B~OL PSYCHIATRY 1990;27:1165-1175
1165
Autonomic Responses to Stress in Vietnam Combat Veterans With Posttraumafic Stress Disorder Miles E. McFall, M. Michele Murburg, Grant N. Ko, and Richard C. Veith
This study tested the hypothesis that combat veterans with posttraumatic stress disorder (PTSD) experience sympathetic nervous system activation in response to war-related laboratory stimuli. Circulating plasma catecholamines, vital signs, and affect ratings were measured in 10 Vietnam combat veteran~ with PTSD and 11 control subjects, during and after viewing combat and noncombat stress films. PTSD subjects responded more strongly than controls to the combat film, with greater increases in plasma epinephrine, pulse, blood pressure, and subjective distress. The increases in autonomic activity of PTSD subjects was more pronounced and long lasting in response to the combat film than to the noncombat film, but type of film had no systematic effect on control subjects' responses. These findings are :onsistent with biological models that posit sympathoadrenal activation in response to memory-evoking cues of traumatic events in PTSD.
Introduction Symptoms of increased arousal, such as hyperalertness, exaggerated startle response, and increased physiological reactivity to stimuli that symbolize a traumatic event, are among the cardinal symptoms of pcsttraumatic stress disorder (FI'SD) (American Psychiatric Association 1987). It has been hypofi~esized that the heightened autonomic arousal associated with PTSD is due, in part, to conditioned activation of the sympathetic nervous system (SNS) (Keane et al. 1985, Kolb 1987). Acco,~dingto this model, unconditioned emotional, behavioral, and physiological responses to life-threatening situations become conditioned to otherwise neutral internal and external stimuli, so that these conditionexl stiml~i~come to elicit elements of the original "fight-flight" response, including increased SNS activation. Empirical support for the actoaomic conditioning hypothesis of PTSD has been provided by a number of studies in which stress-induction analog paradigms were utilized to examine the physiological responses cf Vietnam veterans to combat-related stimuli.
From the University of Washington School of Medicine avd the VA Medical Center, Sea~e (M.E.M., M.M.M., R.C.V.), and the Bronx VA Medical Center and Mount Sinai School of Medicine, the Bronx, NY (G.N.K.). Address reprint requests to Miles E. McFail, Ph.D., VISD Treatment Team, Psychiatry Service (II6A), VA Medical Center, 1660 S. Columbian Way, Seattle, WA 98108. Received June 19, 1989; revised September 28, 1989. This research was supported by NIH Biomedical Research Support Grant #597RR0543-26 administered through the University of Washiag~on School of Medicine. Additional support was provided oy a Career Development Award from the Veterans Adminis~'ation (MMM), by the Veterans Administration Medical Center Geri~-tricResearch Education and Clinical Cen~er, and by the Research Service of the VA. This L~rticleis in the P~Jb!icDomein,
L~J06-3223/90/$O0,O0
1166
toOLPSYCHIATRY 1990;27:1165-1175
M.E. McFall et al.
Blanchard et al. (1982, 1986) demonstrated that combat veterans with PTSD showed significantly greater heart rate (HR) and blood pressure (BP) responses to combat sounds than did nonpsychiatric subjects with and without combat experience. Veterans with FTSD have also been found to exhibit more frontalis electromyogram and skin conductance responsivity than asymptomatic combat veterans when imaging personally meaningful combat trauma situations (Pitman et al. 1987). Finally, Malloy et al. (1983) observed greater increases in HR in veterans with PTSD than in combat-exposed normals or in pa~ien~ with o~ei" p~ychiatric diagnoses during audiovisual presentations of combat situations. Together, these studies indicate that combat veterans with PTSD display greater physiological reactivity to diverse forms of combat-related cues than do patient and nonpatient controls. Preliminary evidence suggests that increased release of catecholamines accompanies the autonomic reactivity associated with PTSD. Five years after the accident at the Three Mile Island nuclear power station, Davidson and Baum (1986) found that residents living within 5 miles of the site exhibited higher resting HR and BP, and higher urinary levels of norepinephrine (NE) than did controls living 80 miles away. Kosten et al. (1987) found higher urinary levels of NE in Vietnam combat veterans with PTSD than in patients with major depression, mania, or schizophrenia. These investigators also reported that urinary epinephrine (EPI) levels were higher in PTSD patients than in depressives and schizophrenics. Finally, Perry et al. (1988) reported a reduction in the number of high-affinity alpha2-adrenergic binding sites in the platelets of Vietnam veterans with FrSD, compared with other psychiatric patient groups and normals. This finding suggests that patients with PTSD may have elevated circulating levels of EPI and/or NE. Measurements of urinary catecholamines and platelet alpha2 receptor binding in these studies do not indicate whether the putative increases in circulating catecholamines are tonic or phasic. Previous studies examining the hypothesis that SNS activity is increased in PTSD have relied upon relatively indirect indices of SNS function (i.e., HR, BP, urinary catecholamines, and platelet mp'na2 receptor binding). The present study is the first to utilize arterialized plasma NE and EPI measurements to test the hypothesis that stimuli symbolic of traumatic combat situations evoke an increase in SNS activity in veterans with PTSD. The intensity and duration of autonomic and emotional responses, as reflected by changes in plasma NE and EPI, in vital signs, and in self-reported affect ratings were assessed in response t.o combat-related and noncombat-related experimental stressors in patients with PTSD and in control subjects without FTSD. It was hypothesized that (1) combat veterans with FrSD would show a greater and longer-lasting response than controls to the combat-related stressor, but not to the noncombat stressor, on measures of physiological and emotional arousal; and (2) increases in emotional arousal and vital signs would be accompanied by increases in circulating levels of plasma catecholamines.
Methods
Subjects PTSD subjects were 10 Vietnam veterans undergoing treatment for PTSD at the Seattle VA Medical Center. Four patients were recruited from the Inpatient Psychiatry Service, ~,ld the remaining 6 were outpatients. Eight subjects were Caucasian, one was MexicanAmerican, and oae was Native American. The mean age for the sample was 40.5 years. These veterans had all served a tour of duty (mean - 11.4 months) in Vietnam as
Autonomic Responses to Stress
BIOL PSYCHIATRY 1990;27:1165-1175
i
167
frontline combat soldiers with the Army or Marine Corps. The average score on the Combat Scale for the sample was 12.0 (SEM -- 0.45), defined by Laufer et al. (1981) as reflecting "high~' combat exposure. PTSD and other Axis I disorders were diagnosed by the Structured Clinical Interview for DSM-lII-R--patient version (Spitzer et al. 1987). All interviews were performed by a doctoral level clinical psychologist with extensive experience in administering structured diagnostic interviews in a PTSD evaluation/treatment facility. Of the 17 DSM-III-R criterion symptoms defining PTSD, subjects endorsed an average of 11.0 (SEM -- 0.79) symptoms. The mean score on the Mississippi Scale for Combat-Related PTSD was 121.3 (SEM -- 4.58) (possible range = 0-175), which is well in excess of the cut-off score of 107 used to identify 80% of veterans with PTSD in previous research (Keane et al. 1988). On the Impact of Event Scale, subjects' average scores were 25.0 (SEM -- 2.03) on the Intrusion subscale (possible range 0-35) and 23.8 (SEM -- 1.76) on the Avoidance subscale (possible range 0-40), exceeding established norms for PTSD patients (Zilberg et al. 1982). Comorbid diagnoses for the PTSD sample were as follows: major depression (40%); major depression, in partial remission (30%); dysthymia (30%); bi~3olar disorder, depressed (10%); generalized anxiety disorder (20%); obsessive-compulsive disorder (10%), social phobia (20%); and adjustment disorder (10%). Nine subjects had a history of substance abuse disorder that had been in remission for at least 2 weeks prior to the study. The literature to date indicates that presence of psychiatric conditions other than PrSD does not influence psychophysiologicai response to combat-related laboratory stressors (McFall et al. 1989). Control subjects (n ffi 11) were two Vietnam combat veterans receiving treatment for psychiatric disorders other than PTSD, an asymptomatic Vietnam combat veteran without PTSD, 4 military veterans without combat exposure (3 of whom were free from psychiatric disorder and I of whom had a mild simple phobia), and 4 nonveterans without mental disorder. The average age for control subjects was 38.2 years. PTSD subjects' weight averaged 117% of ideal body weight, and controls averaged 113% of ideal body weight, as defined by the 1983 Metropolitan Life Insurance Tables. They were free from all medical illness. Participants abstained from alcohol and illicit drugs usage for at least 2 weeks prior to the study, and had not taken psychotropic medications or other medications known to alter plasma catecholamine levels for at least 4 weeks. Finally, subjects refrained from caffeine, nicotine, and food ingestion for 12 hr before the procedure began.
Stimulus Materials The experimental stressors consisted of two 10-min motion pictures depicting noncombatand combat-related situations, respectively. The noncombat film showed the aftermath of serious automobile accidents and contained graphic scenes of automobile wreckage and injured and dead passengers. The combat film was composed of live combat footage taken during the Vietnam War and showed helicopter assaults, firefights, bombing by aircraft, artillery barrages, riverboat patrols, capturing of prisoners, and wounded and dead enemy and American soldiers. On average, subjects judged 77% of the combat film scenes as representative of their own wartime experiences when inquiry was made at ~ e end of the study. Both stressor films were in color and were accompanied by sounds and narration appropriate to the activity taking place. The films were presented on a 20-inch monitor at a distance of 8 feet from the subjects.
1168
BIOL PSYCHIATRY 1990;27:1165-1175
M.E. McFall et al.
In previous similar research (Malloy et al. 1983), the majority of subjects with PTSD became so emotionally distraught when viewing war-related films that they were unable to complete the experiment. Therefore, in order to ensure that subjects would be exposed to both films, and to prevent possible carry-over effects from the combat film to the contrast condition (auto film), the auto film was administered before the combat film in e v e r y case.
Dependent Measures Assessment of subjects' mood state was made throughout the study be self-ratings of 17 descriptive adjectives (e.g., anger, fear, disgust, guilt, etc.). Subjects rated each affect on a five-point scale indicating the extent to which they experienced it "now," so that transient changes in emotional state could be assessed at different times during the study. A total score (possible range 0-68) was calculated for the 17 adjectives at each time point to indicate the magnitude of self-reported negative affect experienced at that moment. BP and HR were measured using an automated ultrasonic detector (Dinamap, Critikon, Tampa, FL). This detector was calibrated to a standard mercury column to within 2% of the column reading. Circulating levels of NE and EPI were measured in arterialized forearm venous plasma. Studies from our laboratory have demonstrated that arterial or arterialized blood provides a centrally mixed sample of total body catecl~,olamine activity, whereas forearm venous blood provides a sample that may be primarily influenced by local factors (Best and Halter 1982, 1985). We have demonstrated in previous studies that forearm venous plasma arterialized by our method contains NE concentrations that are 94% of simultaneous peripheral arterial concentrations (Veith et al. 1984). Ten milliliters of atterialized blood samples for catecholamines were collected in prechilled glass tubes containing EGTA and reduced glutathione, and placed on ice until centrifugatioii at 4"C. Plasma was then stored at - 700(2 until assay. Plasma NE and EPI concentrations were measured by siiigle isotope enzymatic assay (Evans et al. 1978), with duplicate determinations for each sample. The interassay coefficient of variation for the plasma catecholamine assay in this laboratory is 6.5% in the >300 pg/ml range, and 12% in the 100 pg/ml range. The intraassay coefficient of variation is
1165
Autonomic Responses to Stress in Vietnam Combat Veterans With Posttraumafic Stress Disorder Miles E. McFall, M. Michele Murburg, Grant N. Ko, and Richard C. Veith
This study tested the hypothesis that combat veterans with posttraumatic stress disorder (PTSD) experience sympathetic nervous system activation in response to war-related laboratory stimuli. Circulating plasma catecholamines, vital signs, and affect ratings were measured in 10 Vietnam combat veteran~ with PTSD and 11 control subjects, during and after viewing combat and noncombat stress films. PTSD subjects responded more strongly than controls to the combat film, with greater increases in plasma epinephrine, pulse, blood pressure, and subjective distress. The increases in autonomic activity of PTSD subjects was more pronounced and long lasting in response to the combat film than to the noncombat film, but type of film had no systematic effect on control subjects' responses. These findings are :onsistent with biological models that posit sympathoadrenal activation in response to memory-evoking cues of traumatic events in PTSD.
Introduction Symptoms of increased arousal, such as hyperalertness, exaggerated startle response, and increased physiological reactivity to stimuli that symbolize a traumatic event, are among the cardinal symptoms of pcsttraumatic stress disorder (FI'SD) (American Psychiatric Association 1987). It has been hypofi~esized that the heightened autonomic arousal associated with PTSD is due, in part, to conditioned activation of the sympathetic nervous system (SNS) (Keane et al. 1985, Kolb 1987). Acco,~dingto this model, unconditioned emotional, behavioral, and physiological responses to life-threatening situations become conditioned to otherwise neutral internal and external stimuli, so that these conditionexl stiml~i~come to elicit elements of the original "fight-flight" response, including increased SNS activation. Empirical support for the actoaomic conditioning hypothesis of PTSD has been provided by a number of studies in which stress-induction analog paradigms were utilized to examine the physiological responses cf Vietnam veterans to combat-related stimuli.
From the University of Washington School of Medicine avd the VA Medical Center, Sea~e (M.E.M., M.M.M., R.C.V.), and the Bronx VA Medical Center and Mount Sinai School of Medicine, the Bronx, NY (G.N.K.). Address reprint requests to Miles E. McFail, Ph.D., VISD Treatment Team, Psychiatry Service (II6A), VA Medical Center, 1660 S. Columbian Way, Seattle, WA 98108. Received June 19, 1989; revised September 28, 1989. This research was supported by NIH Biomedical Research Support Grant #597RR0543-26 administered through the University of Washiag~on School of Medicine. Additional support was provided oy a Career Development Award from the Veterans Adminis~'ation (MMM), by the Veterans Administration Medical Center Geri~-tricResearch Education and Clinical Cen~er, and by the Research Service of the VA. This L~rticleis in the P~Jb!icDomein,
L~J06-3223/90/$O0,O0
1166
toOLPSYCHIATRY 1990;27:1165-1175
M.E. McFall et al.
Blanchard et al. (1982, 1986) demonstrated that combat veterans with PTSD showed significantly greater heart rate (HR) and blood pressure (BP) responses to combat sounds than did nonpsychiatric subjects with and without combat experience. Veterans with FTSD have also been found to exhibit more frontalis electromyogram and skin conductance responsivity than asymptomatic combat veterans when imaging personally meaningful combat trauma situations (Pitman et al. 1987). Finally, Malloy et al. (1983) observed greater increases in HR in veterans with PTSD than in combat-exposed normals or in pa~ien~ with o~ei" p~ychiatric diagnoses during audiovisual presentations of combat situations. Together, these studies indicate that combat veterans with PTSD display greater physiological reactivity to diverse forms of combat-related cues than do patient and nonpatient controls. Preliminary evidence suggests that increased release of catecholamines accompanies the autonomic reactivity associated with PTSD. Five years after the accident at the Three Mile Island nuclear power station, Davidson and Baum (1986) found that residents living within 5 miles of the site exhibited higher resting HR and BP, and higher urinary levels of norepinephrine (NE) than did controls living 80 miles away. Kosten et al. (1987) found higher urinary levels of NE in Vietnam combat veterans with PTSD than in patients with major depression, mania, or schizophrenia. These investigators also reported that urinary epinephrine (EPI) levels were higher in PTSD patients than in depressives and schizophrenics. Finally, Perry et al. (1988) reported a reduction in the number of high-affinity alpha2-adrenergic binding sites in the platelets of Vietnam veterans with FrSD, compared with other psychiatric patient groups and normals. This finding suggests that patients with PTSD may have elevated circulating levels of EPI and/or NE. Measurements of urinary catecholamines and platelet alpha2 receptor binding in these studies do not indicate whether the putative increases in circulating catecholamines are tonic or phasic. Previous studies examining the hypothesis that SNS activity is increased in PTSD have relied upon relatively indirect indices of SNS function (i.e., HR, BP, urinary catecholamines, and platelet mp'na2 receptor binding). The present study is the first to utilize arterialized plasma NE and EPI measurements to test the hypothesis that stimuli symbolic of traumatic combat situations evoke an increase in SNS activity in veterans with PTSD. The intensity and duration of autonomic and emotional responses, as reflected by changes in plasma NE and EPI, in vital signs, and in self-reported affect ratings were assessed in response t.o combat-related and noncombat-related experimental stressors in patients with PTSD and in control subjects without FTSD. It was hypothesized that (1) combat veterans with FrSD would show a greater and longer-lasting response than controls to the combat-related stressor, but not to the noncombat stressor, on measures of physiological and emotional arousal; and (2) increases in emotional arousal and vital signs would be accompanied by increases in circulating levels of plasma catecholamines.
Methods
Subjects PTSD subjects were 10 Vietnam veterans undergoing treatment for PTSD at the Seattle VA Medical Center. Four patients were recruited from the Inpatient Psychiatry Service, ~,ld the remaining 6 were outpatients. Eight subjects were Caucasian, one was MexicanAmerican, and oae was Native American. The mean age for the sample was 40.5 years. These veterans had all served a tour of duty (mean - 11.4 months) in Vietnam as
Autonomic Responses to Stress
BIOL PSYCHIATRY 1990;27:1165-1175
i
167
frontline combat soldiers with the Army or Marine Corps. The average score on the Combat Scale for the sample was 12.0 (SEM -- 0.45), defined by Laufer et al. (1981) as reflecting "high~' combat exposure. PTSD and other Axis I disorders were diagnosed by the Structured Clinical Interview for DSM-lII-R--patient version (Spitzer et al. 1987). All interviews were performed by a doctoral level clinical psychologist with extensive experience in administering structured diagnostic interviews in a PTSD evaluation/treatment facility. Of the 17 DSM-III-R criterion symptoms defining PTSD, subjects endorsed an average of 11.0 (SEM -- 0.79) symptoms. The mean score on the Mississippi Scale for Combat-Related PTSD was 121.3 (SEM -- 4.58) (possible range = 0-175), which is well in excess of the cut-off score of 107 used to identify 80% of veterans with PTSD in previous research (Keane et al. 1988). On the Impact of Event Scale, subjects' average scores were 25.0 (SEM -- 2.03) on the Intrusion subscale (possible range 0-35) and 23.8 (SEM -- 1.76) on the Avoidance subscale (possible range 0-40), exceeding established norms for PTSD patients (Zilberg et al. 1982). Comorbid diagnoses for the PTSD sample were as follows: major depression (40%); major depression, in partial remission (30%); dysthymia (30%); bi~3olar disorder, depressed (10%); generalized anxiety disorder (20%); obsessive-compulsive disorder (10%), social phobia (20%); and adjustment disorder (10%). Nine subjects had a history of substance abuse disorder that had been in remission for at least 2 weeks prior to the study. The literature to date indicates that presence of psychiatric conditions other than PrSD does not influence psychophysiologicai response to combat-related laboratory stressors (McFall et al. 1989). Control subjects (n ffi 11) were two Vietnam combat veterans receiving treatment for psychiatric disorders other than PTSD, an asymptomatic Vietnam combat veteran without PTSD, 4 military veterans without combat exposure (3 of whom were free from psychiatric disorder and I of whom had a mild simple phobia), and 4 nonveterans without mental disorder. The average age for control subjects was 38.2 years. PTSD subjects' weight averaged 117% of ideal body weight, and controls averaged 113% of ideal body weight, as defined by the 1983 Metropolitan Life Insurance Tables. They were free from all medical illness. Participants abstained from alcohol and illicit drugs usage for at least 2 weeks prior to the study, and had not taken psychotropic medications or other medications known to alter plasma catecholamine levels for at least 4 weeks. Finally, subjects refrained from caffeine, nicotine, and food ingestion for 12 hr before the procedure began.
Stimulus Materials The experimental stressors consisted of two 10-min motion pictures depicting noncombatand combat-related situations, respectively. The noncombat film showed the aftermath of serious automobile accidents and contained graphic scenes of automobile wreckage and injured and dead passengers. The combat film was composed of live combat footage taken during the Vietnam War and showed helicopter assaults, firefights, bombing by aircraft, artillery barrages, riverboat patrols, capturing of prisoners, and wounded and dead enemy and American soldiers. On average, subjects judged 77% of the combat film scenes as representative of their own wartime experiences when inquiry was made at ~ e end of the study. Both stressor films were in color and were accompanied by sounds and narration appropriate to the activity taking place. The films were presented on a 20-inch monitor at a distance of 8 feet from the subjects.
1168
BIOL PSYCHIATRY 1990;27:1165-1175
M.E. McFall et al.
In previous similar research (Malloy et al. 1983), the majority of subjects with PTSD became so emotionally distraught when viewing war-related films that they were unable to complete the experiment. Therefore, in order to ensure that subjects would be exposed to both films, and to prevent possible carry-over effects from the combat film to the contrast condition (auto film), the auto film was administered before the combat film in e v e r y case.
Dependent Measures Assessment of subjects' mood state was made throughout the study be self-ratings of 17 descriptive adjectives (e.g., anger, fear, disgust, guilt, etc.). Subjects rated each affect on a five-point scale indicating the extent to which they experienced it "now," so that transient changes in emotional state could be assessed at different times during the study. A total score (possible range 0-68) was calculated for the 17 adjectives at each time point to indicate the magnitude of self-reported negative affect experienced at that moment. BP and HR were measured using an automated ultrasonic detector (Dinamap, Critikon, Tampa, FL). This detector was calibrated to a standard mercury column to within 2% of the column reading. Circulating levels of NE and EPI were measured in arterialized forearm venous plasma. Studies from our laboratory have demonstrated that arterial or arterialized blood provides a centrally mixed sample of total body catecl~,olamine activity, whereas forearm venous blood provides a sample that may be primarily influenced by local factors (Best and Halter 1982, 1985). We have demonstrated in previous studies that forearm venous plasma arterialized by our method contains NE concentrations that are 94% of simultaneous peripheral arterial concentrations (Veith et al. 1984). Ten milliliters of atterialized blood samples for catecholamines were collected in prechilled glass tubes containing EGTA and reduced glutathione, and placed on ice until centrifugatioii at 4"C. Plasma was then stored at - 700(2 until assay. Plasma NE and EPI concentrations were measured by siiigle isotope enzymatic assay (Evans et al. 1978), with duplicate determinations for each sample. The interassay coefficient of variation for the plasma catecholamine assay in this laboratory is 6.5% in the >300 pg/ml range, and 12% in the 100 pg/ml range. The intraassay coefficient of variation is
