Combat veterans with posttraumatic stress disorder exhibit decreased habituation of the P1 midlatency auditory evoked potential

Life Scienas, Vol. 61, No. 14, pi. 1421-1434,1997 Published by Elsevier Science Inc. Printed in the USA. All rights rcsered 0024-32n5p7 $17.00 + .oo

PIISOO24-3205(97)006&l-7

COMBAT VETERANS WITH POSTTRAUMATIC STRESS DISORDER EXHIBIT DECREASED HABITUATION OF THE P 1 MIDLATENCY AUDITORY EVOKED POTENTIAL Gregory M. Gillette5,6, Robert D. Skinne?, Lisa M. Rasco’, Elliot M. Fielstein5,6, Doyle H. Davis’, James E. Pawelak’, Thomas W. Freeman’,3, Craig N. Kar~on’~~, Frederick A. Boop4, Edgar Garcia-Rill’ Eugene J. Towbin Health Care Center, John L. McClellan Memorial Veterans Hospital, N.Little Rock Division’, N.Little Rock AR; Departments of Anatomg, Psychiatry3, and Neurosurgery4, University of Arkansas for Medical Sciences, Little Rock AR; Vanderbilt University Medical Center Department of Psychiatry5 and Veterans Affairs Medical Center’, Nashville TN (Received

in final

fom June 2.5,1997)

Summary The current study used a paired stimulus paradigm to investigate the PI midlatency auditory evoked potential in Vietnam combat veterans with posttraumatic stress disorder (PTSD) and three comparison groups: alcohol dependents, combat-exposed normals, and combat-unexposed normals. Compared to each comparison group. PTSD subjects exhibited significantly diminished habituation of the Pl potential. Pl potential habituation within the PTSD group, correlated significantly with intensity of PTSD reexperiencing symptoms, such as trauma-related nightmares and flashbacks, These findings are discussed as consistent with a sensory gating defect at the brainstem level in PTSD, and are mother discussed in the context of other psychophysiological measures in PTSD and of Pl potential findings in psychiatric disorders other than PTSD. stress disorder, midlatency auditory evoked potential, pedunculopontinenudeus, combat veterans, sleep disturbances

key WO&: posttraumatic

Auditory evoked potentials have been classified in humans, according to the time of occurrence of the peak amplitude after a stimulus, as short-latency (O-10 msec), midlatency (lo-100 msec), and longlatency (>lOO msec). Long-latency auditory evoked potentials have been studied and results published for numerous psychiatric disorders (l), including PTSD (PTSD)(2,3), which was codified for the first time in the oficial nosology of the American Psychiatric Association in 1980 (4), with two revisions thereafter (56). Paige et al. (2), in a study of combat-related PTSD using a longlatency P2 auditory evoked potential augmentation-reduction paradigm, found that nine of twelve PTSD subjects exhibited reduced P2 evoked potential amplitudes as stimulus intensity increased, as contrasted with five of six combat-exposed normal controls, who exhibited augmented P2 potential amplitudes with increasing stimulus intensity. The authors stated that the results of their study are consistent with “hypotheses that PTSD represents a state of CNS sensitivity and that individuals with

Correspondence to: Gregory M. Gillette, M.D., Psychiatry Service, VAMC, 13 10 24th Avenue South, Nashville TN 37212, Phone (615) 327-4751 X.5937, FAX (615) 321-6375, E-mail [email protected]

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PTSD, when faced with intense stimuli, enter a state of protective inhibition in which the CNS responses to intense stimuli are dampened down to render them more tolerable.” McFarlane et al. (3), using a long-latency P3 auditory target discrimination task paradigm, found that, compared to normal controls, PTSD patients exhibited decreased P3 evoked potential amplitudes that failed to distinguish target from distractor tones. The authors suggested that “greater autonomic reactivity to stimuli by PTSD sufferers may be related in some way to their impaired perceptual evaluation of such stimuli,” and that this impaired perceptual evaluation may be “related to a defect in early stimulus gating.“(3) This terminology used by McFarlane echoes that of “defects in sensory gating” used by Adler et al. (7) in reports of decreased latency, amplitude, and habituation of the Pl midlatency auditory evoked potential in schizophrenia, phenomena replicated in numerous subsequent studies published by several independent investigators (S-10). Results of studies of midlatency auditory evoked potentials have also been published for a variety of neuropsychiatric disorders in addition to schizophrenia, including mania (1 l), major depression (12), autism (13), Alzheimer’s disease (14), narcolepsy (15), and Parkinson’s disease (16), each with an apparently characteristic pattern of alterations from normalcy in latency, amplitude, and habituation. Although midlatency auditory evoked potential studies have heretofore not been published for PTSD, preliminary findings of the current study of the P 1 potential in PTSD have been presented (17), and similar findings have since been independently presented by at least two investigators (18,19). Several specific aspects of the Pl potential and a putative brainstem generator suggest the possibility of Pl potential alterations in PTSD. The Pl potential is elicited by a simple click stimulus and is usually best recorded at the scalp vertex (20-22). Pl potential equivalents with species-specific latencies have been described in the rat (1 l-l 5 msec)(23), cat (20-25 msec)(24,25), and human (4070 msec)(20,26-28). The Pl potential is also referred to as the PI3 potential in the rat, wave A in the cat, and the P50 potential in humans. In all species studied, the Pl potential normally is present in wakefulness and REM sleep and absent in slow-wave sleep (20,24,27), is abolished by scopolamine and restored by physostygmine (22-28), and habituates rapidly (23,25,26). Although numerous central nervous system structures must contribute to generating or modulating the Pl potential, recent experiments utilizing depth electrodes in decerebrate rat and cat preparations indicate that, in response to click stimuli, neurons of the mesopontine tegmental pedunculopontine nucleus (PPN) generate potentials with latency and habituation characteristics similar to those of the P13 potential and Wave A in the intact rat and cat, respectively (21,22), paralleling results of cat experiments by Buchwald et al. in 1981 (25). The fact that acetylcholine is a major neurotransmitter of the PPN would be consistent with effects of scopolamine and physostygmine on the Pl potential, if the PPN is indeed a primary generator of the Pl potential. The PPN, together with the noradrenergic locus coeruleus (LC), is known to mediate various aspects of sleep-wake states (29). PPN neurons discharge during wakefulness and REM sleep but not slowwave sleep, paralleling the presence of the Pl potential in wakefulness and REM sleep and its absence in slow-wave sleep. In contrast, LC neurons discharge during wakefulness and slow-wave sleep but not REM sleep. The PPN has been implicated in generating ponto-geniculo-occipital (PGO) waves in the cat, which are temporally correlated with the REM sleep phasic events associated both with oneiric behavior in cats lacking normal REM sleep muscular atonia after mesopontine tegmental lesions, and with dreaming in humans (29,30). A study of the Pl potential as a measure of PPN activity would be of interest in PTSD patients. considering the close anatomic and physiologic relationship of the PPN with the LC (3 1,32), which has been hypothesized to be dysregulated in PTSD (33,34,35). Because of tbe importance of

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reexperiencing symptoms (36), including trauma-related dreams (4-6), and other predominantly REM-related sleep disturbances (37-41), in the development of PTSD, and because of the emphasis in the theoretical work of Garcia%11 (31) and Reese et al. (32) on the putative role of the PPN as a generator of both normal and abnormal REM sleep and REM sleep phasic events, including dreaming, such a study becomes of even more compelling interest. Additionally, the current study addresses indirectly the possibility suggested by the long-latency evoked potential work of Paige et al. (2) and McFarlane et al. (3) that P2 slope reduction and P3 diminished amplitude and discrimination seen in PTSD subjects may reflect the response of brain structures at the levels of the thalamus and cerebral cortex, respectively, to poorly gated input from the level of the brainstem. In particular. a study of the Pl potential was seen as potentially valuable for a clearer understanding of the possible underlying neurobiology of PTSD. and its symptomatic manifestations. especially REM-related sleep disturbances and intrusive symptoms of traumatic reexperiencing as cardinal phenomenologic manifestations of the disorder. Methods 1.

Subjects

The study group was composed of inpatient combat veterans with PTSD. Comparison groups included currently alcohol dependent inpatient veterans, combat-exposed normals, and combatunexposed normals. All PTSD and comparison group subjects were male, age-comparable. medication-free (except acetaminophen or ibuprofen) for at least one week before testing. without significant current medical disorder, and consecutively recruited from those who met the additional diagnostic criteria described below and who consented to participate. None had taken fluoxetine. neuroleptics, monoamine oxidase inhibitors, or lithium for at least eight weeks before testing. None an important exclusion because half of had a first-degree relative with schizophrenia, phenomenologically normal first-degree relatives of schizophrenics exhibit decreased habituation of the Pl evoked potential (42). After complete description of the study to the subjects. written informed consent was obtained. Presence or absence of PTSD in all subjects was determined by clinical psychiatric interview by an attending psychiatrist, and by Clinician Administered PTSD Scale--One Week Symptom Version (CAPS) (43). administered independently by a ward staff addiction therapist, himself a Vietnam veteran, within one day of evoked potential testing. CAPS also provided PTSD symptom severity ratings. Presence or absence of other Axis I diagnoses in PTSD and alcohol dependent subjects was determined by Structured Clinical Interview for DSM-III-R, Patient Edition (SCID-P)(44). administered by a SCID-P-trained attending psychiatrist. For PTSD and alcohol dependent subjects, diagnoses were confirmed by inpatient ward staff consensus in multidisciplinary meetings. Serial inpatient urinary drug screens and breathalyzer tests on PTSD and alcohol dependent subjects confirmed current alcohol- and drug-free status. For combat-exposed and combat-unexposed normals, Axis I diagnoses other than PTSD were determined by Structured Clinical Interview for DSM-III-R, Non-Patient Edition @CID-NP)(45), administered by a SCID-NP-trained attending psychiatrist. A ward staff social worker with active service military background verified presence or absence of combat exposure in PTSD subjects by review of Form DD214, and in combat controls by review of Veterans Affairs administrative records. No attempt to quantify combat exposure was made. All ratings and diagnoses were determined blind to Pl potential measurements. Fourteen combat veterans with PTSD were recruited from a specialized PTSD inpatient ward at the Veterans Affairs Medical Center (VAMC) in North Little Rock, Arkansas. All met DSM III-R criteria for PTSD. Other than alcohol dependence in remission (seven full, two partial). DSM III-R

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Axis I comorbid diagnoses included only social phobia in one subject and dysthymia in three. Interval since last alcohol dependence was exactly equivalent to interval since last alcohol use, since in all cases relapse of alcohol use met criteria for relapse into alcohol dependence. An estimated 280 admissions to the PTSD ward were screened to recruit the fourteen PTSD subjects who met the criteria of minimal psychiatric and medical comorbidity other than alcohol dependence, the latter.of which was controlled for by inclusion of an alcohol dependent control group. Four PTSD subjects’ Pl potentials were undetectable, and their data were excluded. The remaining ten PTSD subjects had a mean t SD age of 49.2 2 8.2 years. Two were native American, three African-American, five Caucasian. Because of the high prevalence of alcohol dependence history among PTSD subjects in the current study, similar to previously reported prevalence of alcohol dependence history in veterans with PTSD (46), five alcohol dependent comparison subjects were recruited from a substance use disorder ward at the VAMC. All met DSM III-R criteria for alcohol dependence in partial remission for at least one month prior to testing. Interval since last alcohol dependence was exactly equivalent to interval since last alcohol use, since in all cases relapse of alcohol use met criteria for relapse into alcohol dependence. None met DSM III-R criteria for PTSD or any other concurrent Axis I diagnosis. Mean four Caucasian. One had combat _+ SD age was 45.0 t 8.3 years. One was African-American, exposure history. Because of the potentially confounding influence of combat exposure itself, five combat-exposed normal comparison subjects were recruited from staffs of the VAMC, Veterans Affairs Regional Office, and University of Arkansas for Medical Sciences (UAMS). None met DSM III-R criteria for PTSD or any other Axis I diagnosis, except for one with alcohol dependence in full remission for 24 years. Mean + SD age was 49.0 + 1.9 years. All were Caucasian. Seven combat-unexposed normal comparison subjects were recruited from staffs of VAMC and UAMS. None met DSM III-R criteria lifelong for any Axis I diagnosis. Two subjects’ Pl potentials were undetectable, and their data were excluded. Mean + SD age of the remaining five was 45.6 k 4.3 years. All were Caucasian. 2.

Recordinps

Subjects sat in a well-lit, sound-attenuated room with an observation window at UAMS. Gold-plated surface electrodes were afflxed to each subject’s scalp and face with water-soluble conducting paste. Electrode impedance was ~5 Kohms. Pl potentials were recorded at the vertex (Cz) referenced to the frontal (Fz) electrode. Eye movements (EOG) were monitored with canthal leads, muscle activity (EMG) with mentalis muscle leads. Since subjects wore headphones, making earlobe or mastoid leads possibly uncomfortable, the ground lead was subclavicular. Alpha waves were recorded using an occipital lead (Oz) referenced to Cz. Electrode leads were plugged into Grass Instruments 5Pll amplifiers with high resistance input stages. Gain and bandpass settings were: xlOOK and 3-1KHz for Pl; xlOOK and l-300 Hz for Oz; x20K and 3-1KHz for EOG; and xlOK and 30-1KHz for EMG, with a 60 Hz notch filter in use on each amplifier. Fast Fourier Transform analysis showed that the notch filter did not degrade the P 1 potential. Before testing, headphones were positioned and auditory threshold determined for each ear, using the gradable output of a Grass Instruments Audiostimulator STMlO. The test stimulus, a rarefied click of broad frequency spectrum and 0.1 msec duration was set at least 50 dB above threshold, usually at 95 dB, up to 103 dB. A Macintosh Quadra 650 triggered the auditory stimulator to deliver paired click stimuli through headphones at 250, 500, and 1000 msec interstimulw intervals (ISIS). Testing

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consisted of three sessions, randomly ordered, each five to six minutes long, corresponding to the three ISIS. During each session, amplified signals were displayed on an oscilloscope, digitized by a GW Instruments I/O Module, computer-averaged by SuperScope software (47), and stored on hard disk and magnetic tape, using a Neurodata recorder. For each ISI, pairs of stimuli were delivered at 0.2 Hz until sixty-four valid evoked potential pairs were acquired, averaged, and stored, a method similar to that commonly employed in prior human research involving the Pl potential (7,9-12). Potentials with interfering EOG or EMG artifact were excluded manually during testing. Subjects were instructed to keep eyes open and count stimulus pairs to maintain vigilance, which was simultaneously visually monitored. All subjects whose data are included in the analysis kept their eyes open, maintained alertness, and were appropriately verbally responsive and alert between sessions. 3.

Data Analysis

The PI potential following the first stimulus of a pair was identified as the first positive wave following brainstem auditory evoked responses (BAERs)(first 10 msec) and the Pa potential (25-40 msec), manifestations of primary auditory pathway and auditory cortex activity, respectively. In the current study, Pl potential latencies ranged from 42 to 58 msec, comparable to published human latencies (20.2628). Amplitude measurements were performed using the peak-to-peak method (26,28). The peak of the negative Nb potential occurs between the Pa and Pl potentials, and Pl potential amplitude was determined relative to the Nb peak. For instances in which the Nb was poorly defined, amplitude measurements were made from the foot of the Pl potential to its peak. [Figure l] The mean amplitude of the Pl potential induced by the first stimuli (conditioning stimuli) of all accepted pairs for each subject at each IS1 was calculated for amplitude and habituation comparisons between groups. Mean first stimulus Pl potential amplitudes for subjects within each group were summed and averaged to derive group means. Individual and group mean first stimulus Pl potential latencies were calculated in the same way. The mean amplitude of the Pl potential induced by the second stimuli (testing stimuli) of all accepted pairs for each subject at each IS1 was calculated, and mean second stimulus Pl potential amplitudes for subjects within each group were summed and averaged to derive group means for habituation comparisons between groups. For Pl potential first stimulus amplitude, second stimulus amplitude, and first stimulus latency, individual subject means were summed and averaged across all ISIS to derive three variables for correlation with each other. Magnitude of habituation at each IS1 for each subject was determined by dividing the mean amplitude of the Pl potential elicited by the second (testing) stimuli of all pairs at that IS1 by the mean amplitude of the Pl potential elicited by the first (conditioning) stimuli of these pairs. The result was expressed as a ratio, the testing/conditioning ratio, or T/C ratio. The higher the T/C ratio, the lower the habituation, i.e., the more abnormal the result. Using such a measure exploits the fact that the paired stimuli were sufficiently temporally proximate that minor changes in vigilance would affect both responses to a pair of stimuli similarly, maintaining a constant relationship. Mean T/C ratio for each IS1 was calculated for each subject. Mean T/C ratios for each IS1 for each subject within each group were summed and averaged to derive group mean T/C ratios for each ISI. Each CAPS item was scored 0 to 4 for frequency and 0 to 4 for intensity. Intensity and frequency scores for all items in each of three symptom clusters (reexperiencing, avoidance, hyperarousal) were

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COMBATN EXPOSED NORMAL

PTSD

L

0

11

20

11

40

60

11

”

11

1

80 100 120 140 160 180 200220

”

11

’

240 260 280 300 320

Time (msec) Fig. 1 Representative tracings from a PTSD subject and a combat-unexposed normal, averaged over 64 paired auditory stimulus trials. Vertical arrows designate occurrence of stimuli at 0 and 250 msec. Horizontal lines designate onset and peak of Pl potentials. Vertical difference between onset and peak lines for the preceding stimulus constitutes amplitude. summed separately for each subject, yielding six CAPS scores per subject. These six CAPS scores for subjects within each group were summed and averaged to derive six group mean CAPS scores. One-way analysis of variance (ANOVA) was used to examine age; years of education as a proxy measure for socioeconomic status; interval from last alcohol dependence; smoking habits (packs/day); and CAPS reexperiencing, avoidance, and hyperarousal intensity and frequency scores. Post hoc analysis using the Scheffe test was performed on any of these variables found to be significant at ~~0.05 by one-way ANOVA. Measures of Pl potential latency, amplitude, and T/C ratio were subjected to a mixed within-subject repeated measures ANOVA with clinical group assignment as the between-groups factor and IS1 as the within-subjects factor. A conservative degrees of freedom using the Greenhouse-Geisser epsilon (48) was used to analyze main effects and interactions involving IS1 in order to correct for violations of sphericity (49). The adjusted degrees of freedom are computed by multiplying the conventional degrees of freedom by the Greenhouse-Geiser epsilon, a measure of the degree of sphericity which ranges from 0.50 to 1.OO. For these analyses, the epsilon value and appropriately adjusted degrees of freedom rounded to several decimal places are reported. Post-hoc analyses involving IS1 were conducted using paired t-tests (49), adjusting for multiple comparisons using the Bonferroni test. Post-hoc analyses of between-group effects were performed using the Tukey test for all pairwise comparisons. Pearson’s product moment correlation was performed to intercorrelate individual PTSD subjects’ mean Pl potential latency, amplitude, and T/C ratio derived from all ISIS. Pearson’s product moment correlation was performed to correlate CAPS scores with any P 1 potential variable significant for any

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group at ~~0.05 by repeated measures ANOVA and Tukey post hoc tests. SPSS software was used (50). Results One-way ANOVA revealed no statistically significant differences for age Q~0.60) or smoking habits @o&traumatic stress disorder subjects, 1.05Hl.7 packs/day; alcohol dependents, 1.4f0.8; combatexposed normals, 0.7H.3; combat-unexposed normals, O.OfO.0; ~~0.10). One-way ANOVA for years of education reached significance (F(3,21)=30.5 1, pO.O5). Such results might be expected, given that CAPS scores were used in the current study not only to rate symptom severity, but also to contribute, along with information from clinical interviews and SCID-P and SCID-NP, to group assignment. Examining Pl potential habituation effects, a four (group) by three (ISI) mixed repeated measures ANOVA (epsilon=0.787) revealed significant main effects for group (F(3,20)=8.26, p=O.OOl), and for IS1 (F(1.57,31.47)=8.35, p=O.O02). No significant group x IS1 interaction was found to modify the main effects. On post-hoc analysis of the between-groups effect, the PTSD group exhibited significantly greater Pl potential T/C ratio than did each comparison group (all p’sO.50). Examining Pl potential first stimulus amplitude, repeated measures

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ANOVA revealed no significant effect for group (PTSD subjects, 2.5f0.9 pV; alcohol dependents, 1.7f 0.5 uV; combat exposed normals, 2.4kl.6 pV; combat unexposed normals, 2.0f0.9 pV). for ISI, or for group by ISI interaction (all p’s>O.50).

120 -

q PTSD Patients q Alcohol Dependents

100 -

E Combat-Exposed

g 0

80-

‘3 CT

60 -

Normals

q Combat-Unexposed

Normals

0 p

40-

250 msec ISI

500 msec ISI

1000 msec ISI

Fig. 2 Bar graph of mean f S.D. PI potential T/C ratio for each subject group at each ISI. T/C ratio = (2nd stimulus Pl potential amplitude t 1st stimulus PI potential amplitude) x 100. For the 500 msec ISI, N = 4 for the combat exposed normals because of missing data on one subject. For the 250 msec and 1000 msec ISIS, N = 5 for combat exposed normals. For all ISIS, N = 10 for PTSD patients, N = 5 for alcohol dependents, and IG = 5 for combat unexposed normals. Among the PTSD subjects, Pearson’s correlation revealed no significant intercorrelations potential latency, amplitude, and T/C ratio (all p’s >0.30).

between P 1

In view of the virtual absence of PTSD symptoms in subjects of all comparison groups, only PTSD subjects were utilized in correlating CAPS scores and Pl potential T/C ratio. At the 250 msec ISI, PI potential T/C ratio correlated positively and significantly with PTSD subjects’ CAPS reexperiencing intensity scores (Pearson’s r-0.7953, p=O.O06). Correlations between Pl T/C ratio and CAPS reexperiencing intensity progressively attenuated with increasing IS1 in PTSD subjects, failing to reach significance at either the 500 msec IS1 (Pearson’s r=O.412 1, p>O. 10) or at the 1000 msec IS1 (Pearson’s r-0.0479, p>O.lO). [Figure 31 There was no significant correlation of Pl potential T/C ratio with any of the remaining five CAPS variables at any IS1 (al1 p’s>O.lO).

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500 msec ISI

250 msec ISI

OL

1429

1000

msec ISI

I

I

6

1

6

Fig. 3 Correlation between Pl potential T/C ratio at each IS1 and CAPS reexperiencing intensity scores for ten individual PTSD subjects, each represented by an open circle, with best-fit regression line. T/C ratio = (2nd stimulus Pl potential amplitude + 1st stimulus P 1 potential amplitude) x 100. Discussion

1.

Surnmarv of Current Study Findings

Pl potential habituation across all ISIS was significantly decreased in the PTSD group compared to each control group, suggesting a generalized phenomenon rather than one limited to a single ISI. The magnitude of decrease in habituation of the Pl potential in the PTSD group compared to all comparison groups was numerically greatest at the 250 msec ISI, and at this ISI, Pl potential T/C ratio correlated positively and significantly with CAPS reexperiencing intensity scores among PTSD subjects. No statistically significant correlation existed with any other CAPS frequency or intensity scores at any ISI, suggesting that the Pl potential habituation decrement in PTSD subjects may relate most closely to a neurobiological substrate for PTSD reexperiencing symptoms, and less closely to substrates for other specific symptom clusters in PTSD. 2.

Methodologic Considerations

Diagnoses and symptom severity were determined using standardized instruments, CAPS, SCID-P, SCID-NP, administered and scored by clinicians blind to Pl potential measurements. It must be noted that only approximately five percent (14 recruited subjects/estimated 280 screened admissions) of PTSD patients admitted to the specialized inpatient ward met criteria for and consented to participate in the current study, with most admitted PTSD patients excluded for medical complications necessitating standing medications, or for psychiatric comorbidity. PTSD subjects in the current study therefore are not necessarily representative of the population of combat veterans with PTSD utilizing specialized rehabilitation programs at VAMCs, and their Pl potential results may not necessarily be characteristic of such PTSD patients. However, their PI potential results may well be characteristic of persons suffering only PTSD, without medical or psychiatric comorbidities, at least those suffering combat-related PTSD. It would be important for Pl potential methodology to be extended to female patients with PTSD, considering reported gender-based differences in Pl

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potential habituation (51), and to civilians with PTSD related to nonmilitary traumas, with similar rigorous attention to potentially confounding diagnostic and pharmacologic variables. In the current study, several well defined comparison groups were studied to control for the potentially confounding variables of socioeconomic status and alcohol dependence. Since neither alcohol dependent subjects nor combat-exposed normals differed significantly from PTSD subjects in years of education, it is unlikely that education, as a proxy measure of socioeconomic status, accounts for the decrease in habituation of the Pl potential in PTSD subjects compared to that in every control group. Similarly, despite the numerically longer mean interval since last alcohol dependence among the PTSD subjects compared with the alcohol dependent subjects, alcohol dependent subjects did not differ statistically significantly from PTSD subjects in interval since last alcohol dependence, making it unlikely that history of alcohol dependence accounts for the observed decrease in Pl potential habituation in PTSD subjects. In fact, considering the numerically shorter interval since last dependence of the alcohol dependent comparison group, if recent alcohol consumption were a confounding variable raising the T/C ratio, results of the current study might have been predicted in the opposite direction, i.e., with alcohol dependent subjects exhibiting higher rather than lower T/C ratio than that of the PTSD subjects. The apparently normal Pl potential habituation among the small number of alcohol dependent subjects in the current study is consistent with published data on both active alcohol abusers and abstinent alcohol dependents (52). Although combat exposure was not quantified, combat-exposed normals included a veteran awarded the Congressional Medal of Honor, and had all been extensively exposed to trauma in the Vietnam theater, as had the PTSD subjects, making it unlikely that trauma exposure alone accounts for the decrease in Pl potential habituation observed in the PTSD group. It is worth reiterating that all subjects in the current study were consecutively recruited from those persons in each group meeting study criteria and willing to participate, in an attempt to minimize selection bias. Reinforcing the likely validity of the findings in the current study is the fact that at least two independent investigators have presented preliminary findings parallel to those of the current study (18,19). It should be noted that the limited number of subjects in each group in the current study may have precluded demonstrating statistically significant differences in Pl potential habituation between comparison groups. Limited number of subjects in the PTSD group may also have precluded demonstrating a statistically significant correlation between P 1 potential habituation and any other CAPS variable besides reexperiencing intensity. 3.

Contribution

of Current Study to the Psvchonhysiologv

of PTSD

The finding of decreased habituation of the Pl potential in the current study is consistent with speculations expressed by Paige et al. (2) concerning P2 slope reduction, and by McFarlane et al. (3) concerning P3 decreased amplitude and discrimination, that these long-latency phenomena may reflect responses at thalamic and cortical levels, respectively, to actual or perceived excessive sensory input from lower levels of stimulus processing. Neither the current study nor that of Paige et al. (2) or McFarlane et al. (3) was designed to study Pl, P2, and P3 potentials in the same cohort of PTSD subjects. It is not possible to definitively conclude that findings in one study in a given subject cohort concerning a given auditory evoked potential can be generalized to findings of another study with a different auditory evoked potential in different subjects. Nevertheless, the concept of a subthalamic gating defect is consistent with the findings of Jerger et al. (53) that PI potential amplitude and habituation are not affected by attentional manipulations in normal young adults. Jerger et al. (53) state that their “results strongly suggest that P50 suppression reflects a preattentive, or hard-wired aspect of the processing of auditory information,” and cite the conclusion of Buchwald et al. (25) and Erwin et al. (26) that the Pl potential arises from the reticular activating system. Also consistent with this concept is direct neuroanatomic and neurophysiologic evidence already cited of a mesopontine tegmental generator of the Pl evoked potential, specifically the PPN, in the rat and the cat (21-22,25).

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The findings of the current study may also be seen as generally consistent with the description by Orr (54) of other psychophysiologic functions, such as heart rate, skin conductance, and eyeblink electromyogram, which are mediated in part by brainstem structures, as overreactive to intense auditory stimuli in PTSD subjects. The second finding in the current study, namely that of a positive and highly significant correlation of Pl potential T/C ratio with subjectively reported intensity of PTSD reexperiencing symptoms, appears consistent with the statement of Paige et al. (2) that P2 slope reduction “has been seen as a central neurophysiological attenuating response to a level of stimulation which, for a given individual, represents a state of sensory overload.” Emphasis on the level at which stimulation is perceived as excessive for a given individual would seem to permit subjective reports of symptom intensity in electrophysiologic studies, as in the CAPS measurements utilized for correlation with Pl potential T/C ratio in the current study. The absence of any statistically significant correlation of Pl potential T/C ratio with any other CAPS variable suggests that the effect may be most closely related to reexperiencing symptoms, although limited subject numbers may have precluded demonstrating the statistical significance of more subtle correlations. In particular, a significant correlation between Pl potential habituation and hyperarousal symptoms would be important to seek in future studies with a larger number of subjects, given that such symptoms have been postulated to be related to excessive central noradrenergic activity in PTSD (33-35), and given that central noradrenergic hyperactivity has been suggested as contributing to evoked potential gating deficits (52). In this regard, it may be important to note that hyperarousal and reexperiencing symptoms themselves may not be easily distinguished, as evidenced by the movement of the DSM III-R (5) hyperarousal symptom “physiologic reactivity upon exposure to events that symbolize or resemble an aspect of the traumatic event” into the reexperiencing symptom category in DSM IV (6). Adler et al. (7) have proposed that the diminished Pl potential habituation seen in schizophrenic subjects may be due to disinhibition and consequent hyperactivity of the Pl potential generator. At the time of that publication, Adler et al. (7) were postulating that the Pl potential generator was located in the auditory cortex. However, their concept of a disinhibited and hyperactive Pl potential generator as explanatory of diminished Pl potential habituation can be applied to any proposed Pl potential generator, including the PPN postulated by Reese et al. (21,22) and Buchwald et al. (25) to consititute a generator of the Pl potential. A hypothetically disinhibited and hyperactive PPN would be theoretically compatible with both the diminished Pl potential habituation and the correlation of this diminished habituation and CAPS reexperiencing intensity scores observed in the PTSD subjects of the current study, since the PPN is involved in generating both the REM sleep stage and the phasic REM sleep events putatively associated with dreaming (29). Intrusive, recurrent, and distressing trauma-related dreams and wakeful flashbacks constitute cardinal reexperiencing symptoms of PTSD (4-6,37-39), and flashbacks have been postulated, though not yet demonstrated, to constitute the abnormal intrusion of REM sleep phasic events into wakefulness (37). 4.

Current Findings in the Context of the Pl Potential in Other Psychiatric Populations

In the psychiatric context, the Pl potential has been most extensively studied in schizophrenia (7-12) somewhat less extensively in mania (11,12), and by single reports only in various other neuropsychiatric disorders (12-16). Adler et al. (7) reported that in unmedicated schizophrenics, the Pl potential exhibits decreased latency, amplitude, and habituation. They also found significant positive correlations in schizophrenics, but not in normal controls, between Pl potential latency and amplitude, amplitude and habituation, and latency and habituation, and suggested a common underlying mechanism for abnormalities in all three electrophysiologic parameters for the Pl potential in schizophrenics. Neuroleptic-medicated schizophrenics exhibit diminished PI potential

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habituation, but normal latency and amplitude (55). The novel antipsychotic clozapine may constitute an exception, based on pilot data indicating improvement of diminished Pl potential habituation in schizophrenics taking clozapine (56). As noted above, one-half of clinically normal first degree relatives of schizophrenics exhibit normal latency and amplitude but diminished Pl potential habituation (42). Similarly, acutely psychotic manic patients exhibit normal Pl potential latency and amplitude but diminished habituation, the latter of which normalizes with lithium carbonate treatment (11). It is potentially interesting to note that although only posttraumatic stress disorder diagnostic criteria include trauma reexperiencing symptoms, the other disorders studied to date that exhibit diminished habituation of the Pl potential (schizophrenia, autism, psychotic mania, and major depression) all also exhibit frequent sleep disturbances, and schizophrenia, autism, and at least the psychotic presentations of mania and major depresssion exhibit marked perceptual abnormalities. Since each disorder exhibits a relatively characteristic pattern of aberration of latency, amplitude, and habituation of the Pl potential, it is unlikely that the underlying neurobiologic substrates for the common phenomenon of decreased habituation would be identical in all disorders. Nevertheless, the common themes of sleep disturbances and wakeful perceptual alterations may relate to some involvement of the PPN, in addition to other generators or modulators of the Pl potential, in all four of these disorders. In the current study, PTSD subjects differed from all comparison groups only in terms of Pl potential habituation, with no differences in latency or amplitude, similar to findings in acutely psychotic manics (1 l), in those normal first degree relatives of schizophrenics with diminished habituation (42), but different from findings in unmedicated and in neuroleptic-medicated schizophrenics, parameters schizophrenics (7). Furthermore, in the current study, no two electrophysiologic correlated with each other among the PTSD subjects, again differing from findings in unmedicated schizophrenics (7). No pharmacologic trials have been reported in PTSD subjects studied with the Pl potential paradigm. Concerning heritability of Pl potential parameters in PTSD, a large, twin-based study is currently underway designed to address the question of whether reported abnormalities in several evoked potential measures in PTSD, including the Pl potential, reflect consequences of having developed the disorder, or whether they represent a premorbid vulnerability for developing the disorder, or both (R.K. Pitman, personal communication). The underlying neurobiologic substrates accounting for both similarities and differences between Pl potential parameters observed in PTSD patients and in psychiatric patients with other disorders, the responsiveness of these parameters to pharmacologic and psychologic manipulations, their heritability, and their relation to other evoked potentials, can be elucidated only by further research. Acknowledgments Supported by United States Public Health Service grant NS20246 to E.G.R.; the National Science Foundation Experimental Program to Stimulate Competitive Research; Office of Research and Development, Medical Research Service, John L. McClellan Memorial Veterans Hospital and Biomedical Research Foundation, Little Rock AR. Dr. Peter T. Loosen of the Nashville Veterans Affairs Medical Center and Vanderbilt University School of Medicine and Dr. Andrew J. Tomarken of Vanderbilt University College of Arts and Sciences, Nashville TN, reviewed the manuscript and made valuable suggestions. References 1.

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