Volume 44, Number 7, 2007 JRRDJRRD Pages 951–962 Journal of Rehabilitation Research & Development A neuropsychiatric perspective on traumatic brain injury Warren E. Lux, MD Office of the Science Advisor, U.S. Environmental Protection Agency, Washington, DC; Center for Clinical Bioethics, Georgetown University, Washington, DC Abstract—Traumatic brain injury (TBI) due to closed mecha- medicine. In the past 25 years, however, as acute man- nisms causes strain injuries to axons that increase in number agement of both surgical and nonsurgical TBI has and severity as injury severity increases. Axons that project up improved, impaired survivors have become increasingly from the brain stem are vulnerable, even in milder concussive common. And although these survivors face many differ- injuries, and include axons that participate in key monoaminergic ent clinical issues, from epilepsy to motor problems to pathways. Although called diffuse axonal injury, the supra- endocrine disorders, the TBI sequelae that affect their tentorial injury component typically shows an anterior prepon- lives most profoundly are the chronic cognitive and derance in humans. As the injury forces increase, cerebral contusions may be superimposed on the axonal strain injuries, behavioral problems that fall squarely within the domain and these contusions show an anterior preponderance as well. of neuropsychiatry, a discipline that focuses on the rela- The chronic neuropsychiatric manifestations of TBI reflect this tionship between the brain and its role in thinking, emo- injury distribution. In the cognitive sphere, these manifesta- tions, and behavior. Indeed, the paradigmatic historical tions almost always include power function disturbances patient for many of the core issues that now define neu- marked by difficulties with cognitive processing speed, multi- ropsychiatry was a young man from 19th century Ver- tasking, and cognitive endurance. These disturbances may then mont who survived a severe TBI. be followed by disturbances in executive function and self- During the summer of 1848, a 25-year-old railroad awareness as injury severity increases. In the behavioral construction foreman named Phineas Gage was directing sphere, mood disturbances and disorders of behavioral control a blasting operation to clear a path for laying new track and regulation are particularly common. across Vermont for the Rutland & Burlington Railroad. The operation went terribly awry, with the result that a pointed iron rod 3ft. 7 in. in length, 1 1/4in. in diameter, Key words: behavior, cognition, depression, diffuse axonal and 13 1/4 lb in weight was propelled through Gage’s injury, executive function, frontal lobes, mood, neuropsychia- try, rehabilitation, self-awareness, traumatic brain injury. face and head by an errant explosion. The rod entered INTRODUCTION Abbreviations: CT = computed tomography, DAI = diffuse axonal injury, MRI = magnetic resonance imaging, TBI = trau- Seen through the lens of the acute injury and its man- matic brain injury. agement, traumatic brain injury (TBI) would appear at Address all correspondence to Warren E. Lux, MD; U.S. first glance to be far removed from the concerns of what Environmental Protection Agency, 1200 Pennsylvania Ave, could properly be called neuropsychiatry. Rather, it might NW, Mail Code 8105R, Washington, DC 20460; 202-564- seem to be more a neurosurgical disorder or perhaps par- 3746; fax: 202-564-2070. Email: [email protected] ticularly relevant to conventional neurology or sports DOI: 10.1682/JRRD.2007.01.0009 951 952 JRRD, Volume 44, Number 7, 2007 through his left cheek, continued up and through the base syndromes that develop provide a window into the brain of his skull, traversed the anterior portions of his brain, that is compellingly illuminating, if still incomplete. and exited through the frontal bone at the top of his head. Remarkably, Gage survived both the wound and the sub- sequent infection with little in the way of adverse effects PATHOPHYSIOLOGY OF TRAUMATIC BRAIN on his motor function, perception (save for the loss of his INJURY left eye), or intellect. Yet, as described in detail by Dama- sio on the basis of firsthand reports, Gage was an entirely When the head is accelerated and decelerated different person after his physical recovery than he had abruptly in space, particularly when accompanied by a been before [1]. Whereas previously he had been temper- torsional head movement, strain forces are applied to ate, efficient, and capable, after the event he demon- nerve fibers (axons) throughout the brain [3–4]. The strated aberrant social judgment, was unable to regulate resulting axonal strain injuries, collectively referred to as his behavior normally, and could no longer use his vari- diffuse axonal injury (DAI), represent the primary funda- ous physical and intellectual strengths appropriately or mental neuropathological change seen in TBI due to effectively in the real world. closed mechanisms regardless of injury severity, although However, while the relevance of Gage’s disorder to the amount of DAI increases as injury severity increases the newly emerging field of neuropsychiatry was becom- [5]. Strictly speaking, if the head moves abruptly enough, ing evident, traumatic patients of that sort were uncom- as in whiplash injuries, it need not strike or be struck by mon. Today, by contrast, TBI is one of the largest public another object for acceleration-deceleration phenomena health problems for children and young adults in the sufficient to cause an axonal strain injury within the brain United States [2]. Consequently, no modern broad-based to occur [3], and clinicians who work with TBI are famil- review of neuropsychiatry can be complete without iar with cases, usually mild, in which no head impact is addressing the problem of TBI. Yet, paradigmatic as his involved. However, blunt-force trauma produces a partic- case was, Gage’s injury differed from the most common ularly abrupt acceleration-deceleration and is, therefore, injuries of today in one important respect: it was a pene- commonly a factor in these injuries. The most severe trating injury. In penetrating injuries, of course, the injuries tend to be caused by high-speed head impacts region of the brain penetrated puts its particular stamp on against immovable objects as in falls from height and the nature of the chronic cognitive and behavioral motor vehicle accidents, in which victims either strike the sequelae that develop. Today’s injuries, by contrast, are windshield or are ejected from the vehicle [5]. predominantly closed. Gage just happened to injure an Once an axonal strain injury occurs, by whatever area of the brain that is particularly vulnerable to the mechanism, a number of consequences may ensue. First, effects of closed injury and so his is a dramatic, if fortu- axons may be torn apart completely, a phenomenon itous, exemplary case. But other vulnerabilities exist in known as axotomy. These irreversible axonal shearing closed injuries that need to be accounted for in expanding injuries may include gross ones that are immediately vis- our understanding of TBI beyond that provided by ible on neuroimaging studies. Delayed axotomy second- Gage’s injury, instructive as his case has been. A major ary to evolving pathological processes set off by the purpose of this article is the dissection of those vulnera- initial injury has also been well-demonstrated experimen- bilities and the placement of them in the context of the tally [6]. In addition, however, axons may clearly be neuropsychiatric insights derived from Phineas Gage’s case. damaged at a level that does not cause axotomy, although For several reasons then, I will focus on closed inju- the axonal injury may cause alteration of electrophysio- ries in this article. First, they represent a major public logical function [4]. That such damage may be reversible health problem, as has already been pointed out, and is consistent with clinical observations of improvement understanding them provides clinicians with an important after TBI and complete symptomatic recovery in many tool in addressing their neurocognitive and neurobehav- cases of mild TBI. Moreover, other aspects of neuronal ioral consequences. More than that, however, I believe physiology may be altered as well, theoretically either that knowledge of these injuries, their anatomic distribu- reversibly or irreversibly. Levels of chemical neurotrans- tion, their probable neurochemical consequences, and the mitters contained in axons, for example, might be vulner- relationship of their neurobiology to the neuropsychiatric able to such alteration. One such class of agents is the 953 LUX. Neuropsychiatry of TBI monoaminergic neurotransmitters, and several studies are increasingly seen, again with an anterior preponder- suggest that they are indeed affected, both acutely and ance. The undersurfaces of the frontal lobes may also be chronically [7–11]. Although the nature and distribution abraded as they slide over the rough orbital surface of the of the monoaminergic dysfunction following TBI frontal fossa. In addition, very diffuse secondary injuries remains to be more fully characterized, a number of clin- can evolve and make their effects felt throughout the ical syndromes in which these chemical neurotransmit- brain, including at sites far removed from the primary ters have been implicated are common after TBI and will injury [15]. Nonetheless, in most patients, the broad pat- be discussed here. tern determined by the