Shared Neuroendocrine Patterns of Post-Traumatic Stress Disorder and Alexithymia JAMES P. HENRY, MD, PHD, MARK G. HAVILAND, PHD, MICHAEL A. CUMMINGS, MD, DONALD L. ANDERSON, MD, JERALD C. NELSON, MD, JAMES P. MACMURRAY, PHD, WILLIAM H. MCGHEE, MD, EDD, AND RICHARD W. HUBBARD, PHD High norepinephrine/cortisol ratios have been shown to be useful indicators of post-traumatic stress disorder (PTSD). Alexithymia can result from overwhelming stress; thus, we hypothesized that sympathetic-adrenal medullary/hypothalamic-pituitary adrenal ratios would be positively associated with alexithymia severity. In the present study, we correlated 3-methoxy4-hydroxyphenylethylene glycol (MHPG)/adrenocorticotropic hormone (ACTH) and MHPG/ cortisol ratios with self-report Toronto Alexithymia Scale (TAS) scores in a group (n = 17) of nondepressed, formerly alcohol-dependent men. The correlations between the respective ratios and TAS scores were 0.515 (p = 0.034) and 0.561 (p = 0.019) We suggest that increasing degrees of alexithymia are accompanied by an increasing separation of these two endocrine systems and then speculate that this dissociation has an anatomical basis in the lateralization of emotions. Key words: PTSD; alexithymia; norepinephrine; ACTH; cortisol.
INTRODUCTION
The constellation of symptoms associated with post-traumatic stress disorder (PTSD) (lj is comprised of sets that appear incompatible. For example, PTSD patients not only experience painful memories together with vigilance and anger, they also experience contrasting losses of interest in daily activities, feelings of meaninglessness, and often the blunted emotional responses typical of severe alexithymia
From the From the Departments of Psychiatry (J.P.H., M.G.H., M.A.C., D.L.A., J.P.M., W.H.M.), Internal Medicine (J.C.N.), and Pathology (R.W.H.), Loma Linda University School of Medicine, Loma Linda, California Address reprint requests to: James P. Henry, M.D., Ph.D., Department of Psychiatry, Loma Linda University School of Medicine, Loma Linda, CA 92350. Received for publication September 5, 1991; revision received March 24, 1992
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(for a definition and reviews of the alexithymia construct, see Lane and Schwartz (2) and Taylor et al. (3)). Thus, it is not surprising that the neuroendocrine patterns associated with PTSD are puzzling. Kosten et al. (4) and Mason et al. (5), respectively, have documented that PTSD patients have higher urinary norepinephrine and lower urinary-free cortisol than do patients with other psychiatric diagnoses. In fact, while warning elsewhere that our understanding of hypothalamicpituitary adrenal (HPA) dysfunction in PTSD is not complete (6), Mason's group (7) has proposed that a high norepinephrine/cortisol ratio is a biological marker for PTSD. As noted above, alexithymia can result from traumatic events in the social environment (8, 9). As such, it often is recognized and, at times, treated in PTSD patient groups, particularly Vietnam veterans (10). Zeitlin et al. (11), for example, 407
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found that 60% (15/25) of their PTSD patients scored in the alexithymic range on the Toronto Alexithymia Scale (TAS) (12, 13). Moreover, Shipko et al. (14) found that 41% (9/22) of their PTSD sample scored in the alexithymic range on the Schalling-Sifneos Personality Scale (SSPS) (15), and Hyer et al. (16) found that 86% (65/76) of their PTSD patients scored in the alexithymic range on the MMPI alexithymia scale (MMPI-A) (17). The results of the last two studies must be interpreted cautiously, however, for the SSPS (and the revised SSPS (18)) and the MMPIA have been criticized as being inadequate assessment instruments (19-23). Measurement error, for example, may account for part of the two-fold difference in the percentages reported by Shipko et al. (14) and Hyer et al. (16). Given Mason et al.'s (7) findings and the possible common traumatic origin of both PTSD and alexithymia, we hypothesized that alexithymia severity would be positively correlated with sympathetic-adrenal medullary/HPA ratios.
METHODS
Subjects and Procedure Subjects were 17 of 21 participants in a study (24) of thyroid-stimulating hormone (TSH) and prolactin responses to thyrotropin-releasing hormone (TRH) (three subjects in the original sample failed to complete or return their alexithymia questionnaires; one failed to turn in his 24-hour urine sample). Their mean ± SD age was 39.2 ± 3.4 years. Patients were excluded if they were less than 25 or more than 44 years old; did not meet DSM-III-R criteria for alcohol dependence; had a history of dependence on a substance other than alcohol; had abused drugs other than alcohol within 30 days prior to admission; had a DSM-III-R history of bipolar or depressive disorder, schizophrenia, or other psychotic disorders; or had a history of serious medical illness, including hepatic or endocrine disease. (Endocrine screening included
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thyroid palpation, determinations of antithyroid microsomal antibodies, free thyroxine, and TSH.) During their 1st week of inpatient treatment for alcohol dependence, subjects who agreed to participate signed informed consent. On day 15, their transaminases (SGOT and SGPT) were checked, and all were within normal ranges. On day 27, we evaluated participants' depressive state using the 21item structured Hamilton Depression Rating Scale (HDRS) (25, 26); subjects' scores ranged from 1 to 15 (mean ± SD = 5.2 ± 3.3; median = 4). On days 26 and 27 we collected a 24-hour urine sample (0700 to 0700) for 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). On the 28th day (the day of the TRH stimulation test), we drew three baseline blood samples (0800. 0830, and 0900) for adrenocorticotropic hormone (ACTH) and cortisol and then administered the TAS at 1000.
Assays Urinary MHPG: To represent norepinephrine (N) release in the sympathetic nervous system, we used total (conjugated and free) MHPG (27, 28), N's major end metabolite (29). MHPG was determined using high performance liquid chromatography with electrochemical detection (30, 31). The intra-assay coefficient of variation is 6.6%; the inter-assay coefficient of variation is 6.1%. MHPG is expressed in jig/24hour collection period, and normal values range from 1565 to 2305 (95% confidence interval for the mean ± SEM published in Peyrin (32)). Plasma ACTH and serum cortisol: Our adrenocortical system indicators were ACTH and cortisol, increasingly-accepted measures of psychological uncertainty and distress (33, 34). Plasma ACTH was determined using a highly sensitive immunoradiometric assay (35). The intra-assay variation coefficient is 3.0%; the inter-assay variation coefficient is 7.8%. Normal values range from 9 to 52 ng/liter. (Values below the detectable limit [5 ng/liter] were coded as 5 ng/liter.) Our ACTH indicator was the average of the three baseline measurements. Serum cortisol was determined by direct radioimmunoassay (36). The intra-assay coefficient of variation is 6.2%, and the inter-assay coefficient of variation is 10.0%. The normal range is 70 to 180 jtg/liter. Our cortisol indicator was the average of the three baseline measurements. Both assays were performed at the Nichols Institute Reference Laboratories, San Juan Capistrano CA. The normal ranges given here are appropriate benchmarks in that we are evaluat-
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NEUROENDOCRINE PATTERNS OF PTSD & ALEXITHYMIA ing relationships between the various neuroendocrine markers and degree of alexithymia within a subject group. We are not, for instance, comparing these 17 subjects with matched or comparable controls; thus, it is important not to overinterpret the ranges or the means and standard deviations presented in the first part of the "Results" section.
Alexithymia Assessment To measure alexithymia, we used the 26-item TAS (12, 13). a reliable, valid, self-report measure (37, 38). Although the TAS clearly is the most psychometrically sound self-report alexithymia scale, Hendryx et al. (39, 40), Kirmayer and Robbins (41), and Haviland et al. (42) note that it is not without fault. Therefore, in addition to using total TAS scores, we calculated three subscale scores based on Haviland et al.'s (42) most-recent TAS factor analysis with substance abusers: a) an inability to identify feelings and to distinguish them from bodily sensations, and, to a lesser extent, an inability to communicate feelings to others (11 items—TAS-Emotional Awareness Deficits); b) a reduced capacity to daydream (three items—TAS-Reduced Daydreaming); and c) a preference for focusing on external events rather than inner experiences (four items— TAS-External Thinking). We will treat TAS total score (and the three subscale scores) as continuous variables in this study; however, Taylor et al. (12) have established cutoff scores: alexithymic (74 and above) and non-alexithymic (62 and below).
Data Analyses To calculate MHPG/ACTH and MHPG/cortisol ratios, we divided total MHPG by average ACTH and average cortisol. respectively. To estimate the relationships among the variables of interest, we used Pearson product-moment correlation; for the tests of statistical significance, alpha was set at 0.05.
RESULTS
Subjects' total urinary MHPG ranged from 272 /ug/24 hours to 6212 Mg/24 hours (mean ± SD = 2200 ± 1782). This mean was within normal limits; however, nine Psychosomatic Medicine 54:407-415 (1992)
had MHPG values that were below 1565 ^g/24 hours, and seven had values that were above 2305 Mg/24 hours. The average of subjects' three ACTH concentrations ranged from 5 to 27 ng/liter, and the mean ± SD of 13 ± 8 was within normal limits. Seven subjects, however, had average ACTH concentrations that were lower than normal (i.e., below 9 ng/liter), and for three of those, none of the three concentrations was detectable (i.e., below 5 ng/liter). Subjects' average cortisol values ranged from 77 to 157 jig/liter (mean ± SD = 116 ± 24). All average concentrations were within normal limits. A summary of these data is given in Table 1. Total TAS scores ranged from 47 to 90 (mean ± SD = 67 ± 13); six (35.3%) had TAS scores of 74 or above, indicating alexithymia; seven scores were in the nonalexithymic range (62 and below). The correlations between TAS score and the MHPG/ACTH and MHPG/cortisol ratios were moderate, positive, and statistically significant (respective correlations: r = 0.515, p = 0.034 and r = 0.561, p = 0.019; see Figures 1 and 2). To explore these relationships further, we correlated MHPG with ACTH and with cortisol; ACTH with cortisol; and MHPG, ACTH, and cortisol with TAS score. The correlation between MHPG and ACTH was nonsignificant (—0.258) as was the correlation between MHPG and cortisol (0.087). The correlation between ACTH and cortisol was 0.560, p = 0.019. The correlation between total TAS score and MHPG was 0.541, p = 0.024; the correlations between TAS score and ACTH and cortisol, respectively, were negative and nonsignificant (-0.299 and-0.118). The correlations between the TASEmotional Awareness Deficits subscale and the two ratios were similar to those for total TAS score: moderate, positive, 409
|. P. HENRY et al. TABLE 1. Sympathetic-Adrenal Medullary/HPA Axis Ratios and Their Relationships to Toronto Alexithymia Scale Scores TAS Score
MHPC Mg/24 hours
ACTH ng/liter
Cortisol
MHPC/ACTH Ratio"1
MHPC/Cortisol Ratio"
90 87 86 76 75 74 72 69 66 64 61 59 59 55 55 48 47
3281 6212 2625 4192 1537 1041 2629 4202 1218 573 565 4911 576 862 272 1041 1660
5 10 5 14 10 19 5 25 5 20 9 6 27 23 15 5 16
130 113 100 157 90 117 93 110 90 123 77 120 140 143 140 87 143
656.2 621.2 492.2 299.4 159.0 55.8 525.8 170.4 228.4 29.1 65.2 866.7 21.1 36.9 17.7 208.2 106.0
25.2 54.8 26.3 26.8 17.1 8.9 28.2 38.2 13.5 4.7 7.4 40.9 4.1 6.0 1.9 12.0 11.6
TAS = Toronto Alexithymia Scale; MHPG = 3-methoxy-4-hydroxphenylethylene glycol; ACTH = adrenocorticotropic hormone. Correlation with TAS Score: r = 0.515, p = 0.034. 6 Correlation with TAS Score: r = 0.561, p = 0.019.
3
DISCUSSION
200
400
600
800
Catecholamine/ACTH Ratio
Fig. 1. Scatterplot: MHPG (catecholamine)/ACTH Ratio and Toronto Alexithymia Scale Score.
and statistically significant. In contrast, correlations between the two ratios and the other two TAS subscales, Reduced Daydreaming and External Thinking, were negative and nonsignificant. 410
Our data show that in nondepressed, formerly alcohol-dependent men (abstinent for more than 4 weeks), alexithymia is positively correlated with sympathoadrenal/HPA ratios. Despite the fact that our methods differ somewhat, we believe that our results parallel Mason et al.'s (7) finding that PTSD is associated with a high norepinephrine/cortisol ratio. Indeed, the differences Mason's group observed might have been even more striking had they separated their PTSD cases with alexithymia from those without it. Zeitlin et al. (11), for instance, have recently demonstrated that the interhemispheric tactile transfer deficit in PTSD is confined to those cases with alexithymia. We view our findings as preliminary, Psychosomatic Medicine 54:407-415 (1992)
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Catecholamine/Cortisol Ratio
Fig. 2. Scatterplot: MHPG (catecholamine)/Cortisol Ratio and Toronto Alexithymia Scale Score.
however, for several reasons. First, given low statistical power, we were unable to judge small to moderate effects to be statistically significant (for example, the expected negative correlations between TAS scores and ACTH and cortisol). Second, we did not have trauma histories on our patients and, thus, cannot say whether those scoring in the alexithymic range had at some time perceived overwhelming stress (or, conversely, that those who did not, had not). Third, as noted in the "Methods" section, the TAS is not faultless. For example, TAS-Reduced Daydreaming and TAS-External Thinking have been shown to be unrelated to TAS-Emotional Awareness Deficits (40, 42); thus, it is not surprising that their correlations with the respective ratios were considerably different than those for total TAS score and TAS-Emotional Awareness Deficits. (The scale, however, has been revised (TAS-R) (43); because we administered the 43-item pilot version, we could rescore the tests and then run separate analyses using the 23-item TAS-R. The correlations between the various biochemical measures and total TAS-R scores were similar (same signs and essentially same magnitudes) to the Psychosomatic Medicine 54:407-415 (1992)
correlations between the biochemical measures and total TAS scores. Moreover, the statistically significant associations remained significant, and the nonsignificant associations remained nonsignificant.) Finally, a somewhat puzzling finding is that 16 of the 17 subjects' MHPG values fell either above or below the expected "normal" range. As noted in the "Methods" section, the "normal" range we calculated may have given us inadequate benchmarks, although it is similar to the reference range published in Pitman and Orr (44). Clearly, the conclusions we can draw from the present data set are quite limited; however, we believe that our observations and those of others (Mason et al. (7) particularly) suggest that increasing degrees of alexithymia are accompanied by an increasing separation of the sympatho-adrenal and the HPA axes and a failure of the HPA axis to respond as expected. Moreover, alexithymia is associated with left cerebral lateralization ((45); see also Zeitlin et al. (11)); we speculate that this endocrine system separation is related to a dissociation between the cerebral hemispheres. Our reasoning, derived from several investigative lines, is as follow.s. An organism's response to the initial phases of an overwhelmingly stressful situation typically involves simultaneous activation of both the sympatho-adrenal and the HPA axes (46); however, these systems can (and do) operate independently. For instance, extensive new animal data show that the effort involved in maintaining control over the environment is associated with arousal and high catecholamine levels and that HPA activation is associated with the distress induced by the perception that despite every effort this control is being or may 411
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be lost (47, 48). Moreover, stress researchers (de Boer et al. (49)) recently concluded that ".. .presence and absence of expected behavioral consequences (controllability and loss of control, respectively) are attended by selective, but highly dissociated patterns of neurosympathetic, adrenomedullary and adrenocortical output" (p. 691). This is not peculiar to animals. Lundberg and Frankenhaeuser (50) found that in humans, increased norepinephrine is associated with "effort" while increased cortisol marks an independent "distress" factor, and more recently, Lovallo et al. (51) have shown that tasks involving effort without distress primarily activate the norepinephrine system. In short, as Mason et al. (52) have long contended, distinctive emotional states are associated with specific neuroendocrine response patterns. Reviewing the psychoendocrine literature, Mason et al. (7) point to the association of the state of arousal and irritability typical of PTSD with high levels of the effort-related catecholamine, norepinephrine. They contrast this with the unexpectedly low levels of cortisol that usually are associated with successful psychological defenses. The crucial factor determining activation of the sympathoadrenal without the HPA axis is the extent of perceived control. Whether this perception is erroneous and the sense of control a delusion is irrelevant. Mason et al.'s (53) work shows that in states of effective denial where control is perceived as being retained despite a severe challenge to the organism, such as bereavement, the HPA axis may not be activated. Finally, there is clinical support for a proposal that the emotions involved in behavior patterns critical for species survival are subject to the influence of an
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interhemispheric communication system that in different neuroendocrine states determines different degrees of right and left hemispheric participation. Silberman and Weingartner (54), for example, have summarized the convincing evidence from various sources, including stroke patient studies, that functions related to emotions are lateralized. Further, in an extensive review, Davidson and Fox (55) conclude that the left hemisphere is associated with "coping," which involves the fight-flight response; that is, effective control is linked to activation of catecholamines (norepinephrine) and the directed vigilance induced by the locus coeruleus. We propose that higher levels of MHPG indicate greater activation of the left hemisphere and of the effort system associated with it. On the other hand, Davidson and Fox (55) associate the right hemisphere with "appraisal." Terzian (56) long ago showed that powerful feelings of anxious sadness overcame the patient whose left hemisphere had been temporarily disabled by the injection of amytal into the left carotid. By contrast, when there is sudden loss of the right hemisphere, the patient is surprisingly lively and full of well being. Thus, the Wada test (57) also suggests that the "effort" and "distress" systems are lateralized. To recapitulate: If the controls for the sympathetic-adrenal medullary axis are more strongly associated with activation of the left hemisphere and those for the HPA axis are more involved with the right hemisphere, it would explain the failure of cortisol to rise in PTSD (and presumably alexithymia) despite anxiety and concurrent high norepinephrine levels. Although plausible, clearly, more elegant studies are required to test this hypothe-
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415
INTRODUCTION
The constellation of symptoms associated with post-traumatic stress disorder (PTSD) (lj is comprised of sets that appear incompatible. For example, PTSD patients not only experience painful memories together with vigilance and anger, they also experience contrasting losses of interest in daily activities, feelings of meaninglessness, and often the blunted emotional responses typical of severe alexithymia
From the From the Departments of Psychiatry (J.P.H., M.G.H., M.A.C., D.L.A., J.P.M., W.H.M.), Internal Medicine (J.C.N.), and Pathology (R.W.H.), Loma Linda University School of Medicine, Loma Linda, California Address reprint requests to: James P. Henry, M.D., Ph.D., Department of Psychiatry, Loma Linda University School of Medicine, Loma Linda, CA 92350. Received for publication September 5, 1991; revision received March 24, 1992
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(for a definition and reviews of the alexithymia construct, see Lane and Schwartz (2) and Taylor et al. (3)). Thus, it is not surprising that the neuroendocrine patterns associated with PTSD are puzzling. Kosten et al. (4) and Mason et al. (5), respectively, have documented that PTSD patients have higher urinary norepinephrine and lower urinary-free cortisol than do patients with other psychiatric diagnoses. In fact, while warning elsewhere that our understanding of hypothalamicpituitary adrenal (HPA) dysfunction in PTSD is not complete (6), Mason's group (7) has proposed that a high norepinephrine/cortisol ratio is a biological marker for PTSD. As noted above, alexithymia can result from traumatic events in the social environment (8, 9). As such, it often is recognized and, at times, treated in PTSD patient groups, particularly Vietnam veterans (10). Zeitlin et al. (11), for example, 407
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found that 60% (15/25) of their PTSD patients scored in the alexithymic range on the Toronto Alexithymia Scale (TAS) (12, 13). Moreover, Shipko et al. (14) found that 41% (9/22) of their PTSD sample scored in the alexithymic range on the Schalling-Sifneos Personality Scale (SSPS) (15), and Hyer et al. (16) found that 86% (65/76) of their PTSD patients scored in the alexithymic range on the MMPI alexithymia scale (MMPI-A) (17). The results of the last two studies must be interpreted cautiously, however, for the SSPS (and the revised SSPS (18)) and the MMPIA have been criticized as being inadequate assessment instruments (19-23). Measurement error, for example, may account for part of the two-fold difference in the percentages reported by Shipko et al. (14) and Hyer et al. (16). Given Mason et al.'s (7) findings and the possible common traumatic origin of both PTSD and alexithymia, we hypothesized that alexithymia severity would be positively correlated with sympathetic-adrenal medullary/HPA ratios.
METHODS
Subjects and Procedure Subjects were 17 of 21 participants in a study (24) of thyroid-stimulating hormone (TSH) and prolactin responses to thyrotropin-releasing hormone (TRH) (three subjects in the original sample failed to complete or return their alexithymia questionnaires; one failed to turn in his 24-hour urine sample). Their mean ± SD age was 39.2 ± 3.4 years. Patients were excluded if they were less than 25 or more than 44 years old; did not meet DSM-III-R criteria for alcohol dependence; had a history of dependence on a substance other than alcohol; had abused drugs other than alcohol within 30 days prior to admission; had a DSM-III-R history of bipolar or depressive disorder, schizophrenia, or other psychotic disorders; or had a history of serious medical illness, including hepatic or endocrine disease. (Endocrine screening included
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thyroid palpation, determinations of antithyroid microsomal antibodies, free thyroxine, and TSH.) During their 1st week of inpatient treatment for alcohol dependence, subjects who agreed to participate signed informed consent. On day 15, their transaminases (SGOT and SGPT) were checked, and all were within normal ranges. On day 27, we evaluated participants' depressive state using the 21item structured Hamilton Depression Rating Scale (HDRS) (25, 26); subjects' scores ranged from 1 to 15 (mean ± SD = 5.2 ± 3.3; median = 4). On days 26 and 27 we collected a 24-hour urine sample (0700 to 0700) for 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). On the 28th day (the day of the TRH stimulation test), we drew three baseline blood samples (0800. 0830, and 0900) for adrenocorticotropic hormone (ACTH) and cortisol and then administered the TAS at 1000.
Assays Urinary MHPG: To represent norepinephrine (N) release in the sympathetic nervous system, we used total (conjugated and free) MHPG (27, 28), N's major end metabolite (29). MHPG was determined using high performance liquid chromatography with electrochemical detection (30, 31). The intra-assay coefficient of variation is 6.6%; the inter-assay coefficient of variation is 6.1%. MHPG is expressed in jig/24hour collection period, and normal values range from 1565 to 2305 (95% confidence interval for the mean ± SEM published in Peyrin (32)). Plasma ACTH and serum cortisol: Our adrenocortical system indicators were ACTH and cortisol, increasingly-accepted measures of psychological uncertainty and distress (33, 34). Plasma ACTH was determined using a highly sensitive immunoradiometric assay (35). The intra-assay variation coefficient is 3.0%; the inter-assay variation coefficient is 7.8%. Normal values range from 9 to 52 ng/liter. (Values below the detectable limit [5 ng/liter] were coded as 5 ng/liter.) Our ACTH indicator was the average of the three baseline measurements. Serum cortisol was determined by direct radioimmunoassay (36). The intra-assay coefficient of variation is 6.2%, and the inter-assay coefficient of variation is 10.0%. The normal range is 70 to 180 jtg/liter. Our cortisol indicator was the average of the three baseline measurements. Both assays were performed at the Nichols Institute Reference Laboratories, San Juan Capistrano CA. The normal ranges given here are appropriate benchmarks in that we are evaluat-
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NEUROENDOCRINE PATTERNS OF PTSD & ALEXITHYMIA ing relationships between the various neuroendocrine markers and degree of alexithymia within a subject group. We are not, for instance, comparing these 17 subjects with matched or comparable controls; thus, it is important not to overinterpret the ranges or the means and standard deviations presented in the first part of the "Results" section.
Alexithymia Assessment To measure alexithymia, we used the 26-item TAS (12, 13). a reliable, valid, self-report measure (37, 38). Although the TAS clearly is the most psychometrically sound self-report alexithymia scale, Hendryx et al. (39, 40), Kirmayer and Robbins (41), and Haviland et al. (42) note that it is not without fault. Therefore, in addition to using total TAS scores, we calculated three subscale scores based on Haviland et al.'s (42) most-recent TAS factor analysis with substance abusers: a) an inability to identify feelings and to distinguish them from bodily sensations, and, to a lesser extent, an inability to communicate feelings to others (11 items—TAS-Emotional Awareness Deficits); b) a reduced capacity to daydream (three items—TAS-Reduced Daydreaming); and c) a preference for focusing on external events rather than inner experiences (four items— TAS-External Thinking). We will treat TAS total score (and the three subscale scores) as continuous variables in this study; however, Taylor et al. (12) have established cutoff scores: alexithymic (74 and above) and non-alexithymic (62 and below).
Data Analyses To calculate MHPG/ACTH and MHPG/cortisol ratios, we divided total MHPG by average ACTH and average cortisol. respectively. To estimate the relationships among the variables of interest, we used Pearson product-moment correlation; for the tests of statistical significance, alpha was set at 0.05.
RESULTS
Subjects' total urinary MHPG ranged from 272 /ug/24 hours to 6212 Mg/24 hours (mean ± SD = 2200 ± 1782). This mean was within normal limits; however, nine Psychosomatic Medicine 54:407-415 (1992)
had MHPG values that were below 1565 ^g/24 hours, and seven had values that were above 2305 Mg/24 hours. The average of subjects' three ACTH concentrations ranged from 5 to 27 ng/liter, and the mean ± SD of 13 ± 8 was within normal limits. Seven subjects, however, had average ACTH concentrations that were lower than normal (i.e., below 9 ng/liter), and for three of those, none of the three concentrations was detectable (i.e., below 5 ng/liter). Subjects' average cortisol values ranged from 77 to 157 jig/liter (mean ± SD = 116 ± 24). All average concentrations were within normal limits. A summary of these data is given in Table 1. Total TAS scores ranged from 47 to 90 (mean ± SD = 67 ± 13); six (35.3%) had TAS scores of 74 or above, indicating alexithymia; seven scores were in the nonalexithymic range (62 and below). The correlations between TAS score and the MHPG/ACTH and MHPG/cortisol ratios were moderate, positive, and statistically significant (respective correlations: r = 0.515, p = 0.034 and r = 0.561, p = 0.019; see Figures 1 and 2). To explore these relationships further, we correlated MHPG with ACTH and with cortisol; ACTH with cortisol; and MHPG, ACTH, and cortisol with TAS score. The correlation between MHPG and ACTH was nonsignificant (—0.258) as was the correlation between MHPG and cortisol (0.087). The correlation between ACTH and cortisol was 0.560, p = 0.019. The correlation between total TAS score and MHPG was 0.541, p = 0.024; the correlations between TAS score and ACTH and cortisol, respectively, were negative and nonsignificant (-0.299 and-0.118). The correlations between the TASEmotional Awareness Deficits subscale and the two ratios were similar to those for total TAS score: moderate, positive, 409
|. P. HENRY et al. TABLE 1. Sympathetic-Adrenal Medullary/HPA Axis Ratios and Their Relationships to Toronto Alexithymia Scale Scores TAS Score
MHPC Mg/24 hours
ACTH ng/liter
Cortisol
MHPC/ACTH Ratio"1
MHPC/Cortisol Ratio"
90 87 86 76 75 74 72 69 66 64 61 59 59 55 55 48 47
3281 6212 2625 4192 1537 1041 2629 4202 1218 573 565 4911 576 862 272 1041 1660
5 10 5 14 10 19 5 25 5 20 9 6 27 23 15 5 16
130 113 100 157 90 117 93 110 90 123 77 120 140 143 140 87 143
656.2 621.2 492.2 299.4 159.0 55.8 525.8 170.4 228.4 29.1 65.2 866.7 21.1 36.9 17.7 208.2 106.0
25.2 54.8 26.3 26.8 17.1 8.9 28.2 38.2 13.5 4.7 7.4 40.9 4.1 6.0 1.9 12.0 11.6
TAS = Toronto Alexithymia Scale; MHPG = 3-methoxy-4-hydroxphenylethylene glycol; ACTH = adrenocorticotropic hormone. Correlation with TAS Score: r = 0.515, p = 0.034. 6 Correlation with TAS Score: r = 0.561, p = 0.019.
3
DISCUSSION
200
400
600
800
Catecholamine/ACTH Ratio
Fig. 1. Scatterplot: MHPG (catecholamine)/ACTH Ratio and Toronto Alexithymia Scale Score.
and statistically significant. In contrast, correlations between the two ratios and the other two TAS subscales, Reduced Daydreaming and External Thinking, were negative and nonsignificant. 410
Our data show that in nondepressed, formerly alcohol-dependent men (abstinent for more than 4 weeks), alexithymia is positively correlated with sympathoadrenal/HPA ratios. Despite the fact that our methods differ somewhat, we believe that our results parallel Mason et al.'s (7) finding that PTSD is associated with a high norepinephrine/cortisol ratio. Indeed, the differences Mason's group observed might have been even more striking had they separated their PTSD cases with alexithymia from those without it. Zeitlin et al. (11), for instance, have recently demonstrated that the interhemispheric tactile transfer deficit in PTSD is confined to those cases with alexithymia. We view our findings as preliminary, Psychosomatic Medicine 54:407-415 (1992)
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Catecholamine/Cortisol Ratio
Fig. 2. Scatterplot: MHPG (catecholamine)/Cortisol Ratio and Toronto Alexithymia Scale Score.
however, for several reasons. First, given low statistical power, we were unable to judge small to moderate effects to be statistically significant (for example, the expected negative correlations between TAS scores and ACTH and cortisol). Second, we did not have trauma histories on our patients and, thus, cannot say whether those scoring in the alexithymic range had at some time perceived overwhelming stress (or, conversely, that those who did not, had not). Third, as noted in the "Methods" section, the TAS is not faultless. For example, TAS-Reduced Daydreaming and TAS-External Thinking have been shown to be unrelated to TAS-Emotional Awareness Deficits (40, 42); thus, it is not surprising that their correlations with the respective ratios were considerably different than those for total TAS score and TAS-Emotional Awareness Deficits. (The scale, however, has been revised (TAS-R) (43); because we administered the 43-item pilot version, we could rescore the tests and then run separate analyses using the 23-item TAS-R. The correlations between the various biochemical measures and total TAS-R scores were similar (same signs and essentially same magnitudes) to the Psychosomatic Medicine 54:407-415 (1992)
correlations between the biochemical measures and total TAS scores. Moreover, the statistically significant associations remained significant, and the nonsignificant associations remained nonsignificant.) Finally, a somewhat puzzling finding is that 16 of the 17 subjects' MHPG values fell either above or below the expected "normal" range. As noted in the "Methods" section, the "normal" range we calculated may have given us inadequate benchmarks, although it is similar to the reference range published in Pitman and Orr (44). Clearly, the conclusions we can draw from the present data set are quite limited; however, we believe that our observations and those of others (Mason et al. (7) particularly) suggest that increasing degrees of alexithymia are accompanied by an increasing separation of the sympatho-adrenal and the HPA axes and a failure of the HPA axis to respond as expected. Moreover, alexithymia is associated with left cerebral lateralization ((45); see also Zeitlin et al. (11)); we speculate that this endocrine system separation is related to a dissociation between the cerebral hemispheres. Our reasoning, derived from several investigative lines, is as follow.s. An organism's response to the initial phases of an overwhelmingly stressful situation typically involves simultaneous activation of both the sympatho-adrenal and the HPA axes (46); however, these systems can (and do) operate independently. For instance, extensive new animal data show that the effort involved in maintaining control over the environment is associated with arousal and high catecholamine levels and that HPA activation is associated with the distress induced by the perception that despite every effort this control is being or may 411
). P. HENRY et al.
be lost (47, 48). Moreover, stress researchers (de Boer et al. (49)) recently concluded that ".. .presence and absence of expected behavioral consequences (controllability and loss of control, respectively) are attended by selective, but highly dissociated patterns of neurosympathetic, adrenomedullary and adrenocortical output" (p. 691). This is not peculiar to animals. Lundberg and Frankenhaeuser (50) found that in humans, increased norepinephrine is associated with "effort" while increased cortisol marks an independent "distress" factor, and more recently, Lovallo et al. (51) have shown that tasks involving effort without distress primarily activate the norepinephrine system. In short, as Mason et al. (52) have long contended, distinctive emotional states are associated with specific neuroendocrine response patterns. Reviewing the psychoendocrine literature, Mason et al. (7) point to the association of the state of arousal and irritability typical of PTSD with high levels of the effort-related catecholamine, norepinephrine. They contrast this with the unexpectedly low levels of cortisol that usually are associated with successful psychological defenses. The crucial factor determining activation of the sympathoadrenal without the HPA axis is the extent of perceived control. Whether this perception is erroneous and the sense of control a delusion is irrelevant. Mason et al.'s (53) work shows that in states of effective denial where control is perceived as being retained despite a severe challenge to the organism, such as bereavement, the HPA axis may not be activated. Finally, there is clinical support for a proposal that the emotions involved in behavior patterns critical for species survival are subject to the influence of an
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interhemispheric communication system that in different neuroendocrine states determines different degrees of right and left hemispheric participation. Silberman and Weingartner (54), for example, have summarized the convincing evidence from various sources, including stroke patient studies, that functions related to emotions are lateralized. Further, in an extensive review, Davidson and Fox (55) conclude that the left hemisphere is associated with "coping," which involves the fight-flight response; that is, effective control is linked to activation of catecholamines (norepinephrine) and the directed vigilance induced by the locus coeruleus. We propose that higher levels of MHPG indicate greater activation of the left hemisphere and of the effort system associated with it. On the other hand, Davidson and Fox (55) associate the right hemisphere with "appraisal." Terzian (56) long ago showed that powerful feelings of anxious sadness overcame the patient whose left hemisphere had been temporarily disabled by the injection of amytal into the left carotid. By contrast, when there is sudden loss of the right hemisphere, the patient is surprisingly lively and full of well being. Thus, the Wada test (57) also suggests that the "effort" and "distress" systems are lateralized. To recapitulate: If the controls for the sympathetic-adrenal medullary axis are more strongly associated with activation of the left hemisphere and those for the HPA axis are more involved with the right hemisphere, it would explain the failure of cortisol to rise in PTSD (and presumably alexithymia) despite anxiety and concurrent high norepinephrine levels. Although plausible, clearly, more elegant studies are required to test this hypothe-
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