Depression and Cognitive Complaints Following Mild Traumatic Brain Injury

Injury to the brain occurs as a result of contact (or impact) forces, inertial (acceleration or deceleration) forces, or both (14) . The anterior and inferior frontal and temporal areas of the brain are those most commonly and most severely affected by impact forces (15) . Inertial, and particularly rotational, forces stretch and strain white matter in these and other areas (the upper brainstem, the parasagittal white matter of the cerebrum, the corpus callosum, and the gray-white matter junctions of the cerebral cortex), resulting in diffuse (or, more accurately, multifocal) axonal injury (16) .

The conflicts in Iraq and Afghanistan, as well as the use of explosive devices in other regions of political unrest, have called attention to the effects of blast-related TBI (13) . Although primary blast can cause brain injury, the effect of primary blast is greatest at air-tissue interfaces. Thus, primary blast most often damages air-filled organs, such as the lungs and colon, or those at air-fluid (tissue-density) interfaces, such as the tympanic membranes and the eyes (17, 18) . In the absence of a blast wave of a magnitude sufficient to damage the most blast-vulnerable organs, the effect of blast on the brain is uncertain and is a matter of controversy (18) . Secondary and tertiary blast effects are common mechanisms of blast-related TBI, affecting the brain via contact and inertial forces—for example, the sudden acceleration/deceleration and rotation of an individual in a vehicle displaced by the force of the blast or by objects driven by the blast through the vehicle and against the individual’s head.

Biomechanical injury is accompanied by a cascade of injurious intra- and extracellular processes (14, 16) . Injury-induced calcium and magnesium dysregulation, excitatory amino acid excesses, calcium-regulated protein activation, mitochondrial dysfunction, free-radical formation, and proteolysis are major elements of this postinjury cytotoxic cascade and contribute to traumatically induced neuronal injury and cell death. TBI also induces excessive neurotransmitter release, including functionally disruptive elevations in cerebral glutamate, acetylcholine, dopamine, norepinephrine, and serotonin levels (19) . Although intracerebral levels of most of these neurotransmitters appear to normalize in the days to weeks following the injury, chronic cholinergic deficits, as well as chronic primary or secondary dysfunction in dopaminergic, noradrenergic, and serotonergic systems, appear to be relatively common consequences of TBI (19, 20) .

The pathophysiology of TBI is best viewed as a product not only of biomechanical forces but also of the cytotoxic cascade, neurotransmitter disturbances, and intracranial or systemic complications. Although TBI can affect any area of the brain, there is a relatively consistent pattern of regional cerebral vulnerability to injury, whether mild or more severe. That pattern of regional vulnerability explains the types of neuropsychiatric problems commonly experienced by persons with TBI ( Table 1 ).

When a patient presents for evaluation of neuropsychiatric problems that may be the result of a TBI, it is important initially to determine whether the event preceding those problems in fact produced a TBI. The patient is asked first to describe the event; the clinician then determines whether the event involved the application of external physical force (e.g., a blow to the head) or acceleration/deceleration forces (e.g., sudden start, stop, or alteration of the direction of head movement). If an external physical force was present, there needs to be evidence of immediate physiologic disruption of brain function, including loss of consciousness, posttraumatic amnesia, altered mental status of any duration (dazed, confused, “seeing stars”), and/or a focal neurological deficit (2) .

There are several caveats to bear in mind when interpreting this information. First, because of the retrospective nature of evaluating a TBI—days, weeks, or months after the event—the potential for misreporting the event and its immediate neuropsychiatric manifestations is significant. Second, it is difficult to gauge accurately the mechanics, severity, and effects of an injury after the fact. In many cases, an informed but subjective clinical judgment will be required to confirm or rule out the diagnosis of TBI. Third, patients (and some clinicians) frequently misinterpret the immediate sequelae of TBI and their diagnostic implications. For example, a patient unable to recall portions of the event may misinterpret impaired recall due to posttraumatic amnesia as loss of consciousness. Fourth, the absence of evidence supporting a TBI in the medical record does not constitute evidence of absence of a TBI. Many patients with mild TBI do not go to a hospital at the time of injury. Moreover, a recent study (21) demonstrated that for those who did present to a hospital, emergency room records failed to document TBI in 56% of cases that study personnel identified as meeting the Centers for Disease Control and Prevention case definition for mild TBI. Fifth, the patient who states that he or she was “dazed,” “confused,” or “saw stars” may be reporting phenomena consistent with a mild TBI, an acute stress reaction, cerebral dysfunction produced by other injury-related physiologic disturbances (e.g., hypotension, hypoxia, toxin/gas inhalation), or some combination of these. Sixth, conventional clinical neuroimaging of the brain, including MRI, is often interpreted as “normal” in persons with mild TBI. A normal MRI of the brain after mild TBI does not suggest the absence of injury but instead indicates only that any changes in the brain caused by the TBI are below the detection threshold of conventional clinical MRI. There are techniques that may increase the sensitivity of MRI to changes in brain structure resulting from mild TBI, including fluid-attenuated inversion recovery, gradient recalled echo, and susceptibility-weighting techniques, as well as the use of high-field (3-T) scanners. Recent work suggests that diffusion tensor imaging is a promising method for detecting alterations in the integrity of white matter resulting from mild TBI (22, 23), although its application in clinical practice will require refinement to determine its usefulness as a diagnostic measure.

The tendency of medical personnel to miss or misunderstand mild TBI and its consequences is shared by the general public (24, 25) . Such misconceptions raise suspicion and doubt about the veracity of TBI survivors’ clinical complaints, fueled, in part, by portrayals of mild TBI in cartoons and movies as “head injuries” or “concussions” that produce little immediate impairment and from which unrealistically rapid and complete recoveries are made.

After a diagnosis of TBI is made, the next step in the evaluation is to characterize the clinical problems with which the patient presents as well as the relationship of these problems, if any, to the TBI. The neuropsychiatric sequelae of mild TBI include problems with cognition (attention, concentration, executive functioning, memory, and speed of information processing) (19) ; psychiatric symptoms (personality changes, affective disorders, anxiety disorders, psychosis, sleep disorders, aggression, and irritability) (26), and physical problems, such as headache, chronic pain, vision impairment, dizziness, and, rarely, epilepsy (27) . Figure 1 describes the most common posttraumatic neuropsychiatric problems following TBI. While the development and persistence of these symptoms are often described as a “postconcussion syndrome,” these symptoms occur in all severities of TBI. Moreover, it is not clear that they conform to the concept of a “syndrome”: the development of each symptom is not clearly linked to that of any other, and the symptoms’ resolution and response to treatment are frequently uncoupled; that is, they do not necessarily follow the same recovery trajectory (28) .

In general, relatively rapid recovery is expected after mild TBI (see reference 27 for a review), with about half of patients recovering fully by the end of the first month and 80%–90% recovering by 6–12 months after sustaining the injury. Nonetheless, it is our practice to institute treatment when functionally significant neuropsychiatric symptoms are present. Education, counseling, and rehabilitative interventions may facilitate recovery and lessen the likelihood that the patient will develop persistent postconcussive symptoms (29, 30), and hence these are the initial components of neuropsychiatric treatment in this population. Given the absence of compelling evidence that medication treatment hastens recovery in mild TBI, we recommend that the decision to initiate pharmacotherapy be decided in partnership with the patient and his or her family. The goals of pharmacotherapy are to reduce the effects of such symptoms on the patient’s functioning, quality of life, and recovery and to limit the likelihood that the symptoms will become a chronic problem and contribute to long-term disability. Expeditious treatment of depression after TBI is particularly important, because its successful treatment may also alleviate other postconcussive symptoms, such as anergia, insomnia, irritability, and cognitive impairments; reduce suicidal thoughts and/or behavior; and improve psychosocial function and quality of life.

Estimates of posttraumatic depression range from 10% to 77% (see reference 31 for a review). Although depression occurs most often in the first year after TBI, the risk of developing depression remains elevated for decades thereafter. Preinjury factors (such as mood and anxiety disorders, psychosocial dysfunction, and alcohol abuse), injury factors (such as left ventrolateral and dorsolateral injury and serotonergic dysfunction), and postinjury factors (such as postconcussive symptoms, psychosocial dysfunction, and lack of social supports) contribute to the development of depression after TBI, although the relevance of each factor varies among patients (32) . Early posttraumatic depression may be more strongly related to a host-injury interaction, whereas late posttraumatic depression may be more strongly influenced by psychological and psychosocial factors (33 – 35) .

Depression after mild TBI is associated with self-reported increases in the number and perceived severity of other postconcussive symptoms, including headache, dizziness, and blurred vision (36 – 38) . In persons with mild or more severe TBI, depression also increases anger, aggression, the risk of suicidality, and cognitive dysfunction (37, 39 – 41) . However, patient perceptions of impaired daily functioning and experience of other psychosocial changes after TBI may exacerbate depressive symptoms (42) .

After treating depression, treatment of residual cognitive problems is appropriate. Cognitive rehabilitation, usually provided by an occupational therapist, speech therapist, or neuropsychologist, is most useful for the development of compensatory strategies to address difficulties with memory, attention, interpersonal communication skills, and executive function (64, 65) . Cognitive rehabilitation appears best suited to patients who have mild to moderate cognitive impairments, who have relatively well preserved functional independence, and who are motivated to engage in and rehearse these strategies. Pharmacotherapy may be a useful adjunct to cognitive rehabilitation.

The neuroanatomy and neurochemistry of TBI yield two general approaches to the pharmacotherapy of posttraumatic cognitive impairments: catecholaminergic augmentation and cholinergic augmentation (19) . Methylphenidate augments cerebral catecholaminergic function and is the first-line treatment for impaired speed of processing; it may also improve arousal and, to a lesser extent, attention and memory (47) . Pharmacologically similar agents, such as dextroamphetamine, may afford comparable benefits, although there are few studies offering evidence to support their use in this population.

Methylphenidate generally takes effect quickly (within 0.5–1 hour) and loses effect after a few hours. Therefore, the first issue in the administration of this agent is to determine its optimal dose and dosing frequency. Treatment generally begins at 5 mg methylphenidate once daily and is gradually increased, in 5-mg increments, until adequate benefits are achieved or medication intolerance occurs. Methylphenidate may induce mild increases in heart rate and blood pressure, although such changes are relatively infrequent and rarely require treatment discontinuation. Nonetheless, baseline pulse and blood pressure should be obtained and monitored until a final dosage is achieved. In patients with a history of stimulant abuse, the risks of abuse of methylphenidate should be considered carefully before undertaking treatment with this agent. While doses are often in the range of 10–20 mg twice daily (i.e., 0.15–0.30 mg/kg twice daily), some patients may require higher doses (e.g., 40 mg) and greater frequency (3–4 times a day). Individuals requiring relatively high and frequent doses of methylphenidate may benefit from use of longer-acting preparations. In such cases, it also may be useful to obtain blood levels of methylphenidate 90 minutes after ingestion to evaluate patient-specific pharmacokinetics and to use that information to guide considerations regarding the prescription of higher doses.

Placebo-controlled studies suggest that donepezil (66, 67) and rivastigmine (68, 69) may be useful in the treatment of posttraumatic cognitive impairments, and particularly memory impairments. Cholinesterase inhibitor-related improvements in attention and executive functioning have also been reported (see reference 19 for a review), and these agents are sometimes used for this purpose in clinical practice. Consistent with this suggestion, the Neurobehavioral Guidelines Working Group (47) recommended donepezil (5–10 mg daily) to enhance aspects of attention and memory for patients with moderate to severe TBI in subacute and chronic periods of recovery. Based on findings published after the Neurobehavioral Guidelines Working Group report was issued, rivastigmine (3–6 mg daily) is also suggested as an option in the treatment of chronic posttraumatic memory and perhaps attention impairments (68) . In our experience and that of others (70), these agents—alone or in combination with those that augment catecholaminergic function—are also useful in the treatment of posttraumatic cognitive impairments in persons with mild TBI.

Many symptoms that affect individuals with TBI may persist despite the treatments described above. As illustrated in Figure 1, the development and persistence of these symptoms may reflect preinjury problems, the effects of injury, postinjury psychological or social problems, or some combination of these factors. The treatment of these and other posttraumatic neuropsychiatric symptoms is beyond the scope of this article, but information may be found elsewhere (see reference 71 for a review).

Received Nov. 12, 2008; revision received Jan. 18, 2009; accepted Jan. 29, 2009 (doi: 10.1176/appi.ajp.2009.08111676). From the Department of Psychiatry, New York University; Dartmouth Medical School, Lebanon, N.H.; the Brain Injury Rehabilitation Unit, HealthONE Spalding Rehabilitation Hospital, Aurora, Colo.; and the Neurobehavioral Disorders Program, Department of Psychiatry, University of Colorado Denver School of Medicine, Aurora. Address correspondence and reprint requests to Dr. Silver, 40 East 83rd St., New York, NY 10028; [email protected] (e-mail).

Dr. Silver performs independent forensic evaluations of patients with traumatic brain injury for plaintiffs and defense. The other authors report no competing interests.

Supported in part by HealthONE Spalding Rehabilitation Hospital and NIH grants RO1 NS40472-01, RO1 HD048176-01, RO1 NS055020, and R01HD48638.