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Hypnotizability and CSF HVA levels among psychiatric patients
BIOL PSYCHIATRY. 1992;3 ! :95-98
95
BRIEF REPORT
Hypnotizability and CSF HVA Levels Among Psychiatric Patients David Spiegel and Roy King
Introduction Hypnosis is best understood as a special state of concentration characterized by intensity of focus referred to as absorption accompanied by dissociation. To date, most studies of the relationship between hypnosis and brain neurotransmitters have involved endogenous opiates. Though in one study the opiate at~tagonist naloxone partially reversed the effect of hypnotic analgesia during a stressful task (Frid and Singer 1979), hypnotic analgesia works independently of endorphin systems (Nasrallah et al 1979; Goldstein and Hiigard 1975; Spiegel and Albert, 1983). However, Sjoberg and Hollister (1965) observed that amphetamine, which releases dopamine and norepinephrine, enhances hypnotic responsiveness. In order to examine the hypothesis that hypnotizability requires cortical activation involving dopaminergic and frontal lobe activity (Spiegel and Spiegel 1978; Pribram and McGuinness 1975), we chose to look for relationships between hypnotizability and homovanillic acid (HVA), a cerebrospinal fluid metabolite of dopamine partly derived from this brain region. In schizophrenic patients, HVA as measured in lumbar cerebrospinal fluid (CSF) is directly correlated with concentration ability on the Wisconsin Card Sort Task (Weinberger et al 1988) From the Department of Psychiatry and ~..:navioralSciences, Stanford University School of Medici.~.~', Stanford, CA. Address reprint requests to David Spiegel, M.D., Department of Psychiatry, ¢;tanford University School of Medicine, Stanford. CA 94305. Received March 18, 1991; revised .~uly 18, 1991.
© 1992 Society of Biological Psychiatry
and with cortical atrophy (van Kammen et al 1983). Findings among schizophrenics of smaller midsagittal cerebral area (Andreasen et al i!986) and reduced frontal to occipital activity asir~ positron emission tomography (PET) sc~ns (Buchsbaum et al 1982) and xenon 133 inha~ation rCBF scanning (Weinberger et al 19gf~ implicate reduced frontal lobe activity in the pathology of the disease. '1
Method Subjects were a consecutive series of male psychiatric inpatients and male control community volunteers with no past or present history of psychiatric disorder, recruited for a study of CSF monoamine metabolite levels at the Clinical Research Center of the Palo Alto Veterans Administration Medical Center (n - 33). Written informed consent was obtained for all procedures. Patients were diagnosed according to Research Diagnostic Criteria (Spitzer et al 19"/8). The diagnoses were arrived at by consensus of a specially trained research assistant and psychiatrist, who interviewed each patient on separate occasions. The research assistant utilized the Schedule for Affective Disorders and Schizophrenia (SADS) (Spitzer et al 19"/7). The patients' clinical records were then reviewed blindly by a clinical researcher (DS). This review placed patients in the same categories. The seven volunteer subjects were evaluated using the lifetime version of the SADS (SADS-L). Nine patients met RDC for schizophrenia; three for depression superimposed on residual schizophrenia; one for 0006-3223/92/$05.00
96
Brief Report
BIOL PSYCHIATRY 1992;31:95-98
schizoaffective disorder, depressed subtype; and one for schizoaffective disorder, manic subtype. Eight had a diagnosis of major depressive disorder; in the other patient category, two had unspecified functional psychosis and two had other psychiatric diagnoses. This sample was tested for hypnotizability using the Hypnotic Induction Profile (Spiegel and Spiegel 1978) by raters blind to diagnosis and HVA level. The Induction score is composed of five equally weighted items: dissociation, challenged ann elevation, involuntariness of movement, response to the cutoff signal, and sensory alteration, yielding a range of 0-10 points. Thirty-two of the 33 subjects were free from psychotherapeu+,ic medication for a minimum of 14 days. One patient had occasional doses of chloral hydrate during the 2 weeks prior to testing. Subjects fasted prior to the lumbar puncture and remained in bed overnight. The lumbar puncture was performed at approximately 8 o'clock the following morning with the subject in the lateral decubitus position. CSF was collected and frozen immediateij on dry ice. It was stored at -80°C until analysis. Measurements of HVA concentrations were done by gas chro. matography/mass spectroscopy (GC/MS). Cerebrospinal fluid was evaluated blind to diagnosis and hypnotizability. HVA was the only CSF substance analyzed in the study.
Results There were no between-group differences in age, HVA levels, or hypnotizability, using analysis of variance. There was, however, substantial variation within each group in hypnotic responsiveness: schizophrenics 5.6 _+ 2.5, depressed patients 5.1 -4- 3.0, other patients 4.6 _+ 2.6, and controls 4.2 +_ 3.3. There was a significant 0.40 Spearman rank-order correlation (df - 31, p < 0.02) between CSF HVA levels and hypnotizability in the total ~ample (Figure 1). The positive association between hypnotizability and HVA levels nonetheless held within all subgroups (depressed and other patients, normal controls; r = 0.70, df = 17, p < 0.0008) except schizophrenics (df = 12, r = 0.03, NS). HVA levels
were not significantly correlated with age (df = 31, r = -0.18, NS). Discussion Thus, we have ev.dence that the ability to experience hypnosis is associated with levels of the dopamine metabolite HVA in the CSF. Schizophrenics, the only group to show no evidence of significant association between HVA levels and hypnotizability, have a putative disorder of dopaminergic neurons. Furthermore, these patients had been treated with dopamine receptor blockers prior to the study. The alteration of the dopamine system by the disease or its treatment (Carlsson 1988; Meltzer 1988; Bowers 1991; Doran et al 1990) may obscure the relationship between HVA and hypnotic ability. Schizophrenics had the lowest HVA levels with the least variance among the four subgroups (26.8 mg/m _+ 9.3, versus 29.1 _+ 13.4 for depressed patients, 44.3 +_ 20.7 for other patients, and 31.6 _+ 14.1 for controls). Dopaminergic synapses are widely distributed in the frontal cortex. In both vervet monkeys and humans, CSF HVA is correlated with dopamine turnover in the frontal cortex. Cistcr~,~l CSF HVA levels have been correlated most strongly with those in the dorsal-frontal cortex, but also orbital-frontal cortex, the ¢audate, and the putamen (Elsworth et al 1987; Baxter et al 1985; Stanley et al 1985), but less with those in the basal ganglia in primates (EIsworth et al 1987; Stanley et al 1985; van Kammen et al 1983; Brozowski et al 1979; Bacopolous et al 1978). The frontal lobes have been implicated in the embedding of perceptual and motor activity into a pattern of meaning, for example, planning for future activity (Goldman-Rakic 1988). This working memory function is impaired by injection of D I dopamine receptor antagonists into the prefrontal cortex (Sawaguchi and GoldmanRakic 1991). Hypnotic instructions involve altering sensory and motor function. The experience of involuntary movement of the hand, for example, is a consequence of the imagined lightness in the hand. Thus, subjects must link per-
Brief Report
BIOL PSYCHIATRY i 992;3! :95-98
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CSF HVA (ng/ml) Figure 1. Hypnotizability as a function of HVA in the CSF, with regression line.
ception to a previously learned image. This would plausibly involve frontal lobe function. This study suggests a role for dopamine activity, possibly involving the frontal lobes, in hypnotic concentration. Future research might involve tests of frontal lobe activity, functional brain imaging, and studies of the effects of dopamine agonists and blockers on hypnotic concentration. This work was supported by the National Institute of Mental Health, MH 30854 (MHCRC) and MH 23861; J.D. Barchas, M.D., Principal Investigator, the Research Services of the Veterans Administration (SBRC); the John D. and Catherine T. MacArthur Foundation; and the Alan and Laraine Fischer Foundation. Kym Fauli, Ph.D., conducted the CSF HVA assay, assisted by Nina Pascoe and Veronica Rudolph.
References Andreasen N, Nasrallah HA, Dunn V, et al (1986): Structural abnormalities in the frontal system in schizophrenia. Arch Gen Psychiatry 43:136-144. Bacopoulos NG, Maas JW, Hattox SE, Roth RH (1978): Regional distribution of dopamine metabolites in human and primatc brain. Comm PSYchopharmacology 2:281-286.
Baxter LR, Phelps ME, Mazziotta JC, et al (1985): Cerebral metabolic rates for glucose in mood disorders. Arch Gen Psychiatry 42:441-447. Bowers MB (1991): Characteristics of psychotic inpatients with high or low HVA levels at admission. Am J Psychiatry 240-243. Brozowski TJ, Brown RM, Rosvold HE, Goldman PS (1979): Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929-93 I. Buchsbaum MS, Ingvar DH, Kessler R, et al (1982): Cerebral gluco~graphywith positron tomography. Arch Gen Psychiatry 39:251-259. Carlsson A (1988): The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology I: 179-186. Doran AR, Labarca R, Wolkowitz OM, Roy A, Douillet P, Pickar D (1990): Circadian variation of plasma homovanillic acid levels is attenuated by fluphenazine in patients with schizophrenia. Arch Gen Psychiatry 47:558-563. Elsworth JD, Leahy DJ, Roth RH, Redmond DE (1987): Homovanillicacid concentrations in brain, CSF, and plasma as indicators of central dopamine function in primates. J Neural Transm 68:51-62. Frid M, Singer (3 (1979): Hypnotic analgesia in conditions of stress is partially reversed by naloxone. Psychopharmacology 61:211-215. Goldman-Rakic PS (1988): Topography of cognition:
98
BIOL PSYCHIATRY 1992,31 ~95-98
Parallel distributed networks in primate association cortex. Annu Rev Neurosci l 1:137-156. Goldstein E, Hiigard E (1975): Failure of opiate antagonist naloxone to modify hypnotic analgesia. Proc Natl Acad Sci USA 71:1041-1043. Hilgard ER (1977): Divided Consciousness: Multiple Controls i,~Human Thought and Action. New York: Wiley. Meltzer HY (1988): New insights into schizophrenia through atypical antipsychotic drugs. Neuropsy. chopharmacology 1:193-196. Nasrallah HA, Holley T, Janowsky DS (1979): Opiate antagonism fails to reverse hypnotic-induced analgesia. Lancet I: 1335. Pribram K, McGuinness D (1975): Arousal, activation and effort in the control of attention. Psychol Rev 82:116-149. Sawaguchi T, Goldman-Rakic P (1991): D1 dopamine receptors in prefrontal cortex: Involvement in working memory. Science 8:947-950. Sjoberg BM, Hollister LE (1965): The effects of psychotomimetic drugs on primary suggestibility. Fsychopharrnaco!ogia 8:251-262. Spin,gel D, Albert L (1983): Naloxone fails to reverse hypnotic alleviation of chronic pain. Psycho. pharmacology 81:140-143. Spiegel D, Bloom JR (1983): Group therapy and hypnosis reduce metastatic breast carcinoma pain. Psychosom Med 45:333-339.
Brief Report
Spiegel H, Spiegel D (1978): Trance and Treatment: Clinical Uses of Hypnosis, (Reprinted). New York: Basic Books. Washington, DC: American Psychiatric Press, 1987. Spitzer RL, Endicott J, Robins E (1977): Research Diagnostic Criteria (RDC)for a Selected Group of Functio,~aiDisorders. BiometricsResearch, New York State Psychiatric Institute. Spitzer RL, Endicott J, Robins E (1978): Research Diagnostic Criteria: Rationale and reliability. Arch Gen Psychiatry 36:773-782. Stanley M, Traskman-BendzL, Dorovini-ZisK (1985): Correlations between aminergic metabolites simultaneouslyobtained from human CSF and brain. Life Sci 37:1279-1286. van Kammen DP, Mann LS, Sternberg DE, et al (1983): Dopamine 13-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenics with brain atrophy. Science 220:974-977. Weinberger DR, Berman KF, Zec RF (1986): Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia.Arch Gen Psychiatry 43: ! 14124. Weinberger DR, Berman KF, lllowsky BP (1988): Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: Ill. A new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry ~5:60Q-615.
95
BRIEF REPORT
Hypnotizability and CSF HVA Levels Among Psychiatric Patients David Spiegel and Roy King
Introduction Hypnosis is best understood as a special state of concentration characterized by intensity of focus referred to as absorption accompanied by dissociation. To date, most studies of the relationship between hypnosis and brain neurotransmitters have involved endogenous opiates. Though in one study the opiate at~tagonist naloxone partially reversed the effect of hypnotic analgesia during a stressful task (Frid and Singer 1979), hypnotic analgesia works independently of endorphin systems (Nasrallah et al 1979; Goldstein and Hiigard 1975; Spiegel and Albert, 1983). However, Sjoberg and Hollister (1965) observed that amphetamine, which releases dopamine and norepinephrine, enhances hypnotic responsiveness. In order to examine the hypothesis that hypnotizability requires cortical activation involving dopaminergic and frontal lobe activity (Spiegel and Spiegel 1978; Pribram and McGuinness 1975), we chose to look for relationships between hypnotizability and homovanillic acid (HVA), a cerebrospinal fluid metabolite of dopamine partly derived from this brain region. In schizophrenic patients, HVA as measured in lumbar cerebrospinal fluid (CSF) is directly correlated with concentration ability on the Wisconsin Card Sort Task (Weinberger et al 1988) From the Department of Psychiatry and ~..:navioralSciences, Stanford University School of Medici.~.~', Stanford, CA. Address reprint requests to David Spiegel, M.D., Department of Psychiatry, ¢;tanford University School of Medicine, Stanford. CA 94305. Received March 18, 1991; revised .~uly 18, 1991.
© 1992 Society of Biological Psychiatry
and with cortical atrophy (van Kammen et al 1983). Findings among schizophrenics of smaller midsagittal cerebral area (Andreasen et al i!986) and reduced frontal to occipital activity asir~ positron emission tomography (PET) sc~ns (Buchsbaum et al 1982) and xenon 133 inha~ation rCBF scanning (Weinberger et al 19gf~ implicate reduced frontal lobe activity in the pathology of the disease. '1
Method Subjects were a consecutive series of male psychiatric inpatients and male control community volunteers with no past or present history of psychiatric disorder, recruited for a study of CSF monoamine metabolite levels at the Clinical Research Center of the Palo Alto Veterans Administration Medical Center (n - 33). Written informed consent was obtained for all procedures. Patients were diagnosed according to Research Diagnostic Criteria (Spitzer et al 19"/8). The diagnoses were arrived at by consensus of a specially trained research assistant and psychiatrist, who interviewed each patient on separate occasions. The research assistant utilized the Schedule for Affective Disorders and Schizophrenia (SADS) (Spitzer et al 19"/7). The patients' clinical records were then reviewed blindly by a clinical researcher (DS). This review placed patients in the same categories. The seven volunteer subjects were evaluated using the lifetime version of the SADS (SADS-L). Nine patients met RDC for schizophrenia; three for depression superimposed on residual schizophrenia; one for 0006-3223/92/$05.00
96
Brief Report
BIOL PSYCHIATRY 1992;31:95-98
schizoaffective disorder, depressed subtype; and one for schizoaffective disorder, manic subtype. Eight had a diagnosis of major depressive disorder; in the other patient category, two had unspecified functional psychosis and two had other psychiatric diagnoses. This sample was tested for hypnotizability using the Hypnotic Induction Profile (Spiegel and Spiegel 1978) by raters blind to diagnosis and HVA level. The Induction score is composed of five equally weighted items: dissociation, challenged ann elevation, involuntariness of movement, response to the cutoff signal, and sensory alteration, yielding a range of 0-10 points. Thirty-two of the 33 subjects were free from psychotherapeu+,ic medication for a minimum of 14 days. One patient had occasional doses of chloral hydrate during the 2 weeks prior to testing. Subjects fasted prior to the lumbar puncture and remained in bed overnight. The lumbar puncture was performed at approximately 8 o'clock the following morning with the subject in the lateral decubitus position. CSF was collected and frozen immediateij on dry ice. It was stored at -80°C until analysis. Measurements of HVA concentrations were done by gas chro. matography/mass spectroscopy (GC/MS). Cerebrospinal fluid was evaluated blind to diagnosis and hypnotizability. HVA was the only CSF substance analyzed in the study.
Results There were no between-group differences in age, HVA levels, or hypnotizability, using analysis of variance. There was, however, substantial variation within each group in hypnotic responsiveness: schizophrenics 5.6 _+ 2.5, depressed patients 5.1 -4- 3.0, other patients 4.6 _+ 2.6, and controls 4.2 +_ 3.3. There was a significant 0.40 Spearman rank-order correlation (df - 31, p < 0.02) between CSF HVA levels and hypnotizability in the total ~ample (Figure 1). The positive association between hypnotizability and HVA levels nonetheless held within all subgroups (depressed and other patients, normal controls; r = 0.70, df = 17, p < 0.0008) except schizophrenics (df = 12, r = 0.03, NS). HVA levels
were not significantly correlated with age (df = 31, r = -0.18, NS). Discussion Thus, we have ev.dence that the ability to experience hypnosis is associated with levels of the dopamine metabolite HVA in the CSF. Schizophrenics, the only group to show no evidence of significant association between HVA levels and hypnotizability, have a putative disorder of dopaminergic neurons. Furthermore, these patients had been treated with dopamine receptor blockers prior to the study. The alteration of the dopamine system by the disease or its treatment (Carlsson 1988; Meltzer 1988; Bowers 1991; Doran et al 1990) may obscure the relationship between HVA and hypnotic ability. Schizophrenics had the lowest HVA levels with the least variance among the four subgroups (26.8 mg/m _+ 9.3, versus 29.1 _+ 13.4 for depressed patients, 44.3 +_ 20.7 for other patients, and 31.6 _+ 14.1 for controls). Dopaminergic synapses are widely distributed in the frontal cortex. In both vervet monkeys and humans, CSF HVA is correlated with dopamine turnover in the frontal cortex. Cistcr~,~l CSF HVA levels have been correlated most strongly with those in the dorsal-frontal cortex, but also orbital-frontal cortex, the ¢audate, and the putamen (Elsworth et al 1987; Baxter et al 1985; Stanley et al 1985), but less with those in the basal ganglia in primates (EIsworth et al 1987; Stanley et al 1985; van Kammen et al 1983; Brozowski et al 1979; Bacopolous et al 1978). The frontal lobes have been implicated in the embedding of perceptual and motor activity into a pattern of meaning, for example, planning for future activity (Goldman-Rakic 1988). This working memory function is impaired by injection of D I dopamine receptor antagonists into the prefrontal cortex (Sawaguchi and GoldmanRakic 1991). Hypnotic instructions involve altering sensory and motor function. The experience of involuntary movement of the hand, for example, is a consequence of the imagined lightness in the hand. Thus, subjects must link per-
Brief Report
BIOL PSYCHIATRY i 992;3! :95-98
•
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CSF HVA (ng/ml) Figure 1. Hypnotizability as a function of HVA in the CSF, with regression line.
ception to a previously learned image. This would plausibly involve frontal lobe function. This study suggests a role for dopamine activity, possibly involving the frontal lobes, in hypnotic concentration. Future research might involve tests of frontal lobe activity, functional brain imaging, and studies of the effects of dopamine agonists and blockers on hypnotic concentration. This work was supported by the National Institute of Mental Health, MH 30854 (MHCRC) and MH 23861; J.D. Barchas, M.D., Principal Investigator, the Research Services of the Veterans Administration (SBRC); the John D. and Catherine T. MacArthur Foundation; and the Alan and Laraine Fischer Foundation. Kym Fauli, Ph.D., conducted the CSF HVA assay, assisted by Nina Pascoe and Veronica Rudolph.
References Andreasen N, Nasrallah HA, Dunn V, et al (1986): Structural abnormalities in the frontal system in schizophrenia. Arch Gen Psychiatry 43:136-144. Bacopoulos NG, Maas JW, Hattox SE, Roth RH (1978): Regional distribution of dopamine metabolites in human and primatc brain. Comm PSYchopharmacology 2:281-286.
Baxter LR, Phelps ME, Mazziotta JC, et al (1985): Cerebral metabolic rates for glucose in mood disorders. Arch Gen Psychiatry 42:441-447. Bowers MB (1991): Characteristics of psychotic inpatients with high or low HVA levels at admission. Am J Psychiatry 240-243. Brozowski TJ, Brown RM, Rosvold HE, Goldman PS (1979): Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929-93 I. Buchsbaum MS, Ingvar DH, Kessler R, et al (1982): Cerebral gluco~graphywith positron tomography. Arch Gen Psychiatry 39:251-259. Carlsson A (1988): The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology I: 179-186. Doran AR, Labarca R, Wolkowitz OM, Roy A, Douillet P, Pickar D (1990): Circadian variation of plasma homovanillic acid levels is attenuated by fluphenazine in patients with schizophrenia. Arch Gen Psychiatry 47:558-563. Elsworth JD, Leahy DJ, Roth RH, Redmond DE (1987): Homovanillicacid concentrations in brain, CSF, and plasma as indicators of central dopamine function in primates. J Neural Transm 68:51-62. Frid M, Singer (3 (1979): Hypnotic analgesia in conditions of stress is partially reversed by naloxone. Psychopharmacology 61:211-215. Goldman-Rakic PS (1988): Topography of cognition:
98
BIOL PSYCHIATRY 1992,31 ~95-98
Parallel distributed networks in primate association cortex. Annu Rev Neurosci l 1:137-156. Goldstein E, Hiigard E (1975): Failure of opiate antagonist naloxone to modify hypnotic analgesia. Proc Natl Acad Sci USA 71:1041-1043. Hilgard ER (1977): Divided Consciousness: Multiple Controls i,~Human Thought and Action. New York: Wiley. Meltzer HY (1988): New insights into schizophrenia through atypical antipsychotic drugs. Neuropsy. chopharmacology 1:193-196. Nasrallah HA, Holley T, Janowsky DS (1979): Opiate antagonism fails to reverse hypnotic-induced analgesia. Lancet I: 1335. Pribram K, McGuinness D (1975): Arousal, activation and effort in the control of attention. Psychol Rev 82:116-149. Sawaguchi T, Goldman-Rakic P (1991): D1 dopamine receptors in prefrontal cortex: Involvement in working memory. Science 8:947-950. Sjoberg BM, Hollister LE (1965): The effects of psychotomimetic drugs on primary suggestibility. Fsychopharrnaco!ogia 8:251-262. Spin,gel D, Albert L (1983): Naloxone fails to reverse hypnotic alleviation of chronic pain. Psycho. pharmacology 81:140-143. Spiegel D, Bloom JR (1983): Group therapy and hypnosis reduce metastatic breast carcinoma pain. Psychosom Med 45:333-339.
Brief Report
Spiegel H, Spiegel D (1978): Trance and Treatment: Clinical Uses of Hypnosis, (Reprinted). New York: Basic Books. Washington, DC: American Psychiatric Press, 1987. Spitzer RL, Endicott J, Robins E (1977): Research Diagnostic Criteria (RDC)for a Selected Group of Functio,~aiDisorders. BiometricsResearch, New York State Psychiatric Institute. Spitzer RL, Endicott J, Robins E (1978): Research Diagnostic Criteria: Rationale and reliability. Arch Gen Psychiatry 36:773-782. Stanley M, Traskman-BendzL, Dorovini-ZisK (1985): Correlations between aminergic metabolites simultaneouslyobtained from human CSF and brain. Life Sci 37:1279-1286. van Kammen DP, Mann LS, Sternberg DE, et al (1983): Dopamine 13-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenics with brain atrophy. Science 220:974-977. Weinberger DR, Berman KF, Zec RF (1986): Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia.Arch Gen Psychiatry 43: ! 14124. Weinberger DR, Berman KF, lllowsky BP (1988): Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: Ill. A new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry ~5:60Q-615.