Andrew S. Kayser,* Michael E. Ballard* &
Mark D’Esposito
What is TBI (DSM–5 and clinical markers)
Traumatic brain injury (TBI) is a term that refers to an event in history, rather than to a syndrome or disorder. The current consensus defines TBI as an alteration in brain function, or other evidence of brain pathology, caused by an external force (Menon et al., 2010). While the TBI event is momentary, and alterations in function or pathology can be transient, symptoms and complications of a brain injury may persist beyond the initial trauma. Chronic symptoms are more common with more severe TBIs, but may also be present following mild TBIs. In addition, TBIs are differentiated by whether the skull and dura remain intact during the injury. Closed- head TBIs are most common, and will be the focus of this chapter. Penetrating TBIs include injuries in which the skull and dura are violated, and are frequently complicated by a variety of other factors associated with exposing the brain parenchyma to the outside environment, including infection. Due to such complications, penetrating TBIs will not be discussed further.
The above definition of TBI is operationalized by the presence of specific symptoms or signs. One of the most widely used sets of criteria, that of the American College of Rehabilitative Medicine (Menon et al., 2010), requires one of the following for the diagnosis: Loss of consciousness, amnesia, the presence of focal neurological deficits, or any alteration in mental state at the time of injury. These features are generally captured by other sets of criteria as well. For example, the most recent version of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders(DSM-5) is the first version of the manual that affords a detailed consideration of TBI and its neuropsychiatric sequelae. The DSM- 5 diagnosis requires one or more criteria including loss of consciousness, loss of memory surrounding the event (post-traumatic amnesia), or neurological signs such as loss of smell (anosmia) or unilateral weakness (hemiparesis). The DSM-5 also permits evidence of neural injury based on neuroimaging, or new or worsened seizures as evidence of a TBI (American Psychiatric Association, 2013).
Once the diagnosis is established, TBIs have traditionally been categorized into mild, moderate, and severe grades based upon the severity of the injury. Level of consciousness is typically evaluated using the Glasgow Coma Scale (GCS), a 15- point multidimensional assessment that grades the severity of alteration on three domains: eye opening, verbal response, and motor response (Teasdale & Jennett, 1974). Mild TBIs, otherwise known as concussions, are by far the most common grade of TBI (e.g., as a result of sports injuries, falls, or motor vehicle accidents).
They are characterized by a GCS score >13 at the time of evaluation; a transient loss of consciousness, confusion or disorientation, lasting less than 30 minutes after the injury; and less than 24 hours of amnesia surrounding the event. Moderate TBIs are associated with a GCS score of 9–12, loss of consciousness persisting between 30 minutes and 24 hours, and 1–7 days of post-traumatic amnesia.
Severe TBIs are associated with a GCS score <8, greater than 24 hours of loss consciousness, and greater than 7 days of amnesia.
A clinician-administered interview is the primary method for diagnosing a TBI, but caveats have long been apparent. Because TBI diagnoses are typically made retrospectively, it can be difficult to confidently and accurately characterize alterations of consciousness or neurological impairments related to a remote TBI event. Moreover, the events are often not witnessed or thoroughly assessed at the time; rather, they are based on the patient’s own recollection, which can be compromised by the TBI itself. Subsequent to the diagnosis, it can also be quite challenging to definitively attribute cognitive, emotional, behavioral, or other symptoms to a single TBI (or to multiple TBIs), due to the fact that a TBI may exacerbate premorbid disorders or increase the risk of developing comorbid disorders (e.g., post-traumatic stress disorder/PTSD). Furthermore, the presence of other sequelae of trauma, such as vertigo or musculoskeletal injuries, can result in nausea, pain, and/or insomnia, which themselves can contribute to cognitive and other functional impairments (Wortzel & Arciniegas, 2014).
Recent years have seen a growing appreciation for the mechanism of injury as a distinguishing feature of TBIs, particularly with the increased use of improvised explosive devices (IEDs) in military conflicts and terror attacks. There are three primary mechanisms of TBI: Blunt trauma related to an object striking the head, injury related to rapid acceleration/deceleration, and blast exposure. While each of these mechanisms can cause an insult to the brain, evidence suggests that they can potentially have different effects on brain function and therefore manifest different symptom profiles as a result. Briefly, blunt force trauma can lead to cerebral edema and inflammation at the site of the impact, as well as contralateral injury (so-called contrecoup injury) as the brain rebounds against the inside of the skull.
Trauma that includes significant acceleration, whether rotational or linear in trajectory, can induce axon shearing. Blast injuries are often associated with both blunt and acceleration-related trauma, but also include pressure-induced neuronal changes. A detailed description of these differences is beyond the scope of this chapter, but for a relatively recent review see McAllister (2011).
Certain brain regions are more susceptible to injury. These areas include those in close proximity to bony protuberances of the skull (e.g., ventral frontal and anterior temporal cortices), perhaps most relevant in the context of injuries related to blunt trauma; areas that are most subject to angular acceleration/deceleration (e.g., superficial and anterior cortical regions, the gray-white matter junction, and the rostral brainstem); and those proximal to air- or fluid-filled areas, which are most vulnerable to pressure changes resulting from a blast (e.g., the basal ganglia, which abut the fluid-filled lateral ventricles of the brain) (McAllister, 2011). Once incurred, an insult to the brain can trigger a complex chain of adverse events at the neuronal level. These sequelae include axonal shearing and degeneration; excess release of neurotransmitters such as catecholamines (particularly dopamine) and glutamate, the latter of which can be excitotoxic; excess calcium influx; and inflammatory responses and cell death cascades (McAllister, 2011).
Given the breadth of location, severity, and mechanism of TBIs, a range of symptoms is common beyond acute loss of consciousness and amnesia. Because frontal and anterior temporal regions are most likely to be compromised by a TBI – and these regions are part of networks responsible for attention, Working Memory (WM), and other Executive Functions (EFs, including higher cognitive functions such as inhibitory and emotional self-control, multitasking, and decision- making) – a constellation of cognitive, behavioral, and emotional symptoms can be at least transiently experienced. Moreover, because these cognitive functions rely upon distributed brain networks (Christophel, Klink, Spitzer, Roelfsema, &
Haynes, 2017), they may be particularly vulnerable to TBI-induced disruption of linking white matter tracts. The most common symptoms of a mild TBI are fatigue, headache, visual disturbances, memory loss, dizziness, impairments in sleep, and irritability or other emotional disturbances including depressed mood. Other symptoms include nausea, loss of smell, and increased sensitivity to light and sounds.
Many of these symptoms, particularly pain, emotional disturbance, and insomnia, can contribute to cognitive impairments, in addition to the brain injury itself (Alexander, 1995). This overlap can make it very difficult to definitively assess for cognitive symptoms that are related to a TBI, but independent of other symptoms or comorbid disorders. Nonetheless, and irrespective of the proportional contri - bution from these etiologies, one of the most commonly noted cognitive symptoms after TBI is a perceived decline in WM, addressed in more detail in the following section.
Working Memory (WM) and related Executive Function (EF) deficits
Working Memory in TBI
Approximately 10–15% of individuals who have sustained a mild TBI report chronic cognitive and behavioral problems, and the numbers are substantially higher among moderate and severe TBI patients (McAllister, Flashman, McDonald, & Saykin,
2006). The most common complaints often relate to WM, which refers to the capacity to temporarily store and manipulate information in mind for the purpose of achieving a particular goal. Such deficits are consistent with the particular vulnerability of the frontal lobes and related circuitry (e.g., white matter connec - tions, particularly involving dorsolateral regions and their catecholaminergic inputs and glutamatergic outputs) to insult from TBI, as described above. WM is governed by a complex interaction of brain regions and transmitter systems, and impairments can be expected following injury to any component; thus, because of its widely- distributed underpinnings (Christophel et al., 2017), WM may be more vulnerable than cognitive processes that are subserved by more specialized regions, such as elemental motor planning and vision. A number of theories of WM exist (for a review, see Baddeley, 2012; D’Esposito & Postle, 2015). One of the first, and still most influential, theories of WM, proposed by Baddeley and Hitch in the mid- 1970s, regard WM as a multicomponent process. The core component, a central executive system, is tasked with allocating attention and processing resources, a function that is particularly critical when more than one cognitive process must be carried out simultaneously. In turn, the central executive coordinates separate
“slave systems”, including (1) a phonological loop, which temporarily stores auditory and language information; (2) a visuospatial sketchpad, which temporarily stores visual and spatial information; and (3) an episodic buffer system, which links WM to long-term memory and serves to integrate information from the other subordinate systems. Other theories posit that WM is not separable, but rather an attentional focus on representations from short-term memory (STM) or long-term memory (LTM) (for a review, see Baddeley, 2012; D’Esposito & Postle, 2015).
Owing to the potential specialization of certain areas of the frontal cortex for specific WM component processes/systems, the type of deficit can provide insights into the neural substrates affected.
Despite frequent reports of WM problems among TBI patients, only some studies have found significant performance impairments on standard laboratory measures that probe WM. Equivocal findings in this regard are likely due to a combination of multiple factors, including known issues related to diagnosis and assessment.
Specifically, the retrospective nature of the diagnosis, combined with heterogeneous injury mechanisms, severity of injury, and the brain regions/systems affected within study samples, conspire to add “noise” to the clinical picture. In addition, laboratory-based WM measures vary in both the memoranda (e.g., visual versus auditory items) and the cognitive demands required by the relevant tasks, which can affect their sensitivity and specificity. Nonetheless, a meta-analysis of 21 studies concluded that individuals who have sustained a moderate–severe TBI typically display significant deficits in visuospatial WM (Cohen’s d = .69), verbal WM (Cohen’s d= .37), and verbal short-term memory (STM; Cohen’s d= .41), relative to controls (Dunning, Westgate, & Adlam, 2016). Importantly, this meta-analysis revealed that a longer time post-injury was associated with greater decrements in verbal WM and verbal STM skills, and that verbal WM deficits were larger among individuals who were older at the time of injury. A meta-analysis of 27 childhood
studies of moderate–severe TBI found that affected children typically exhibited deficits in the central executive and phonological loop components of WM, but not in the visuospatial sketchpad. (To date, no studies have specifically probed the episodic buffer in childhood TBI patients (Phillips, Parry, Mandalis, & Lah, 2017).) Supportive of these findings, patients with a history of severe, closed-head TBI displayed a greater slowing of performance on a simple visual reaction time task when another task (counting, short-term memory) was added (McDowell, Whyte,
& D’Esposito, 1997). Similar results have been obtained by other dual-task paradigm studies of TBI patients, including findings that patients are especially impaired in their capacity to perform more demanding stages (2-back, 3-back) of the classic n-back continuous WM task, compared to matched uninjured controls (Perlstein et al., 2004). In that study, as in others, deficits were more pronounced among moderate and severe TBI patients than mild TBI patients. While there is evidence of WM deficits in mild TBI patients as well, they are less consistently found and tend to be less severe than in moderate–severe TBI patients.
Neuroimaging studies have provided insights into the neural mechanisms underlying WM deficits in TBI patients. In particular, functional magnetic resonance imaging (fMRI) studies have been useful in attempting to link abnormal brain function (or activation profiles) to particular WM impairments in this population. However, as a whole these studies have provided equivocal results, with some reporting hyperactivation in patients performing WM tasks, and others reporting hypoactivation, and still others finding both hyper- and hypoactivation.
A recent meta-analysis of 14 fMRI studies of mild TBI that employed WM measures provided evidence that a principal reason for these conflicting findings may lie in the nature of the assessments. Some WM tasks are dynamic and continuous in nature, and therefore require a greater level of cognitive control, particularly those in which subjects must continuously update and/or manipulate information in WM. In contrast, other tasks may simply require temporary maintenance of information in WM over a brief, uninterrupted delay period. Thus, mild TBI patients may display hyperactivation in key WM brain regions while performing tasks requiring a high level of cognitive control (high load, continuous, complex), whereas hypoactivation may be paradoxically more likely when patients perform simpler (low load, discrete) WM tasks (Bryer, Medaglia, Rostami, & Hillary, 2013). This profile of results has been interpreted as evidence that low WM-load tasks reveal a reduced capacity to recruit relevant executive processing resources, while more complex WM tasks reveal compensatory or aberrant recruitment of resources. It remains unclear to what extent these abnormal brain activation patterns in TBI patients result from anatomical/structural abnormalities and alterations to neuromodulatory, particularly catecholaminergic, systems.
An important caveat when considering the research summarized above is that these studies focused almost exclusively on uncomplicated closed head injury, and screened out patients with comorbid disorders. Thus, less is known about the extent to which complications related to the TBI itself or to other disorders might exacerbate WM deficits in TBI patients.
Related EF deficits
As discussed above, other higher-order deficits have been linked to TBI, including changes in mood and anxiety. With respect to Executive Function in particular, a long history of research has shown that real-world impairments can be seen in Executive Functions not always easily captured by standard neuropsychological testing, including impairments in social function, multitasking, and planning/goal setting. Nevertheless, neuropsychological tests have revealed some evidence of deficits in “classic” Executive Functions, such as task switching and response inhibition (Cristofori & Levin, 2015), that can improve over time. In a study of recovery in 260 subjects following mild TBI, for example, significant improvements were seen over one year in multiple domains that were impaired at baseline, including Executive Functions captured by the well-known Stroop and symbol- digit coding tasks (Barker-Collo et al., 2015). In the Stroop task, subjects must inhibit their prepotent tendency to read a word in order to name the color of the font in which the word is presented – e.g., to state “red” in response to the word
“green” printed in red font – while in the most common symbol–digit coding tasks, subjects must match a previously-paired symbol corresponding to each number in a list of digits as quickly as possible. Notably, European ancestry was also predictive of better performance in this study, pointing to cultural confounds in such assessments (Barker-Collo et al., 2015). Of course, patients, especially those with a history of mild TBI, can often report their deficits. In a study of one such self-report measure, the BRIEF-A, Donders and colleagues found that in a mild TBI sample of 100 patients, higher scores, indicating greater impairment, correlated strongly with premorbid history of outpatient psychiatric treatment (Donders &
Strong, 2016). Thus, elevated scores seen on these self-report measures are not immune from the diagnostic confounds mentioned earlier. To this end, studies to assess the validity of metrics of Executive Function have been helpful. For example, slowing on the well-known Trails B test, a task in which subjects must draw lines that alternate sequentially between numbers and letters scattered on a page, may differentiate mild TBI patients from controls, but other executive tests may not (Demery, Larson, Dixit, Bauer, & Perlstein, 2010). Importantly, questionnaires designed to obtain parental ratings of Executive Function in children may, like self-report data in adults, differentially weight factors related to premorbid function and the brain injury itself (Donders & DeWit, 2016).
Factors governing resiliency
The above findings have contributed to recent research efforts aiming to elucidate the factors that determine resiliency to TBI – i.e., those that confer protective effects and vulnerability. Considerable evidence indicates that younger age at the time of injury (except for pediatric TBI, which can have more profound effects on neural development) is a predictor of improved outcome following TBI, as is greater intellectual ability and socioeconomic status (for a brief review, see Holland &
Schmidt, 2015). Much focus has also been directed at genes, such as those originally related to Alzheimer’s pathology. As noted above, brain injury can compromise the capacity of neurons to process cellular detritus, and can therefore lead to an increased accumulation of potentially harmful misfolded proteins that interfere with other cellular functions. The APOE gene, the ⑀4 allele of which is one of the known risk factors for late-onset sporadic Alzheimer’s disease, has been most intensely scrutinized as one such potential factor. Nevertheless, a meta-analysis of 10 studies found no reliable evidence of a difference in the magnitude of WM deficits between APOE ⑀4-carriers and noncarriers with TBI, regardless of injury severity (Padgett, Summers, & Skilbeck, 2016). Other potential candidate genes that confer resilience to TBI symptoms include functional polymorphisms in genes that regulate inflammation (interleukin 1 & 6) and neural repair and plasticity machinery (nerve growth factor, BDNF); however, additional studies are needed to confirm initial findings (McAllister, 2015). Psychological factors may also contribute to resiliency. As documented elsewhere in this chapter, for example, a premorbid history of increased somatization may lead to more persistent symptoms following a TBI event.
Neurological profile
The more chronic neurological sequelae of mild TBI have traditionally been captured by the diagnosis of post-concussive syndrome. This constellation of symptoms includes headaches, light and sound sensitivity, non-specific dizziness, insomnia and resultant fatigue, irritability, anxiety, and mood changes (Alexander, Shuttleworth-Edwards, Kidd, & Malcolm, 2015). Classically, these symptoms are time-limited, with recovery expected over a period not more than approximately three months. As for the characterization of TBI itself, however, these symptoms are non-specific, in that they occur frequently in individuals without a history of TBI. These issues are exacerbated by the aforementioned difficulties in diagnosis of TBI and the heterogeneity of the precipitating events. One prospective study from Lithuania, for example, demonstrated that a TBI group and a matched control group with a history of minor injury without TBI demonstrated similar rates of many symptoms, such as headache, over the course of one year following the sentinel event; furthermore, initial differences in memory and dizziness between the two groups were rendered insignificant once variables pertaining to education and socioeconomic status were included (Mickeviciene et al., 2004). Similarly, studies in college athletes and others have shown that the duration of post-concussive syndromes is directly correlated with the degree of pre-injury somatization (Nelson et al., 2016), and that a substantial fraction of pediatric patients who have headaches persisting for longer than three months both meet criteria for medication overuse headache and improve once the use of short-acting analgesics is curtailed (Heyer
& Idris, 2014). More broadly, some larger reviews and consensus statements have emphasized that numerous factors, including the generally historical nature of the