Electrophysiologic Assessment of Mild TBI

Electrophysiologic Assessment of Mild TBI David B. Arciniegas, MD Medical Director, Brain Injury Rehabilitation Unit HealthONE Spalding Rehabilitation Hospital Director, Neurobehavioral Disorders Program Associate Professor of Psychiatry and Neurology University of Colorado School of Medicine

Electrophysiology and TBI Clinical electrophysiology offers a variety of powerful and informative methods by which to study cerebral function and dysfunction after mild traumatic brain injury (TBI) Electroencephalography (EEG) was the first clinical diagnostic tool to provide evidence of abnormal brain function due to TBI (1-3)

Electrophysiology and TBI Such early observations laid the foundation for continued investigation of mild TBI using more sophisticated electrophysiological assessment and investigative techniques as they developed Quantitative EEG (QEEG) and brain electrical activity mapping (BEAM) Evoked potentials (EPs) Event-related potentials (ERPs) Magnetoencephalography (MEG) and magnetic source imaging (MSI)

Spatial Resolution (log millimeter) Spatiotemporal Resolution Comparisons Brain EEG MEG PET and SPECT FMRI Ion Channel Optical Dyes Single Unit Patch Clamp Highly Invasive Slightly Invasive Non-Invasive Millisecond Time Resolution (log msec) Hour

Electrophysiology and TBI There have been attempts by some manufacturers to develop and market ready-to-use electrophysiologic assessment technologies for the purpose of diagnosing mild TBI However, the use of such technologies (and the literature upon which that use is predicated) is not a simple matter

Outline Review briefly the principles of clinical electrophysiology and common electrophysiologic assessment techniques Survey findings from studies of persons with mild TBI using these techniques Discuss limitations of these technologies and their applications to-date Suggest future directions regarding the role electrophysiologic assessment in the study and treatment of persons with mild TBI

Neurophysiologic Basis of Electrophysiologic Recordings The cerebral cortex is organized into six distinct layers, or laminae These layers are numbered I-VI from outside (cortical surface) to inside (gray-white junction) These layers develop as neurons migrate during neurogenesis The apical dendrites of the pyramidal cells (in the molecular layer) are connected to neurons in lower layers in a columnar fashion

Electrochemical Activity within Cortical Columns Cortical columns are oriented radially with respect to the most superficial aspect of the cortical mantle The EPSPs and IPSPs at the dendrites of these cortical columns generate electrical dipoles A. B. A. Gyral dipoles project radially with respect to the surface of the head immediately overlying them B. Sulcal dipoles project tangentially with respect to the surface of the head immediately overlying them Source: Arciniegas, Anderson, and Rojas 2005

Reticulothalamocortical Circuits Cortex Thalamocortical (glutamate) GABA Thalamus Reticular Excitatory Inhibitory Sensory relay Reticulothalamic (cholinergic) Reticulocortical (DA, NE, 5-HT, ACh) (Adapted from Mesulam 2000)

Neurophysiologic Rhythms In clinical electrophysiological recordings, cerebral neurophysiologic rhythms are organized into four categories: beta (12.5 25 Hz) alpha (7.5 12.5 Hz) theta (4 7.5 Hz) delta (< 4 Hz) These rhythms reflect different states of engagement of cortical neurons within the local groups, corticothalamic circuits, and reticulothalamocortical networks in which they participate

Neurophysiologic Rhythms Both fast and slow cortical rhythms are generated during wakefulness however, faster rhythms are the predominant types in awake adults Background rhythm (the rhythm of the awake brain at rest) usually alpha in the awake record of adults slower background rhythms (slowing) in the awake record of adults are generally abnormal

Clinical Neurophysiologic Recording Methods Electroencephalography Quantitative EEG (QEEG) and brain electrical activity mapping (BEAM) Evoked potentials (EPs) Event-related potentials (ERPs) Magnetoencephalography (MEG) and magnetic source imaging (MSI)

Electrical vs. Magnetic Recording EEG, QEEG, EP, and ERP techniques record electrical activity radial > tangential MEG and MSI record magnetic activity tangential > radial

EEG and Quantitative EEG Standardized recording methods (the 10-20 International System of Electrode Placement) are used Various arrangements of recording channels create views (montages) of cortical electrical activity Analysis of findings within and between these montages is used to identify and localize abnormal activity Digital recording combined with software-assisted analytic methods permits quantitative EEG (QEEG) analyses A: Referential montage B: Bipolar montage C: transverse bipolar montage

Quantitative EEG Typical data derived from QEEG spectral analysis: frequency composition over a given period absolute and relative amplitude within a frequency range or at specific channels: µv/cycle/second absolute and relative power within a frequency range or at specific channels: µv 2 /cycle/second coherence: analogous to cross-correlation in the frequency domain between activity in two channels phase: a measure of timing of activity between two channels symmetry: between homologous pairs of electrodes

Evoked and Event-Related Potentials Evoked potentials (EPs) reflect automatic sensory information processing along the pathways from sensation to primary sensory cortex Event-related potentials (ERPs) are regarded as reflecting later and more complex cognitive, sensory, or motor information processing The distinction between EPs and ERPs is somewhat arbitrary, but EPs develop 1 150 ms post-stimulus ERPs develop 70 500 ms post-stimulus

Evoked and Event-Related Potentials EPs and ERPs are named according to their: polarity (P or N) latency (ms) post-stimulus the sensory or motor modality in which they are evoked

Magnetoencephalography A cerebral neurophysiologic recording technique that is complementary to EEG Superconducting quantum interference devices used to record cortically generated magnetic fields through current induction As with EEG, pairing magnetic field detectors creates channels for signal recording and these channels can be arranged to create recording montages May be used to measure magnetic evoked fields (EFs), analogous to recording EPs

Magnetoencephalography MEG is an attractive technique with which to evaluate cerebral dysfunction after TBI However, its availability and application to TBI research and clinical practice are limited by: the equipment (very expensive) need for a magnetically shielded environment in which to record MEG (very expensive) the engineering and operational costs of MEG recording systems (very expensive) the expertise needed to interpret MEG data

EEG and Mild TBI Generalized or focal slowing and attenuated posterior alpha may occur in the first several hours after mild TBI among adults (5;6) Geets et al. (1983) (7) recorded EEG within 48 hours of documented mild TBI and found abnormalities in: LOC < 2 minutes: 17% of 100 subjects LOC > 2 minutes: 56% of 25 subjects

EEG and Mild TBI Similar frequencies (15-51%) of EEG abnormalities after mild TBI are reported elsewhere (8-12), but are not always seen (8;9;13;14) Typical findings include slowing, generalized bursts, and focal abnormalities slowing, when present, may still be in the normal range (low alpha) and evident only when compared to late post-injury EEG

EEG and Mild TBI EEG abnormalities often resolve completely within three months post-injury (11;12) and remain in as few as 10% of individuals with mild TBI at 1-year post injury poor correspondence between clinical and EEG findings throughout the post-injury period (6) poor correspondence between EEG and CT, MRI, or SPECT abnormalities (6;15) a low voltage posterior alpha EEG pattern is as likely a sign of anxiety as it is a sequela of mild TBI (6)

EEG and Mild TBI The presence or absence of EEG abnormalities after the acute post-injury period following mild TBI is of uncertain clinical significance in many cases Routine use of EEG in the clinical assessment of persons with mild TBI is not recommended When used at all, it is probably best reserved for use in the evaluation for EEG correlates of posttraumatic epilepsy

QEEG and Mild TBI QEEG has been used: to investigate posttraumatic cerebral dysfunction as a diagnostic assessment for mild TBI as a metric for the evaluation and prediction of outcome following mild TBI Given the scope and complexity of the literature on this subject (see [6;16]), the review of QEEG and mild TBI presented here focuses on a limited set of findings and controversies

QEEG Findings Mild TBI QEEG has been used to define the types and/or patterns of EEG abnormalities among persons with mild TBI (12;17-22) Among the most consistently reported (23-25) QEEG findings in mild TBI are: increased coherence and decreased phase between frontal and temporal areas reduced differences in alpha and beta power between anterior and posterior cortical regions reduced alpha power posteriorly

QEEG and MRI (27-29) White matter T2 relaxations times inversely correlated with decreased short-distance coherence and positively correlated with longer-distance coherence correlate with increased frontal polar delta amplitude Gray matter T2 relaxation times correlate with increased slow frequencies, well defined alpha peak frequency, and decreased left temporal alpha and beta amplitude correlate more strongly with decrease anteroposterior alpha coherence than do white matter T2 relaxation times The QEEG-MRI findings were interpreted as reflecting reduced integrity of the protein/lipid neural membranes and diminished efficiency of neural systems following mild TBI

QEEG and DAI Kane et al. (1998) (30) investigated the relationship between QEEG and autopsy-confirmed DAI in 10 subjects with severe TBI the only correlation was between DAI and interhemispheric coherence in the alpha band at the temporo-occipital site no other QEEG-DAI relationships were observed Although drawn from a small sample size, the failure to find an electrophysiologic-pathological relationship between QEEG indices, and particularly coherence, and DAI after severe TBI raises concerns about the validity of suggesting such a relationship in mild TBI

QEEG and Neurobiology of Mild TBI Nonetheless, relatively consistent observations across studies and laboratories suggest the possibility that additional study may yield insights regarding the neurobiology of mild TBI Additional research is needed to determine whether QEEG findings: correspond to other neuroimaging, neuropathology, and clinical (symptoms, cognition) obtain at the group level, at the single-subject level, or both offer information regarding prognosis and/or treatment selection

QEEG and Neuropsychiatric Sequelae of Mild TBI Very few studies employ QEEG to investigate the neurophysiologic correlates of posttraumatic neuropsychiatric symptoms Among problems that have been studied include: posttraumatic sleep disturbances (38;39) hostility (40) treatment-resistant depression (41) the postconcussive syndrome (17;19;22;42)

QEEG and PCS Montgomery et al. (1991) (20) studied 26 men admitted to hospital after a mild TBI (PTA < 12 hours) Subjects were studied clinically and electrophysiologicall at day baseline and week 6, and clinically at 6 months post-tbi Reported excess of bitemporoparietal theta initially that resolved in most subjects by 6 weeks Although a minority had persistent symptoms at six month, brainstem EPs were more strongly related to this finding than was QEEG

QEEG and PCS Watson et al. (1995) (17) studied 26 men admitted to the ED after a mild TBI (PTA < 12 hours) Subjects were studied at day 0, day 10, week 6, and 1 year post-tbi They reported significantly decreased alpha-theta ratio between post-injury days 0 and 10 by day 10, a baseline level was established

Watson et al. (1995) cont. QEEG recovery correlated with symptom counts six weeks post-injury Slower electrophysiologic recovery was associated with more severe postconcussive symptoms Relative delay in left temporal recovery was associated with residual psychiatric morbidity (Present State Examination scores) at 12 months post-injury

QEEG and PCS Chen et al. (2006) (43) compared 60 subjects (within 24 hrs of TBI) and 30 healthy controls TBI subjects had: significant increases in the average power of low alpha (8-9.8 Hz) an increased low alpha/high alpha ratio reduced theta/low alpha and increased theta/high alpha ratios Findings suggests a traumatically-related shift to lower alpha frequency

Chen et al. (2006) cont. After 3 months, 5% of subjects continued to demonstrate this pattern of QEEG abnormality Chen et al. suggested this pattern might constitute a neurophysiological bases for persistent postconcussive symptoms Unfortunately, their suggestion was not coupled with presentation of PCS symptoms vs. QEEG findings at their 3-month follow-up

QEEG and PCS Korn et al. (2005) (22) studied 17 subjects with mild TBI (GCS >12) who were > 1 month post-injury and had symptoms consistent with ICD-10 PCS Report increased delta (1.5 5 Hz) and decreased alpha (8.5 12 Hz) power among subjects with persistent postconcussive symptoms QEEG abnormalities were focal and widely distributed throughout neocortical areas, and corresponded to SPECT-derived evidence of blood brain barrier breakdown

QEEG, PCS, and Neuropsychiatric Symptoms QEEG investigations of the neurophysiologic correlates of posttraumatic neuropsychiatric and/or functional problems may yield information that informs on the neurobiology of such problems and therefore also their treatment It is possible that QEEG may offer information regarding neurophysiologic recovery QEEG findings might be used to predict treatment response, whether to pharmacologic or other rehabilitative interventions Additional studies addressing these issues are needed

QEEG as a Mild TBI Diagnostic Study QEEG findings were used to develop diagnostic discriminant functions (23-25;31) statistically-based pattern recognition on QEEG data renders a probability statement regarding the likelihood of that pattern fitting best with one diagnosis (mtbi) or another (normal) It has been suggested that these QEEG-based diagnostic discriminant functions might be useful clinically and medicolegally

QEEG as a Mild TBI Diagnostic Study The most widely discussed mild TBI discriminant function (23-25) makes a number of counterintuitive claims, the most concerning of which are that the QEEG data are unaffected by drowsiness, sleep, or medications well known to affect EEG When applied by Thornton (1999) to 39 subject with and without TBI, the Thatcher diagnostic discriminant function yielded: positive in 81% of patients who had no LOC positive in 71% patients who had LOC false positive rate of 52% on prospectively tested normal subjects

QEEG as a Mild TBI Diagnostic Study These QEEG discriminant functions do not address the more important clinical question of differential diagnosis At least one of the QEEG variables that discriminates between mild TBI and normal controls (especially decreased posterior alpha amplitude and power and increased theta) is present among subjects with anxiety It seems likely that this or other variables will also be present in other neuropsychiatric conditions (e.g., depression, substance abuse, headache, etc.) (6;32)

QEEG as a Mild TBI Diagnostic Study Prospective, blinded, replication studies performed by independent investigators without relevant commercial conflicts of interest are needed to: ascertain the accuracy of the presently-available TBI discriminant functions clarify the variables to be entered into QEEG diagnostic discriminant functions resolve the influence of confounds (drowsiness, sleep, psychoactive medications) on QEEG data determine whether these discriminant functions distinguishes TBI from other neuropsychiatric conditions Until such studies are published, routine use of mild TBI QEEG discriminant functions is not recommended (6;33;34)

EPs, ERPs, and Mild TBI Short latency EPs of various types have been used to investigate mild TBI, PCS, and specific postconcussive symptoms When studies report positive findings using shortlatency EPs, most identify such abnormalities in only 10-30% of persons with mild TBI (21; 45-54) the most common finding in delayed latency reduced amplitude is also described Mild TBI can produce EP abnormalities similar in type to those seen after severe TBI, but does so infrequently

EPs, ERPs, and Mild TBI Among persons with postconcussive symptoms, the relationship between short-latency EPs and such symptoms is variable (16;48;50;55;56) Freed and Hellerstein (1997) (57) observe visual EP abnormalities in 78% of patients with mild TBI presenting for optometric rehabilitation 12-18 months later, the same VEP abnormalities were still present in 78% of patients that had not been treated but only 38% of patients treated optometrically nature of the relationship is not clear, but merits further study

EPs, ERPs, and Mild TBI TBI and P50 suppression studies in our laboratory P50 physiology (Arciniegas et al. 1999; 58) and frequency of abnormal findings (59) P50 physiology and hippocampal volumetric correlation (Arciniegas et al. 2001) Pharmacologic probe study of P50 physiology (59)

Study Hypotheses 1) Subjects with TBI and symptoms of impaired auditory gating, attention, and memory will be nonsuppressors of the P50 evoked waveform response to paired auditory stimuli 2) Subjects with TBI and symptoms of impaired auditory gating, attention, and memory will demonstrate hippocampal volume reductions on magnetic resonance imaging as compared to normal controls 3) Cholinergic augmentation strategies in affected patients will normalize P50 suppression

Study 1a: P50 ratio (TBI vs. control) Box-whisker plot of P50 ratio differences between the TBI and control groups using the nonparametric Kolmogorov- Smirnov test. TBI group in this plot includes subjects with mild, moderate, and severe TBI, and demonstrates a significant difference (p<.001) in P50 ratio between the groups. Box-whisker plot of the effect of group on P50 ratio using MANOVA (p<.001). Planned post-hoc comparisons using Tukey s HSD test for unequal sample sizes demonstrates significant differences between each TBI sub-group and the control group (p<.001 for each comparison) and no statistically significant differences between the TBI subgroups. Arciniegas et al. 2000

Study 1b: P50 ratio findings in TBI 41 subjects (85.4%) with usable P50 data P50 suppression: 7.3% mildly abnormal P50 suppression: 12.2% markedly abnormal P50 nonsuppression: 81.5% Arciniegas et al. 2004

Study 2: P50 Ratios and Hippocampal Volumes Analysis of the effect of group (n=10 each) on hippocampal volume using a two-way ANCOVA, with total brain volume as the covariate. There is a highly significant overall effect of group on hippocampal volume (F=11.9, df(1,17), p<.003). There is no group by hemisphere interaction, suggesting that the bilateral hippocampal volume loss in the TBI group is relatively symmetric. Analysis of the effect of group (NC=10, m/mtbi=4, stbi=6) on hippocampal volume using a two-way ANCOVA, with total brain volume as the covariate. There is a significant effect of group on hippocampal volume (F=5.8, df(2,16), p<.015). There are significant differences in hippocampal volumes between each TBI group and the normal comparison group, but not between TBI groups. No group by hemisphere interaction. Arciniegas et al. 2001

Study 3: Pharmacologic Probe Study 10 subjects (9 women) with persistent post-tbi gating, attention, and memory complaints 8 mild TBI 2 > mild TBI All P50 nonsuppressors Mean SD Median Age 45.3 9 49 Gender 1.9 Education 16 2.6 16.5 Time since injury 9.4 11.9 5 Duration of PTA 71 139 3.5 MMSE 29.1 1.1 29.5 Subjects randomized into a double-blind, placebo-controlled, crossover design study donepezil HCl 5 mg daily x 6 weeks, followed by donepezil HCl 10 mg daily x 6 weeks, then crossover to placebo with identical titration schedule OR placebo x 6 weeks, followed by another placebo x 6 weeks, then crossover to donepezil 5 mg x 6 weeks, followed by donepezil 10 mg x 6 weeks Arciniegas et al. 2004

Study 3: Pharmacologic Probe Study There was a significant effect of treatment condition on P50 ratio (F=4.7, df=4,36, p<.004), with relative normalization of P50 ratio during treatment with low-dose donepezil HCl but not high-dose donepezil HCl or placebo. Post-hoc analysis demonstrates a significant difference between donepezil HCl 5mg at all other conditions, but no difference between those other conditions. Cholinesterase inhibition using low-dose donepezil normalized P50 nonsuppression in 60% of subjects treated in this study. Arciniegas et al. 2004

Summary and Implications of P50 Studies P50 nonsuppression and hippocampal volume loss are associated with persistent posttraumatic gating, attention, and memory complaints The presence of these cognitive complaints predicted electrophysiologic and structural abnormality regardless of initial injury severity Cholinergic augmentation using donepezil HCl significantly improved P50 suppression Findings are consistent with the cholinergic hypothesis of posttraumatic cognitive impairment

EPs, ERPs, and Mild TBI Long-latency EPs/ERPs are widely regarded as markers of cortically-mediated stimulus detection, categorization, attention, and allocation of cerebral resources for cognitive tasks Long-latency EPs and ERPs have been used extensively in the study of TBI-related cognitive impairments and the postconcussive syndrome (55;60;62-76)

Long-Latency ERPs Abnormalities of the N2, P300, and other ERPs suggest reduced and inefficient allocation of attentional processing resources after mild TBI P300a findings delayed development: slowed novel stimulus detection reduced amplitude: inadequate allocation of attentional resources to novelty detection (e.g., inattention) increased amplitude (frontal lobe lesions [63]): excessive allocation of attention processing resources to novelty detection (e.g., distractibility) functional recovery may occur with normalization of P300 latency and amplitude (60;76) or despite chronically reduced P300 amplitudes (70;75)

Long-Latency ERPs P300 ERP abnormalities, like P50 ERP abnormalities, may persist into the late post-injury period Decreased amplitude and prolonged latency of the P300 occur under conditions of relative cholinergic depletion (77) P300 abnormalities may be normalized during administration of cholinesterase inhibitors (78;79)

Long-Latency ERPs Pratap-Chand et al. (1988) (60) noted the links between posttraumatic cholinergic dysfunction, P300 abnormalities, cognitive dysfunction suggested use of the P300a as a metric in the investigation cholinergic pharmacotherapies for posttraumatic cognitive dysfunction echoes (heralds, actually) our studies using the P50 ERP for this purpose

Long-Latency ERPs Additional investigations clarifying these electrophysiological-neurochemical relationships are needed Their results may suggest a role for EPs and ERPs in the identification of neurochemical dysfunction and the selection of treatments for cognitive impairment due to TBI

Summary Clinical electrophysiology offers many noninvasive methods with which to studying cerebral dysfunction after mild TBI The temporal resolution of electrophysiologic assessment methods exceeds that of other advanced neuroimaging techniques, though at the cost of comparable spatial resolution

Summary Electrophysiologic assessment methods may yield data that supports a clinical diagnosis of mild TBI findings from these measures are not specific to TBI, but instead reflect any number of conditions that disturb brain function None of these technologies is used appropriately at present as a stand-alone diagnostic test

Summary These technologies are used best in the investigatation of the neurobiological bases of specific posttraumatic neuropsychiatric problems due to mild TBI Among these, middle- and long-latency ERPs, QEEG, and MEG appear to offer the greatest promise

Summary Electrophysiologic investigations may particularly fruitful if they yield information that: better defines the neurobiology of the posttraumatic symptom in question guides pharmacological and rehabilitative interventions give rise to markers that identify individuals best suited to specific treatment a priori distinguishes between treatment responders vs. non-responders

Acknowledgements Lawrence E. Adler, MD Jeannie Topkoff, BS, BSN C. Alan Anderson, MD Christopher M. Filley, MD Veterans Health Administration HealthONE Spalding Rehabilitation Hospital