Mild traumatic brain injury (mTBI) includes concussion, sub-concussion, and most exposures to explosive blast from improvised explosive devices. mTBI is the most common traumatic brain injury affecting military personnel; however, it is the most difficult to diagnose and the least well understood. It is also recognized that some mTBIs have persistent, and sometimes progressive, long-term debilitating effects. Increasing evidence suggests that a single traumatic brain injury can produce long-term gray and white matter atrophy, precipitate or accelerate age-related neurodegeneration, and increase the risk of developing Alzheimer’s disease, Parkinson’s disease, and motor neuron disease. In addition, repetitive mTBIs can provoke the development of a tauopathy, chronic traumatic encephalopathy. We found early changes of chronic traumatic encephalopathy in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed. Four of the five veterans with early-stage chronic traumatic encephalopathy were also diagnosed with posttraumatic stress disorder. Advanced chronic traumatic encephalopathy has been found in veterans who experienced repetitive neurotrauma while in service and in others who were accomplished athletes. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus; septal abnormalities; and abnormal deposits of hyperphosphorylated tau as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy has clinical and pathological features that overlap with post concussion syndrome and post traumatic stress disorder, suggesting that the three disorders might share some biological underpinnings.

1. Introduction

In military settings, most traumatic brain injuries (TBIs) are mild TBIs (mTBIs). For U.S. forces deployed to Afghanistan and Iraq in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND), blast exposure is the leading cause of mTBI, although service members are also susceptible to concussions [1]. Estimates of the prevalence of mTBI among returning service members range from 15.2% to 22.8%, affecting as many as 320,000 troops [1–4]. Despite their frequency, the acute and long-term effects of mTBI have been a relatively unexplored area of medical inquiry until very recently. Undoubtedly, the “invisible” nature of mTBI, notably the lack of any external physical evidence of damage to the head or brain, has been a major factor contributing to the impression of inconsequentiality. However, there is accumulating evidence that some individuals develop persistent cognitive and behavioral changes after mild neurotrauma. In addition, the relative contributions of physical injury or psychic stress to chronic sequelae after mTBI remain a matter of debate– a discussion that began during World War I regarding the basis for “shell shock,” and that continues today concerning the relative contributions of posttraumatic stress disorder (PTSD) and physical brain injury to persistent symptoms after mTBI.

The first large-scale evidence of military-related mTBI occurred in World War I (1914–1918) in association with the frequent use of high explosives in trench warfare. Service members who experienced high doses of explosive artillery fire sometimes developed shell shock or “commotio cerebri,” a mysterious condition characterized by headache, amnesia, inability to concentrate, difficulty sleeping, depression, and suicidality [5–7]. At the time, it was unclear whether shell shock was a maladaptive, psychiatric condition related to the stresses of combat or whether the condition was caused by physical injury to the brain. Despite the lack of any pathological studies on the brains of individuals diagnosed with shell shock, wartime committees entreated with the responsibility to inquire into the entity declared the disorder to have psychiatric origins [7].

Shortly thereafter, Harrison Martland, a New Jersey pathologist, drew attention to a symptom complex that affected professional boxers, “Punch Drunk,” a condition well known to boxing enthusiasts that appeared to result from repeated sublethal blows to the head [8]. Martland described unsteadiness of gait, mental confusion, and slowing of muscular movements occasionally combined with hesitancy in speech, tremors of the hands, and nodding of the head. Later, Winterstein summarized the psychiatric manifestations of approximately 50 professional boxers and noted impairment of intelligence, mental dullness, difficulty concentrating, paranoia, and garrulousness [9]. Johnson later added memory loss, dementia, rage reactions, and morbid jealousy to the clinical syndrome [10]. In the scattered, small case series of “dementia pugilistica” reported over the next half century, the condition was variously referred to as “traumatic progressive encephalopathy” and later as “chronic traumatic encephalopathy” (CTE) to highlight the chronic and progressive nature of the disorder [11,12]. In 1973, Corsellis, Bruton, and Freeman-Browne detailed the neuropathological findings found in the brains of 15 retired boxers and correlated the pathological findings with retrospective clinical symptoms [13]. The authors noted gross neuropatho-logical changes of cerebral atrophy, enlargement of the lateral and third ventricles, thinning of the corpus callosum, cavum septum pellucidum with fenestrations, and cerebellar scarring. General cell stains and Von Braunm€uhl’s silver stain were used to demonstrate neuronal loss in the cerebellar tonsils and substantia nigra, neurofibrillary degeneration of the substantia nigra and cerebral cortex, and senile plaques in approximately one quarter of the cases. The authors speculated that pathology in the limbic structures (such as the hippocampus, medial temporal lobe, and fornix) was responsible for impairments in learning and memory, that pathology in the substantia nigra accounted for the Parkinsonian features, and that pathology in the septal cortex for the abnormal rage reactions.

1.2. Chronic effects of TBI