Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

‘Concussion’ is not a true diagnosis

In current usage, ‘concussion’ describes a clinical presentation, but does not identify the underlying pathological process and therefore cannot be considered a true diagnosis. However, mounting evidence indicates diffuse axonal injury as a likely pathological substrate for concussion, thereby providing a framework to develop true diagnostic criteria

Are mild head injuries as mild as we think? Neurobehavioral concomitants of chronic post-concussion syndrome

BACKGROUND: Mild traumatic brain injury (MTBI) can sometimes lead to persistent postconcussion symptoms. One well accepted hypothesis claims that chronic PCS has a neural origin, and is related to neurobehavioral deficits. But the evidence is not conclusive. In the attempt to characterise chronic MTBI consequences, the present experiment used a group comparison design, which contrasted persons (a) with MTBI and PCS, (b) MTBI without PCS, and (c) matched controls. We predicted that participants who have experienced MTBI but show no signs of PCS would perform similar to controls. At the same time, a subgroup of MTBI participants would show PCS symptoms and only these volunteers would have poorer cognitive performance. Thereby, the performance deficits should be most noticeable in participants with highest PCS severity. METHOD: 38 patients with a single MTBI that had occurred at least 12 month prior to testing, and 38 matched controls, participated in the experiment. A combination of questionnaires and neuropsychological test batteries were used to assess the extent of PCS and related deficits in neurobehavioral performance. RESULTS: 11 out of 38 MTBI participants (29%) were found to suffer from PCS. This subgroup of MTBI patients performed poorly on neuropsychological test batteries. Thereby, a correlation was found between PCS symptom severity and test performance suggesting that participants with more pronounced PCS symptoms performed worse in cognitive tasks. In contrast, MTBI patients with no PCS showed performed similar to matched control. We further found that loss of consciousness, a key criterion for PCS diagnosis, was not predictive of sustained PCS. CONCLUSION: The results support the idea that MTBI can have sustained consequences, and that the subjectively experienced symptoms and difficulties in everyday situations are related to objectively measurable parameters in neurocognitive function

Evaluation of brain damage resulting from penetrating and non-penetrating captive bolt stunning using lambs

ObjectiveTo compare the brain damage in sheep resulting from penetrating and non-penetrating captive bolt stunning.DesignThe unrestrained heads of anaesthetised lambs were impacted in the temporal region with penetrating and non-penetrating captive bolt pistols (humane stunners) using a constant charge. Two hours after head impact, brains were perfusion-fixed with 4% paraformaldehyde. Coronal sections were stained with haematoxylin and eosin and immunohistochemically for amyloid precursor protein, a sensitive marker of axonal and neuronal reaction in brains after trauma. Pathological changes in these brains were then quantified by morphometric analysis.ResultsThe skull was fractured in 50% of lambs after a non-penetrating head impact and in all animals after a penetrating head wound. Impact contusions were present in 80% of lambs receiving a non-penetrating head injury and in all of those with a penetrating wound. Total contusion area was similar in both groups. Amyloid precursor protein-positive axons and neurons, and haemorrhage, were widely distributed in the brain after both head impact types, but there was no statistically significant difference between the two groups. Multifocal necrosis of the cerebellar granular layer was found in all lambs with non-penetrating head injury, but in none with a penetrating injury.ConclusionsThe structural brain damage, a mixture of focal and diffuse injury, produced by penetrating and non-penetrating captive bolt pistols was overall similar and of sufficient severity to suggest that both types of weapon are acceptable for euthanasia

Brain damage in pigs produced by impact with a non-penetrating captive bolt pistol

ObjectiveTo assess the effect of impact with a nonpenetrating captive bolt pistol in pigs by studying the resulting traumatic brain injury (TBI) and to compare the pathological changes with those found previously in the brains of sheep using a similar experimental paradigm.ProcedureThe unrestrained heads of six, anaesthetised, 7- to 8-week-old, Large White pigs were impacted in the temporal region with a nonpenetrating captive bolt pistol. Four hours postimpact, brains were perfusion-fixed with 4% paraformaldehyde. Coronal sections from six levels along the brain were cut and stained with haematoxylin and eosin and immunohistochemically for amyloid precursor protein, a sensitive marker of axonal injury (AI) in the brain after trauma.ResultsTBI in pigs was characterised only by very mild AI, whereas AI in sheep after captive bolt impact to the same head region was much more severe and widely distributed and often associated with vascular damage such as contusions, subarachnoid and intraparenchymal haemorrhage.ConclusionsTBI in pigs was much less severe than in sheep after non-penetrating mechanical impact of similar magnitude, confirming the importance of interspecies differences in determining an appropriate physical method of euthanasia