Auditory Event-Related Potentials to Tone Stimuli in Combat-Related Posttraumatic Stress Disorder

Auditory Event-Related Potentials to Tone Stimuli in Combat-Related Posttraumatic Stress Disorder Linda J. Metzger, Scott P. Orr, Natasha B. Lasko, and Roger K. Pitman

This study attempted to replicate findings of abnormal auditory event-related potentials (ERPs) in posttraumatic stress disorder (PTSD) in a sample of Vietnam combat veterans. Veterans with combat-related PTSD, divided into unmedicated (unmed-PTSD, n 5 12) and medicated (med-PTSD, n 5 22) groups, and veterans without PTSD (non-PTSD, n 5 10) completed a three-tone “oddball” target detection task while ERPs were measured. Individuals with comorbid panic disorder (PD) were excluded from the primary analyses. Parietal P3 amplitude to the target tone was significantly smaller in unmed-PTSD compared to med-PTSD and non-PTSD groups. These differences did not remain significant when an adjustment was made for level of depression. Parietal P3 amplitude was also negatively correlated with state anxiety. Secondary analyses within the unmed-PTSD group indicated that participants with comorbid PD (n 5 3) had the largest parietal P3 amplitudes to target tones. Results are consistent with attentional or concentration deficits in PTSD and highlight the importance of considering comorbid diagnoses. The absence of ERP differences between med-PTSD and non-PTSD participants suggests that psychotropic medication may normalize these deficits. © 1997 Society of Biological Psychiatry Key Words: Posttraumatic stress disorders, auditory event-related potentials, psychophysiology, psychotropic drugs BIOL PSYCHIATRY 1997;42:1006 –1015

Introduction Evidence provided by two studies of auditory eventrelated brain potentials (ERPs) in posttraumatic stress disorder (PTSD) suggest that individuals with this syndrome suffer from higher-order information processing abnormalities. In a mixed civilian trauma population, McFarlane et al (1993) found abnormal ERPs to infre-

From the Research Service, VA Medical Center, Manchester, New Hampshire; and the Department of Psychiatry, Harvard Medical School, Boston, Massachusetts. Address reprint requests to Linda J. Metzger, PhD, VA Research Service, 228 Maple Street, Second Floor, Manchester, NH 03103. Received November 21, 1996; revised December 23, 1996.

© 1997 Society of Biological Psychiatry

quent distractor and target stimuli during a three-tone auditory “oddball” task in PTSD patients compared to matched controls. Specifically, N2 latencies were longer, and P3 amplitudes smaller, in PTSD patients. PTSD patients were also slower to make button-press responses to target tones. Charles et al (1995) replicated findings of smaller P3 amplitudes to target stimuli in assault victims with PTSD using a two-tone auditory oddball paradigm, but did not explore other potential ERP component abnormalities or performance measures. Those investigators concluded that these ERP abnormalities suggest deficits in distinguishing and evaluating environmental cues and may index the concentration difficulties characteristic of this 0006-3223/97/$17.00 PII S0006-3223(97)00138-8

Auditory ERPs in PTSD

disorder (symptom D.3, DSM-IV, American Psychiatric Association 1994). In normal individuals, N2 latency has been found to increase as stimulus discrimination becomes more difficult (Na¨a¨ta¨nen 1992). It has been well documented that P3 amplitude is directly related to the task relevance and inversely related to the probability of the eliciting event. Although there is debate regarding the functional significance or theoretical interpretation of the P3 component, its amplitude is commonly viewed to reflect factors such as conscious effort or attentional resources allocated to stimulus processing (see Pritchard 1981) and updating of short-term memory (Donchin and Coles 1988; cf. Verleger 1988, 1991). Far from being unique to PTSD, N2 latency and P3 amplitude abnormalities in auditory oddball, as well as other, paradigms have been observed in a variety of clinical populations. In fact, abnormal amplitudes and latencies have been found across clinical populations for each of the characteristic ERP components elicited by oddball-like paradigms. Longer N2 latencies have been observed in patients with depression, alcoholism, and schizophrenia (Sandman et al 1987) and Huntington’s (Ho¨mberg et al 1986), Parkinson’s and Alzheimer’s diseases (Goodin and Aminoff 1986; Holt et al 1995). Attenuated P3 amplitudes have been reported in a wide range of disorders, including depression (Bruder et al 1995; Diner et al 1985), obsessive– compulsive disorder (Beech et al 1983; Ciesielski et al 1981), schizophrenia (Friedman et al 1982; McCarley et al 1991), attentiondeficit/hyperactivity disorder (ADHD; Klorman et al 1991), reading disabled disorder (Holcomb et al 1985), dementia (Goodin et al 1978; Holt et al 1995; Pfefferbaum et al 1984b), and alcoholism (Pfefferbaum et al 1991). Attenuated P3 amplitudes have also been observed in individuals at risk for alcoholism (Polich et al 1994), supporting a “trait” aspect of this ERP abnormality. Even ethanol consumption has been found to attenuate P3 amplitudes in healthy individuals (Lukas et al 1990). These findings suggest that ERP abnormalities index both trait- and state-related functional impairments in cognitive processing, rather than disorder-specific psychopathologies. The normalization of abnormal ERP components following treatment additionally supports the notion that they may serve as state markers for psychopathology. Studies employing the auditory oddball paradigm have found normalization of N1 latencies and amplitudes (Coffman et al 1989) and of P3 amplitudes (Gangadhar et al 1993) in depressed patients following electroconvulsive therapy. Blackwood et al (1987) found that P3 amplitudes normalized in depressed patients after various treatments including tricyclic antidepressants, monoamine oxidase inhibitors, lithium, electroconvulsive therapy, and/or cognitive

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therapy, but not in a group of schizophrenic patients after treatment with neuroleptics (also see Ford et al 1994). Several studies have demonstrated that children with ADHD show improved performance and increased P3 amplitudes in tests of sustained attention following stimulant therapy (see Klorman et al 1991). The magnitude of postdrug increase in P3 amplitude has been found to successfully predict the long-term benefits of such therapy (Young et al 1995). Thus, ERPs may provide a useful tool for monitoring cognitive changes during pharmacotherapy (Blackwood and Muir 1990; Partiot et al 1991). The goal of the present study was to examine the status of auditory ERP components in combat-related PTSD. Using the three-tone auditory oddball task employed by McFarlane et al (1993), we assessed the amplitudes and latencies of the N1, P2, N2, and P3 ERP components elicited by tones differing in their frequencies of presentation and informational value in Vietnam combat veterans with and without PTSD. Furthermore, over half of the PTSD patients were taking psychotropic medication at the time of the procedure. This presented the opportunity to explore potential ERP differences related to medication status. Clark et al (1996) observed increased P3 amplitude in panic disorder. In PTSD participants with comorbid panic disorder, the two disorders could be expected to exert opposite effects on P3 amplitude, making it difficult to formulate predictions for such individuals. For this reason, the data from participants with comorbid panic disorder were only included in a secondary analysis.

Methods and Materials Participants Participants consisted of 35 male Vietnam combat veterans. All were administered the Structured Clinical Interview for DSM-III-R (SCID; Spitzer et al 1992); 32 were also administered the Clinician Administered PTSD Scale: Current and Lifetime Diagnosis Version (CAPS; Blake et al 1995). Participants were classified according to DSMIII-R PTSD diagnostic status by means of the CAPS (or the SCID for the 3 participants who were not given the CAPS). Twenty-five participants had current PTSD; 10 had no lifetime PTSD (non-PTSD group). Participants with lifetime but not current PTSD, i.e., with past PTSD, were excluded. Data from 9 participants with comorbid panic disorder were included in a secondary analysis. Of the 25 participants with current PTSD, 8 were not currently prescribed any psychotropic medications, and 1 agreed to temporarily discontinue medication for 2 weeks prior to the laboratory procedure (unmed-PTSD group, n 5 9). The remaining 16 (med-PTSD group) were taking

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one or more prescribed psychotropic drugs as follows: 11 were on a selective serotonin reuptake inhibitor (fluoxetine or sertraline), 6 on trazadone, 1 on a tricyclic antidepressant, 4 on lithium, 1 on carbamazepine, 4 on a neuroleptic, 2 on buspirone, and 1 on a benzodiazepine. (Some participants were on more than one psychotropic medication.) Current comorbid Axis I disorders, diagnosed by means of the SCID, in the unmed-PTSD group (n 5 9) included 4 major depression, 2 dysthymia, 1 simple phobia, and 1 generalized anxiety. Current comorbid Axis I disorders in the med-PTSD group (n 5 16) included 2 bipolar, 9 major depression, 9 dysthymia, 2 social phobia, 4 simple phobia, 2 obsessive– compulsive, 4 generalized anxiety, and 1 cannabis abuse. (Some unmed-PTSD and med-PTSD participants had more than one comorbid disorder.) Current comorbid Axis I disorders in the non-PTSD group (n 5 10) were limited to a single participant, who had major depression, dysthymia, and social phobia. Participant candidates with a history of an organic mental disorder or schizophrenia, or with current mania, melancholia, or alcohol or other substance dependence were excluded.

Psychometrics Psychometric measures included the Combat Exposure Scale (Keane et al 1989), Mississippi Scale for CombatRelated PTSD (Keane et al 1988), Beck Depression Inventory (BDI; Beck et al 1979), and State-Trait Anxiety Inventory (Spielberger et al 1970).

accuracy were equally emphasized. Participants engaged in a series of practice trials until they demonstrated their ability to perform the task. Reaction times to target stimuli and the numbers of correct responses and false alarms were recorded. Electroencephalogram (EEG) activity was recorded during the oddball task from the midline sites (Fz, Cz, and Pz; 10 –20 System; Jasper 1958) using tin electrodes embedded in a nylon cap (Electro-Cap International) and referenced to linked earlobes. Electro-oculogram (EOG) activity was recorded at the outer canthus and infraorbitally to the left eye. Impedances were kept below 5 kV. Signals were amplified with a bandpass of 0.1– 40 Hz using Coulbourn High Gain Bioamplifiers and digitized and stored using a Neuro Scan system (Neuro Scan, Inc) at 500 Hz from 100 msec pre- to 900 msec post-stimulus onset. Trials with excessive eye-movement artifact (EOG range 6 85 mV) were excluded. Prior to averaging waveforms, signals were digitally filtered at 0.1–14 Hz (12 dB/octave). Peak and latency measures for N1, P2, and P3 were determined from each participant’s averaged waveforms for each stimulus type using a Neuro Scan automated scoring program. N1 was defined as the most negative point between 70 and 170 msec, P2 as the most positive point between 150 and 250 msec, and P3 as the most positive point between 300 and 500 msec, poststimulus onset. Following standard procedures, N2 was derived from difference waveforms by subtracting ERPs to common tones from ERPs to target and distractor tones. N2 was defined as the most negative point between 200 and 325 msec preceding P3. Selected peaks were verified by visual inspection.

Procedure Participants performed a three-tone auditory oddball task (Pfefferbaum et al 1984a) requiring the identification of infrequent target tones (2000 Hz) embedded in a series of infrequent distractor (500 Hz) and frequent common tones (1000 Hz). There were 285 stimulus presentations: 40 target, 40 distractor, and 205 common tones. All tones were generated by STIM software (Neuro Scan, Inc) and were 70 dB with 10-msec rise and fall times and 70 msec in duration. Tones were presented binuarally over Realistic Nova 40 headphones in a pseudorandom order such that no two infrequent tones occurred consecutively. Interstimulus intervals ranged randomly from 1950 to 2050 msec. Testing occurred in a sound-attenuated room connected via wires to an adjoining portion of the laboratory in which the experimental apparatus was located. Participants were seated upright in a comfortable armchair; they were instructed to keep their eyes closed throughout the task and to press a button with their dominant hand when they heard the target tone. Speed and

Analyses Demographic, psychometric, and performance data were examined using one-way analyses of variance (ANOVAs) with group (unmed-PTSD, med-PTSD, and non-PTSD) as a between-subjects factor followed by Tukey’s pairwise comparisons as appropriate. The ERP amplitudes and latencies for each component were examined using separate three-factor analyses of variance for repeated measures (ANOVARs) with group as a between-subjects factor, and stimulus (target, distractor, and common) and site (Fz, Cz, and Pz) as repeated measures. Statistical probabilities for the effects involving repeated measures were corrected using the Geiser–Greenhouse procedure. The overall ANOVARs were followed by additional statistical comparisons as appropriate. Finally, Pearson correlations were computed between ERP indices associated with significant group effects and psychometric and demographic measures.

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Table 1. Group Mean (SD) Demographic, Psychometric, and Performance Data, with Results of Analyses of Variance non-PTSD (N, n 5 10)

Age (years) Educational level Combat exposure Total CAPS score Mississippi scale Trait anxiety State anxiety Beck Depression Inventory Reaction time to targets (msec) Correct responses to target stimuli Incorrect responses to distractor stimuli Incorrect responses to common stimuli

unmed-PTSD (P, n 5 9)

med-PTSD (M, n 5 16)

Mean

(SD)

Mean

(SD)

Mean

(SD)

F

df

p

Tukey’s testsa

50.9 14.9 23.5 7.4 67.8 31.9 31.3 6.4 541

(3.2) (2.4) (7.9) (9.4) (18.3) (10.3) (9.6) (6.1) (153)

47.7 12.9 29.3 61.6 112.4 62.0 54.2 27.1 457

(3.7) (1.4) (9.4) (18.2) (19.5) (10.1) (12.2) (10.3) (93)

46.9 13.8 30.6 73.5 127.2 57.4 54.1 27.1 472

(2.5) (2.3) (5.8) (20.5) (16.4) (5.1) (11.4) (8.7) (111)

5.70 2.14 2.95 45.23 38.38 36.22 14.87 20.34 1.24

2,32 2,31 2,32 2,29 2,32 2,28 2,31 2,28 2,30

.008 .13 .07 , .001 , .001 , .001 , .001 , .001 .30

P, M , N — — P, M . N M.P.N P, M . N P, M . N P, M . N —

38.4

(4.6)

39.1

(2.3)

39.7

(0.6)

,1

2,28

ns

—

1.2

(1.7)

1.3

(1.5)

1.7

(2.6)

,1

2,28

ns

—

2.9

(3.7)

6.8

(3.5)

4.9

(7.7)

,1

2,28

ns

—

Letters indicate group comparisons for which p , .05.

a

Results Demographic, Psychometric, and Performance Data Group means (and SDs) for demographic, psychometric, and performance data are presented in Table 1. Significant differences between groups were limited to the non-PTSD participants being older and showing less abnormal scores on all psychometric measures compared to both the unmed-PTSD and med-PTSD group. Additionally, medPTSD participants had significantly higher Mississippi scores than unmed-PTSD participants. Unmed-PTSD and med-PTSD participants did not significantly differ on any other psychometric measure. There were no significant group differences for reaction time to the target tones and response accuracy, indicating that the groups performed the task comparably well.

ERP Data There were no differences among the groups in the number of artifact-free trials retained for common [F(2,32) , 1, ns], distractor [F(2,32) , 1, ns], and target [F(2,32) , 1, ns] averaged waveforms. One non-PTSD participant demonstrated an aberrant negative voltage at the Fz site following the P2 component to both target and distractor tones, making it impossible to derive meaningful N2 and P3 component scores. Group grand average waveforms for common, distractor, and target tones are presented in Figure 1. Visual inspection reveals the typical topographical distribution of P3, i.e., maximal deflection at Pz to target and distractor

tones. Also following the expected topographical distribution, N1 appears maximal at Fz across tone types. Several significant interactions emerged involving group differences for P3 amplitude and N1 latency (see Table 2). These findings are described below, followed by the decomposition of stimulus and site effects. There were no significant group main effects or interactions for N1 amplitude, P2 or N2 amplitude or latency, or P3 latency. P3 AMPLITUDE.

As presented in Table 2, results revealed significant group 3 stimulus and group 3 site interactions for P3 amplitude, suggesting that the groups’ P3 amplitudes differed according to electrode site and type of tone. Separate ANOVARs were performed for each site to decompose these interactions. Results revealed a significant group 3 stimulus [F(4,64) 5 3.0, p 5 .02] interaction at Pz, indicating that the groups differed in their response to the various tones at this site. Separate ANOVAs for each stimulus type further indicated that the groups only differed in their response to target tones [F(2,32) 5 3.2, p 5 .05]; planned pairwise comparisons incorporating the full ANOVA error term revealed significantly smaller P3 amplitudes (see Table 3) in unmedPTSD compared to both med-PTSD and non-PTSD participants. A table containing comorbid diagnoses, psychotropic medication, and parietal P3 amplitude for each participant is available to interested readers upon request. In light of findings of decreased P3 amplitude in depression, we also performed an analysis of covariance (ANCOVA) of P3 amplitudes to target tones at Pz in

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Figure 1. Group grand average waveforms at midline sites.

unmed-PTSD versus non-PTSD participants, using BDI score as the covariate; this yielded F9(1,14) 5 2.3, p 5 .15. The same analysis in unmed-PTSD versus med-PTSD participants yielded F9(1,18) 5 3.9, p 5 .07. Although the difference in the mean P3 amplitude to distractor tones at Pz in the unmed-PTSD (mean 5 8.9, SD 5 4.0) versus non-PTSD (mean 5 12.1, SD 5 3.6) group was not statistically significant, the observed effect size of .84 s was somewhat larger than the .66 s effect size obtained by McFarlane et al (1993), suggesting insufficient power in the present study to detect this difference. Finally, only measures of state anxiety were significantly related to P3 amplitude at Pz; higher levels of self-reported state anxiety were associated with smaller P3 amplitudes [r(32) 5 2.34, p , .05]. N1 LATENCY. For N1 latency, results revealed significant group 3 site and group 3 stimulus 3 site interactions (see Table 2), suggesting that the groups’ N1 latencies differed according to electrode site and type of tone. These interactions were further examined by means of separate ANOVARs for each site. Results indicated that the groups did not significantly differ in the latency of the N1 component, although there were trends at Pz for a difference among the groups [F(2,32) 5 2.6, p 5 .09] and a

group 3 stimulus interaction [F(4,64) 5 2.0, p 5 .10]. Inspection of the pattern of means (see Table 3) suggests that unmed-PTSD participants had longer N1 latencies than non-PTSD and med-PTSD participants to target tones at this site. Because of the overall number of analyses performed, however, no further statistical tests were conducted.

Stimulus and Site Effects N1. The amplitude of the N1 component was larger to distractor [F(1,34) 5 12.1, p , .001] and target tones [F(1,34) 5 5.0, p 5 .03] compared to common tones. It was also larger at Fz than Cz [F(1,34) 5 7.2, p 5 .01] and larger at Cz than Pz [F(1,34) 5 101.3, p , .001]. The latency of the N1 component also differed across both stimuli and sites. The N1 component occurred earlier to common compared to distractor tones [F(1,34) 5 17.3, p , .001]; it occurred earlier at Cz compared to Fz [F(1,34) 5 10.7, p 5 .002] and Pz [F(1,34) 5 4.7, p 5 .04]. P2. P2 amplitude and latency differed across sites; the amplitude was larger at Cz compared to both Fz [F(1,34) 5 20.5, p , .001] and Pz [F(1,34) 5 25.2, p , .001], and occurred earlier at Cz than Fz [F(1,34) 5 6.2, p 5 .02] and

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Table 2. Midline ANOVAR Results for the Target, Distractor, and Common Stimuli Amplitude Factor N1 Group Stimulus Site Group 3 stimulus Group 3 site Stimulus 3 site Group 3 stimulus P2 Group Stimulus Site Group 3 stimulus Group 3 site Stimulus 3 site Group 3 stimulus N2 Group Stimulus Site Group 3 stimulus Group 3 site Stimulus 3 site Group 3 stimulus P3 Group Stimulus Site Group 3 stimulus Group 3 site Stimulus 3 site Group 3 stimulus

Latency

F

df

p

F

df

3 site

, 1.0 6.9 88.5 , 1.0 2.0 1.2 , 1.0

2,32 2,64 2,64 4,64 4,64 4,128 8,128

ns , .001 , .001 ns .12 .32 ns

1.1 8.0 5.0 1.0 2.9 , 1.0 2.4

2,32 2,64 2,64 4,64 4,64 4,128 8,128

.35 .001 .02 .41 .05 ns .05

3 site

, 1.0 1.0 16.7 , 1.0 1.5 2.3 , 1.0

2,32 2,64 2,64 4,64 4,64 4,128 8,128

ns .35 , .001 ns .21 .07 ns

, 1.0 2.5 9.6 1.3 , 1.0 , 1.0 1.3

2,32 2,64 2,64 4,64 4,64 4,128 8,128

ns .10 , .001 .27 ns ns .26

3 site

, 1.0 1.7 5.8 , 1.0 1.9 5.9 , 1.0

2,31 1,31 2,62 2,31 4,62 2,62 4,62

ns .20 .005 ns .12 .01 ns

, 1.0 , 1.0 3.3 3.1 , 1.0 , 1.0 , 1.0

2,31 1,31 2,62 2,31 4,62 2,62 4,62

ns ns .05 .06 ns ns ns

3 site

, 1.0 30.6 17.4 2.6 2.6 11.4 1.3

2,31 2,62 2,62 4,62 4,62 4,124 8,124

ns , .001 , .001 .05 .05 , .001 .28

1.2 2.0 4.6 , 1.0 1.9 2.7 , 1.0

2,31 2,62 2,62 4,62 4,62 4,124 8,124

.31 .14 .02 ns .13 .05 ns

Pz [F(1,34) 5 16.6, p , .001]. P2 also occurred earlier at Fz than Pz [F(1,34) 5 4.3, p 5 .05]. N2. The amplitude of N2 was larger at Fz [F(1,33) 5 8.5, p 5 .006] and Cz [F(1,33) 5 14.2, p , .001] compared to Pz, and its peak occurred earlier at Pz than Fz [F(1,33) 5 6.2, p 5 .02]. To locate the source of the stimulus 3 site interaction, separate ANOVARs were performed for each site. At Cz, N2 was larger to target compared to distractor tones [F(1,32) 5 5.3, p 5 .03]. P3. The amplitude of the P3 component was larger to target [F(1,33) 5 29.5, p , .001] and distractor [F(1,33) 5 88.4, p , .001] tones compared to common tones, and was larger at Pz compared to Fz [F(1,33) 5 31.8, p , .001] or Cz [F(1,33) 5 33.6, p , .001]. The latency of the P3 component was shorter at Cz than at Fz [F(1,33) 5 4.1, p 5 .05] or Pz [F(1,33) 5 4.2, p 5 .05]. The significant interaction between stimulus and site was examined by separate ANOVARs for each site. Results indicated that

p

P3 latency differed across tones only at Fz [F(1,33) 5 4.1, p 5 .05]; contrasts indicated that the P3 component occurred earlier to target tones than to distractor [F(1,33) 5 6.3, p 5 .02] or common [F(1,33) 5 9.3, p 5 .004] tones.

Secondary Analyses: The Impact of Comorbid Panic Disorder on ERPs ANOVARs of N1, P2, N2, and P3 amplitude and latency measures, including the 9 individuals with comorbid panic disorder (med-PTSD, n 5 3; unmed-PTSD, n 5 6), revealed similar significance levels for the main effects and interactions for stimulus and site; however, the main effects and interactions involving differences among the groups were no longer significant. Furthermore, a scatter plot of P3 amplitudes at the Pz site indicated that the three unmed-PTSD participants diagnosed with comorbid panic disorder had the largest P3 amplitudes to the target tones within this group (p 5 .005, Mann–Whitney U test; see

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Table 3. Mean Amplitude and Latency of ERP Components at Midline Sites to Common, Distractor, and Target Tones Amplitude (mV) Fz

N1 Commons

Distractors

Targets

P2 Commons

Distractors

Targets

N2 Distractors

Targets

P3 Commons

Distractors

Targets

Latency (msec)

Cz

Pz

Fz

Cz

Pz

Group

Mean

(SD)

Mean

(SD)

Mean

(SD)

Mean

(SD)

Mean

(SD)

Mean

(SD)

non-PTSD unmed-PTSD med-PTSD non-PTSD unmed-PTSD med-PTSD non-PTSD unmed-PTSD med-PTSD

29.1 27.5 28.0 29.8 29.2 28.8 29.2 28.4 28.8

(3.4) (2.4) (2.5) (3.3) (2.7) (4.5) (4.6) (3.6) (3.7)

27.1 26.0 27.8 27.7 28.3 29.3 27.3 27.1 29.0

(2.6) (2.2) (3.4) (2.7) (2.9) (4.7) (3.7) (3.1) (5.0)

23.7 23.0 24.1 24.3 25.4 25.2 23.9 24.1 24.0

(2.0) (2.5) (1.9) (1.8) (3.1) (2.9) (2.8) (2.5) (3.2)

113.6 116.0 115.9 120.0 125.1 120.0 118.4 116.9 116.2

(8.5) (10.6) (7.2) (11.3) (15.1) (11.4) (9.6) (11.3) (11.6)

106.8 112.7 114.5 114.6 119.8 117.9 115.4 114.9 117.4

(11.7) (9.2) (7.0) (7.8) (13.8) (15.1) (8.3) (10.6) (13.0)

110.8 117.1 117.6 124.2 133.6 119.0 108.8 134.2 116.2

(16.6) (27.2) (13.3) (15.7) (20.1) (16.0) (17.4) (24.0) (18.3)

non-PTSD unmed-PTSD med-PTSD non-PTSD unmed-PTSD med-PTSD non-PTSD unmed-PTSD med-PTSD

5.0 4.2 4.8 4.2 4.3 4.5 4.9 3.1 4.5

(2.3) (2.8) (4.1) (3.6) (3.7) (6.6) (3.8) (2.6) (5.8)

7.0 6.8 6.2 7.2 6.5 5.5 6.5 4.6 4.7

(2.1) (2.8) (4.5) (3.9) (2.2) (5.5) (3.4) (2.3) (5.4)

4.1 3.8 4.1 3.7 3.2 4.4 4.4 2.2 5.0

(1.5) (2.9) (3.2) (2.5) (3.5) (3.9) (2.5) (3.1) (5.4)

231.0 230.4 231.0 224.0 232.9 227.5 225.0 223.1 212.0

(17.3) (18.5) (23.3) (18.7) (17.6) (22.7) (21.7) (23.9) (21.6)

224.0 220.0 220.5 210.2 224.4 230.2 211.8 218.2 213.6

(19.6) (21.4) (26.0) (25.0) (23.6) (19.5) (27.0) (26.0) (22.9)

243.2 234.2 233.8 226.2 236.9 231.9 239.6 223.6 227.4

(9.9) (15.7) (24.6) (30.4) (17.1) (25.2) (18.1) (33.6) (30.8)

non-PTSD unmed-PTSD med-PTSD non-PTSD unmed-PTSD med-PTSD

22.5 22.4 22.7 23.4 24.0 23.8

(2.1) (3.6) (3.5) (3.0) (4.4) (3.8)

22.0 22.6 23.0 23.8 25.2 24.6

(1.9) (2.4) (2.5) (3.6) (6.7) (5.2)

22.3 23.2 21.4 21.3 23.8 21.2

(2.2) (3.1) (1.3) (2.2) (3.0) (4.0)

242.7 228.0 236.2 237.6 232.4 255.5

(42.2) (42.7) (33.1) (23.8) (20.5) (29.3)

237.8 236.2 230.5 229.4 218.2 250.5

(39.1) (43.2) (38.8) (20.4) (19.0) (30.7)

229.0 227.6 219.2 227.2 226.4 242.0

(26.7) (43.6) (33.4) (19.1) (23.8) (32.0)

non-PTSD unmed-PTSD med-PTSD non-PTSD unmed-PTSD med-PTSD non-PTSD unmed-PTSD med-PTSD

4.5 5.2 4.1 8.4 7.7 6.6 8.8 5.8 5.7

(3.7) (4.1) (4.0) (5.7) (7.1) (5.2) (5.0) (5.2) (5.2)

2.2 4.4 4.6 7.1 7.2 9.4 6.9 4.8 7.8

(1.9) (4.1) (4.0) (2.7) (4.7) (5.1) (3.7) (3.2) (5.3)

5.8 5.7 5.6 12.1 8.9 11.8 13.6 7.5 12.4

(2.7) (3.0) (2.7) (3.6) (4.0) (4.8) (5.2) (4.1) (6.3)

349.4 373.3 380.1 358.2 365.8 349.9 343.1 336.0 347.6

(35.9) (51.2) (73.7) (23.4) (35.1) (48.9) (21.4) (32.5) (49.0)

318.6 340.4 351.6 337.0 340.7 372.1 329.4 337.8 361.8

(33.3) (39.2) (60.6) (58.0) (41.9) (66.8) (27.0) (33.1) (59.7)

353.4 354.9 356.4 368.4 365.8 377.9 358.0 362.2 348.0

(63.6) (38.6) (54.3) (26.2) (36.2) (60.0) (24.5) (28.3) (26.5)

Figure 2). The group mean P3 amplitude at Pz for these 3 unmed-PTSD participants (mean 5 18.5, SD 5 4.0) was considerably larger than the mean for the remaining 9 unmed-PTSD participants without comorbid panic disorder (mean 5 7.5, SD 5 4.1). This pattern did not hold for the med-PTSD participants (p 5 .90, Mann–Whitney U test).

Discussion Results from the present study replicate findings of diminished P3 amplitude in PTSD (Charles et al 1995; McFarlane et al 1993). In addition, the present results suggest that P3 amplitude in individuals with PTSD is influenced by at least four factors. First, the ERP abnormalities

observed in the unmedicated PTSD veterans were not shown by the medicated PTSD veterans, despite the fact that medicated veterans reported higher levels of PTSD symptomatology as measured by the Mississippi scale. This finding raises the possibility that medication can normalize ERPs, and possibly restore cognitive function in PTSD, as has been reported in other psychopathological conditions discussed above; however, ERP normalization in medicated patients does not appear to be associated with reduced PTSD symptom report. Because medication status was not directly manipulated in the present study, firm conclusions cannot be drawn. Inferences are also limited by the wide variety of psychotropic agents that veterans were taking. The P3 amplitude results obtained in unmedicated

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Figure 2. Scatter plot of P3 amplitudes at the parietal site; data from participants with comorbid panic disorder are shown in black.

PTSD veterans were also strongly influenced by the presence of comorbid panic disorder. Compared to the non-PTSD veterans, the 9 unmedicated PTSD veterans without panic disorder produced significantly smaller P3 amplitudes to the target tones at the parietal site, whereas the 3 unmedicated PTSD veterans with panic disorder produced nonsignificantly larger P3 amplitudes. These results are consistent with findings that panic disorder is characterized by increased P3 amplitudes (Clark et al 1996). The PTSD sample of McFarlane et al (Alexander McFarlane, personal communication, 1995) did not include participants with comorbid panic disorder. McFarlane et al noted evidence supporting a positive relationship between level of noradrenergic activity and P3 amplitude (Pineda et al 1991). In panic disorder, increased noradrenergic activity is supported by heightened sensitivity to the a2-antagonist yohimbine (Charney et al 1984). Southwick et al (1993) found that a subgroup of PTSD patients, who were more likely to have panic disorder, also displayed heightened sensitivity to yohimbine. The present finding that the 3 veterans with panic disorder displayed the largest P3 amplitudes to target tones within the unmedicated PTSD group is consistent with increased noradrenergic activity in this PTSD subgroup. Finally, in the veterans without panic disorder, a meaningful portion of the variance in P3 amplitude to target stimuli at the parietal site was explained by depressive symptoms, and it was significantly related to levels of self-reported state anxiety. These findings suggest that diminished P3 amplitudes in PTSD may be partially

accounted for by the depressive or anxiety symptoms that often accompany this disorder. There was an unfortunate age confound in the present study, with non-PTSD participants being significantly older than both unmedicated PTSD and medicated PTSD participants. This confound, however, cannot account for the finding of smaller P3 amplitudes in unmedicated PTSD veterans, because aging is typically associated with a progressive diminishing of P3 amplitude (Pfefferbaum et al 1984a; Picton et al 1984). The differences in age, if anything, should have produced results opposite to those obtained. Findings in the present study hint at a possible abnormality in N1 latency at the parietal site for the unmedicated PTSD veterans. Although not found in the PTSD group studied by McFarlane et al (1993), and not measured by Charles et al (1995), increased N1 latencies have been observed in schizophrenia (Sandman et al 1987), depression (Coffman et al 1989), Alzheimer’s (Holt et al 1995), Huntington’s (Goodin and Aminoff 1986) and Parkinson’s (Wright et al 1993) diseases, and acquired immunodeficiency syndrome (Schroeder et al 1994; Takakuwa et al 1993), however, because potential N1 latency differences in the present study fell short of statistical significance and were limited to the parietal site, whereas the N1 component is traditionally dominant at frontocentral sites, N1 latency abnormalities in PTSD can only be regarded as speculative. Finally, results of the present study did not replicate the findings of McFarlane et al (1993) of delayed N2 compo-

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nents or longer reaction times to target tones in PTSD participants. The absence of these findings, along with equally high response accuracy across groups, suggests that PTSD participants in the present study did not experience increased difficulty with task performance. Furthermore, these findings are consistent with the notion that P3 amplitude may be more sensitive to cognitive deficits than measures of task performance (Nuechterlein 1990) and suggest that future studies should employ a more cognitively demanding task in the search for a performance correlate of diminished P3 amplitude in PTSD. As noted in the introduction and suggested by results in the present study, ERP abnormalities are not diagnostically specific. They may, however, provide clues regarding underlying cognitive deficits. The diminished P3 amplitudes observed in the unmedicated PTSD veterans studied here are consistent with deficits in higher-level information processing, specifically decreased allocation of attentional resources in stimulus evaluation or the updating of short-term memory. In summary, the present

L.J. Metzger et al

results provide further support for the contention that ERP abnormalities, specifically diminished P3 amplitude, may serve as an index of disturbed concentration in PTSD (McFarlane et al 1993). New evidence, however, is also provided suggesting that abnormalities in P3 amplitude may be 1) partially related to depressive and anxiety symptoms; 2) reversed by the presence of comorbid panic disorder; and 3) normalized with psychotropic medication. These findings highlight the importance of considering the role of comorbid diagnoses in future research. They also suggest that prospective, double-blind studies of the effect of selected medications on event-related potentials in PTSD may be worth undertaking.

Supported by NIMH postdoctoral Research Fellowship Award 5F32MH10315. The authors thank Drs. Brian O’Donnell, Stephen Paige, and Steven Woodward for helpful comments and suggestions during manuscript preparation. Heike Croteau provided technical assistance and Michael Macklin assisted with participant recruitment and counseling.

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