With Jane Brown, Psy.D.*

Traumatic brain injury (TBI) afflicts people of all ages and genders, and the severity of injury ranges from concussion to more severe injury, with wide-ranging, variable symptomology and outcomes. Treatment options have generally been lacking for the early syndromes and late presentations of TBI and the associated neurobehavioral and neuropsychiatric symptoms. With increasing recognition of the contribution of neuro-inflammation as a major mediating factor in animal models and human translational studies, there is the prospect for improving the understanding of the mechanisms of TBI, and developing therapeutic strategies to improve the outcomes of the millions of people affected each year. 

DEFINITIONS 
TBI results from an impact to the head with resultant disruption of normal brain functioning.  Various forces cause TBI including blunt trauma, acceleration and deceleration forces, and blast injures that result in localized and immediate damage along the impacted areas, as well as secondary and delayed damage to much broader areas of cerebral and central nervous system (CNS) functions. Systemic and neuro-inflammatory mechanisms result from disruption of the blood-brain barrier (BBB) that normally delimits its immune privileged status, at the time of, or after the insult, are important mediators of neurological outcome of TBI.  The motor, cognitive, emotional, and psychosocial consequences of TBI can be devastating and long-lasting leading to deterioration of one or more domains of adaptive functioning, with loss of independent function and safe performance of activities. The associated symptoms and neurobehavioral changes can mimic the psychiatric manifestation of an endogenous psychiatric disorder. It is important to distinguish the manifestations of brain pathology resulting from TBI from concomitant endogenous psychiatric and adjustment disorders as well as, the neuropsychiatric manifestations of TBI from other organic brain syndrome that manifest both neurocognitive impairment and emotional and behavioral changes. 

EPIDEMIOLOGY
An estimated 10 million deaths and hospitalizations relate to TBI worldwide annually, with an estimated 57 million people with one or more episodes of TBI. These figures likely underestimate the true burden of this condition as not all countries have TBI-specific treatment and reporting programs.  The Centers for Disease Control and Prevention (CDC) estimate an average of 50,000 deaths, 235,000 hospitalizations, and 1,111,000 emergency department visits annually in the United States (U.S.) due to TBI. This data may also underestimate the full impact of TBI as many mild injuries go undiagnosed, and not all those experiencing TBI seek treatment.  Substance abuse can play an indirect role in TBI as greater than 50% of patients with TBI have elevated blood alcohol levels at the time of injury.  Sports-related TBI are probably underreported and unrecognized due to inadvertent concussion especially if loss of consciousness is uncertain. Yet there may be significant impact on cognition.  The CDC estimates that 1.6 to 3.8 million sports-related concussions occur in the US annually with many affected athletes failing to obtain expert subspecialty treatment. A single concussion increases the risk of a second or subsequent event thereafter, with approximately 5% to 15% of individuals with documented mild TBI remaining permanently symptomatic, and a similar percentage of affected individuals remaining symptomatic for their entire lives. Prior TBI of any severity appears to place an individual at increased risk of a repeat TBI with each occurrence engendering the need for possible long-term care. With about  2% of the U.S. population or 3 to 5 million persons requiring assistance in the performance of activities of daily living (ADL) due to preceding TBI, and an expected expense of 1 million dollars per individual in cost of related care and medical expenditures, the estimated financial burden of TBI is a staggering 60 billion dollars annually. 
Psychiatric disorders may emerge after TBI.  Up to 56.5% of participants that were administered a structured clinical interview using the terminology of the of the fourth edition of the Diagnostic Statistical Manual soon after injury and prospectively afterward, were given a new diagnostic classification not present prior to injury that varied from 62% to 36% over time.  Anxiety, mood and substance-use disorders were the most common diagnostic classes, often presenting co-morbidly with depression being the commonest concomitant diagnosis.  TBI may be one of several other risk factors in the emergence of a neuropsychiatric disorder in affected patients, added to younger age, low educational level, and a pre-injury disorder, the latter with an odds ratio (OR) of 2.44 [95% confidence intervals (CI), 1.41-4.25], including attention deficit disorders and substance use.  
The leading causes of TBI include falls, motor vehicle accidents, unintentional and intentional injury. When the causes of injury are examined in relation to different age groups, falls are a leading cause of TBI in young children and elderly adults, and motor vehicle accidents, sports concussion, bicycle accidents, and suicidal attempts and commonest in adolescents and young adults. While blast injury leads the causes of TBI in combat soldiers, the success of motor vehicle safely measures has led to an increase in the frequent of firearm-related TBI mortality.    

NEUROPATHOLOGICAL CHANGES 
Concussion, contusions, diffuse axonal injury, epidural, subdural, subarachnoid, intra-parenchymal, intraventricular hemorrhage, and cranial nerve injuries are all associated with primary TBI.  Secondary injury takes the form of hypoxic or ischemic damage, hydrocephalus, cerebral edema, swelling, and metabolic cellular damage.  These alterations in brain structure and morphology occur concurrently with, and contribute to, changes in endogenous neurochemical, cellular calcium homeostasis, excitotoxicity, mitochondrial dysfunction, increased free radical generation, and systemic inflammatory and neuro-inflammatory mechanisms. Collectively, these alterations lead to reduced neuroplasticity and resultant tissue damage. The resultant structural, functional, and metabolic changes associated with TBI, no matter how subtle, appear to underlie the observed alterations in neurocognitive functioning that include disturbances of attention, memory, and executive functioning. Problems with attention and memory are particularly problematic, as disruption of these basic cognitive functions may significantly interfere with the ability to execute more complex, higher order functioning of daily life required for academic, vocational, or social functioning. 
There may not be consistent and definitive correlations between damage to specific regions or processes and the occurrence of distinct neuropsychiatric symptoms in specific affected patients.  However, incipient damage to the prefrontal cortex, frontal and anterior temporal regions, amygdala, hippocampus, basal ganglia, and thalamus, areas included in the limbic lobe and particularly vulnerable in TBI, can also occur in limbic encephalitis, with resultant changes in mood, attention, and impulsive control disorders as TBI. Disturbances in serotonin, glutamate and dopamine neurotransmission are described in animal models and as in TBI patients. Low levels of serotonin are classically associated with emotional changes, disinhibition and aggression, which are common neuropsychiatric issues after TBI.  Disruption in hippocampal functioning and morphology have been associated with both cognitive impairments and mood disorders.

NEUROINFLAMMATORY MECHANISMS 
These is an expanding literature of the role of altered systemic and brain immunity in the course of TBI and concussion that includes the nonspecific release and production of brain and systemic cytokines and chemokines that activate brain cell receptors, the net effect of which are to limit the spread of the injury and restore homeostatic balance. However, the switch to a second wave of autoimmunity inherent in the adaptive immune response culminates in the infiltration by immune T-cells and B-cells across the disrupted BBB, with the production of antigen-specific antibodies. The importance of heightened cell-mediated immunity is in the possibility of immune reactivation by a subsequent injury such as another neuro-inflammatory stimulus or infectious process that subsequently reopens the BBB, exposing memory immune cells to self-antigens leading to a variety of post-traumatic syndromes. 

CASE ILLUSTRATION 
A teenager without a previous psychiatric history had several concussive injuries associated with a sleigh ride, basketball, and hazing at school followed by cognitive and neurobehavioral impairments suggesting limbic encephalitis. There was a history of treated Lyme exposure and endocrinopathy.  There were symptoms of apathy, anhedonia, lack of decision-making and goal-directed behavior, extreme fatigue, attention and memory impairment, irritability, and severely disrupted sleep cycles and drives for eating and drinking.  Initial evaluation by specialists in the fields of neurology, psychiatry, and concussion hypothesized the deteriorating neurocognitive, emotional, and adaptive functioning were due to an endogenous psychiatric disorder and the adjustment sequela of mild concussion. The patient was repeatedly diagnosed with major depressive disorder (MDD) despite absence of the prototypical negative emotional load and sadness.  Psychiatric treatment modalities and behavioral modification were ineffective.  Final neurological evaluation showed evidence of concomitant neuropathy and autonomic instability. Notably, brain neuroimaging showed overlapping abnormal enhancement by magnetic resonance imaging (MRI), and nearly overlapping deficits employing 18Fluorodeoxyglucose positron emission tomography (PET) and nuclear medicine single photon emission tomography (SPECT) indicative of cerebral hypometabolism and perfusion deficits across the BBB. Lumbar spinal fluid analysis showed minor pleocytosis. Treatment with intravenous immune globulin (IVIg) for altered humoral and cell-mediated immunity associated with remote concussive/TBI led to observed clinical improvement.   This case illustrates the challenge of differentiating the neuropsychiatric manifestations of TBI from a primary emotional or psychiatric disorder, particularly in a patient not previously affected.  Pseudo-depression, a condition associated with frontal lobe dysfunction characterized by apathy, indifference, and loss of initiative, like disorders of diminished motivation (DDM), may be clues to the presentation of a neuropsychiatric disorder reflective of disturbed brain function following TBI.  

IMPLICATIONS FOR THERAPY 
Misdiagnosis of TBI as an endogenous psychiatric disorder may lead to a delay in the provision of necessary neurological and neuropsychological interventions aimed at restoring brain function.  Early and mild psychiatric symptoms following a TBI may be the best indicator of underlying neurophysiological, neurocognitive, and neuropsychiatric changes of altered brain pathology.  Beyond the important role of cognitive remodeling through intensive neurobehavioral therapy, there are prospects for immune modulatory therapy early and late in the course of the disorder to mediate the outcome of TBI due to coexisting neuroimmunologic mechanisms, especially when affected patients present with wide-ranging and variable symptomatology.    

*[email protected]