Visualization of thalamic calcium influx with quantitative susceptibility mapping as a potential imaging biomarker for repeated mild traumatic brain injury.

A key event in the pathophysiology of traumatic brain injury (TBI) is the influx of substantial amounts of Ca2+ into neurons, particularly in the thalamus. Detection of this calcium influx in vivo would provide a window into the biochemical mechanisms of TBI with potentially significant clinical implications. In the present work, our central hypothesis was that the Ca2+ influx could be imaged in vivo with the relatively recent MRI technique of quantitative susceptibility mapping (QSM). Wistar rats were divided into five groups: naive controls, sham-operated experimental controls, single mild TBI, repeated mild TBI, and single severe TBI. We employed the lateral fluid percussion injury (FPI) model, which replicates clinical TBI without skull fracture, performed 9.4 Tesla MRI with a 3D multi-echo gradient-echo sequence at weeks 1 and 4 post-injury, computed susceptibility maps using V-SHARP and the QUASAR-HEIDI technique, and performed histology. Sham, experimental controls animals, and injured animals did not demonstrate calcifications at 1 week after the injury. At week 4, calcifications were found in the ipsilateral thalamus of 25-50% of animals after a single TBI and 83% of animals after repeated mild TBI. The location and appearance of calcifications on stained sections was consistent with the appearance on the in vivo susceptibility maps (correlation of volumes: r = 0.7). Our findings suggest that persistent calcium deposits represent a primary pathology of repeated injury and that FPI-QSM has the potential to become a sensitive tool for studying pathophysiology related to mild TBI in vivo.

Circulating microRNAs as biomarkers in traumatic brain injury.

Preclinical and clinical studies can be greatly improved through the inclusion of diagnostic, prognostic, predictive or pharmacodynamics biomarkers. Circulating microRNAs (miRNAs) represent highly stable targets that respond to physiological and pathological changes. MicroRNA biomarkers can be detected by highly sensitive and absolutely quantitative methods currently available in most clinical laboratories. Here we review preclinical and clinical studies that have examined circulating miRNAs as potential diagnostic and prognostic biomarkers. We also present data that suggests pharmacodynamics biomarkers can be identified that are associated with neuroprotection in general. Although circulating miRNA can serve as useful tools, it is clear their expression profiles are highly sensitive to changing conditions and are influenced by a broad range of parameters including age, sex, body mass index, injury severity, time of collection, as well as methods of processing, purification and detection. Thus, considerable effort will be required to standardize methods and experimental design conditions before circulating miRNAs can prove useful in a heterologous injury like TBI. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

Convulsive seizures and EEG spikes after lateral fluid-percussion injury in the rat.

The rat lateral fluid-percussion injury (FPI) model has been used extensively to study post-traumatic epilepsy (PTE). Epidemiological studies have reported that the risk of PTE is higher after more severe injury. Adult, male Wistar rats subjected to different atmospheric pressures of injury during FPI showed great variability in injury severity when functional behavior was determined based on the Neurological Severity Score (NSS) assessment. When NSS was used to select rats with the most severe FPI-induced brain injury, 63% of rats experienced at least one convulsive seizure 2-5 weeks after FPI. This same cohort of rats (i.e., selected for severe TBI based on NSS) were significantly more susceptible to PTZ-induced seizures compared to sham controls. Video/EEG recordings from a second cohort of rats with severe FPI-induced injury (based on NSS) showed a similar incidence and frequency of spike wave discharges between rats with severe TBI and sham controls. However, the rate of isolated EEG spikes was greater in rats with severe FPI-induced injury compared to sham controls. These data suggest that convulsive seizures can be obtained in FPI-treated rats when NSS is used as an inclusion criterion to select rats with severe injury. Furthermore, although spike-wave discharges were equally prevalent in rats with severe FPI and sham controls, spontaneous spikes were more prevalent in the rats with severe FPI.

Administration of low dose methamphetamine 12 h after a severe traumatic brain injury prevents neurological dysfunction and cognitive impairment in rats.

We recently published data that showed low dose of methamphetamine is neuroprotective when delivered 3 h after a severe traumatic brain injury (TBI). In the current study, we further characterized the neuroprotective potential of methamphetamine by determining the lowest effective dose, maximum therapeutic window, pharmacokinetic profile and gene expression changes associated with treatment. Graded doses of methamphetamine were administered to rats beginning 8 h after severe TBI. We assessed neuroprotection based on neurological severity scores, foot fault assessments, cognitive performance in the Morris water maze, and histopathology. We defined 0.250 mg/kg/h as the lowest effective dose and treatment at 12 h as the therapeutic window following severe TBI. We examined gene expression changes following TBI and methamphetamine treatment to further define the potential molecular mechanisms of neuroprotection and determined that methamphetamine significantly reduced the expression of key pro-inflammatory signals. Pharmacokinetic analysis revealed that a 24-hour intravenous infusion of methamphetamine at a dose of 0.500 mg/kg/h produced a plasma Cmax value of 25.9 ng/ml and a total exposure of 544 ng/ml over a 32 hour time frame. This represents almost half the 24-hour total exposure predicted for a daily oral dose of 25mg in a 70 kg adult human. Thus, we have demonstrated that methamphetamine is neuroprotective when delivered up to 12 h after injury at doses that are compatible with current FDA approved levels.