Neurobehavioral sequelae of traumatic brain injury: evaluation and management

Abstract

Traumatic brain injury (TBI) is a universal public health problem. A recent review of epidemiological studies in Europe suggests an incidence of 235 hospitalized cases (including fatalities) per 100,000 population 1. In the US, the incidence is estimated at 150 per 100,000 population 2. Less data is available from other regions of the world, but TBI is acknowledged as a significant problem worldwide. Of note is that the incidence rates are calculated from hospitalized cases only, and do not include injured individuals who do not seek or have access to care. Thus, the actual incidence of injury is probably 3 to 4 fold larger than the quoted numbers. Most studies suggest that the incidence rates for TBI are greatest in the second and third decades of life, with a secondary increase in the elderly stemming from falls 2,3. Males are more likely to suffer a TBI than females 2,3. In developed countries, there has been a reduction in the mortality rates associated with TBI over the last several decades, generally attributed to improved systems of trauma care and improved motor vehicle safety design. Many individuals with mild traumatic brain injury and virtually all individuals who survive moderate and severe TBI are left with significant long-term neurobehavioral sequelae 4–6. Thus, the reduction in TBI-associated mortality rates 7 has led to a significant increase in the number of individuals with long-term neurobehavioral disorders related to TBI 8,9. Brain trauma can be caused in a number of ways, including mechanisms which penetrate the substance of the brain (e.g., projectiles) and those that do not. This paper focuses on non-penetrating injuries. Despite different contexts and instruments, the physics and biomechanics underlying damage to the brain from non-penetrating injuries have some common features. This results in certain brain regions being at greater risk for damage than others and allows for some general statements to be made about typical profiles of brain injury associated with trauma. The assessment and treatment of the neurobehavioral sequelae of TBI follow logically from an understanding of this injury profile. There are two broad categories of forces that result in brain injury: contact (or impact) and inertial (acceleration or deceleration). Contact injuries result from the brain coming into contact with an object (which might include the skull, or some external object). Contact mechanisms often result in damage to scalp, skull, and brain surface (e.g., contusions, lacerations, hematomas) (10). Frequent sites of such injury are the anterior temporal poles, lateral and inferior temporal cortices, frontal poles, and orbital frontal cortices. Inertial injury results from rapid acceleration or deceleration of the brain that produces shear, tensile, and compression forces. These forces have maximum impact on axons and blood vessels, resulting in axonal injury, tissue tears, and intracerebral hematomas. These mechanisms also produce more widespread or diffuse injury (diffuse axonal injury) to white matter. Particular areas of vulnerability include the corpus callosum, the rostral brainstem, and subfrontal white matter 10. Many injuries result from a mixture of both forces, and injury from both occurs immediately (referred to as primary injury), and may also evolve over time (secondary injury). Secondary injury is caused by a variety of factors, such as hypoxia, edema, and elevated intracranial pressure. In addition, mechanical distortion of the neurons results in massive release of neurotransmitters, with subsequent triggering of excitotoxic injury cascades 11. Although this probably occurs throughout the brain, the excitotoxic cascades and other forms of secondary injury such as hypoxia/ischemia have a disproportionate effect on certain brain regions, such as the hippocampus, even in the context of an otherwise fairly mild injury 12. The emergence of explosive devices (particularly “improvised explosive devices”) as primary mode of attack in the conflicts in Iraq and Afghanistan, as well as in other regions of political unrest, has called attention to the effects of “blast injury”. Explosions generate a rapidly moving wave of over-heated, over-pressurized air, followed by a low pressure trough. These waves are particularly damaging to air and fluid filled organs and cavities, and can be associated with significant brain injury as well 13–15. At this time it is not known whether the effects of blast injury on the brain are related to the mechanical effects of the pressurized wave, with distortion of vascular tissue, neural tissue or both, the inertial effects of being buffeted by the alternating high and low pressure events, or some other mechanism. It is clear that other injury mechanisms often come into play, including impact mechanisms (coming into contact with an object), inertial (rapid acceleration/deceleration of the brain), and penetrating injuries from shrapnel or debris. Thus, the typical profile of injury involves a combination of primary injury (occurs at time of application of force) and secondary injury (evolves over time subsequent to the primary injury) as well as a combination of focal and diffuse injury. Furthermore, although the damage may be diffuse or multifocal, there are certain brain regions which are highly vulnerable to injury and account for the high rate of challenging behavior and probably the increased rates of psychiatric illness that are associated with TBI. These include the frontal cortex and sub-frontal white matter, the deeper midline structures including the basal ganglia, the rostral brainstem, and the temporal lobes including the hippocampi. In addition to the profile of regional brain injury described above, there is evidence that neurotransmitters with important roles in maintaining cognitive and behavioral homeostasis are altered in TBI. For example, there is significant dysfunction of catecholaminergic systems associated with TBI 16–18. There is also evidence of altered central cholinergic tone 19–23 following trauma. The cholinergic system plays an important role in many cognitive domains, particularly memory and attention 24 and may play a role in the genesis of mood disorders, particularly depression 25. The serotonergic system is activated in TBI, with increased levels of serotonin particularly evident in areas of significant tissue damage and in association with lowered regional cerebral glucose utilization 10,. 26–28 Initial and persistent cognitive deficits are the most common complaints after TBI 29,30 and the major hindrance to normalization in the areas of independent living, social re-adaptation, family life, and vocational endeavors 31,32. Several cognitive domains are predictably impaired, including frontal executive functions (problem solving, set shifting, impulse control, self-monitoring) 33,35, attention 36,37, short-term memory and learning 38–43, speed of information processing 44,45, and speech and language functions 46–49. Obviously, these are not completely independent domains, and there is typically a mixture of deficits of varying degrees across domains. Survivors and family/caregivers frequently describe alterations in emotional and behavioral regulation as “changes in personality”. This takes two different forms: exaggeration of pre-injury traits, or fundamental changes in response patterns. Within the latter category, careful inspection usually reveals that this can be further parsed into alterations in the frequency or intensity of predictable responses to environmental cues or stimuli, or unpredictable response patterns. Several common clusters of symptoms that characterize the “personality changes” are recognizable. One problem area is that of impulsivity. This may be manifest in verbal utterances, physical actions, snap decisions, and poor judgment flowing from the failure to fully consider the implications of a given action. This is closely related to the concept of stimulus boundedness, in which the individual responds to the most salient cue in the environment or attaches exaggerated salience to a particular cue, without regard to previously determined foci of attention or priorities. A second problem area is that of irritability. Survivors may be described as more irritable or more easily angered. Although a particular cue might be perceived as a legitimate aggravation, the response is characteristically out of proportion to the precipitating stimulus. Responses can range from verbal outbursts to dangerous aggressive and assaultive behavior. This modulatory deficit differs in intensity, onset, and duration from the pre-injury pattern for any given individual. A third area is that of affective instability. Survivors and family/caregivers frequently describe exaggerated displays of emotional expression, out of proportion to both the precipitating stimulus and the pre-injury range of response to similar stimuli. Cues that previously elicited momentary sadness now precipitate weeping or crying. Events which in the past might provoke a frown or reply laced with irritation now result in loud angry verbal outbursts associated with marked sympathetic arousal. Additional characteristics include a paroxysmal onset, brief duration, and subsequent remorse. This phenomenon occurs in other central nervous system disorders and has been called pathological affect, affective lability, pseudobulbar affect, and affective incontinence 51. The burden of the above changes in personality and behavior is often complicated by a surprising and at times devastating lack of awareness of these changes 52,53. The injured individual may be unable to appreciate that his or her behavior is different, in stark contrast to family/caregivers, who are painfully aware that the injured individual has changed in fundamental ways and will often provide detailed lists of these changes. Alternatively, an individual with TBI may have a vague sense that he or she is different or “not who I used to be” and yet struggle to define the specific ways in which his/her behavior or personality differs from prior to the injury. Individuals with TBI are less likely to be aware of changes in behavior and executive function than changes in more concrete domains such as motor function 54. Furthermore, the degree of awareness has been found to correlate with functional and vocational outcome in many 55–58, though not all 59, studies. The literature suggests that lack of awareness of illness is not simply a function of global cognitive deficits, but perhaps is more related to frontal-executive dysfunction 60,61. In individuals with TBI, this dimension is frequently the focus of family/caregiver concern, yet is often not recognized by the individuals themselves 8,62–66. Even when the individual admits to some difficulties, he or she is often unable to predict the implications of these deficits in current or future social situations. Another problem area is that of apathy. The underlying deficit associated with apathy is in the realm of motivated behavior 67. Although not as overtly disturbing as some of the other changes described above, it can be a focus of concern and is frequently the reason that injured individuals fail to progress in rehabilitation programs. It is often misinterpreted as laziness or depression and may be linked somewhat paradoxically to aggression when attempts to engage the individuals in activities in which they have little interest can precipitate assaultive behavior 68. Apathy is quite common after TBI. Kant et al 69 found that it occurred (mixed with depression) in 60% of their sample. Andersson et al 70 found that almost half of their individuals with TBI had significant degrees of apathy. Deficits in motivated behavior can occur in association with injury to the circuitry of “reward” 68,71. Key nodal points in this circuitry include the amygdala, hippocampus, caudate, entorhinal and cingulate cortices, the ventral tegmental area and the medial forebrain bundle. Catecholaminergic systems, particularly the mesolimbic dopaminergic system, appear to play critical roles in the modulation of the reward system 68,71. A full discussion of the neuroanatomical substrates of the above behaviors is beyond the scope of this paper. However, the link between the injury profile in a typical TBI and some of these behaviors is fairly simply understood. Five major frontal-subcortical circuits have been identified, of which three have significant roles in non-motor forms of behavior 72. Each of these three circuits can affect motivated behavior, though in somewhat different ways. Damage to the dorsolateral prefrontal cortex and its circuitry impairs executive functions such as working memory, decision making, problem solving and mental flexibility. Damage to the orbitofrontal cortex and related nodal points impairs intuitive reflexive social behaviors and the capacity to self-monitor and self-correct in real time within a social context. Damage to anterior cingulate and related circuitry impairs motivated and reward-related behaviors. Damage to medial temporal regions impairs other aspects of memory and the smooth integration of emotional memory with current experience and real-time assessment of stimulus salience. The frontal-subcortical circuits responsible for these critical domains of higher intellectual function and empathic, motivated, nuanced human behavior are highly vulnerable to injury in the typical TBI. In addition to the changes in cognition, behavior, and personality described above, a significant body of evidence suggests that TBI results in an increased relative risk of developing various psychiatric disorders, including mood and anxiety disorders, substance abuse and psychotic syndromes 73–76. For example, Kopenen et al 76 studied 60 individuals 30 years after their TBI and found that almost half (48%) developed a new Axis I psychiatric disorder after their injury. The most common diagnoses were depression, substance abuse, and anxiety disorders. Rates of lifetime and current depression (26%; 10%), panic disorder (8%; 6%), and psychotic disorders (8%; 8%) were higher than rates found in the et al studied on years after TBI. A significant number of individuals had Axis I disorders prior to injury. 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