are often normal, putting them at risk for repeated mTBI (rmTBI). There is a need for more sensitive imaging techniques capable of detecting subtle neurophysiological alterations after injury. We examined neurochemical and white matter changes using diffusion tensor imaging of the whole brain and proton magnetic resonance spectroscopy of the hippocampi at 7 Tesla in 18-day-old male rats at 7 days after mTBI and rmTBI. Traumatic axonal injury was assessed by beta-amyloid precursor protein accumulation using immunohistochemistry. A significant decrease in fractional anisotropy and increase in axial and radial diffusivity were observed in several brain regions, especially in white matter regions, after a single mTBI versus sham and more prominently after rmTBI. In addition, we observed accumulation of beta-amyloid precursor protein in the external capsule after mTBI and rmTBI. mTBI and rmTBI reduced the N-acetylaspartate/creatine ratio (NAA/Cr) and increased the myoinositol/creatine ratio (Ins/Cr) versus sham. rmTBI exacerbated the reduction in NAA/Cr versus mTBI. The choline/creatine (Cho/Cr) and (lipid/Macro Molecule 1)/creatine (Lip/Cr) ratios were also decreased after rmTBI versus sham. Diffusion tensor imaging findings along with the decrease in Cho and Lip after rmTBI may reflect damage to axonal membrane. NAA and Ins are altered at 7 days after mTBI and rmTBI likely reflecting neuro-axonal damage and glial response, respectively. These findings may be relevant to understanding the extent of disability following mTBI and rmTBI in the immature brain and may identify possible therapeutic targets.

Diffusion Tensor Imaging-Based Studies at the Group-Level Applied to Animal Models of Neurodegenerative Diseases

“…In a similar repeated-hit model, DTI has revealed disruption of axonal integrity in multiple white matter structures, irrespective of microhemorrhage detection (Robinson et al, 2017 ); substantial white matter damage was detected by DTI, together with histological approaches, in juvenile mice subject to repeated mild TBI (Yu et al, 2017 ; Lee et al, 2018 ). Similar alterations have been detected in rat models of repeated TBI (Calabrese et al, 2014 ; Singh et al, 2016 ; Wright et al, 2016 ; Qin et al, 2018 ; Kao et al, 2019 ) as well as in juvenile rat (Fidan et al, 2018 ; Wortman et al, 2018 ; Wright et al, 2018 ) or mouse (Rodriguez-Grande et al, 2018 ; Clément et al, 2020 ) cohorts subject to TBI. A few studies have applied ex-vivo DTI to obtain high-resolution maps of axonal disruption upon TBI, both in mouse (Weiss et al, 2020 ) and in rat (Donovan et al, 2014 ; Laitinen et al, 2015 ) models of brain trauma.…”

Neuroradiological Changes Following Single or Repetitive Mild TBI

“…Comparing three hits to one hit showed a similar pattern of change underscoring a dose effect of repeated head injury on the brainstem and cerebellum. The decrease in FA values in white matter tracts following head injury is well established in the clinical literature (Shenton et al, 2012) and again reported by Wright et al (2017) in rmTBI using the momentum exchange model and most recently by Fidan et al (2018) in a closed head cortical impact model. The resulting putative changes to gray matter microarchitecture show a distinct separation between forebrain and hindbrain (see 3D sagittal representation in Figure 2).…”

“…Wright et al (2017) clearly showed sex differences in behavior, imaging, and molecular markers in 30–38-day adolescent rats following rmTBI with momentum exchange. RmTBI using control cortical impact on immature 18-day male mice causes changes in white matter FA values and neurochemistry (Fidan et al, 2018). Would the neuroradiological data presented here be different between males and females and dependent upon age of injury?…”

Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats

“…The rotational and linear biomechanical forces that produce mTBI typically result in diffuse damage to white matter throughout the brain as axons are particularly sensitive to stretching induced injury ( Bigler, 2001 ; Buki and Povlishock, 2006 ; Fidan et al , 2018 ). A secondary consequence of mTBI in the initiation of neurometabolic cascades whereby cytokines are upregulated, there are changes in the subunits of N-methyl-D-aspartate receptors, broad and non-specific glutamate release, efflux of potassium ions and influxes of calcium and sodium, which causes the over-activation of ATP-dependent membrane pumps to restore ionic concentrations ( Giza and Hovda, 2014 ; Sun et al , 2019 ).…”