Steven S. L. Pan Jerry Y. P. Chiang
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absent SEPs had very high positive predictive values (92–100 percent) for unfavorable outcome. In children with TBI, the likelihood of awakening from coma despite bilaterally absent SEP response was approximately 7 percent (10, 15). In a recent study by Lew et al. (6), bilat-eral absence of cortically recorded median nerve SEP within 8 days of severe TBI (Glasgow Coma Scale 8) was strongly predictive (p 0.005) of the worst functional outcome, namely, death or persistent vegetative state. In the above study, specificity and positive predictive values of absent SEP response for death or persistent vegetative state were as high as 100 percent at 6 months post-TBI.
In addition to SEP, there have been efforts to com-bine other evoked potential studies using so called “multi-modality evoked potentials.” Shin et al. performed BAEP and SEP in TBI patients, and compared the results with clin-ical outcome (11). Although neither of the electrophysio-logic measurements showed significant correlation with the cognitive level at a one-year follow-up, SEP increased the predictive value of initial clinical parameters including Ran-cho Los Amigos Scale or age. As for visual evoked poten-tial (VEP), it has been utilized independently to evaluate visual impairment such as post-traumatic vision syndrome after brain injury (17, 18).
Several factors must be taken into consideration dur-ing the interpretation and analysis of the SEP waveform.
For example, peripheral neuropathy of the nerve being stimulated may prolong the latency of cortically recorded potentials. Evoked responses recorded from the brainstem and cervical spine should be reviewed to rule out con-current spinal cord injury. To distinguish central pathol-ogy from peripheral patholpathol-ogy, central conduction time (from the brainstem or Erb’s point to the cortical level) can be used (19). Increased level of sedation may reduce the amplitude of cortical SEP. Therefore, when the SEP amplitude is too small, it is prudent to repeat the test after removal of sedation (10). All things considered, decisions regarding continuation of life support should not depend totally upon SEP testing, but instead rely on overall
clinical status, together with other laboratory findings and, most of all, family input.
BRAINSTEM AUDITORY EVOKED POTENTIALS
Brainstem Auditory Evoked Potentials (BAEPs, also known as BAER, brainstem auditory evoked response) represent the electrophysiologic response of the central nervous system to repeated click stimuli, and is character-ized by a pattern of 5 neurogenic waves (20). The BAEP wave I originates from the cochlear nerve, and wave II arises from the cochlear nucleus. Waves III, IV, and V orig-inate from the superior olivary complex, lateral lemniscus, and inferior colliculus, respectively. An example of normal BAEP waveform is illustrated in Figure 13-2.
Prolongations of interpeak intervals between I–III, III–V, or I–V have been reported in patients with TBI, (11, 21–24). The most ominous finding is complete absence of a repeatable waveform. In a study on comatose children and adolescents with traumatic brain injury, BAEP abnormality was found to be about 40 percent of the 62 patients tested (25). In a meta-analysis, it was con-cluded that normal BAEP obtained within the first week of TBI onset had a very good prognostic value for awak-ening from coma (26), while EEG did not have much clin-ical utility. However, another independent study showed that the presence of BAEP in post-coma unawareness patients did not have any significant prognostic value, because the presence of normal BAEP in these patients may merely suggest that the brainstem had been spared despite significant injury above the brainstem (27).
In mild TBI, prolongation of BAEP wave I and III latencies had been observed soon after concussion, and prolongation of BAEP interpeak intervals (between wave I and V) had been noted from the first day of TBI (28).
In other studies of persistent post-concussion syndrome, no significant BAEP latency delays were found (29). In more severe cases of TBI, prolonged interpeak interval persisted for several weeks (28, 30, 31). It should also be FIGURE 13-1
Normal SSEP waveforms from stimulation of left median nerve at the wrist
FIGURE 13-2
Normal brainstem auditory evoked potential waveform
ELECTROPHYSIOLOGIC ASSESSMENT TECHNIQUES: EVOKED POTENTIALS AND ELECTROENCEPHALOGRAPHY 159
noted that when more rigorous normative values were applied (abnormality defined as greater than 2.5 SD, rather than 2.0 SD, from the mean), no abnormalities in BAEP were noted after mild TBI (32). Also, in a group of amateur boxers (N = 47) who supposedly had repeated concussions, no differences in BAEP results were observed when compared to other athletes with low risk of TBI (33). There have been several studies on BAEP to deter-mine its correlation with dizziness. In patients with post-concussion syndrome, the BAEP alterations were not associated with dizziness or abnormal vestibular function (34). In another study involving patients with mild head injury, significantly prolonged BAEP latency was observed. However it was not correlated with outcome after 3 months (35).
The value of BAEP for hearing screening has already been established in newborns because of its objective nature and ease of use (36, 37). Due to co-existing cognitive prob-lems, it is sometimes difficult to detect hearing dysfunction in TBI patients, especially in the early stages of recovery (38).
This may result in delays in audiological, surgical, and reha-bilitative interventions. Review of literature from 1975 to 2001 showed that the incidence of hearing problems for var-ious degrees of TBI varied from 7 to 50 percent (25, 39–43).
A recent review of inpatient records from a TBI unit showed that 17 percent of moderate to severe TBI patients showed abnormal behavioral audiograms after the injury (44). If hearing screenings with BAEP were performed prospectively on all moderate-to-severe TBI patients, the incidence could be higher than 17 percent. In a study on 40 TBI patients (22), BAEP results were compared with behavioral audiom-etry, and the authors concluded that BAEP was more diagnostic than pure tone audiometry in the evaluation of brainstem dysfunction. In conclusion, the utility of BAEP in TBI may be limited to evaluation of brainstem dysfunc-tion and hearing impairment (45).
ELECTROENCEPHALOGRAM
Conventional electroencephalogram (EEG) measures electrical activity generated by the brain via surface elec-trode recording. An example of ongoing EEG is illustrated in Figure 13-3. Traditional EEG studies typically involve subjective and qualitative analysis, although efforts are being made to objectively quantify the EEG data, such as Fourier Transform (FT) of the frequency bands. With advances in computer-based signal processing technology, quantitative EEG (QEEG) analyses may gain wider use in evaluating TBI patients (46).
Conventional EEG
There are four basic components in EEG waveforms.
Alpha waves (8–12 Hz) are seen in the awake but relaxed
state, while beta waves (12–30 Hz) are observed in the fully awake state. Delta waves are the slowest waves (less than 4 Hz), which are related to nondreaming deep sleep.
Theta waves (4–8 Hz) also are associated with hypnotic or meditation states of consciousness. These waves are affected by age and recording sites. The pathologic brain wave patterns include focal or generalized spikes observed in patients with convulsive disorders. Other pathologic patterns vary from overall slowing to altered proportion of waves. Burst suppression pattern is characteristically seen during the induction stage of anesthesia. It is typi-cally shown as a mixed pattern of high-voltage bursts and low-voltage suppression period, which are also related to anoxia, coma, and brain damage (47, 48).
EEG patterns have been empirically used to assess the severity of TBI and to predict their functional outcome (49). In 1973, Bricolo (49) reported that EEG is a useful evaluation tool for comatose TBI patients. They found that subjects with “spindle patterns” had relatively favor-able prognosis, and patients with monophasic or slow dis-organized electric activity patterns without response to environmental stimuli had much higher mortality rate.
Synek (50) studied the EEG patterns of patients with cere-bral anoxia or head injury, and concluded that those who responded to external stimuli were usually associated with good outcomes. Some other favorable EEG patterns included normal activity, rhythmic theta activity, frontal rhythmic delta activity, and spindle pattern. On the other hand, epileptiform activity, nonreactive, low-amplitude delta activity, and burst suppression patterns with inter-ruptions of isoelectricity were associated with poor prog-nosis. Needless to say, patients with complete isoelectric EEG activity had the highest mortality.
FIGURE 13-3
Continuous electroencephalography recording by surface electrodes
Although EEG analyses may provide some prog-nostic information for patients with severe TBI, there are issues with their application in mild TBI. Jacome et al.
(51) found no EEG abnormality in 24-hour ambulatory EEG monitoring of mild TBI patients. One and a half decades later, Voller et al. (52) did a combined EEG/MRI study. Again, no EEG abnormalities were observed in mild TBI patients. Even in patients with structural lesion per MRI, no focal change in EEG was noted. Based on the aforementioned studies, conventional EEG analysis is not highly regarded as either a diagnostic or prognostic tool in evaluating the patients with mild TBI.
Quantitative Electroencephalography Quantitative electroencephalography (QEEG) is based on highly sophisticated computation of EEG signals. The fundamental element of QEEG is spectral analysis, which decomposes the complex EEG signal into various com-ponent frequencies. The amount of alpha (8–12 Hz), beta (12–30 Hz), delta (0–4 Hz), and theta (4–8 Hz) compo-nent activity contained in the EEG signals are quantita-tively isolated and stored in digitized format for further analysis. Topographical mapping of different frequency bands (sometimes referred to as BEAM, brain electrical activity mapping) can be made based on the results of spectral analyses. QEEG has clinical value in certain neu-rologic abnormalities such as epilepsy, cerebrovascular disease, and dementia (53). However, experts in neuro-physiology have not completely reached their consensus regarding the clinical utility of QEEG in mild head injury, moderate head injury, or post-concussion syndrome (53–56).
Due to the availability of digital recording and computer-based real-time quantitative analyses, many researchers have devoted their time and efforts to explor-ing QEEG as a tool for evaluatexplor-ing TBI patients. Bricolo et al. (57) first studied comatose TBI patients by spectral EEG analysis. They suggested that interhemispheric fre-quency band asymmetries were associated with poor out-come. In contrast, patients with spontaneous EEG power spectrum variability and persistence or return of EEG activity within the alpha or theta frequency were corre-lated with favorable prognosis. (58, 59).
Comparing the predictive values between QEEG and Glasgow Coma Scale (GCS) in severe TBI patients, Karnaze et al. (60) showed that altered spectral patterns were correlated with better survival, and its predictive value was equivalent to, but not significantly higher than that of GCS. Thatcher et al. (61) compared QEEG, GCS, brainstem auditory evoked potential (BAEP), and Com-puted Tomography (CT) in outcome prediction of 162 comatose TBI patients. EEG phase pattern was demon-strated to be the most prognostic, followed by EEG coher-ence, GCS, and brain CT, respectively. Alster et al. (62)
also demonstrated that spectral EEG analyses were more predictive of brain injury outcomes than GCS and BAEPs.
Thatcher et al. (63) compared QEEG patterns between patients with mild TBI and age-matched controls.
An overall classification accuracy of 94.8 percent was reported. Mild TBI subjects showed increased coherence and reduced phase in frontal and temporal areas, decreased alpha band amplitudes in the parieto-occipital territories, and reduced spectral power difference across anterior/pos-terior cortical regions. Tebano (64) also performed spec-tral EEG analysis in persons with brain injury. Their results showed that mild TBI patients had a shift in peak alpha frequency band toward lower frequency values. Twelve years later, Cudmore (65) also demonstrated that EEG coherence pattern differentiated controls from patients with mild TBI. Increased alpha/theta ratio was observed in mild TBI patients (66), possibly due to reduced theta activity, with relatively stable alpha activities.
In summary, these studies imply that QEEG findings may be better than conventional EEG in studying mild TBI patients. However, inter-research comparison and meta-analysis are problematic due to lack of standardized techniques and inconsistent inclusion/exclusion criteria.
In addition, QEEG analyses are derived from vast amount of data points over various recording electrodes, and researchers typically use multiple analyses to derive the results. Consequently, type I error is a major concern, and multiple inter-electrode comparisons may yield some “sta-tistically significant” but not “clinically meaningful”
results.
PAIN-RELATED POTENTIAL (P250) Deep brain stimulation (DBS) of various brain regions (e.g., mesencephalic reticular formation or the thalamic center median-parafascicular (CM-Pf) complex) has been used to evaluate or even promote recovery from the per-sistent vegetative state (PVS). To monitor clinical utility of DBS, the late positive wave of cortical potentials elicited by painful stimuli (pain-related potential, P250) has been investigated (67–69). In chronic vegetative state, the depressed P250 was temporarily enhanced by DBS.
A persistent enhancement of the P250 was also correlated with better clinical outcome (67). The P250 may provide objective and quantitative information regarding the level of cortical responsiveness to painful stimuli in persons in low level neurological states following brain injury.
P50
The P50-evoked response is the event-related potential (ERP) response around 50 msec to auditory stimuli (P50 ERP). This potential is recorded at the scalp, and reflects the cholinergically dependent, hippocampally mediated,
ELECTROPHYSIOLOGIC ASSESSMENT TECHNIQUES: EVOKED POTENTIALS AND ELECTROENCEPHALOGRAPHY 161
and pre-attentive process of sensory gating to auditory stimuli (70, 71). Traditionally, paired auditory stimuli are used for P50 study. The procedure is as follows: First, hearing threshold (in dBSPL) is determined, and the audi-tory stimuli are presented at 25–45 dB SPL above the hearing threshold (72). Employing the International 10–20 System of Electrode Placement (73), the P50 poten-tial is recorded at Cz-A1 with a ground electrode at A2.
Pairs of auditory stimuli (1 msec duration, 20Hz–12kHz) are presented with certain intra-pair (around 0.5 sec) and inter-stimulus (around 10 sec) interval. An overall grand average is obtained for both the conditioning and test P50 responses. The P50 latency and amplitude can be identi-fied by computer algorithm (72, 74).
The P50 ratio (in percentage) is the amplitude ratio of the test P50 to the conditioning P50. Examples of P50 suppression and nonsuppression are illustrated in Figure 13-4. It is used as an index for auditory sensory gat-ing (72). P50 suppression is defined as a P50 ratio of 40 percent, and P50 nonsuppression is 60 percent. P50 ratio between 40 and 60 is considered as an indetermi-nate P50 suppression (72). Arciniegas et al. reported that the P50 ratio was significantly increased in TBI (75).
Interestingly, the P50 ratios of different TBI subgroups, categorized by duration of post-traumatic amnesia (PTA) did not show significant difference from one another.
Those TBI subjects with similar level of cognitive impair-ment at the time of testing demonstrated similar amount of abnormal P50 suppression despite varying severity of initial brain injury. In another study (72), the frequency of P50 nonsuppression was investigated in patients with persistent posttraumatic attention and/or memory impairment. Preliminary analysis showed that the major-ity of TBI subjects have discernable P50 response, and that P50 nonsuppression is common among TBI patients with subjective symptoms of attention and memory
impairments, providing some evidence that clinically impaired auditory gating is variably correlated with P50 nonsuppression.
Regarding the source of P50 potential, it has been sug-gested that the generator is located at the hippocampus (74, 76, 77). Sensory gating process may facilitate stimulus selec-tion and informaselec-tion processing, which are important for attention and memory function (72). It was suggested that impaired sensory gating cause attention and memory impairments after TBI (78), and that abnormal P50 find-ings may be a useful marker for cholinergic dysfunction (72, 75, 79, 80). In summary, these studies suggest that the P50 response may be useful not only for evaluating cognitive dysfunction, but also for monitoring pharmacological inter-ventions in TBI.
EVENT-RELATED POTENTIALS/P300 Event-related potentials (ERPs) are cognitive potentials recorded over the scalp. They have been regarded by psy-chophysiologists as indicators of information processing, which may not be fully appreciated by measuring behav-ioral performance alone (6, 81, 82). In the active ERP par-adigm, the subject is asked to discriminate a rare/target stimulus (typically with occurrence rate of 20 percent) from an interrupted series of frequent/nontarget stimuli (80 percent occurrence rate) (83). When averaged appro-priately, the target stimuli generate a prominent positive peak (P300) approximately 300 msec after stimulus onset (83–85). The P300 response reflects active attention, work-ing memory, and the ability to detect novel stimuli among a series of similar signals (81, 84, 86, 87). Amplitude of P300 reflects the amount of cerebral activity required to process information and maintain working memory as the controlled environment is updated with incoming sensory input (86). Studies have shown that the P300 latency is a reliable indicator of stimulus classification speed, which is independent from the response selection processes (88, 89). Traditionally, simple auditory and visual tasks such as tone and color recognition have been widely employed in ERP testing due to its ease of use (83, 86, 90, 91). Although these tasks are rather primitive when com-pared with other paradigms (e.g., word recognition, affect recognition), simpler tasks have the advantage of gener-ating larger amplitudes and shorter latencies, which in turn simplify the data analysis process. An example of normal auditory P300 response is shown in Figure 13-5. The waveform was recorded at an Cz electrode, using an active oddball paradigm with pure tones as stimuli.
Not surprisingly, P300/ERP studies have been applied to patients with cognitive impairments (92) and psychi-atric disorders (93, 94). For comatose patients who are unable to participate actively in the testing process, the pas-sive ERP paradigm can be used (6, 95–98). Several brain FIGURE 13-4
P50 suppression and nonsuppression (72)
injury studies utilized simple tones as stimuli (7, 95–99), which yielded P300 responses in about 30 percent of apparently comatose patients. Preserved P300 seemed to predict the emergence from coma (95, 99, 100) and higher chance of recovery (90 percent or higher) in long-term follow-up (95, 99, 101). However, the absence of P300 did not exclusively prognosticate ominous outcome (6).
Based on recent data published by various researchers (6, 101, 102), it was apparent that preserved P300 component was associated with good clinical out-comes, while it was coincidentally noted that the N100 component also correlated with favorable outcome. In one study (101), investigators recorded auditory P300 potentials using three different passive paradigms both in normal subjects and in patients with severe consciousness impairment after TBI. Results showed that the N100 latency was longer, with significantly depressed amplitude in TBI patients than in normal subjects. It suggested that cognitive processing of exogenous sensory stimuli may still take place, albeit with some delay, when the patients’
level of consciousness appeared to be severely impaired.
Although the N100 response was thought to be associ-ated with passive perception of incoming sound (103), there is evidence to suggest its involvement with alert-ness and stimulus processing (81). Based on the above-mentioned studies, it is possible that both the N100 and P300 components are associated with active information processing (101, 102, 104).
To increase the ecologic validity of the ERP task, recent studies employed speech stimuli such as patients’
names (6, 101, 105). From a theoretical standpoint, a per-son’s own name would generate a more robust ERP response. By comparing three different speech targets (subject’s own name, the word “mommy,” and a mean-ingless speech sound), a recent study demonstrated that the subject’s name was indeed a viable target for eliciting cognitive ERP (102).
ERP testing has also been used to monitor effects of caffeine, nicotine, alcohol intake, and various psychos-timulants. Caffeine and nicotine increased the P300 amplitude and shortened the latency, while acute alco-hol consumption decreased the amplitude and prolonged the latency (81). Anderer et al. compared the pharmaco-logic effects of various drugs in healthy subjects. While methylphenidate and citalopram enhanced P300 in vari-ous cortical regions, lorazepam and haloperidol depressed P300 component (106). From a theoretical perspective, ERP might be a useful tool in evaluating the pharmaco-logic effect of various so called “cognitive enhancers”
after brain injury.
In summary, ERP may be valuable in investigating residual cognitive function of patients with TBI because of its noninvasive nature (107) and superior temporal res-olution (108). Also, using multi-channel recording, ERP may contribute to localization of certain brain activities based on dipole theory. With advances in computer tech-nology, ERP may complement behavioral testing in the comprehensive evaluation of cognitive function.
CONCLUSION
So far, we have discussed use of various electrophysio-logic measurements for persons with TBI. SEP is a reli-able prognosticator for ominous outcome after severe TBI. Combining ERP with SEP increases the power for predicting a favorable outcome. P300 and P50 are valu-able in evaluating pharmacological effects of various drugs on cognitive function. The utility of BAEP in TBI is limited to evaluation of brainstem dysfunction and hearing impairment, rather than actual cognitive func-tion. Although conventional EEG and QEEG have their inherent limitations, they may gain wider use as tech-nology improves and more standardized studies are performed.
Neuro-imaging studies, such as MRI (magnetic resonance imaging) or fMRI (functional MRI) have been used to obtain structural information along with electro-physiologic information (109–112). While ERP measure-ment can provide high temporal resolution for evaluation of cognitive processing, fMRI detects regional changes of brain activity in response to specific task performance.
However, most of these combination studies (using imag-ing and electrophysiologic measurements) have been per-formed on psychiatric patients, and have been rarely applied to persons with TBI. As for future research, the addition of electrophysiologic and neuro-imaging studies may provide comprehensive, objective, and valid assess-ments of cognitive status in persons with TBI, and may be useful in prognostication of long-term functional outcome.
FIGURE 13-5
Normal auditory event-related potential (ERP) waveforms from pure tone (1000 Hz versus 500 Hz) discrimination task
ELECTROPHYSIOLOGIC ASSESSMENT TECHNIQUES: EVOKED POTENTIALS AND ELECTROENCEPHALOGRAPHY 163
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