Traumatic Brain Injury (TBI)

Traumatic brain injury is conventionally split into two phases. The primary injury is mechanical and instantaneous: contusion, axonal shearing from rotational acceleration, vascular tearing. The secondary injury develops over hours to days and is where treatment might plausibly act, comprising glutamate excitotoxicity and calcium overload, mitochondrial failure, oxidative damage, barrier breakdown, oedema with raised intracranial pressure, and a sustained microglial response. Severity is graded by the Glasgow Coma Scale: thirteen to fifteen mild, nine to twelve moderate, eight or below severe.

Preclinically it is reproduced by controlled cortical impact, fluid percussion, weight drop or blast exposure, each with a different mechanical signature. Clinically the trial record is dominated by negative results. A very large randomised trial of corticosteroids was stopped early because mortality was higher in the treated arm, overturning decades of practice. Progesterone, strongly supported by animal data, failed in two large phase 3 trials. On the diagnostic side, a blood test measuring glial fibrillary acidic protein and UCH-L1 was authorised in the United States in 2018 to help decide which mild injuries need a head CT.

The reason this field disappoints is heterogeneity. Traumatic brain injury is a mechanism of injury, not a disease, and it collects patients with different lesion types, ages and comorbidities into single trials, while each animal model reproduces one mechanism cleanly.

The specific error to guard against is attribution during spontaneous recovery. Most mild injuries resolve substantially within weeks without treatment, so anything taken during that window appears to work, and marketing for unapproved recovery peptides leans on that timing plus rodent histology from one impact model.