Neurophysiologic Findings in Veterans with Traumatic Brain Injuries

Educational Objectives

The goal of this program is to improve management of sequelae of traumatic brain injuries (TBIs). After hearing and assimilating this program, the clinician will be better able to:

1. Assess the risk for development of cognitive symptoms in veterans following exposure to traumatic brain injury (TBI).
2. Correlate electrophysiologic changes with sequelae of TBI.
3. Measure the magnitude of additional impacts of TBI through use of magnetic resonance imaging and cerebrospinal fluid biomarkers.

Summary

Incidence: ≥33% of veterans suffering from mild traumatic brain injury (mTBI) report ongoing cognitive symptoms; veterans may experience injuries ranging from TBIs to repetitive head injuries (RHIs; typically subconcussive); blast injuries are typically unique to veterans; exposure to contact sports may occur before or during military service; most exposures result from mTBI; loss of consciousness (LOC) usually occurs ≤30 min and presents in 80% of mTBIs; a minority of injuries present as moderate to severe TBI with LOC >30 min; RHIs are primarily represented by subconcussive injuries; it is suspected that ≈20% of Operation Enduring Freedom veterans experienced some kind of mTBI

Documentation: document all moderate to severe TBIs and some mTBIs; many mTBIs and RHIs are never clinically evaluated; document any head injuries or impacts from premilitary, military, and postmilitary life; document the number of exposures and the age at each exposure, along with the number of years spent in sports and the military; use a list of possible exposures for RHIs (eg, artillery, guns, paratrooping, boxing)

Postconcussive symptoms: include headache, mood changes, irritability, light and sound sensitivity, changes in attention and concentration, memory difficulty, vertigo, ataxia, and sleep difficulties (eg, sleep fragmentation, daytime sleepiness, fatigue); often resolve within days to weeks, but 33% of veterans experience chronic symptoms

Factors which influence the impacts of TBI on brain function

Posttraumatic stress disorder (PTSD): co-occurs in ≤50% of cases of mTBI; may increase the risk for poor cognitive outcomes following TBI; a theory exists that patients with PTSD and prior mTBI may have larger deficits in executive function and emotional processing, though there is conflicting evidence that the number of mTBIs increases the risk for long-term cognitive deficits, implying TBI itself causes changes in brain structure and function; Clausen et al (2021) found that veterans with mTBI or subconcussive blast injuries have slower processing speeds than patients without blast exposure, after controlling for PTSD and depression

Apolipoprotein E (ApoE) gene: facilitates lipid uptake, transport, and distribution; the major allelic variants are ApoE-ɛ2, ApoE-ɛ3, and ApoE-ɛ4; a major genetic risk determinant for late-onset Alzheimer disease (ApoE-ɛ4 confers increased risk, while ApoE-ɛ2 is protective); may play a role in neurotrauma recovery and the risk for future neural degeneration after head injury exposure; Merritt et al (2021) found that ApoE-ɛ4 is associated with lower standard memory scores after TBI in veterans, and ApoE-ɛ2 offers a protective effect, though the same is untrue with regard to executive function

Remote TBIs: older studies show older veterans with remote TBIs tend to have slower processing speeds and difficulty with executive function, compared with veterans without TBIs; subgroup analysis revealed more severe deficits with multiple mTBIs or moderate-to-severe TBI

Risk for dementia

mTBI, LOC, and RHI: mTBI increases risk for dementia regardless of presence of LOC, which augments risk; >1 TBI further increases risk, and moderate-to-severe TBI provides the greatest risk; RHI is a more significant risk factor than a single mTBI, but it is unclear how many mTBIs equate to RHI; it is unclear how much known military-related RHI is deemed excessive, and no exposure risk thresholds for military service members have been established in the diagnosis of chronic traumatic encephalopathy (CTE); when RHIs are combined with TBI with LOC, worse outcomes are realized with regard to mood and cognition, compared with non-TBI without LOC

Posttraumatic stress disorder: doubles the risk for all-cause dementia (includes Alzheimer disease [AD] and frontotemporal dementia), before and after excluding TBI; Gardner et al (2014) found that veterans ≥55 yr of age with TBI had the greatest increased relative risk (RR), compared with all veterans in the VA system; slightly lower RR was noted for veterans who visited the emergency department (ED) for any cause, and RR was comparably lower for veterans who visited the ED for any non-TBI trauma

Mild childhood head injuries: potentially additive; the first mTBI may result in a subacute postconcussive period that resolves in young adulthood; as mTBIs and head impacts accumulate over time, there may be extension of the postconcussive period with increased dementia risk in later life with impairments in memory, attention, and processing speed

Event-related potentials: measured using quantitative electroencephalography; time-locked to different repetitive tasks; inexpensive, noninvasive, direct measures of brain physiology; a repeated stimulus produces an electrophysiologic response (waveform), and a grand average waveform is created for each type of response; veterans wear a headset with electrodes and press a button when a target tone is heard and ignore standard tones (lower frequencies) and distractor tones

Auditory oddball paradigm: evaluates the P200 component (positive-going peak that occurs ≈200 ms after stimulus onset; associated with attention and working memory); Turk et al (2021) discovered that veterans with remote head injury had decreased P200 amplitude and associated impaired stimulus classification and processing

Visual oddball paradigm: Campbell et al (2021) — veterans with comorbid PTSD and TBI exhibited increased amplitude of the N200 component (negative-going peak occurring near the time of the P200 component; exhibits maximal amplitude on the frontocentral scalp; thought to reflect cognitive control and index degree of stimulus novelty; involved in response inhibition) directly following exposure to negative stimuli vs following neutral stimuli; veterans with TBI and PTSD showed increased responsiveness to distractors; event-related potentials (ERPs) could be a measure of attention and inhibition associated with diagnoses of TBI and PTSD, but not PTSD severity; Korgaonkar et al (2021) — observed increased N200 amplitude in veterans with PTSD or mTBI (ie, relatively similar ERP profiles), compared with controls, during response inhibition trials; PTSD and mTBI may have similar neural mechanisms for impairments in response inhibition; an increase in N200 amplitude in the TBI group may reflect the need for a greater cognitive effort during response inhibition

Impacts of neurodegenerative conditions on memory: the majority of patients with CTE report memory impairment at initial presentation; the dual-process model of memory involves familiarity (general sense of knowing something or someone; thought to be supported by the entorhinal and parahippocampal regions; associated with the frontal N400 [FN400] ERP component) and recollection (recall of specific details about a previous encounter; supported by the hippocampus; associated with the late positive complex); τ protein deposition occurs in the medial temporal lobes during stage III and may help researchers understand how familiarity and recollection may be changing in neurodegenerative conditions (eg, CTE, dementia); reduced recollection and familiarity may serve as a behavioral correlate of neurodegeneration, based on other studies noting that familiarity is spared in normal aging but affected in Alzheimer disease (AD); previous studies show reduced recollection and familiarity in individuals with mild cognitive impairment and mild AD, compared with older healthy controls

Assessment of effort in veterans with prior TBIs: core effort during neuropsychological testing decreases the accuracy of findings and complicates the clinical diagnosis of TBI, representing a potential barrier to diagnosis in younger veterans; one study showed that P3b target amplitude predicted cognitive status regardless of behavioral effort and outcome; ERPs are non-manipulatable measures that allow reliable detection of different populations when combined with standard measures of effort

Diagnostic updates

Magnetic resonance imaging: may reveal white matter microhemorrhages following TBI; though magnetic resonance imaging (MRI) is not currently used in clinical settings due to lack of correlation between imaging findings and cognitive outcomes (secondary to low sensitivity and specificity); Piantino et al (2020) — noted a positive correlation between number of mTBIs sustained and number and volume of periventricular spaces (PVSs) visible on MRI; poor sleep quality increases PVS with each subsequent mTBI exposure; possible mechanisms include impaired glymphatic clearance of inappropriate or misfolded proteins (eg, τ); Martindale et al (2021) — blast pressure exposure is independently associated with hippocampal volume loss after correcting for PTSD and other mTBI exposures

Cerebrospinal fluid measures: Turk et al (2021) — found elevated postmortem levels of phosphorylated τ₂₃₁ (p-τ₂₃₁) and decreased postmortem levels of amyloid-ß peptide 42 (Aß₄₂) in patients with early-stage and late-stage CTE, compared with controls and patients with AD; levels help distinguish between AD and CTE; Clark et al (2021) — total tau (t-τ) and p-τ CSF levels are increased in older veterans with remote TBI after controlling for age and ApoE4 status; no relationship was noted with regard to levels of Aß₄₂; correlations were noted within the TBI group between processing speed and higher levels of p-τ and t-τ

Readings

Ally BA, Gold CA, Budson AE. An evaluation of recollection and familiarity in Alzheimer's disease and mild cognitive impairment using receiver operating characteristics. Brain Cogn. 2009;69(3):504-13. doi: 10.1016/j.bandc.2008.11.003; Campbell AM, Elbogen EB, Johnson JL, et al. Event related potentials indexing the influence of emotion on cognitive processing in veterans with comorbid post-traumatic stress disorder and traumatic brain injury. Clin Neurophysiol. 2021;132(7):1389-1397. doi: 10.1016/j.clinph.2021.03.017; Clark AL, Weigand AJ, Bangen KJ, et al. Higher cerebrospinal fluid tau is associated with history of traumatic brain injury and reduced processing speed in Vietnam-era veterans: a Department of Defense Alzheimer's Disease Neuroimaging Initiative (DOD-ADNI) study. Alzheimers Dement (Amst). 2021;13(1):e12239. doi:10.1002/dad2.12239; Clausen AN, Bouchard HC; VA Mid-Atlantic MIRECC Workgroup, et al. Assessment of neuropsychological function in veterans with blast-related mild traumatic brain injury and subconcussive blast exposure. Front Psychol. 2021;12:686330. doi:10.3389/fpsyg.2021.686330; Gardner RC, Burke JF, Nettiksimmons J, et al. Dementia risk after traumatic brain injury vs nonbrain trauma: the role of age and severity. JAMA Neurol. 2014; 71(12):1490-1497. doi:10.1001/jamaneurol.2014.2668; Korgaonkar MS, Williamson T, Bryant RA. Neural activity during response inhibition in mild traumatic brain injury and posttraumatic stress disorder. Neurobiol Stress. 2021;14:100308. doi: 10.1016/j.ynstr.2021.100308; Martindale SL, Shura RD, Rostami R, et al. Research letter: blast exposure and brain volume. J HeadTrauma Rehabil. 2021;36(6):424-428. doi:10.1097/HTR.0000000000000660; Merritt VC, Lange RT, Lippa SM, et al. Apolipoprotein e (APOE) ε4 genotype influences memory performance following remote traumatic brain injury in U.S. military service members and veterans. Brain Cogn. 2021; 154:105790. doi:10.1016/j.bandc.2021.105790; Piantino J, Schwartz DL, Luther M, et al. Link between mild traumatic brain injury, poor sleep, and magnetic resonance imaging: visible perivascular spaces in veterans. J Neurotrauma. 2021;38(17):2391-2399. doi:10.1089/neu.2020.7447; Staresina BP, Duncan KD, Davachi L. Perirhinal and parahippocampal cortices differentially contribute to later recollection of object- and scene-related event details. J Neurosci. 2011;31(24):8739-8747. doi:10.1523/JNEUROSCI.4978-10.2011; Turk KW, Marin A, Schiloski KA, et al. Head injury exposure in veterans presenting to memory disorders clinic: an observational study of clinical characteristics and relationship of event-related potentials and imaging markers. Front Neurol. 2021;12:626767. doi:10.3389/fneur.2021.626767; Turk KW, Geada A, Alvarez VE, et al. A comparison between tau and amyloid-β cerebrospinal fluid biomarkers in chronic traumatic encephalopathy and Alzheimer disease. Alzheimers Res Ther. 2022;14(1):28. doi:10.1186/s13195-022-00976-y.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Turk was recorded virtually at Virtual 6th Annual Chronic Traumatic Encephalopathy Conference, held on October 27, 2022 and presented by Boston University School of Medicine. For information about upcoming CME activities from this presenter, please visit https://cme.bu.edu/. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

NE140301

Expiration:

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