Neurobehavioral sequelae of traumatic brain injury: evaluation and management

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.

RELATIONSHIP OF PROFILE OF INJURY TO NEUROBEHAVIORAL SEQUELAE

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

CHANGES IN COGNITION

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.

CHANGES IN PERSONALITY

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.

RELATIONSHIP OF PROFILE OF INJURY TO PERSONALITY CHANGES

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.

RELATIONSHIP OF TBI TO PSYCHIATRIC DISORDERS

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 significantly higher than base rates found in the Epidemiologic Catchment Area (ECA) study 77. Hibbard et al 74 studied 100 adults on average 8 years after TBI. A significant number of individuals had Axis I disorders prior to injury. After TBI, the most frequent diagnoses were major depression and anxiety disorders (i.e., post-traumatic stress disorder (PTSD), obsessive-compulsive disorder and panic disorder). Almost half (44%) of individuals had two or more disorders. More recently, this group reported a longitudinal study of 188 individuals enrolled within four years of injury and assessed at yearly intervals on at least two occasions 78. Once again, they found elevated rates (compared to population base rates as reported in the ECA study) of psychiatric disorders (depression and substance abuse) prior to injury. Subsequent to TBI there were increased rates of depression, PTSD, and other anxiety disorders. This was particularly true of those with pre-injury psychiatric disorders. Furthermore, the rates were greatest at the initial assessment point after injury and stabilized or decreased over time. Van Reekum et al 75 carefully reviewed the literature on the relationship of TBI to a variety of psychiatric disorders and, using the ECA data for baseline rates, concluded that TBI was associated with an increase in the relative risk for several psychiatric disorders. Others have also reported increased indicators of psychiatric illness after TBI and increased medical costs associated with those indicators 79,80.

As with any potentially disabling condition, individuals with TBI report a variety of symptoms in different domains (discouragement, frustration, fatigue, anxiety, etc.). Not all of these symptoms will rise to the level of a disorder. However, constellations of symptoms that are consistent and sustained over time (usually weeks), and that are of sufficient severity to interfere with social or occupational function or quality of life, are legitimately considered disorders. In the studies cited above, standardized criteria encompassing those principles were used and thus argue strongly that TBI acts as a gateway for the development of many psychiatric disorders. The consistent observation that individuals who sustain a TBI have higher base rates of psychopathology prior to injury also suggests that there is a reciprocal interaction: psychopathology predisposes to TBI, and TBI in turn predisposes the individual to develop psychiatric disorders.

In addition to the psychiatric disorders noted above, a concern has been raised about the relationship of TBI to dementia. Many individuals with TBI who have significant impairments in memory and executive function meet the DSM-IV definition of dementia. However, the larger issue is whether exposure to a TBI increases the risk of a progressive dementing disorder such as Alzheimer's disease later on. At this time it is not possible to say definitively whether TBI, particularly mild TBI, is a risk factor for that disease. This topic has been recently reviewed by Jellinger 81, who concluded that both Alzheimer's disease and TBI are associated with abnormalities in amyloid and tau protein deposition, and that several epidemiological studies have suggested either that Alzheimer's disease occurs with increased frequency in individuals with TBI or that the age of onset of the disease is reduced after TBI relative to non-injured controls. It may be that the reduced cognitive reserve associated with TBI facilitates earlier symptom manifestation of dementia in individuals destined to develop Alzheimer's disease 82.

NEUROPSYCHIATRIC ASSESSMENT

It is clear from the above that a careful assessment of neurobehavioral problems should be an important component of the evaluation and rehabilitation of individuals with TBI. Furthermore, the pattern of sequelae should make sense from the injury. The process of elucidating the profile of brain injury, evaluating the profile of current signs and symptoms, and mapping the latter onto the former to assess goodness of fit is essentially the work of the neuropsychiatric evaluation. Signs and symptoms which are not accounted for by the profile of injury must be explained on another basis or the profile of injury should be re-assessed.

It should be taken into account, however, that the cognitive deficits which frequently accompany a TBI alter the neuropsychiatric assessment, particularly the history taking. The presence of short-term memory deficits, problems with sequencing events in time, and difficulties with self-monitoring and self-awareness can make it very challenging for an individual to give a clear and consistent history. This puts the onus on the clinician to identify other sources of information (family members, friends, employers, primary medical/school/vocational records) that can help clarify the history and current clinical picture.

The assessment of the effects of an injury must start with a thorough understanding of what the individual was like prior to the injury. In the absence of such information, there is a significant risk of misattributing life-long traits, characteristics, and behaviors to the brain injury. Ideally, such baseline information is obtained shortly after the injury. The more time that passes from the point of injury, the greater the tendency to (mis)attribute more and more to the injury.

Once the baseline picture is complete, the clinician is positioned to accurately assess the changes that have occurred since the time of the injury. It is important to carefully review the functional domains that are frequently affected by injury, including cognition, personality, mood regulation, speech/language, mobility, and higher order domains such as vocational performance, major role performance within the family or equivalent context.

It is important to emphasize that temporal association does not guarantee causality. There are several ways that neurobehavioral change can be associated with brain injury. Change may be a direct effect of the insult to neural tissue with subsequent disruption of the functions subserved by the damaged tissue. Alternatively, the change may reflect the development of a new illness or disorder that is the driving force behind the behavioral change. Moreover, behavioral change could be caused by the meaning of the accident or injury, being a reaction to a loss of self-esteem due to disfiguring injury, loss of mobility, or unemployment. Finally, changes in environment such as living situation, change in caregivers, or change in routine or flow of daily life can have an enormous impact on the behavior and adaptation of an individual with brain injury or other neuropsychiatric illness. An individual showing new, aggressive outbursts associated with a change in residential care may be better served by further training of the residential provider rather than by the massive use of medications. On the other hand, if this patient has clear evidence of orbitofrontal damage, it may be that his threshold for tolerating frustration is so lowered that treatment will require both medication approaches and environmental manipulation. The proper assessment and formulation of the relative weighting or contribution of each of the above factors to the genesis of the challenging behaviors frames what can be termed a neurobiopsychosocial paradigm. It differs from more traditional psychiatric assessments with respect to the critical importance placed on understanding the profile of regional brain injury, and the array of complex behavioral circuitry that this profile would reasonably disrupt. Thus, the work of the neuropsychiatric assessment can be summarized as the process of matching the profile of brain injury with the changes that have occurred in cognition, behavior, and overall function, and gauging the “goodness of fit” between predicted and actual outcomes. This is followed by an interpretative process whereby the clinician assigns relative weights to the various contributions made by the neural, biological, psychological, and social components. Treatment interventions should flow logically from this formulation. It is important to point out that even experienced clinicians can make mistakes in this process, due to the complexity of clinical presentations and the incomplete data available. Thus, the final critical component to this process is the regular re-evaluation of intervention efficacy. Each formulation should be hypothesis driven and each intervention flow logically and in an empirically testable fashion from this formulation (e.g., “I believe the increase in aggression is due to depression, thus I will prescribe antidepressants”). Poor or incomplete response to the intervention should prompt a re-evaluation and formulation of a new and testable hypothesis. It is acceptable to be wrong, it is not acceptable to engage in sloppy thinking.

PRINCIPLES IN TREATMENT

Due to cognitive and sensorimotor deficits associated with TBI, clinical presentations of common psychiatric disorders may not meet standard diagnostic criteria as outlined in the DSM. Thus, it is reasonable to have “relaxed fit” criteria when making a diagnosis in individuals with TBI. It is important to point out that there are two broad factors that contribute to the neurobehavioral sequelae of TBI: the injury induced changes in personality and the increased rate of psychiatric disorders. A problem arises when the latter presents as a heightening or worsening of the former. For example, it is quite common for an individual with TBI to have a baseline of increased irritability or lowered frustration tolerance. It is also quite common for these traits to be exaggerated in the presence of a superimposed episode of depression or mania (or some other psychiatric disorder). If the clinician does not carefully tease out the post-injury baseline and clearly ascertain whether there is a change, it is easy to misinterpret the challenging behavior.

It is best to have a clear sense of what is causing the challenging behavior before designing a treatment plan. Yet, many clinicians are inclined to prescribe antipsychotics or selective serotonin reuptake inhibitors without knowing, or at least formulating a hypothesis for what they are treating. This is a symptomatic approach, similar to treating a fever associated with a bacterial infection with acetaminophen but not antibiotics. In the neuropsychiatric arena, the symptomatic approach should be one of last resort after having carefully ruled in or out the presence of an Axis I disorder (e.g., depression, mania, psychosis), neuromedical conditions that would account for the behavior (e.g., complex partial seizures, pain, iatrogenic complications, medication side effects), or factors in the environment that are causing the change in behavioral symptoms.

There are times, for example when data is difficult to obtain or when the neurological deficits through which challenging behaviors are being expressed are severe, that one is at a loss to account for the etiology of a given behavior or behaviors, and thus not clear about a treatment strategy. A fallback position is to conceptualize the cluster of behaviors as if they were a particular syndrome or as if they represented what Tariot et al 83,84 have termed a “behavioral metaphor”. For example, an individual expressing increased negativism, loss of interest in activities, and/or self-destructive or self-injurious behavior might be conceptualized as having a depressive syndrome and thus could reasonably be prescribed an antidepressant regimen. An individual with increased irritability, increased arousal and activation, and a significant reduction in sleep might be conceptualized as having an irritable manic-like syndrome and thus reasonably started on a mood stabilizer. The critical issue is that these are testable hypotheses and should be treated as such. Target behaviors and baseline frequencies should be identified prior to treatment and an adequate but time-limited trial prescribed. It should be clearly decided what the endpoint is and, if the desired goal is not attained, the medication should be discontinued and an alternative conceptual scheme considered.

Individuals with cognitive impairment have a heightened sensitivity not only to medications, but to the environment in which they live. Stimulus boundedness refers to the tendency to be very sensitive to events in the immediate environment, perhaps related to difficulty with components of attention, including complex, selective, and sustained attention, and resultant problems in prioritizing incoming stimuli and in gating out stimuli that would ordinarily be deemed of secondary importance. At its essence this may be a problem assigning or decoding proper salience to the constant influx of environmental cues and stimuli.

Fondness for routine refers to the sensitivity of individuals with cognitive deficits to changes in routine or schedule. This may relate to the afore-mentioned deficits in executive function, in which difficulties with problem solving and mental flexibility can be quite apparent. Individuals will often respond with anxiety, irritability, or even catastrophic reactions to these changes in routine.

Injured and non-injured individuals alike base much of minute to minute and long-term decisions and actions on their predictions of what response a given action will produce. Increasing the probability of favorable responses and decreasing the likelihood of undesirable responses are powerful forces in shaping behavior. Individuals existing in an environment in which the same behaviors elicit different responses from different people or the same people at different times can become confused, anxious, and agitated.

It is critical to carefully consider the above factors when performing a neuropsychiatric assessment. To ignore the environment and factors that may be provoking challenging behaviors will greatly reduce the efficacy of any prescribed medication, even if it is the proper one. On the other hand, without the properly prescribed medication, even massive efforts at applying behavioral analysis and environmental manipulation may be in vain. The therapeutic issue then should not be “Do we prescribe a drug, or write a behavioral plan?”. The question is better framed as “Which medicine prescribed in the context of what changes in environment and strategies for shaping behavior has the best potential for success?”.

CONCLUSIONS

Attention to the diagnosis and management of the neurobehavioral sequelae of TBI can serve a critical role in advancing the rehabilitative process. It requires a knowledge and understanding of the profile of regional structural and neurochemical injury associated with the typical TBI and how that profile predicts the common neurobehavioral sequelae. Careful assessment requires an accurate description of the individual's functional and neurobehavioral status prior to the injury and how that has changed subsequent to the injury. It is helpful to be aware of the problems in diagnosis in individuals who have a fluctuating behavioral baseline, who may have significant cognitive deficits, or in whom the usual connection between internal feeling state and external behaviors may be uncoupled. Treatment should follow from a clearly articulated diagnostic scheme and should be time-limited and re-evaluated in the presence of poor or incomplete response.