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One fact is that other injuries often co-occur with traumatic brain Injury (TBI), thus event related potentials (ERPs) elicited using electroencephalography (EEG) machines like NeuralScan by Medeia often reflect the sum of both injuries. The second fact is that cognitive function includes domains from knowledge, attention, memory and working memory, judgment and evaluation, reasoning and “computation” to problem solving and decision-making. The third is that cross-border mental or neurocognitive or non-traumatic brain disorders that exhibit similar symptoms post-TBI will exhibit impairments in similar domains. Therefore, what if observing similar a) altered EEG-functional connectivity in post-TBI as in Alzheimer’s, epileptic seizures, schizophrenia, stroke etc or b) altered network geometries in postTBI as in CNS tumors, depression etc is the status quo? What if the reason we are not able to identify pathognomic ERP-markers of cognitive impairment post-TBI that are highly specific and sensitive is simply because we are not thinking as the brain does? What if trying to validate ERP markers of TBI-severity and cognitive function post-TBI in the same manner one validates a candidate diagnostic test is what’s wrong in the first place? Is it possible that domainand symptom-based identification, management and treatment of cognitive-impairments or TBI-severity are the way to go? *Correspondence to: Jonathan RT Lakey, PhD, MSM, Department of Surgery, 333 City Blvd West, Suite 1600, Orange, CA 92868, USA, E-mail: jlakey@uci.edu Received: March 11, 2020; Accepted: April 06, 2020; Published: April 10, 2020 Introduction Three key features influencing traumatic brain injury (TBI), management and rehabilitation outcomes are; a) psychiatric post-TBI sequelae, b) neurological and neuropsychiatric post-TBI sequelae and c) other injuries co-existing with TBI. The prevalence of some of the psychiatric post-TBI sequelae include; depression: 18.5%–61%, mania: 4.20%, obsessive-compulsive disorder (OCD):1.6%–15%, posttraumatic stress disorder (PTSD): 3%–27.1%, psychosis: 0.7%, alcohol-related disorders: 34.9%–51%, and that of personality changes like, apathy: 34.5%, affective lability: 5%–32.7%, aggression: 16.4%–33.7% [1-11]. Computerized tomography (CT) imaging of individuals with depression following TBI exhibited decreased bilateral hippocampal and left prefrontal grey matter volume and lesions in the left frontal, dorsolateral and basal ganglia [12-15]. Subjects with mania post-TBI had seizures and showed temporal basal pole lesions [16-18]. Individuals with OCD following TBI showed damage in the oribitofrontal and cingulate cortex and caudate nucleus [19-21]. Similarly in cases of PTSD post-TBI cerebrospinal fluid (CSF) of S–100B levels increased [22]. Psychosis post-TBI with frontal and temporal lobe damage had electroencephalography (EEG) abnormalities; seizures and cognitive impairment was global [23-27]. Individuals with alcohol-related disorders post-TBI showed generalized brain atrophy, reduction in prefrontal cortical (PFC) volume and EEG studies revealed changes in their event-related potential (ERP) patterns; however these patterns returned to no-alcohol-consumption post-TBI patterns if individuals observed abstinence from alcohol (28-30). Personality changes like apathy seen in individuals post-TBI was characterized by subcortical damage while those with, affective lability and aggression exhibited frontal lobe damage [11,28-33]. Neurological and neuropsychiatric post-TBI sequelae seen include neurodegenerative diseases (Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)), attentiondeficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and schizophrenia [34-45]. The homology between TBI and its psychiatric, neurological and neuropsychiatric post-TBI sequelae has been found to extend from its symptoms, to cortical regions involved, to functional connectivity and synchronization of EEGs to exist between genomic signatures (in a landmark study in 2017) from blood and brain (Figure 1a) [46]. The study used a rodent TBI model to illustrate how TBI imposed a predisposition to the post-TBI psychiatric, neurological and neuropsychiatric sequelae seen. The finding was that TBI affected gene regulatory mechanisms (key driver (KD) genes) involved in cerebral homeostasis influencing epigenomic programming, splicing and transcription factors, and novel network regulators. Simply put, TBI affected KD genes adversely resulting in an increased predisposition to developing ADHD, ASD, PD, AD, PTSD, epilepsy/seizures, stroke, depression and schizophrenia post-TBI. Another confounding factor in most TBI studies is that while most TBI studies compare healthy controls versus those with TBI, none clearly stipulate that individuals with only TBI and no other general injury were studied [47]. However, it is natural that cortical EEG, qEEG patterns would reflect the sum of both TBI and general injuries an Miranda P (2020) Event-related-potential (ERP) markers of traumatic brain injury (TBI) severity and cognitive function – Understanding how the brain works and thinks post TBI J Syst Integr Neurosci, 2020 doi: 10.15761/JSIN.1000225 Volume 7: 2-12 individual has sustained or is recovering from as illustrated in (Figure 1b). Post-TBI symptoms experienced by individuals with TBI range from mild to severe range from nausea, confusion, dizziness, blurred vision, headaches, agitation, to mood changes while neurocognitive impairments range from memory, attention, executive functioning, to processing speed [48-53]. These symptoms can persist from a few days, weeks, months, and years to a lifetime [48,49]. There are tests to assess post-TBI symptoms due to moderate and severe TBI [54-59]. Mild TBI still poses a problem as its symptoms manifest later in certain instances or are transient, nevertheless the symptoms can affect the quality of life, education, employment, performance, the social and relationship domain and in some cases even endanger life [48,49]. However as early as 1993 it was clearly established that post-trauma consequences of mTBI were not always mild and that electrophysiology (EEG) could contribute significantly to a better understanding, management and treatment of the same [50]. In instances where impairments require more sensitive and fine-grained tests using EEG and event-related potentials (ERPs) could provide an endogenous viewpoint of cognitive processes and changes in cortical function, aspects that imaging cannot capture. In this context the present paper examines if domainand symptom-based EEG and ERP markers of cognitive-impairments or TBI-severity using EEG machines like NeuralScan by Medeia would be a more appropriate approach. Auditory evoked potentials (AEPs) The cognitive domains memory, attention, and processing speed are most commonly affected following TBI [51-53]. Alterations/ impairments in these domains can be accessed via the neural correlates of the auditory system to which they are innately intertwined via AEPs [54-61]. Figure 2a presents the AEP components (adapted from Gaetz & Bernstein, 2001) that include early AEPs (auditory brainstem response (ABR), complex ABR (cABR)), auditory middle latency response (AMLR), and auditory late latency response (ALLR) [51,62]. Figure 3 presents an illustrated example of how AEPs can be recorded using EEG machines like NeuralScan. Among click-evoked ABR studies; latencies and amplitude of waveforms-I, -III, and -V were similar for mTBI (n=19) and no TBI (n=29) in a study by Gallun et al., concussed (n=11) showed a delayed wave-III latency versus control (n=12) participants and reduced interpeak latency difference was seen in mTBI (n=15) versus 35 controls [63-65]. FFR a component of the complex ABR was reduced and slower responses to fundamental frequency (F0) and poor pitch coding was seen in concussion (n=20) versus control (n=20) participants in a study by Kraus et al. [66]. In terms of click-evoked ABR and AMLR studies: Munjal, Panda, and Pathak studied 50 controls versus mTBI=100, moderate TBI=150, severe TBI=40) [67]. With severity of TBI wave-latency and I-V interpeak latency of ABR increased while AMLR's showed decreased amplitude of Na and Pa components [66]. Soustiel et al. found prolonged Na and Pa waveforms in 15 of the 40 mTBI participants versus 23 controls, while Drake et al. found prolonged latency of Pa and reduced amplitude of Pa and Na waveforms in 20 participants with mTBI versus 20 controls [68,69]. A pulse-evoked AMLR study by Arciniegas et al. on mTBI=5, moderate TBI=6, severe TBI=9 versus 20 control showed significant differences in P50 amplitude and P50 ratio between mTBI and controls [70]. Figure 1. Factoring in Homology and the other-injury factor when looking for markers of TBIand neurocognition [46,47] Figure 2. Auditory evoked potentials (AEPs) Miranda P (2020) Event-related-potential (ERP) markers of traumatic brain injury (TBI) severity and cognitive function – Understanding how the brain works and thinks post TBI J Syst Integr Neurosci, 2020 doi: 10.15761/JSIN.1000225 Volume 7: 3-12 AERPs evoked using auditory oddball tasks showed overall prolonged P3 latencies and reduced amplitude of N1, P2, and P3 waveforms in concussed (n=40) groups study by Gosselin et al. [71]. However, smaller P2 amplitudes were seen in 20 symptomatic versus 20 asymptomatic collegiate athletes versus 20 control participants. Solbakk et al. observed reduced N2 and P3 amplitudes in mTBI (n=15) participants versus 13 controls [72]. Decrease P3b amplitude with increased latency was observed by Pratap-Chand et al. in 20 participants with mTBI versus 20 matched controls [73]. Segalowitz et al. used four auditory oddball tasks to elicit AERPs [74]. Reduced amplitudes of P3a and P3b were observed in 10 participants with mTBI versus 12 controls. High school athletes (n=30) were studied by Thériault et al. [75]. Small

journal of systems and integrative neuroscience

Event-related-potential (ERP) markers of traumatic brain injury (TBI) severity and cognitive function – Understanding how the brain works and thinks post TBI