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Autonomic activity in relation to symptom ratings and reaction time in unmedicated patients with schizophrenia
Schizophrenia Research 79 (2005) 257 – 270 www.elsevier.com/locate/schres
Autonomic activity in relation to symptom ratings and reaction time in unmedicated patients with schizophrenia Theodore P. Zahn a,*, David Pickar b,1 a
Laboratory of Brain and Cognition, National Institutes of Health, Bldg. 10. Rm. 4C104, MSC 1366, Bethesda, MD 20892-1366, United States b Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, MD 20892, United States Received 9 December 2004; received in revised form 25 May 2005; accepted 27 May 2005 Available online 11 July 2005
Abstract Problem: High autonomic base levels and low responsivity are frequently observed in unmedicated patients with schizophrenia. We previously reported that patients in the present cohort, compared to normal controls, had high autonomic tonic baselines and low reactivity to the meaningful stimuli in a reaction time (RT) task but not to novel but innocuous stimuli. This paper explores further the role of autonomic activity in the pathogenesis of schizophrenia by relating differences in the autonomic variables among patients to symptom ratings and RT. Methods: Electrodermal activity and heart rate were recorded during rest, a tone series, and a RT task in 73 patients with schizophrenia taking placebo. Symptoms were rated with the Brief Psychiatric Rating Scale. Results: Patients with higher autonomic baselines both at rest and under mild stress and those with greater electrodermal responsivity to both simple tones and the RT stimuli had more severe positive, bactiveQ, and total symptoms than patients with lower baselines and responsivity. RT was slower in patients with higher baselines. Conclusions: High autonomic activity in general, reactivity as well as base levels, under all conditions used in this study was associated with symptom severity independent of differences from controls. Thus elevated autonomic activity and responsivity may themselves be disturbing or index states that are disturbing in schizophrenia. Some patients might attempt to cope with novel or demanding situations and stimuli by a passive-avoidant strategy of low attention and effort in order to attenuate their responsivity. Less symptomatic patients may better cope in this manner. D 2005 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Electrodermal activity; Heart rate; Symptoms; Reaction time
1. Introduction * Corresponding author. Tel.: +1 301 594 8039; fax: +1 301 480 0546. E-mail address: [email protected] (T.P. Zahn). 1 Present Address: Gabriel Pharma, LLC and Potomac Pharma, Inc., Cabin John, MD, United States. 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.05.025
Investigators have been seeking markers of pathology in schizophrenia in autonomic nervous system (ANS) activity for many years. Compared to controls patients with schizophrenia as a group have usually
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been found to have impaired ANS responsivity to both innocuous and significant stimulation and higher resting baseline ANS activity, as measured by electrodermal activity (EDA) and heart rate (HR; Zahn et al., 1991, 2001). There is variability in the results of these studies depending on the nature of the patient sample and methodology. This report is concerned with relating differences in ANS activity among patients to differences in symptoms to elucidate further the role of ANS activity in the pathology of schizophrenia. The basic question is whether and how ANS activity is related to the overall severity of the illness and/or is differentially related to different classes of symptoms. Most previous studies have focused on the skin conductance orienting response (SCOR) to novel but innocuous tones. Reports that 50% or more of patients with schizophrenia fail to give SCORs to the first two or three tones (bnonrespondersQ—NRs; Bernstein et al., 1982) raised the obvious question if such patients were clinically different from brespondersQ (Rs) who give one or more SCOR to the first two or three tones. The results have been mixed. In one group of studies NRs have shown higher ratings on both positive and negative symptoms than Rs. Using the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962) with mixed groups of medicated and unmedicated patients both Straube (1979), who tested acute patients, and Bernstein et al. (1981), using chronic patients, reported NRs higher than Rs on Emotional Withdrawal and Conceptual Disorganization but lower on Excitement. Similarly, Kim et al. (1993), in medicated chronic patients, and Zahn et al. (1997), in 20 unmedicated adolescents with childhood-onset schizophrenia, reported that NRs were higher than Rs on the Schedule for the Assessment of Negative Symptoms (SANS; Andreasen, 1983), the Schedule for the Assessment of Positive Symptoms (SAPS; Andreasen, 1984), and on various BPRS items and factors representing both negative and positive symptoms. In all these studies about 50% or more of the patients were NRs. However results in the same direction were also obtained with 13 unmedicated acute patients none of whom were NRs (Bartfai et al., 1984). Patients who failed to habituate in 11 trials had lower Psychosis and Global Psychopathology scores on the Comprehensive Psy-
chopathological Rating Scale (CPRS) than habituators (Asberg et al., 1978). In several studies, however, SCORs were not related significantly to symptoms. These include studies on unmedicated patients (Zahn et al., 1981), medicated patients (Schiffer et al., 1996) and one where only some patients were medicated (Alm et al., 1984) but in 21 unmedicated patients NRs scored higher on a Delusional Mood item than Rs. Three other studies in this group controlled for the anticholinergic level of the drugs, (Green et al., 1989; Perry et al., 1995; Schlenker et al., 1995). However in the latter study NRs were lower in BPRS Excitement. Perry et al. (1995) used Rorshach slides which were to be interpreted as stimuli, so they were not truly innocuous. Finally, in contrast to the first group of studies, a few studies have reported more psychopathology in more responsive patients. Gruzelier (1976) reported that in patients with less than 5 years hospitalization ward nurses rated Rs as more manic, anxious, assaultive, and attention-demanding than NRs; there were no such differences in a very chronic group. In 13 unmedicated chronic inpatients, only two of whom were NRs, ratings of overall severity were higher in non-habituators than in habituators (Deakin et al., 1979). Bartfai et al. (1987) reported that in 18 medicated patients, nonhabituators had more auditory hallucinations than habituator Rs and NRs, but there were no differences on more global CPRS factors. Dawson et al. (1992) found a significant positive correlation between trials to habituation of the SCOR and only a BPRS Activation factor in 56 medicated acute male patients soon after hospital admission (13 female patients did not show this result). However, in the same patients (males only) tested several months later as outpatients, all taking fluphenazine decanoate, habituation related positively to several BPRS factors and the total score. In a within-subjects design Dawson et al. (1994) reported more NRs (but not more SCORs) among bremittedQ patients than in the same patients when they were more symptomatic. Finally, Brekke et al. (1997) reported positive correlations between responder status and the BPRS total score in 40 outpatients living in community care. In summary, these studies are inconclusive about if and how the SCOR relates to psychopathology. Differences among studies in medication, chronicity, or
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methodology by themselves do not seem able to account for the marked variability in findings. For example tone intensity ranged from 60 dB to 85 dB in all three groups of studies. It may be of interest that more symptoms were reported in less responsive patients in three of the four samples of unmedicated patients, but these had small sample sizes and in two of these (Bartfai et al., 1984; Zahn et al., 1997) the samples may be atypical (no NRs and childhood onset patients, respectively). The differences between the two studies from Bartfai’s laboratory (Bartfai et al., 1984, 1987), in which the patients differed in both medication and chronicity, suggest possible interactions between these two variables. About the most definite conclusion is that there is no support for differential relationships of the SCOR to positive and negative symptoms. There are problems with this almost exclusive focus on SCOR Rs and NRs. In recent years there have been several failures to confirm a marked excess of NRs in schizophrenia (Dawson et al., 1994; see Zahn et al., 1991 for earlier studies; Zahn et al., 2001). Other ANS measures such as elevated frequency of nonspecific skin conductance responses (NS-SCR), skin conductance level (SCL), and HR during resting conditions might be more reliable markers for schizophrenia than SCOR NR (Zahn et al., 1991, 2001). Investigators have rather consistently reported positive correlations of NS-SCRs and/or SCL with ratings on positive and active symptoms (Dawson et al., 1992 [outpatient test]; Gruzelier, 1976; Maina et al., 1995; Olbrich and Mussgay, 1987; Zahn et al., 1997). However Olbrich and Mussgay (1987) and Maina et al., 1995 also reported negative correlations of baseline EDA with hallucinatory activity. This is surprising because hallucinations are considered positive symptoms and, indeed, they may be a source of bspontaneousQ SCRs in schizophrenia (Cooklin et al., 1983). Three studies reported lower baselines in patients with more negative symptoms (Green et al., 1989, Maina et al., 1995; Zahn et al., 1997), but in the inpatients of Dawson et al. (1992) NS-SCR was correlated positively with Emotional Withdrawal from the BPRS. Thus, for tonic baselines, unlike the SCOR, there is some evidence of differential relationships with symptom type, although reports of positive correlations of baselines with ratings of overall severity are not uncommon (Brekke et al.,
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1997; Dawson et al., 1992 [outpatient test]; Deakin et al., 1979; Zahn et al., 1981 [discharge test]). Similarly, Dawson et al. (1994) found lower EDA and HR in their patients when remitted than when symptomatic. The Brekke et al. (1997) study included mental arithmetic and speech stress conditions, finding that larger increases in EDA were associated with low total BPRS ratings. A third area that has received some attention is that of laterality of EDA. Patients with larger SCORs on the right hand vs the left hand had more negative symptoms, but those with the opposite lateral difference had more florid symptoms (Gruzelier and Manchanda, 1982). One problem in most previous studies is medication. In those with mixed medicated and unmedicated patients medication status may be confounded with clinical variables. Using patients on several different medications is problematic because drugs differing in anticholinergic actions differ in their effects on EDA (Green et al., 1989; Schnur, 1990) but may not differ on their effects on symptoms. Even low anticholinergic drugs lower EDA (Zahn et al., 2001) and might affect EDA and symptoms differently in different patients. In addition the narrow focus on SCORs and resting baseline EDA limit the generality of the conclusions. In the present study BPRS ratings and ANS activity were examined using a wider array of variables than in previous studies, a relatively large sample, and medication-free patients. The protocol included a reaction time task as well as an orienting paradigm and a rest period. This allows assessment of the relationships of clinical state and task performance with baseline ANS activity under both passive and activated conditions, with responsivity to significant as well as innocuous stimuli. HR as well as EDA was examined. Patient volunteers (N = 73) were taking a placebo, having been withdrawn from neuroleptics for research purposes. They are part of a larger group (Zahn et al., 2001); this report includes just those who were rated on the BPRS. Compared to nonpatient controls the patients had higher tonic baseline NS-SCR, SCL and HR during rest and passive listening to tones, smaller increments in these during instructions for a task, but still higher SCL and HR (but not NS-SCRs) during task instructions. Patients also had lower electrodermal responsivity to signifi-
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cant (i. e. task-related) stimuli, but were not different on SCORs (Zahn et al., 2001). In addition the patients had smaller increments in responsivity to significant compared to less significant stimuli, and disproportionately low electrodermal responsivity for a given tonic activation level as indicated by a lower ratio of SCORs to NS-SCRs. The most straightforward basis for predicting the results is that the most deviant patients on these variables will be the most symptomatic. A second hypothesis is suggested by findings that neuroleptics, which reduce symptoms, also reduce both ANS base levels and responsivity (Schnur, 1990; Zahn et al., 1991, 2001). Thus more symptomatic patients should have both higher base levels and responsivity than less symptomatic patients. A third hypothesis is that ANS responsivity might be inversely related especially to negative symptoms and baseline ANS activity might be directly related particularly to positive symptoms (Zahn et al., 1991).
2. Method 2.1. Participants The patients were recruited over a 13-year period (1983–1995) from other hospitals and the psychiatric community to participate in a number of different research protocols and were currently living on a small, well staffed research ward in the Clinical Center of the National Institutes of Health. Diagnoses were made using modified research diagnostic criteria on the basis of a consensus meeting involving blind record review and structured diagnostic interviews. For research purposes a placebo trial was given to all patients at some time during their stay at the Clinical Center. All patients gave written informed consent to be tested in this specific protocol in addition to the overall treatment protocol. Tests were done on 73 patients (51 male) taking a placebo in double blind protocols. The patients were medication free for a median of 20 days, semi-interquartile range = 5.1, minimum = 13 days. The mean (Fs.d.) age was 31.2 (F 7.6) years, number of years ill was 11.3 (F7.9), number of prior hospitalizations was 5.5 (F6.0), and age of first symptoms was (19.8 F 4.8).
2.2. Apparatus and procedure Physiological recording was done on a Grass polygraph (Model 7B), the output of which was digitized by a PDP-11 computer for off-line editing and analysis. Skin conductance (SC) was recorded bilaterally by a constant voltage (0.5 v) method from the distal phalanges of the middle and ring fingers using Beckman Ag/AgCl electrodes, electrode collars 0.8 cm. in diameter, and 0.5% KCl electrode paste. HR was recorded by a tachograph from the electrocardiogram (Lead II). The procedure began at least 10 min after the SC electrodes were applied in order to allow for hydration. The equipment and procedure remained the same throughout the study. There were 4 periods in the procedure: 1) A 5-min rest period. At the outset participants were told that they should try to relax, but stay awake, that after a few minutes there would be a series of tones or ’beeps’, and that they did not have to do anything except to continue to relax. 2) A Tones period in which ten 1000 Hz 80 dB (re .0002 dynes/cm2) pure tones of 1.5 s duration, rise time = .1 s were presented every 30 to 50 s through a speaker. Tones were generated by a Med Associates voltage-controlled oscillator and amplifier. 3) RT instructions. Participants were instructed that: On each trial a ready light would come on; when s/ he was ready s/he should depress a telegraph key and keep it down until a tone (’beep’) sounded; at this time s/he should release the key as quickly as possible; we were timing how fast s/he responded to the beep. The instructions were followed by a demonstration and at least 4 practice trials to ensure that the procedure was understood. 4) Simple warned RT. Nine trials with 4 s preparatory intervals (PIs) were followed by 9 with 8 s PIs. Patients were told when the PI was increased. The inter-trial interval was randomly distributed between 8 and 14 s by the computer (mean = 11 s). 2.3. Data reduction The following 4 variables were averaged over the combined rest period and the intervals between tone
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presentations, and separately for the task instruction period: 1. The rate of nonspecific SCRs per minute (NSCR/ min) for SCRs of at least 0.02 AS in amplitude and natural-logarithm transformed to reduce skew. 2. SCL in AS, measured at 1 min intervals during rest and instruction periods and before each tone, was averaged for each period and natural-logarithm transformed. 3. Mean HR in beats per min. 4. HR variability the mean difference between maximum and minimum HR for successive 10 s epochs during the period. The frequency and magnitudes of elicited SCRs (minimum amplitude 0.02 AS, onset latency 1–4 s) were calculated separately for simple tones (SCORs), the RT ready signal (and associated key press), and the RT stimulus (and associated finger-lift response). SCR magnitudes were square-root transformed. Mean RT in ms was averaged across the two preparatory intervals and natural-logarithm transformed. For EDA variables for just the rest and tones periods, right and left hand values were averaged. Because the RT task was performed with the right hand by all patients, and this might artificially potentiate right hand EDA, only left hand data were analyzed for the RT instructions, the RT task, and all difference scores. In addition to these simple measures five more complex measures were derived: 1. A bBaseline Z-scoreQ, representing global autonomic activation, was computed by averaging zscores for NSCR/min, SCL, and HR. 2. The difference between the mean base levels in the Instructions period and those in the preceding tones
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period. For SCL the latter measure was the minimum value. 3. The ratio of SCORs to NSCR/min during the tones period: (2*SCOR)/((NSCR/min)+ .5). Ratios for the two hands were averaged. Patients with zero scores for both SCORs and NSCR/min (N = 5) were given the value of 1. 4. Two difference scores: SCRs to the RT stimulus minus SCORs to the simple tones and minus SCRs to the ready signal. In addition to the absolute differences brelativeQ differences, for which the absolute difference were divided by their sum, were analyzed. 5. Electrodermal laterality was determined for SCOR responders by comparison of the mean SCOR magnitude from the right and left hands. For the nine nonresponders, laterality was determined from the mean SCL during the tones period. 2.4. Brief Psychiatric Rating Scale (BPRS) Each patient was rated weekly on an extended (24 item) BPRS (Pickar et al., 1986; Tarell and Schulz, 1988) by the psychiatrist responsible for his/her clinical care. Raters were in daily contact with their patients and nursing staff but blind as to treatment regimen. Although a number of different raters were involved over the course of this study, they were all trained in the use of the BPRS by senior staff. The data presented here are from ratings made during the same week as the psychophysiological test. Table 1 shows the subscales used in the present study. These are similar to those developed by Overall (1974) based on a factor analysis except that the Pos and Neg scales each includes an additional item from the extended version of the BPRS.
Table 1 BPRS subscales: component items, means, standard deviations (SD), and mean per component item Subscale and items
Mean
SD
Per item
Anxiety–depression (AD: anxiety, guilt, depressive mood) Paranoid–suspicious (PS: hostility, suspiciousness, uncooperativeness) Activation (Act: tension, excitement, motor hyperactivity) Positive symptoms (Pos: conceptual disorganization, hallucinatory behavior, unusual thought content, distractibility) Negative symptoms (Neg: emotional withdrawal, motor retardation, blunted affect, loss of functioning) BPRS total (Tot: 24 items)
7.6 8.4 7.2 13.4
3.3 3.7 3.1 5.3
2.5 2.8 2.4 3.3
13.3
4.0
3.3
65.2
18.9
2.7
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Table 2 Correlations of Brief Psychiatric Rating Scale (BPRS) subscales and total, and mean Reaction Time (RT) with baseline ANS variables during rest and tones and instruction periods, N = 73 Variable
AD PS
Act Pos Neg Tot
Rest and tones Ln NSCR/minute Ln SC level Mean heart Rate HR Variability Baseline Z-score
.26* .18 .43** .18 .16 .24* .13 .25* .24* .25*
.27* .22 .09 .27* .13 .14 .10 .25* .29* .37** .14 .32** .27* .29* .33** .34** .33** .35** .14 .35**
RT task instructions§ Ln NSCR/minute .29* .12 .15 .10 .03 Ln SC level .50** .25* .20 .16 .12 Mean heart rate .20 .29* .36** .40** .11 HR variability .16 .21 .16 .18 .28* Baseline Z-score .42** .34** .35** .35** .14 Reaction time (ln[ms]) .12 .26* .48** .40** .16
RT .26* .10 .28* .12 .31**
.17 .02 .31** .05 .37** .31** .26* .01 .42** .24* .40** .NA
*p b 05, **p b 01. AD=Anxiety–depression; PS=Paranoid-suspicious; Act=Activation; Pos=Positive symptom; Neg=Negative symptom; Tot=Total BPRS score; SCR=Skin conductance responses; HR=Heart rate; Baseline Z-score=Mean of the standard scores for Ln NSCR/minute, Ln SC level and HR. §Left hand data only used for electrodermal variables.
Post-hoc comparisons of individual means were done by the Tukey Studentized Range Test. In addition to the univariate ANOVAs a multivariate ANOVA was done to test the simultaneous hypothesis of no difference between groups for any of the dependent variables. In order to control for sex differences, for those variables for which there was an indication of a possible sex difference, as indicated by either a t-test or Mann–Whitney Rank Sum test for which p b .2, the two means were equated by adding or subtracting the mean difference from each of the female scores before the analyses. None of the BPRS scales showed a sex difference by those criteria but men were higher than women on NSCR/min during Rest and Tones and SCL during both periods. Women were higher than men on SCR magnitude to the RT stimulus. The sex corrections were made in these variables before they were used into any combination variables.
3. Results 3.1. Baseline (Tonic) ANS activity
2.5. Data analyses Pearson correlations were used to assess the relationships of baseline ANS activity to BPRS ratings and RT. Separate sets of correlations were computed for the combined rest and tones periods, the RT instruction period, and the increments in baselines from the preceding tones period to the RT instructions. In addition, we computed partial correlations of the ANS measures during the instructions with the values during rest partialled out. Because of the large number of correlations computed a test of the hypothesis that all correlations are zero (Steiger, 1980) was made for each matrix. Analyses of variance (ANOVA) were used for SCRs because of the gross departure from normality of their distributions due to a large proportion of zero responses. In these, the distribution of SCRs was divided into roughly equal thirds, with the constraint that closely clumped values were not separated into different subgroups. This was used as the independent variable in one-way ANOVAs with the BPRS subscales and Tot and RT as dependent variables. Tests of trend using orthogonal polynomials were also done.
Table 2 shows correlations of BPRS ratings and RT with baseline ANS measures during the rest and tones periods and the instruction period. All correlations are positive showing that, in general, more symptomatic patients have higher baseline ANS activity. Neg symptoms, however, were related only to HR variability. The condition (rest or
Table 3 Partial correlations of Brief Psychiatric Rating Scale (BPRS) subscales and total, and mean Reaction Time (RT) with baseline ANS variables during the instruction period controlling for the values in the tones period (left hand only) Variable
AD
PS
Ln NSCR/minute Ln SC level Mean heart rate HR variability Baseline Z-score
.19y .31** .18y .17 .23*
.00 .04 .01 .03 .02 .23* .22y .22y .10 .11 .23* .13 .24* .27* .19y .09 .23* .14 .05 .05 .04 .03 .05 .13 .10 .05 .04 .00 .10 .22y
Act
Pos
Neg
Tot
RT
N = 73. y.05 b p b .10; *p b .05; **p b .01. AD=Anxiety–depression; PS=Paranoid–suspicious; Act=Activation; Pos=Positive symptom; Neg=Negative symptom; Tot=Total BPRS score; SCR=Skin conductance responses; HR=Heart rate; Baseline Z-score=Mean of the standard scores for Ln NSCR/minute, Ln SC Level and HR.
T.P. Zahn, D. Pickar / Schizophrenia Research 79 (2005) 257–270 Table 4 Mean F s.d. of BPRS ratings for skin conductance orienting response nonresponders to all 10 tones and responders Rating scale
Nonresponders
Responders
t
p
Number of patients Paranoid–suspicious Negative symptoms Total BPRS
9 6.4 F 2.1 11.1 F 2.3 56.8 F 11.3
64 8.5 F 3.8 13.5 F 4.0 65.9 F 19.3
2.51 2.60 2.03
.03 .02 .06
BPRS=Brief Psychiatric Rating Scale.
task-instructions) affected the relationships very little. Slow RT was associated with high ratings on several symptoms and with high resting ANS activity, but only with HR in the instruction period. A multiple regression analysis showed that RT and the Baseline Z-scores for the instructions each were significant independent predictors of clinical state, accounting for 24% of the variance of BPRS Tot. This is significantly greater than the variance accounted for by any of those variables by themselves. The hypothesis that all correlations are zero was rejected for both matrixes in Table 2 (X 235 = 172.2 and X 241 = 222.4, both p b .001). Table 3 shows the partial correlations of BPRS ratings and RT with baseline ANS measures during the instructions controlling for values during the preceding tones period. Where substantial relationships exist the more responsive patients were more symptomatic, although they tended to have faster RT. Correlations of the simple uncorrected differences between the instructions and tones values were generally similar but of lower magnitude, an exception being that the increment in Ln NSCR/minute was marginally negatively correlated with Act, Pos, and Tot, and its correlation with RT was .32 ( p b .01). Both these matrices were different from zero; for the raw differences X 235 = 58.5 ( p b .05) and for the partial rs X 235 = 61.0 ( p b .01).
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3.2. Orienting responses Using the conventional criterion of no SCORs on either hand to the first 3 tones, 15 patients (21%) were NRs. There were no differences on the BPRS between the NRs and the 58 Rs. However the nine patients who failed to respond to any of the 10 tones had less severe paranoid and negative symptoms than Rs and marginally lower Total BPRS scores (Table 4). A simultaneous test for all scales approached significance ( p = .052). Further analyses of the SCOR data were done using ANOVAs on 3 levels of responsivity in order to assess the entire range better. These also show that the least responsive patients were the least symptomatic (Table 5). For SCOR frequency this was significant for only the AD factor, but patients with the smallest SCOR magnitudes also had the fewest paranoid and total symptoms. The linear trends across the three groups were significant ( p b .02) for all of these variables. A multivariate test on all scales was not significant for either frequency or magnitude. The ratio of SCORs to nonspecific SCRs (Table 6) was also related to symptoms, but in a nonlinear manner. Patients with low ratios were more symptomatic than those with moderate ratios, but those with the highest ratios tended to have high symptom ratings as well. The quadratic trend was significant for all listed BPRS scales; for RT only the linear trend was significant ( p b .03). The multivariate test of all scales was significant ( p b .04). 3.3. Responsivity during the RT task The most responsive patients to the stimuli in the RT task were the most symptomatic (Table 7). For the RT ready signal this was true only for AD, but the magnitude of SCRs to the RT stimulus showed significant relationships with
Table 5 Mean F s.d. of BPRS ratings for patients differing on frequency and magnitude of Skin Conductance Orienting Responses (SCOR) Responsivity category Rating scale
Low
Medium
High
A. SCOR Frequency Number of patients Anxiety-depressiona B. SCOR magnitude (AS) Number of patients Anxiety–depressionb Paranoid–suspiciousa Total BPRSa
b2 24 6.5 F 2.7 b.11 21 6.1 F 2.2 6.7 F 2.2 56.5 F 12.1
2–5 27 7.1 F 2.7 .11.38 27 7.3 F 2.8 8.7 F 3.0 66.8 F 16.2
N5 22 9.1 F 4.1 N.38 22 9.1 F 4.1 9.3 F 4.9 69.7 F 23.7
BPRS = Brief Psychiatric Rating Scale. a High differed from low at p b .05 by the Tukey Studentized Range Test (TSRT). b High differed from low at p b .01 by the TSRT. * The Welch test of significance was used because of inhomogeneous variance.
F
p
4.10
.021
4.98 4.91* 4.59*
.010 .012 .015
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Table 6 Mean F s.d. of BPRS ratings for patients differing on the ratio of SCORs to the rate of nonspecific SCRs per minute (NSCR/min) in the tones period: [(2*SCOR) / (NSCR/minute + 5)] Responsivity category Rating scale
Low
Medium
High
Overall
SCOR/(NSCR/min) Number of patients Paranoid–suspiciousa,b Activationc,d Positive symptomsb Total BPRSa,b Reaction time (ln[ms])b,e
b1.25 24 9.2 F 3.3 8.9 F 3.5 15.0 F 5.1 71.5 F 16.9 6.27 F .48
1.25–2.15 26 6.7 F 3.1 5.8 F 2.2 11.6 F 4.7 56.4 F 15.5 5.85 F .51
N2.15 23 9.1 F 4.2 6.9 F 3.0 13.2 F 5.5 67.2 F 20.7 5.79 F .53
F
p
Quadratic F
p
3.90 6.89 2.91 4.83 6.42
.025 .002 .061 .011 .003
7.79 8.27 4.17 8.93 2.30
.007 .006 .045 .004 ns
BPRS=Brief Psychiatric Rating Scale; SCOR=Skin Conductance Orienting Response; SCR=Skin Conductance Response. *The Welch test of significance was used because of inhomogeneous variance. a High differed from Medium at p b .10 by the Tukey Studentized Range Test (TSRT). b Low differed from Medium at p b .05 by the TSRT. c Low differed from Medium at p b .01 by the TSRT. d Low differed from High at p b .10 by the TSRT. e Low differed from High at p b .01 by the TSRT.
AD, PS and the total BPRS, and there was a trend for Pos symptoms. Although the linear trends (not shown) were also significant at the same levels or better for each of the results shown in Table 7, it is clear that only the High group differed appreciably from the other two which were similar. The overall multivariate tests were not significant however. Differences between responsivity to the task-relevant RT stimulus and that to simple tones (SCORs) were related to symptoms in a non-linear fashion as shown by the significant quadratic trends (Table 8). Because the number and
magnitudes of SCORs were greatest in the Negative groups on the raw difference scores, and those for the SCRs to the RT stimulus were greater in the High groups, ( p b .002 for all), the brelativeQ differences were thought to be more appropriate. Patients who were relatively the most responsive to the RT stimulus as well as those relatively the most responsive to the tones were more symptomatic on most subscales and the total BPRS than those with moderate differences or no difference. However, analyses of absolute differences produced similar results. Weaker results in the
Table 7 Mean F s.d. of BPRS ratings for patients differing in electrodermal responsivity during the RT task Responsivity category Rating scale
Low
A. RT ready: SCR frequency Number of patients Anxiety–depressiona B. RT ready: SCR magnitude(AS) Number of patients Anxiety–depressionb C. RT stimulus: SCR magnitude Number of patients Anxiety–depressionc Paranoid–suspiciousd Positive symptomse Total BPRSa
b2 22 6.7 F 2.8 b.16 22 6.5 F 2.6 b.2 23 6.4 F 2.7 7.0 F 2.5 12.2 F 5.3 59.4 F 14.7
Medium 2–4.5 25 6.6 F 2.5 .16–.32 25 6.4 F 2.4 .2–.37 23 6.7 F 2.4 7.1 F 2.7 11.6 F 3.5 58.4 F 12.8
High N4.5 21 8.5 F 3.2 N.32 21 9.1 F 3.0 N.37 22 8.6 F 3.2 9.5 F 4.4 14.8 F 5.8 70.8 F 21.4
BPRS=Brief Psychiatric Rating Scale; RT=Reaction Time; SCR=Skin conductance response. a High differed from Low at p b .10 and from Medium at p b .05 by the Tukey Studentized Range Test (TSRT). b High differed from Low and Medium at p b .01 by the TSRT. c High differed from Low at p b .05 and from Medium at p b .10 by the TSRT. d High differed from Low and Medium at p b .05 by the TSRT. e High differed from Medium at p b .10 by the TSRT.
F
p
3.19
.048
7.42
.002
4.19 4.06 2.68 3.82
.020 .022 .076 .027
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Table 8 Mean F s.d. of BPRS ratings and total RT for patients differing in the absolute or relative difference in electrodermal responsivity to the RT stimuli and that to simple tones (SCOR; Relative Difference=[RT Stim SCOR] / [RT Stim + SCOR + 1]) Responsivity category Rating Scale a
A. RT Stim. SCOR: freq. Number of patients Anxiety–depressionb Paranoid–suspiciousc,d Activation Positive symptomsd Total BPRSc,e B. RT Stim SCOR Mag Number of patients Anxiety–depressionb,f Positive symptoms Total BPRSe
Neg
Low
High
Overall
Quadratic
b.08 22 8.0 F 2.8 9.0 F 3.3 7.5 F 2.9 13.2 F 5.4 67.1 F15.6 b .07 AS 23 7.5 F 2.6 12.4 F 5.7 62.1 F17.2
.08–0.15 25 6.2 F 2.3 6.4 F 2.3 5.9 F 1.8 11.2 F 3.9 55.0 F 11.6 .07–.06 20 5.7 F 1.8 11.5 F 2.8 56.2 F 10.1
N0.15 21 7.8 F 3.3 8.5 F 4.1 7.6 F 4.1 14.3 F 5.4 67.5 F 21.7 N.06 25 8.3 F 3.4 14.3 F 5.6 68.6 F 20.4
F
p
F
p
2.88 4.33 3.42* 2.48 4.41
.064 .018 .043 .092 .016
5.70 8.43 4.84 4.46 8.83
.020 .005 .031 .038 .005
6.90* 2.46 3.81*
.003 .098 .030
9.35 2.03 4.25
.004 NS .043
BPRS=Brief Psychiatric Rating Scale; RT=Reaction Time; Stim.=Stimulus; SCOR=Skin Conductance Orienting Response; Neg=Negative; Freq=Frequency; Mag.=Magnitude. a Relative Difference Scores. b Low differed from Neg at p b .10 by the Tukey Studentized Range Test (TSRT). c Low differed from Neg at p b .05 by the TSRT. d High differed from Low at p b .10 by the TSRT. e High differed from Low at p b .05 by the TSRT. f High differed from Low at p b .01 by the TSRT. * The Welch test of significance was used because of inhomogeneous variance.
same direction are shown for absolute magnitude differences. The relative differences for magnitude were not significant. The multivariate test was significant for frequency ( p b .02). The above differences contrast with a lack of differences on the BPRS but slow RT in patients with decrements in SCR frequency and magnitude from the RT ready signal to the RT stimulus compared to those showing increments or no change (Table 9). The High groups showed more and larger SCRs to the RT stimulus, but the SCRs to the Ready
signal did not differ among the three groups. Neither multivariate test was significant. 3.4. Electrodermal lateral asymmetry Table 10 shows that patients with larger SCOR magnitudes (or SCL for nonresponders) on the left hand had marginally higher Total BPRS ratings than those with larger right hand EDA. However, when just the male patients were considered, this difference was significant and there were
Table 9 Mean F s.d. of BPRS ratings and total RT for patients differing in the relative change in electrodermal responsivity to the RT stimuli from that for the RT ready signal (e.g. [RT Stim Ready] / [RT Stim + Ready + 1]) Rating Scale
Neg
A. RT Stim. Ready: Frequency Number of Patients Reaction Time (ln[ms])a,b B. RT Stim. Ready: Mag. (AS) Number of patients Reaction time (ln[ms])c
b0 24 6.16 F 49 b0 24 6.04 F .53
Low 0–0.11 21 5.77 F .46 0–0.13 24 5.92 F .53
High N0.12 23 5.75 F .45 N0.15 20 5.70 F .33
BPRS=Brief Psychiatric Rating Scale; RT=Reaction Time; Stim.=Stimulus; Neg=Negative; Mag.=Magnitude. a High differed from Neg at p b .01 by the Tukey Studentized Range Test (TSRT). b Low differed from Neg at p b .05 by the TSRT. c High differed from Neg at p b .10 by the TSRT. * The Welch test of significance was used because of inhomogeneous variance.
F
pb
5.96
.005
3.82*
.030
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Table 10 Mean F s.d. of BPRS ratings for patients differing in lateral dominance of EDA Rating scale
Right dom (R N L)
Left dom (L N R)
t
p
A. All patients Number of patients Total BPRS
38 61.1 F17.6
35 68.7 F 19.2
1.75
.09
B. Males only Number of patients Anxiety–depression Positive symptoms Total BPRS Reaction time (ln[ms])
25 6.4 F 2.1 11.6 F 4.2 57.4 F 14.3 5.77 F .42
26 8.2 F 2.7 15.0 F 5.8 70.1 F18.7 6.07 F .58
2.59 2.39 2.71 2.18
.02 .03 .01 .04
BPRS=Brief Psychiatric Rating Scale; EDA=Electrodermal Activity; Dom = Dominance.
differences for higher AD and Pos ratings and slower RT in the left N right group as well. The overall multivariate test for the male data was significant ( p b .02).
4. Discussion 4.1. Tonic baselines Patients with the highest ANS activity were the most symptomatic, especially for positive symptoms, which include the classic cognitive disturbances uniquely associated with schizophrenia, and for more nonspecific mood and activation symptoms. The results for the rest and tones periods are generally consistent with the studies reviewed earlier. In addition, we show here that those relationships were similar when the patients were active (e. g. during the task instructions and practice trials). Because HR variability is an index of cholinergic activity (Larsen et al., 1986) the positive correlations between Neg ratings and HR variability supports the conjecture of Tandon and Greden (1989) that cholinergic hyperactivity is related to the pathogenesis of negative symptoms. However, this is not specific to Neg symptoms as this variable is related to most symptom factors in the rest and tones periods and to BPRS Tot in both periods. Possibly motor restlessness might account for some of these relationships, but we did not measure this. Patients with greater increases in SCL and HR from rest to task conditions showed relatively weaker
tendencies to be more symptomatic. Those with greater increases in NSCR/min did not show this but had faster RT. These weak and somewhat inconsistent relationships and the similarity of the correlation matrices for the two conditions are not surprising because increments in base levels from rest to the stress of a task are small in patients with schizophrenia compared to controls (Zahn et al., 1991, 2001). 4.2. Elicited SCRs. Tables 4, 5, and 7 all show more symptoms in more responsive patients. However, on the usual measure of SCOR Rs vs NRs, based on just the first two or three trials, where there is little consensus in previous studies, our results are congruent with those studies that found no differences in symptoms. The lower symptomotology in patients with no SCORs to any tone (Table 4) is similar to the data of Dawson et al. (1994). Previous studies have not examined SCR magnitudes and have only infrequently involved SCRs to taskrelated stimuli. It is of interest that although the magnitudes of SCORs and SCRs to the RT stimuli showed monotonic relationships to symptoms the shapes of the curves differed. The high symptom ratings in medium SCOR responders suggests that even moderate responding to an innocuous stimulus indicates an bunhealthyQ level of ANS sensitivity to stimulation in schizophrenia, while the low symptom ratings in moderate responders to the task-relevant RT stimulus may reflect a moderate degree of attention or effort, an adaptive response more likely in less symptomatic patients. This difference was not due to the high (N 70) BPRS ratings in the five patients who could not perform the RT task; they were split 3 and 2 in the middle and high SCOR groups, and their contributions to the means of the two groups were about equal. We did not confirm some previous reports of SCOR hypoactivity and low EDA in patients with severe negative symptoms. This might be due to the nature of the sample. The patients all had volunteered for a program which promised innovative and carefully monitored treatments, and thus they were motivated to improve their psychological condition. Although this seems incompatible with a high level of negative symptoms, BPRS Neg ratings (3.3 per item) were not low and were the same as for Pos.
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However, negative symptoms can be secondary to positive symptoms (Buchanan et al., 1996). It is reasonable to assume that these secondary symptoms may be prominent in the present patient cohort, all of whom were recently withdrawn from medication. It is possible that only primary negative symptoms correlate with low EDA, so prominent secondary negative symptoms may add an extraneous source of variability to this measure. Some support for this is that Pos and Neg ratings were correlated .53, mainly due to higher Pos ratings in patients in the upper third of the Neg distribution than those in medium and low Neg groups. Despite this, partialling out Pos scores did not yield the expected negative correlations of Neg with ANS activity. Patients with either high or low ratios of SCORs to nonspecific SCRs were more symptomatic than those with moderate ratios (Table 6). Post hoc analyses of the components separately showed that, as might be expected, compared to the other two groups the low group had high NSCR/min and the high group had a high number of SCORs. Thus, patients with low or moderate values on both component variables were the least symptomatic. The slow RT in the low group is consistent with the positive correlation of RT with NSCR/min (Table 2), but the fast RT in the High group seems paradoxical given the high symptom ratings in that group. Similar quadratic trends were observed for the RT stimulus SCRsSCOR differences in relation to symptoms (Table 8). It is generally assumed that elicited SCRs are influenced by both general electrodermal responsivity and the attention or effort elicited by the signal quality of the stimulus (as established by instructions), so difference scores for stimuli differing in task-relevance should control for overall responsivity to some extent. The high symptom ratings for the two extreme groups suggest that these patients had either too little (Neg groups) or excessive (High groups) effort on the task compared to the Medium groups. For SCR frequency the results for the relative difference scores seem not attributable to the separate components because these were not related to BPRS ratings. For the magnitude differences the Neg group had greater SCOR magnitudes than the other two groups ( p b .0001), but both Neg and High groups had greater SCR magnitudes to the RT stimulus and higher EDA during the Rest and Tones period than the
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Mod group (quadratic trends: p b .001). Because low EDA is associated with low symptom ratings, the data suggest that the absolute magnitude differences are influenced by the overall reactivity of the electrodermal system more than by attention or effort. 4.3. Reaction time and laterality Slow RT is a hallmark characteristic of schizophrenia and may partially index attention or working memory, qualities that are not directly assessed by the BPRS. It was slower in patients with more active, positive, and total symptoms, and like symptoms it was especially impaired in patients with high HR under both passive and active conditions and in those with high EDA at rest. The latter finding could explain the slow RT in patients with small increments in NSCR/min in the instructions and in those with low ratio of SCORs to NSCR/min. These data suggest that patients more stressed by the test situation in general may be particularly impaired in attention possibly due to interference or distraction caused by the cognitive concomitants of their symptoms. However, unlike symptoms, RT was not related to the responsivity to the RT stimulus or to its difference from SCORs. Possibly the faster RT expected in the Low and Medium RT stimulus groups and the Medium groups on the difference variables by virtue of their low symptoms was offset by limitations in effort by those patients. Nevertheless, the RT findings as a whole suggest that slow RT is not simply due to low effort and/or that the assumption that the difference scores just reflect effort is incorrect. The markedly slow RT in those patients who gave more and larger SCRs to the ready signal than to the RT stimulus (Table 9) suggests that they failed to differentiate between more or less bimportantQ stimuli and/or had difficulty shifting attention from the key press to the more task-relevant stimulus and key release. The specificity of these relationships to RT but not to symptoms, contrasted with the reverse specificity of the RT stimulusSCOR difference, suggests that these two difference scores reflect different aspects of the pathology of schizophrenia. This is not apparent from comparisons of patients with normal controls. The laterality results for the males support the findings of Gruzelier and Manchanda (1982) of great-
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er florid symptoms in patients with larger left than right hand EDA, but do not confirm their association of negative symptoms with the opposite asymmetry. This may be due to the influence of secondary negative symptoms in this group that was discussed earlier. 4.4. Conclusions With respect to the predictions made in the Introduction, the simple notion that patients more deviant from controls would be more symptomatic is supported by the tonic baseline data, which was higher in more symptomatic patients, but it is inconsistent with the higher symptom ratings in patients with greater electrodermal responsivity. The present patients had elevated baselines but were similar to controls on SCORs and had reduced tonic and phasic responsivity to task-related situations and stimuli (Zahn et al., 2001). The data are more consistent with predictions suggested by the effects of neuroleptics where reduced symptoms are accompanied by reductions in both base levels and responsivity. However, there were inconsistencies here as well: reduction of symptoms by fluphenazine had, at best, small and variable effects on HR, the SCOR/NS-SCR ratio, and RT and there were increases in the difference between SCRs to the RT stimulus and SCORs (Zahn et al., 2001). There was little support for the hypothesis of differential autonomic concomitants of positive and negative symptoms. In addition, of course, many effects of both diagnosis and medication on ANS activity were not manifested in their relation to symptoms. An alternative hypothesis based on the role of ANS activity in schizophrenia may account better for the data. The higher symptom ratings in patients with higher levels of both ANS baselines and responsivity suggests that either elevated ANS activity is itself disturbing or indexes a process or state that is somehow toxic or disturbing to patients with schizophrenia. This hypothesis is consistent with findings that significant life events and interactions with high bexpressed emotionQ relatives are conducive to elevated ANS activity and to earlier relapse of patients in remission (Tarrier et al., 1979) and that increases in ANS activity precede the onset of episodes of psychosis (Hazlett et al., 1997).
Regardless of the direction of causation of these relationships, it seems plausible that elevated ANS activity could become associated with disturbing prodromal subjective states and acquire an aversive quality. This might lead to an increased sensitivity to environmental events so that seemingly non-threatening or non-noxious situations that increase ANS activity would have an aversive quality. Some patients might attempt to cope with novel or task-related situations and stimuli by a passive-avoidant strategy of low attention and effort in order to attenuate their responsivity. This hypothesis is similar to Nuechterlein and Dawson’s (1984) idea that such coping involves bwithdrawing physically or psychologically from all environmental stimuliQ (p. 306) which may lead to SCOR nonresponding. Straube (1979) also concluded that nonresponding constitutes a bprotective mechanismQ in schizophrenia. Our data, as well as those of Dawson et al. (1992, 1994), suggest that it is the less symptomatic patients who are better able to cope in this manner. Regarding attenuated responsivity as part of a coping strategy could help explain the seemingly paradoxical findings that less symptomatic patients are more deviant from controls on several task-related responsivity variables than more symptomatic patients: low symptom patients had smaller values on these while controls had higher mean values than the patients as a group (Zahn et al., 2001). A similar paradox is seen, of course, in the effects of medication which increases hyporesponsivity in schizophrenia. This suggests that levels of ANS responsivity that are moderate and adaptive for controls may be excessive for patients. Coping with demanding situations by reductions in ANS responsivity may reduce discomfort and symptoms in the short term as shown here, but it may also be counterproductive in terms of prognosis. Low responsivity to task-related stimuli and situations were predictive of poor short-term outcome in unmedicated patients (Zahn et al., 1981). Finally, the results support the conclusion from the literature review that the differences in results between studies are not due merely to differences in medication. There is a general similarity of the present results to those of the outpatients of Dawson et al. (1992) who were medicated but presumably were not severely ill on the average. On the other hand the results contrast with those from this laboratory obtained
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under identical conditions on unmedicated adolescents with childhood-onset schizophrenia (Zahn et al., 1997). In those patients SCOR NRs had more symptoms of all types than Rs and those with low baseline EDA had more negative symptoms. It was the first author’s impression that those patients were generally much more severely ill than most patients in the present study, and they have recently been shown to have a developmental brain anomaly (loss of gray matter) that is correlated with symptom severity (Thompson et al., 2001). This suggests that the differences among studies may be largely due to differences in the population sampled. Finding better clinical markers with which to compare patients in different studies would enhance further progress in this area. Acknowledgements The authors thank Thalene T. Mallus for expert assistance in data collection and analysis, and to the professional and nursing staffs of Ward 4E of the NIH Clinical Center for ratings and many other valuable clinical aspects of the study. References ¨ st, L.G., O ¨ hman, A., 1984. ElectroderAlm, T., Lindstrom, L.H., O mal non-responding in schizophrenia: relationships to attentional, clinical, biochemical, computed tomographical and genetic factors. Int. J. Psychophysiol. 1, 195 – 208. Andreasen, N.C., 1983. The Scale for the Assessment of Negative Symptoms (SANS). University of Iowa, Iowa City. Andreasen, N.C., 1984. The Scale for the Assessment of Positive Symptoms (SAPS). University of Iowa, Iowa City. Asberg, M., Montgomery, S.A., Perris, C., Schalling, D., Sedvall, G., 1978. A comprehensive psychopathological rating scale. Acta Psychiatr. Scand. 271, 5 – 27. Bartfai, A., Edman, G., Levander, S.E., Schalling, D., Sedvall, G., 1984. Bilateral skin conductance activity, clinical symptoms and CSF monoamine metabolite levels in unmedicated schizophrenics, differing in rate of habituation. Biol. Psychol. 18, 201 – 218. Bartfai, A., Levander, S.E., Nyback, H., Schalling, D., 1987. Skin conductance nonresponding and nonhabituation in schizophrenic patients. Acta Psychiatr. Scand. 75, 321 – 329. Bernstein, A.S., Taylor, K.W., Starkey, P., Juni, S., Lubowsky, J., Paley, H., 1981. Bilateral skin conductance, finger pulse volume, and EEG orienting response to tones of differing intensities in chronic schizophrenics and controls. J. Nerv. Ment. Dis. 169, 513 – 528.
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Bernstein, A.S., Frith, C.D., Gruzelier, J.H., Patterson, T., Straube, E., Venables, P.H., Zahn, T.P., 1982. An analysis of the skin conductance orienting response in samples of American, British, and German schizophrenics. Biol. Psychol. 14, 155 – 211. Brekke, J.S., Raine, A., Ansel, M., Lencz, T., Bird, L., 1997. Neuropsychological and psychophysiological correlates of psychosocial functioning in schizophrenia. Schizophr. Bull. 23, 19 – 28. Buchanan, R.W., Brandes, M., Breier, A., 1996. Treating negative symptoms: pharmacological strategies. In: Breier, A. (Ed.), The New Pharmacology of Schizophrenia. American Psychiatric Press, Washington, DC, pp. 179 – 204. Cooklin, R., Sturgeon, D., Leff, J., 1983. The relationship between auditory hallucinations and spontaneous fluctuations of skin conductance in schizophrenia. Br. J. Psychiatry 142, 47 – 52. Dawson, M.E., Nuechterlein, K.H., Schell, A.M., Mintz, J., 1992. Concurrent and predictive electrodermal correlates of symptomatology in recent-onset schizophrenic patients. J. Abnorm. Psychology 101, 153 – 164. Dawson, M.E., Nuechterlein, K.H., Schell, A.M., Gitlin, M., Ventura, J., 1994. Autonomic abnormalities in schizophrenia: state or trait indicators. Arch. Gen. Psychiatry 51, 813 – 824. Deakin, J.F.W., Baker, H.F., Frith, C.D., Joseph, M.H., Johnstone, E.C., 1979. Arousal related to excretion of noradrenaline metabolites and clinical aspects of unmedicated chronic schizophrenic patients. J. Psychiatr. Res. 15, 57 – 65. Green, M.F., Nuechterlein, K.H., Satz, P., 1989. The relationship of symptomatology and medication to electrodermal activity in schizophrenia. Psychophysiology 26, 148 – 157. Gruzelier, J.H., 1976. Clinical attributes of schizophrenic skin conductance responders and non-responders. Psychol. Med. 6, 245 – 249. Gruzelier, J., Manchanda, R., 1982. The syndrome of schizophrenia: relations between electrodermal response, lateral asymmetries and clinical ratings. Br. J. Psychiatry 141, 488 – 495. Hazlett, H., Dawson, M.E., Schell, A.M., Nuechterlein, K.H., 1997. Electrodermal activity as a prodromal sign in schizophrenia. Biol. Psychiatry 41, 111 – 113. Kim, D.K., Shin, Y.M., Kim, C.E., Cho, H.S., Kim, Y.S., 1993. Electrodermal responsiveness, clinical variables, and brain imaging in male chronic schizophrenics. Biol. Psychiatry 33, 786 – 793. Larsen, P.B., Schneiderman, N., Pasin, R.D., 1986. Physiological bases of cardiovascular psychophysiology. In: Coles, M.G.H., Donchin, E., Porges, S.W. (Eds.), Psychophysiology: Systems, Processes, and Applications. Guilford Press, New York, pp. 122 – 165. Maina, G., Barzega, G., Bellino, S., Bogetto, F., Ravizza, L., 1995. Type I and type II schizophrenia: relations between tonic electrodermal activity and clinical ratings before and after haloperidol treatment. Psychiatry Res. 57, 49 – 56. Nuechterlein, K.H., Dawson, M.E., 1984. A heuristic vulnerability/ stress model of schizophrenic episodes. Schizophr. Bull. 10, 300 – 312. Olbrich, R., Mussgay, L., 1987. Spontaneous fluctuations of electrical skin conductance and the actual clinical state in schizophrenics. Psychopathology 20, 18 – 22.
270
T.P. Zahn, D. Pickar / Schizophrenia Research 79 (2005) 257–270
Overall, J.E., 1974. The brief psychiatric rating scale in psychopharmacology research. Mod. Probl. Pharmacopsychiatry 7, 67 – 78. Overall, J.E., Gorham, D.R., 1962. The brief psychiatric rating scale. Psychol. Rep. 10, 799 – 812. Perry, W., Felger, T., Braff, D., 1995. The relationship between skin conductance hyporesponsivity and perseverations in schizophrenia patients. Biol. Psychiatry 44, 459 – 465. Pickar, D., Labarca, R., Doran, A.R., Wolkowitz, O.M., Roy, A., Breier, A., Linnoila, M., Paul, S.M., 1986. Longitudinal measurement of plasma homovanillic acid in schizophrenic patients: correlation with psychosis and response to neuroleptic treatment. Arch. Gen. Psychiatry 43, 669 – 676. Schiffer, R.A., Sigal, M., Mintz, M., 1996. Delayed habituation of the skin-conductance orienting response correlates with impaired performance in the Wisconsin Card Sorting Task in Schizophrenia. Psychiatry Res. 65, 107 – 112. Schlenker, R., Cohen, R., Hubmann, W., Mohr, F., Walheim, C., Watzl, H., Werther, P., 1995. Electrodermal and vascular orienting response in schizophrenic patients: relationship to symptoms and medication. E. Arch. Psychiatry Clin. Neurosci. 245, 152 – 158. Schnur, D.B., 1990. Effects of neuroleptics on electrodermal activity in schizophrenic patients: A review. Psychopharmacology 102, 429 – 437. Steiger, J.H., 1980. Tests for comparing elements of a correlation matrix. Psychol. Bull. 87, 245. Straube, E., 1979. On the meaning of electrodermal nonresponding in schizophrenia. J. Nerv. Ment. Dis. 167, 601 – 611. Tandon, R., Greden, J.F., 1989. Cholinergic hyperactivity and negative schizophrenic symptoms: a model of cholinergic/dopaminergic interactions in schizophrenia. Arch. Gen. Psychiatry 46, 745 – 753.
Tarell, J.D., Schulz, S.C., 1988. Nursing assessment using the BPRS: a structured interview. Psychopharmacol. Bull. 24, 105 – 111. Tarrier, N., Vaughn, C., Lader, M.H., Leff, J.P., 1979. Bodily reactions to people and events in schizophrenics. Arch. Gen. Psychiatry 36, 311 – 315. Thompson, P.M., Vidal, C., Giedd, J.N., Gochman, P., Blumenthal, J., Nicolson, R., Toga, A.W., Rapoport, J.L., 2001. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proceedings of the National Academy of Sciences, vol. 98, pp. 11650 – 11655. Zahn, T.P., Carpenter, W.T.J., McGlashan, T.H., 1981. Autonomic nervous system activity in acute schizophrenia: II. Relationships to short term prognosis and clinical state. Arch. Gen. Psychiatry 38, 260 – 266. Zahn, T.P., Frith, C.D., Steinhauer, S.R., 1991. Autonomic functioning in schizophrenia: electrodermal activity, heart rate, pupillography. In: Steinhauer, S.R., Gruzelier, J.H., Zubin, J. (Eds.), Handbook of Schizophrenia, Vol 5: Neuropsychology, Psychophysiology and Information Processing. Elsevier, Amsterdam, pp. 185 – 224. Zahn, T.P., Jacobsen, L.K., Gordon, C.T., McKenna, K., Frazier, J.A., Rapoport, J.L., 1997. Autonomic nervous system markers of psychopathology in childhood-onset schizophrenia. Arch. Gen. Psychiatry 54, 904 – 912. Zahn, T.P., Pickar, D., van Kammen, D.P., 2001. Neuroleptic effects on autonomic activity in schizophrenia: between- and withinsubject paradigms and comparison with controls. Schizophr. Bull. 27, 503 – 515.
Autonomic activity in relation to symptom ratings and reaction time in unmedicated patients with schizophrenia Theodore P. Zahn a,*, David Pickar b,1 a
Laboratory of Brain and Cognition, National Institutes of Health, Bldg. 10. Rm. 4C104, MSC 1366, Bethesda, MD 20892-1366, United States b Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, MD 20892, United States Received 9 December 2004; received in revised form 25 May 2005; accepted 27 May 2005 Available online 11 July 2005
Abstract Problem: High autonomic base levels and low responsivity are frequently observed in unmedicated patients with schizophrenia. We previously reported that patients in the present cohort, compared to normal controls, had high autonomic tonic baselines and low reactivity to the meaningful stimuli in a reaction time (RT) task but not to novel but innocuous stimuli. This paper explores further the role of autonomic activity in the pathogenesis of schizophrenia by relating differences in the autonomic variables among patients to symptom ratings and RT. Methods: Electrodermal activity and heart rate were recorded during rest, a tone series, and a RT task in 73 patients with schizophrenia taking placebo. Symptoms were rated with the Brief Psychiatric Rating Scale. Results: Patients with higher autonomic baselines both at rest and under mild stress and those with greater electrodermal responsivity to both simple tones and the RT stimuli had more severe positive, bactiveQ, and total symptoms than patients with lower baselines and responsivity. RT was slower in patients with higher baselines. Conclusions: High autonomic activity in general, reactivity as well as base levels, under all conditions used in this study was associated with symptom severity independent of differences from controls. Thus elevated autonomic activity and responsivity may themselves be disturbing or index states that are disturbing in schizophrenia. Some patients might attempt to cope with novel or demanding situations and stimuli by a passive-avoidant strategy of low attention and effort in order to attenuate their responsivity. Less symptomatic patients may better cope in this manner. D 2005 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Electrodermal activity; Heart rate; Symptoms; Reaction time
1. Introduction * Corresponding author. Tel.: +1 301 594 8039; fax: +1 301 480 0546. E-mail address: [email protected] (T.P. Zahn). 1 Present Address: Gabriel Pharma, LLC and Potomac Pharma, Inc., Cabin John, MD, United States. 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.05.025
Investigators have been seeking markers of pathology in schizophrenia in autonomic nervous system (ANS) activity for many years. Compared to controls patients with schizophrenia as a group have usually
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been found to have impaired ANS responsivity to both innocuous and significant stimulation and higher resting baseline ANS activity, as measured by electrodermal activity (EDA) and heart rate (HR; Zahn et al., 1991, 2001). There is variability in the results of these studies depending on the nature of the patient sample and methodology. This report is concerned with relating differences in ANS activity among patients to differences in symptoms to elucidate further the role of ANS activity in the pathology of schizophrenia. The basic question is whether and how ANS activity is related to the overall severity of the illness and/or is differentially related to different classes of symptoms. Most previous studies have focused on the skin conductance orienting response (SCOR) to novel but innocuous tones. Reports that 50% or more of patients with schizophrenia fail to give SCORs to the first two or three tones (bnonrespondersQ—NRs; Bernstein et al., 1982) raised the obvious question if such patients were clinically different from brespondersQ (Rs) who give one or more SCOR to the first two or three tones. The results have been mixed. In one group of studies NRs have shown higher ratings on both positive and negative symptoms than Rs. Using the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962) with mixed groups of medicated and unmedicated patients both Straube (1979), who tested acute patients, and Bernstein et al. (1981), using chronic patients, reported NRs higher than Rs on Emotional Withdrawal and Conceptual Disorganization but lower on Excitement. Similarly, Kim et al. (1993), in medicated chronic patients, and Zahn et al. (1997), in 20 unmedicated adolescents with childhood-onset schizophrenia, reported that NRs were higher than Rs on the Schedule for the Assessment of Negative Symptoms (SANS; Andreasen, 1983), the Schedule for the Assessment of Positive Symptoms (SAPS; Andreasen, 1984), and on various BPRS items and factors representing both negative and positive symptoms. In all these studies about 50% or more of the patients were NRs. However results in the same direction were also obtained with 13 unmedicated acute patients none of whom were NRs (Bartfai et al., 1984). Patients who failed to habituate in 11 trials had lower Psychosis and Global Psychopathology scores on the Comprehensive Psy-
chopathological Rating Scale (CPRS) than habituators (Asberg et al., 1978). In several studies, however, SCORs were not related significantly to symptoms. These include studies on unmedicated patients (Zahn et al., 1981), medicated patients (Schiffer et al., 1996) and one where only some patients were medicated (Alm et al., 1984) but in 21 unmedicated patients NRs scored higher on a Delusional Mood item than Rs. Three other studies in this group controlled for the anticholinergic level of the drugs, (Green et al., 1989; Perry et al., 1995; Schlenker et al., 1995). However in the latter study NRs were lower in BPRS Excitement. Perry et al. (1995) used Rorshach slides which were to be interpreted as stimuli, so they were not truly innocuous. Finally, in contrast to the first group of studies, a few studies have reported more psychopathology in more responsive patients. Gruzelier (1976) reported that in patients with less than 5 years hospitalization ward nurses rated Rs as more manic, anxious, assaultive, and attention-demanding than NRs; there were no such differences in a very chronic group. In 13 unmedicated chronic inpatients, only two of whom were NRs, ratings of overall severity were higher in non-habituators than in habituators (Deakin et al., 1979). Bartfai et al. (1987) reported that in 18 medicated patients, nonhabituators had more auditory hallucinations than habituator Rs and NRs, but there were no differences on more global CPRS factors. Dawson et al. (1992) found a significant positive correlation between trials to habituation of the SCOR and only a BPRS Activation factor in 56 medicated acute male patients soon after hospital admission (13 female patients did not show this result). However, in the same patients (males only) tested several months later as outpatients, all taking fluphenazine decanoate, habituation related positively to several BPRS factors and the total score. In a within-subjects design Dawson et al. (1994) reported more NRs (but not more SCORs) among bremittedQ patients than in the same patients when they were more symptomatic. Finally, Brekke et al. (1997) reported positive correlations between responder status and the BPRS total score in 40 outpatients living in community care. In summary, these studies are inconclusive about if and how the SCOR relates to psychopathology. Differences among studies in medication, chronicity, or
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methodology by themselves do not seem able to account for the marked variability in findings. For example tone intensity ranged from 60 dB to 85 dB in all three groups of studies. It may be of interest that more symptoms were reported in less responsive patients in three of the four samples of unmedicated patients, but these had small sample sizes and in two of these (Bartfai et al., 1984; Zahn et al., 1997) the samples may be atypical (no NRs and childhood onset patients, respectively). The differences between the two studies from Bartfai’s laboratory (Bartfai et al., 1984, 1987), in which the patients differed in both medication and chronicity, suggest possible interactions between these two variables. About the most definite conclusion is that there is no support for differential relationships of the SCOR to positive and negative symptoms. There are problems with this almost exclusive focus on SCOR Rs and NRs. In recent years there have been several failures to confirm a marked excess of NRs in schizophrenia (Dawson et al., 1994; see Zahn et al., 1991 for earlier studies; Zahn et al., 2001). Other ANS measures such as elevated frequency of nonspecific skin conductance responses (NS-SCR), skin conductance level (SCL), and HR during resting conditions might be more reliable markers for schizophrenia than SCOR NR (Zahn et al., 1991, 2001). Investigators have rather consistently reported positive correlations of NS-SCRs and/or SCL with ratings on positive and active symptoms (Dawson et al., 1992 [outpatient test]; Gruzelier, 1976; Maina et al., 1995; Olbrich and Mussgay, 1987; Zahn et al., 1997). However Olbrich and Mussgay (1987) and Maina et al., 1995 also reported negative correlations of baseline EDA with hallucinatory activity. This is surprising because hallucinations are considered positive symptoms and, indeed, they may be a source of bspontaneousQ SCRs in schizophrenia (Cooklin et al., 1983). Three studies reported lower baselines in patients with more negative symptoms (Green et al., 1989, Maina et al., 1995; Zahn et al., 1997), but in the inpatients of Dawson et al. (1992) NS-SCR was correlated positively with Emotional Withdrawal from the BPRS. Thus, for tonic baselines, unlike the SCOR, there is some evidence of differential relationships with symptom type, although reports of positive correlations of baselines with ratings of overall severity are not uncommon (Brekke et al.,
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1997; Dawson et al., 1992 [outpatient test]; Deakin et al., 1979; Zahn et al., 1981 [discharge test]). Similarly, Dawson et al. (1994) found lower EDA and HR in their patients when remitted than when symptomatic. The Brekke et al. (1997) study included mental arithmetic and speech stress conditions, finding that larger increases in EDA were associated with low total BPRS ratings. A third area that has received some attention is that of laterality of EDA. Patients with larger SCORs on the right hand vs the left hand had more negative symptoms, but those with the opposite lateral difference had more florid symptoms (Gruzelier and Manchanda, 1982). One problem in most previous studies is medication. In those with mixed medicated and unmedicated patients medication status may be confounded with clinical variables. Using patients on several different medications is problematic because drugs differing in anticholinergic actions differ in their effects on EDA (Green et al., 1989; Schnur, 1990) but may not differ on their effects on symptoms. Even low anticholinergic drugs lower EDA (Zahn et al., 2001) and might affect EDA and symptoms differently in different patients. In addition the narrow focus on SCORs and resting baseline EDA limit the generality of the conclusions. In the present study BPRS ratings and ANS activity were examined using a wider array of variables than in previous studies, a relatively large sample, and medication-free patients. The protocol included a reaction time task as well as an orienting paradigm and a rest period. This allows assessment of the relationships of clinical state and task performance with baseline ANS activity under both passive and activated conditions, with responsivity to significant as well as innocuous stimuli. HR as well as EDA was examined. Patient volunteers (N = 73) were taking a placebo, having been withdrawn from neuroleptics for research purposes. They are part of a larger group (Zahn et al., 2001); this report includes just those who were rated on the BPRS. Compared to nonpatient controls the patients had higher tonic baseline NS-SCR, SCL and HR during rest and passive listening to tones, smaller increments in these during instructions for a task, but still higher SCL and HR (but not NS-SCRs) during task instructions. Patients also had lower electrodermal responsivity to signifi-
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cant (i. e. task-related) stimuli, but were not different on SCORs (Zahn et al., 2001). In addition the patients had smaller increments in responsivity to significant compared to less significant stimuli, and disproportionately low electrodermal responsivity for a given tonic activation level as indicated by a lower ratio of SCORs to NS-SCRs. The most straightforward basis for predicting the results is that the most deviant patients on these variables will be the most symptomatic. A second hypothesis is suggested by findings that neuroleptics, which reduce symptoms, also reduce both ANS base levels and responsivity (Schnur, 1990; Zahn et al., 1991, 2001). Thus more symptomatic patients should have both higher base levels and responsivity than less symptomatic patients. A third hypothesis is that ANS responsivity might be inversely related especially to negative symptoms and baseline ANS activity might be directly related particularly to positive symptoms (Zahn et al., 1991).
2. Method 2.1. Participants The patients were recruited over a 13-year period (1983–1995) from other hospitals and the psychiatric community to participate in a number of different research protocols and were currently living on a small, well staffed research ward in the Clinical Center of the National Institutes of Health. Diagnoses were made using modified research diagnostic criteria on the basis of a consensus meeting involving blind record review and structured diagnostic interviews. For research purposes a placebo trial was given to all patients at some time during their stay at the Clinical Center. All patients gave written informed consent to be tested in this specific protocol in addition to the overall treatment protocol. Tests were done on 73 patients (51 male) taking a placebo in double blind protocols. The patients were medication free for a median of 20 days, semi-interquartile range = 5.1, minimum = 13 days. The mean (Fs.d.) age was 31.2 (F 7.6) years, number of years ill was 11.3 (F7.9), number of prior hospitalizations was 5.5 (F6.0), and age of first symptoms was (19.8 F 4.8).
2.2. Apparatus and procedure Physiological recording was done on a Grass polygraph (Model 7B), the output of which was digitized by a PDP-11 computer for off-line editing and analysis. Skin conductance (SC) was recorded bilaterally by a constant voltage (0.5 v) method from the distal phalanges of the middle and ring fingers using Beckman Ag/AgCl electrodes, electrode collars 0.8 cm. in diameter, and 0.5% KCl electrode paste. HR was recorded by a tachograph from the electrocardiogram (Lead II). The procedure began at least 10 min after the SC electrodes were applied in order to allow for hydration. The equipment and procedure remained the same throughout the study. There were 4 periods in the procedure: 1) A 5-min rest period. At the outset participants were told that they should try to relax, but stay awake, that after a few minutes there would be a series of tones or ’beeps’, and that they did not have to do anything except to continue to relax. 2) A Tones period in which ten 1000 Hz 80 dB (re .0002 dynes/cm2) pure tones of 1.5 s duration, rise time = .1 s were presented every 30 to 50 s through a speaker. Tones were generated by a Med Associates voltage-controlled oscillator and amplifier. 3) RT instructions. Participants were instructed that: On each trial a ready light would come on; when s/ he was ready s/he should depress a telegraph key and keep it down until a tone (’beep’) sounded; at this time s/he should release the key as quickly as possible; we were timing how fast s/he responded to the beep. The instructions were followed by a demonstration and at least 4 practice trials to ensure that the procedure was understood. 4) Simple warned RT. Nine trials with 4 s preparatory intervals (PIs) were followed by 9 with 8 s PIs. Patients were told when the PI was increased. The inter-trial interval was randomly distributed between 8 and 14 s by the computer (mean = 11 s). 2.3. Data reduction The following 4 variables were averaged over the combined rest period and the intervals between tone
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presentations, and separately for the task instruction period: 1. The rate of nonspecific SCRs per minute (NSCR/ min) for SCRs of at least 0.02 AS in amplitude and natural-logarithm transformed to reduce skew. 2. SCL in AS, measured at 1 min intervals during rest and instruction periods and before each tone, was averaged for each period and natural-logarithm transformed. 3. Mean HR in beats per min. 4. HR variability the mean difference between maximum and minimum HR for successive 10 s epochs during the period. The frequency and magnitudes of elicited SCRs (minimum amplitude 0.02 AS, onset latency 1–4 s) were calculated separately for simple tones (SCORs), the RT ready signal (and associated key press), and the RT stimulus (and associated finger-lift response). SCR magnitudes were square-root transformed. Mean RT in ms was averaged across the two preparatory intervals and natural-logarithm transformed. For EDA variables for just the rest and tones periods, right and left hand values were averaged. Because the RT task was performed with the right hand by all patients, and this might artificially potentiate right hand EDA, only left hand data were analyzed for the RT instructions, the RT task, and all difference scores. In addition to these simple measures five more complex measures were derived: 1. A bBaseline Z-scoreQ, representing global autonomic activation, was computed by averaging zscores for NSCR/min, SCL, and HR. 2. The difference between the mean base levels in the Instructions period and those in the preceding tones
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period. For SCL the latter measure was the minimum value. 3. The ratio of SCORs to NSCR/min during the tones period: (2*SCOR)/((NSCR/min)+ .5). Ratios for the two hands were averaged. Patients with zero scores for both SCORs and NSCR/min (N = 5) were given the value of 1. 4. Two difference scores: SCRs to the RT stimulus minus SCORs to the simple tones and minus SCRs to the ready signal. In addition to the absolute differences brelativeQ differences, for which the absolute difference were divided by their sum, were analyzed. 5. Electrodermal laterality was determined for SCOR responders by comparison of the mean SCOR magnitude from the right and left hands. For the nine nonresponders, laterality was determined from the mean SCL during the tones period. 2.4. Brief Psychiatric Rating Scale (BPRS) Each patient was rated weekly on an extended (24 item) BPRS (Pickar et al., 1986; Tarell and Schulz, 1988) by the psychiatrist responsible for his/her clinical care. Raters were in daily contact with their patients and nursing staff but blind as to treatment regimen. Although a number of different raters were involved over the course of this study, they were all trained in the use of the BPRS by senior staff. The data presented here are from ratings made during the same week as the psychophysiological test. Table 1 shows the subscales used in the present study. These are similar to those developed by Overall (1974) based on a factor analysis except that the Pos and Neg scales each includes an additional item from the extended version of the BPRS.
Table 1 BPRS subscales: component items, means, standard deviations (SD), and mean per component item Subscale and items
Mean
SD
Per item
Anxiety–depression (AD: anxiety, guilt, depressive mood) Paranoid–suspicious (PS: hostility, suspiciousness, uncooperativeness) Activation (Act: tension, excitement, motor hyperactivity) Positive symptoms (Pos: conceptual disorganization, hallucinatory behavior, unusual thought content, distractibility) Negative symptoms (Neg: emotional withdrawal, motor retardation, blunted affect, loss of functioning) BPRS total (Tot: 24 items)
7.6 8.4 7.2 13.4
3.3 3.7 3.1 5.3
2.5 2.8 2.4 3.3
13.3
4.0
3.3
65.2
18.9
2.7
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Table 2 Correlations of Brief Psychiatric Rating Scale (BPRS) subscales and total, and mean Reaction Time (RT) with baseline ANS variables during rest and tones and instruction periods, N = 73 Variable
AD PS
Act Pos Neg Tot
Rest and tones Ln NSCR/minute Ln SC level Mean heart Rate HR Variability Baseline Z-score
.26* .18 .43** .18 .16 .24* .13 .25* .24* .25*
.27* .22 .09 .27* .13 .14 .10 .25* .29* .37** .14 .32** .27* .29* .33** .34** .33** .35** .14 .35**
RT task instructions§ Ln NSCR/minute .29* .12 .15 .10 .03 Ln SC level .50** .25* .20 .16 .12 Mean heart rate .20 .29* .36** .40** .11 HR variability .16 .21 .16 .18 .28* Baseline Z-score .42** .34** .35** .35** .14 Reaction time (ln[ms]) .12 .26* .48** .40** .16
RT .26* .10 .28* .12 .31**
.17 .02 .31** .05 .37** .31** .26* .01 .42** .24* .40** .NA
*p b 05, **p b 01. AD=Anxiety–depression; PS=Paranoid-suspicious; Act=Activation; Pos=Positive symptom; Neg=Negative symptom; Tot=Total BPRS score; SCR=Skin conductance responses; HR=Heart rate; Baseline Z-score=Mean of the standard scores for Ln NSCR/minute, Ln SC level and HR. §Left hand data only used for electrodermal variables.
Post-hoc comparisons of individual means were done by the Tukey Studentized Range Test. In addition to the univariate ANOVAs a multivariate ANOVA was done to test the simultaneous hypothesis of no difference between groups for any of the dependent variables. In order to control for sex differences, for those variables for which there was an indication of a possible sex difference, as indicated by either a t-test or Mann–Whitney Rank Sum test for which p b .2, the two means were equated by adding or subtracting the mean difference from each of the female scores before the analyses. None of the BPRS scales showed a sex difference by those criteria but men were higher than women on NSCR/min during Rest and Tones and SCL during both periods. Women were higher than men on SCR magnitude to the RT stimulus. The sex corrections were made in these variables before they were used into any combination variables.
3. Results 3.1. Baseline (Tonic) ANS activity
2.5. Data analyses Pearson correlations were used to assess the relationships of baseline ANS activity to BPRS ratings and RT. Separate sets of correlations were computed for the combined rest and tones periods, the RT instruction period, and the increments in baselines from the preceding tones period to the RT instructions. In addition, we computed partial correlations of the ANS measures during the instructions with the values during rest partialled out. Because of the large number of correlations computed a test of the hypothesis that all correlations are zero (Steiger, 1980) was made for each matrix. Analyses of variance (ANOVA) were used for SCRs because of the gross departure from normality of their distributions due to a large proportion of zero responses. In these, the distribution of SCRs was divided into roughly equal thirds, with the constraint that closely clumped values were not separated into different subgroups. This was used as the independent variable in one-way ANOVAs with the BPRS subscales and Tot and RT as dependent variables. Tests of trend using orthogonal polynomials were also done.
Table 2 shows correlations of BPRS ratings and RT with baseline ANS measures during the rest and tones periods and the instruction period. All correlations are positive showing that, in general, more symptomatic patients have higher baseline ANS activity. Neg symptoms, however, were related only to HR variability. The condition (rest or
Table 3 Partial correlations of Brief Psychiatric Rating Scale (BPRS) subscales and total, and mean Reaction Time (RT) with baseline ANS variables during the instruction period controlling for the values in the tones period (left hand only) Variable
AD
PS
Ln NSCR/minute Ln SC level Mean heart rate HR variability Baseline Z-score
.19y .31** .18y .17 .23*
.00 .04 .01 .03 .02 .23* .22y .22y .10 .11 .23* .13 .24* .27* .19y .09 .23* .14 .05 .05 .04 .03 .05 .13 .10 .05 .04 .00 .10 .22y
Act
Pos
Neg
Tot
RT
N = 73. y.05 b p b .10; *p b .05; **p b .01. AD=Anxiety–depression; PS=Paranoid–suspicious; Act=Activation; Pos=Positive symptom; Neg=Negative symptom; Tot=Total BPRS score; SCR=Skin conductance responses; HR=Heart rate; Baseline Z-score=Mean of the standard scores for Ln NSCR/minute, Ln SC Level and HR.
T.P. Zahn, D. Pickar / Schizophrenia Research 79 (2005) 257–270 Table 4 Mean F s.d. of BPRS ratings for skin conductance orienting response nonresponders to all 10 tones and responders Rating scale
Nonresponders
Responders
t
p
Number of patients Paranoid–suspicious Negative symptoms Total BPRS
9 6.4 F 2.1 11.1 F 2.3 56.8 F 11.3
64 8.5 F 3.8 13.5 F 4.0 65.9 F 19.3
2.51 2.60 2.03
.03 .02 .06
BPRS=Brief Psychiatric Rating Scale.
task-instructions) affected the relationships very little. Slow RT was associated with high ratings on several symptoms and with high resting ANS activity, but only with HR in the instruction period. A multiple regression analysis showed that RT and the Baseline Z-scores for the instructions each were significant independent predictors of clinical state, accounting for 24% of the variance of BPRS Tot. This is significantly greater than the variance accounted for by any of those variables by themselves. The hypothesis that all correlations are zero was rejected for both matrixes in Table 2 (X 235 = 172.2 and X 241 = 222.4, both p b .001). Table 3 shows the partial correlations of BPRS ratings and RT with baseline ANS measures during the instructions controlling for values during the preceding tones period. Where substantial relationships exist the more responsive patients were more symptomatic, although they tended to have faster RT. Correlations of the simple uncorrected differences between the instructions and tones values were generally similar but of lower magnitude, an exception being that the increment in Ln NSCR/minute was marginally negatively correlated with Act, Pos, and Tot, and its correlation with RT was .32 ( p b .01). Both these matrices were different from zero; for the raw differences X 235 = 58.5 ( p b .05) and for the partial rs X 235 = 61.0 ( p b .01).
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3.2. Orienting responses Using the conventional criterion of no SCORs on either hand to the first 3 tones, 15 patients (21%) were NRs. There were no differences on the BPRS between the NRs and the 58 Rs. However the nine patients who failed to respond to any of the 10 tones had less severe paranoid and negative symptoms than Rs and marginally lower Total BPRS scores (Table 4). A simultaneous test for all scales approached significance ( p = .052). Further analyses of the SCOR data were done using ANOVAs on 3 levels of responsivity in order to assess the entire range better. These also show that the least responsive patients were the least symptomatic (Table 5). For SCOR frequency this was significant for only the AD factor, but patients with the smallest SCOR magnitudes also had the fewest paranoid and total symptoms. The linear trends across the three groups were significant ( p b .02) for all of these variables. A multivariate test on all scales was not significant for either frequency or magnitude. The ratio of SCORs to nonspecific SCRs (Table 6) was also related to symptoms, but in a nonlinear manner. Patients with low ratios were more symptomatic than those with moderate ratios, but those with the highest ratios tended to have high symptom ratings as well. The quadratic trend was significant for all listed BPRS scales; for RT only the linear trend was significant ( p b .03). The multivariate test of all scales was significant ( p b .04). 3.3. Responsivity during the RT task The most responsive patients to the stimuli in the RT task were the most symptomatic (Table 7). For the RT ready signal this was true only for AD, but the magnitude of SCRs to the RT stimulus showed significant relationships with
Table 5 Mean F s.d. of BPRS ratings for patients differing on frequency and magnitude of Skin Conductance Orienting Responses (SCOR) Responsivity category Rating scale
Low
Medium
High
A. SCOR Frequency Number of patients Anxiety-depressiona B. SCOR magnitude (AS) Number of patients Anxiety–depressionb Paranoid–suspiciousa Total BPRSa
b2 24 6.5 F 2.7 b.11 21 6.1 F 2.2 6.7 F 2.2 56.5 F 12.1
2–5 27 7.1 F 2.7 .11.38 27 7.3 F 2.8 8.7 F 3.0 66.8 F 16.2
N5 22 9.1 F 4.1 N.38 22 9.1 F 4.1 9.3 F 4.9 69.7 F 23.7
BPRS = Brief Psychiatric Rating Scale. a High differed from low at p b .05 by the Tukey Studentized Range Test (TSRT). b High differed from low at p b .01 by the TSRT. * The Welch test of significance was used because of inhomogeneous variance.
F
p
4.10
.021
4.98 4.91* 4.59*
.010 .012 .015
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Table 6 Mean F s.d. of BPRS ratings for patients differing on the ratio of SCORs to the rate of nonspecific SCRs per minute (NSCR/min) in the tones period: [(2*SCOR) / (NSCR/minute + 5)] Responsivity category Rating scale
Low
Medium
High
Overall
SCOR/(NSCR/min) Number of patients Paranoid–suspiciousa,b Activationc,d Positive symptomsb Total BPRSa,b Reaction time (ln[ms])b,e
b1.25 24 9.2 F 3.3 8.9 F 3.5 15.0 F 5.1 71.5 F 16.9 6.27 F .48
1.25–2.15 26 6.7 F 3.1 5.8 F 2.2 11.6 F 4.7 56.4 F 15.5 5.85 F .51
N2.15 23 9.1 F 4.2 6.9 F 3.0 13.2 F 5.5 67.2 F 20.7 5.79 F .53
F
p
Quadratic F
p
3.90 6.89 2.91 4.83 6.42
.025 .002 .061 .011 .003
7.79 8.27 4.17 8.93 2.30
.007 .006 .045 .004 ns
BPRS=Brief Psychiatric Rating Scale; SCOR=Skin Conductance Orienting Response; SCR=Skin Conductance Response. *The Welch test of significance was used because of inhomogeneous variance. a High differed from Medium at p b .10 by the Tukey Studentized Range Test (TSRT). b Low differed from Medium at p b .05 by the TSRT. c Low differed from Medium at p b .01 by the TSRT. d Low differed from High at p b .10 by the TSRT. e Low differed from High at p b .01 by the TSRT.
AD, PS and the total BPRS, and there was a trend for Pos symptoms. Although the linear trends (not shown) were also significant at the same levels or better for each of the results shown in Table 7, it is clear that only the High group differed appreciably from the other two which were similar. The overall multivariate tests were not significant however. Differences between responsivity to the task-relevant RT stimulus and that to simple tones (SCORs) were related to symptoms in a non-linear fashion as shown by the significant quadratic trends (Table 8). Because the number and
magnitudes of SCORs were greatest in the Negative groups on the raw difference scores, and those for the SCRs to the RT stimulus were greater in the High groups, ( p b .002 for all), the brelativeQ differences were thought to be more appropriate. Patients who were relatively the most responsive to the RT stimulus as well as those relatively the most responsive to the tones were more symptomatic on most subscales and the total BPRS than those with moderate differences or no difference. However, analyses of absolute differences produced similar results. Weaker results in the
Table 7 Mean F s.d. of BPRS ratings for patients differing in electrodermal responsivity during the RT task Responsivity category Rating scale
Low
A. RT ready: SCR frequency Number of patients Anxiety–depressiona B. RT ready: SCR magnitude(AS) Number of patients Anxiety–depressionb C. RT stimulus: SCR magnitude Number of patients Anxiety–depressionc Paranoid–suspiciousd Positive symptomse Total BPRSa
b2 22 6.7 F 2.8 b.16 22 6.5 F 2.6 b.2 23 6.4 F 2.7 7.0 F 2.5 12.2 F 5.3 59.4 F 14.7
Medium 2–4.5 25 6.6 F 2.5 .16–.32 25 6.4 F 2.4 .2–.37 23 6.7 F 2.4 7.1 F 2.7 11.6 F 3.5 58.4 F 12.8
High N4.5 21 8.5 F 3.2 N.32 21 9.1 F 3.0 N.37 22 8.6 F 3.2 9.5 F 4.4 14.8 F 5.8 70.8 F 21.4
BPRS=Brief Psychiatric Rating Scale; RT=Reaction Time; SCR=Skin conductance response. a High differed from Low at p b .10 and from Medium at p b .05 by the Tukey Studentized Range Test (TSRT). b High differed from Low and Medium at p b .01 by the TSRT. c High differed from Low at p b .05 and from Medium at p b .10 by the TSRT. d High differed from Low and Medium at p b .05 by the TSRT. e High differed from Medium at p b .10 by the TSRT.
F
p
3.19
.048
7.42
.002
4.19 4.06 2.68 3.82
.020 .022 .076 .027
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Table 8 Mean F s.d. of BPRS ratings and total RT for patients differing in the absolute or relative difference in electrodermal responsivity to the RT stimuli and that to simple tones (SCOR; Relative Difference=[RT Stim SCOR] / [RT Stim + SCOR + 1]) Responsivity category Rating Scale a
A. RT Stim. SCOR: freq. Number of patients Anxiety–depressionb Paranoid–suspiciousc,d Activation Positive symptomsd Total BPRSc,e B. RT Stim SCOR Mag Number of patients Anxiety–depressionb,f Positive symptoms Total BPRSe
Neg
Low
High
Overall
Quadratic
b.08 22 8.0 F 2.8 9.0 F 3.3 7.5 F 2.9 13.2 F 5.4 67.1 F15.6 b .07 AS 23 7.5 F 2.6 12.4 F 5.7 62.1 F17.2
.08–0.15 25 6.2 F 2.3 6.4 F 2.3 5.9 F 1.8 11.2 F 3.9 55.0 F 11.6 .07–.06 20 5.7 F 1.8 11.5 F 2.8 56.2 F 10.1
N0.15 21 7.8 F 3.3 8.5 F 4.1 7.6 F 4.1 14.3 F 5.4 67.5 F 21.7 N.06 25 8.3 F 3.4 14.3 F 5.6 68.6 F 20.4
F
p
F
p
2.88 4.33 3.42* 2.48 4.41
.064 .018 .043 .092 .016
5.70 8.43 4.84 4.46 8.83
.020 .005 .031 .038 .005
6.90* 2.46 3.81*
.003 .098 .030
9.35 2.03 4.25
.004 NS .043
BPRS=Brief Psychiatric Rating Scale; RT=Reaction Time; Stim.=Stimulus; SCOR=Skin Conductance Orienting Response; Neg=Negative; Freq=Frequency; Mag.=Magnitude. a Relative Difference Scores. b Low differed from Neg at p b .10 by the Tukey Studentized Range Test (TSRT). c Low differed from Neg at p b .05 by the TSRT. d High differed from Low at p b .10 by the TSRT. e High differed from Low at p b .05 by the TSRT. f High differed from Low at p b .01 by the TSRT. * The Welch test of significance was used because of inhomogeneous variance.
same direction are shown for absolute magnitude differences. The relative differences for magnitude were not significant. The multivariate test was significant for frequency ( p b .02). The above differences contrast with a lack of differences on the BPRS but slow RT in patients with decrements in SCR frequency and magnitude from the RT ready signal to the RT stimulus compared to those showing increments or no change (Table 9). The High groups showed more and larger SCRs to the RT stimulus, but the SCRs to the Ready
signal did not differ among the three groups. Neither multivariate test was significant. 3.4. Electrodermal lateral asymmetry Table 10 shows that patients with larger SCOR magnitudes (or SCL for nonresponders) on the left hand had marginally higher Total BPRS ratings than those with larger right hand EDA. However, when just the male patients were considered, this difference was significant and there were
Table 9 Mean F s.d. of BPRS ratings and total RT for patients differing in the relative change in electrodermal responsivity to the RT stimuli from that for the RT ready signal (e.g. [RT Stim Ready] / [RT Stim + Ready + 1]) Rating Scale
Neg
A. RT Stim. Ready: Frequency Number of Patients Reaction Time (ln[ms])a,b B. RT Stim. Ready: Mag. (AS) Number of patients Reaction time (ln[ms])c
b0 24 6.16 F 49 b0 24 6.04 F .53
Low 0–0.11 21 5.77 F .46 0–0.13 24 5.92 F .53
High N0.12 23 5.75 F .45 N0.15 20 5.70 F .33
BPRS=Brief Psychiatric Rating Scale; RT=Reaction Time; Stim.=Stimulus; Neg=Negative; Mag.=Magnitude. a High differed from Neg at p b .01 by the Tukey Studentized Range Test (TSRT). b Low differed from Neg at p b .05 by the TSRT. c High differed from Neg at p b .10 by the TSRT. * The Welch test of significance was used because of inhomogeneous variance.
F
pb
5.96
.005
3.82*
.030
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Table 10 Mean F s.d. of BPRS ratings for patients differing in lateral dominance of EDA Rating scale
Right dom (R N L)
Left dom (L N R)
t
p
A. All patients Number of patients Total BPRS
38 61.1 F17.6
35 68.7 F 19.2
1.75
.09
B. Males only Number of patients Anxiety–depression Positive symptoms Total BPRS Reaction time (ln[ms])
25 6.4 F 2.1 11.6 F 4.2 57.4 F 14.3 5.77 F .42
26 8.2 F 2.7 15.0 F 5.8 70.1 F18.7 6.07 F .58
2.59 2.39 2.71 2.18
.02 .03 .01 .04
BPRS=Brief Psychiatric Rating Scale; EDA=Electrodermal Activity; Dom = Dominance.
differences for higher AD and Pos ratings and slower RT in the left N right group as well. The overall multivariate test for the male data was significant ( p b .02).
4. Discussion 4.1. Tonic baselines Patients with the highest ANS activity were the most symptomatic, especially for positive symptoms, which include the classic cognitive disturbances uniquely associated with schizophrenia, and for more nonspecific mood and activation symptoms. The results for the rest and tones periods are generally consistent with the studies reviewed earlier. In addition, we show here that those relationships were similar when the patients were active (e. g. during the task instructions and practice trials). Because HR variability is an index of cholinergic activity (Larsen et al., 1986) the positive correlations between Neg ratings and HR variability supports the conjecture of Tandon and Greden (1989) that cholinergic hyperactivity is related to the pathogenesis of negative symptoms. However, this is not specific to Neg symptoms as this variable is related to most symptom factors in the rest and tones periods and to BPRS Tot in both periods. Possibly motor restlessness might account for some of these relationships, but we did not measure this. Patients with greater increases in SCL and HR from rest to task conditions showed relatively weaker
tendencies to be more symptomatic. Those with greater increases in NSCR/min did not show this but had faster RT. These weak and somewhat inconsistent relationships and the similarity of the correlation matrices for the two conditions are not surprising because increments in base levels from rest to the stress of a task are small in patients with schizophrenia compared to controls (Zahn et al., 1991, 2001). 4.2. Elicited SCRs. Tables 4, 5, and 7 all show more symptoms in more responsive patients. However, on the usual measure of SCOR Rs vs NRs, based on just the first two or three trials, where there is little consensus in previous studies, our results are congruent with those studies that found no differences in symptoms. The lower symptomotology in patients with no SCORs to any tone (Table 4) is similar to the data of Dawson et al. (1994). Previous studies have not examined SCR magnitudes and have only infrequently involved SCRs to taskrelated stimuli. It is of interest that although the magnitudes of SCORs and SCRs to the RT stimuli showed monotonic relationships to symptoms the shapes of the curves differed. The high symptom ratings in medium SCOR responders suggests that even moderate responding to an innocuous stimulus indicates an bunhealthyQ level of ANS sensitivity to stimulation in schizophrenia, while the low symptom ratings in moderate responders to the task-relevant RT stimulus may reflect a moderate degree of attention or effort, an adaptive response more likely in less symptomatic patients. This difference was not due to the high (N 70) BPRS ratings in the five patients who could not perform the RT task; they were split 3 and 2 in the middle and high SCOR groups, and their contributions to the means of the two groups were about equal. We did not confirm some previous reports of SCOR hypoactivity and low EDA in patients with severe negative symptoms. This might be due to the nature of the sample. The patients all had volunteered for a program which promised innovative and carefully monitored treatments, and thus they were motivated to improve their psychological condition. Although this seems incompatible with a high level of negative symptoms, BPRS Neg ratings (3.3 per item) were not low and were the same as for Pos.
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However, negative symptoms can be secondary to positive symptoms (Buchanan et al., 1996). It is reasonable to assume that these secondary symptoms may be prominent in the present patient cohort, all of whom were recently withdrawn from medication. It is possible that only primary negative symptoms correlate with low EDA, so prominent secondary negative symptoms may add an extraneous source of variability to this measure. Some support for this is that Pos and Neg ratings were correlated .53, mainly due to higher Pos ratings in patients in the upper third of the Neg distribution than those in medium and low Neg groups. Despite this, partialling out Pos scores did not yield the expected negative correlations of Neg with ANS activity. Patients with either high or low ratios of SCORs to nonspecific SCRs were more symptomatic than those with moderate ratios (Table 6). Post hoc analyses of the components separately showed that, as might be expected, compared to the other two groups the low group had high NSCR/min and the high group had a high number of SCORs. Thus, patients with low or moderate values on both component variables were the least symptomatic. The slow RT in the low group is consistent with the positive correlation of RT with NSCR/min (Table 2), but the fast RT in the High group seems paradoxical given the high symptom ratings in that group. Similar quadratic trends were observed for the RT stimulus SCRsSCOR differences in relation to symptoms (Table 8). It is generally assumed that elicited SCRs are influenced by both general electrodermal responsivity and the attention or effort elicited by the signal quality of the stimulus (as established by instructions), so difference scores for stimuli differing in task-relevance should control for overall responsivity to some extent. The high symptom ratings for the two extreme groups suggest that these patients had either too little (Neg groups) or excessive (High groups) effort on the task compared to the Medium groups. For SCR frequency the results for the relative difference scores seem not attributable to the separate components because these were not related to BPRS ratings. For the magnitude differences the Neg group had greater SCOR magnitudes than the other two groups ( p b .0001), but both Neg and High groups had greater SCR magnitudes to the RT stimulus and higher EDA during the Rest and Tones period than the
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Mod group (quadratic trends: p b .001). Because low EDA is associated with low symptom ratings, the data suggest that the absolute magnitude differences are influenced by the overall reactivity of the electrodermal system more than by attention or effort. 4.3. Reaction time and laterality Slow RT is a hallmark characteristic of schizophrenia and may partially index attention or working memory, qualities that are not directly assessed by the BPRS. It was slower in patients with more active, positive, and total symptoms, and like symptoms it was especially impaired in patients with high HR under both passive and active conditions and in those with high EDA at rest. The latter finding could explain the slow RT in patients with small increments in NSCR/min in the instructions and in those with low ratio of SCORs to NSCR/min. These data suggest that patients more stressed by the test situation in general may be particularly impaired in attention possibly due to interference or distraction caused by the cognitive concomitants of their symptoms. However, unlike symptoms, RT was not related to the responsivity to the RT stimulus or to its difference from SCORs. Possibly the faster RT expected in the Low and Medium RT stimulus groups and the Medium groups on the difference variables by virtue of their low symptoms was offset by limitations in effort by those patients. Nevertheless, the RT findings as a whole suggest that slow RT is not simply due to low effort and/or that the assumption that the difference scores just reflect effort is incorrect. The markedly slow RT in those patients who gave more and larger SCRs to the ready signal than to the RT stimulus (Table 9) suggests that they failed to differentiate between more or less bimportantQ stimuli and/or had difficulty shifting attention from the key press to the more task-relevant stimulus and key release. The specificity of these relationships to RT but not to symptoms, contrasted with the reverse specificity of the RT stimulusSCOR difference, suggests that these two difference scores reflect different aspects of the pathology of schizophrenia. This is not apparent from comparisons of patients with normal controls. The laterality results for the males support the findings of Gruzelier and Manchanda (1982) of great-
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er florid symptoms in patients with larger left than right hand EDA, but do not confirm their association of negative symptoms with the opposite asymmetry. This may be due to the influence of secondary negative symptoms in this group that was discussed earlier. 4.4. Conclusions With respect to the predictions made in the Introduction, the simple notion that patients more deviant from controls would be more symptomatic is supported by the tonic baseline data, which was higher in more symptomatic patients, but it is inconsistent with the higher symptom ratings in patients with greater electrodermal responsivity. The present patients had elevated baselines but were similar to controls on SCORs and had reduced tonic and phasic responsivity to task-related situations and stimuli (Zahn et al., 2001). The data are more consistent with predictions suggested by the effects of neuroleptics where reduced symptoms are accompanied by reductions in both base levels and responsivity. However, there were inconsistencies here as well: reduction of symptoms by fluphenazine had, at best, small and variable effects on HR, the SCOR/NS-SCR ratio, and RT and there were increases in the difference between SCRs to the RT stimulus and SCORs (Zahn et al., 2001). There was little support for the hypothesis of differential autonomic concomitants of positive and negative symptoms. In addition, of course, many effects of both diagnosis and medication on ANS activity were not manifested in their relation to symptoms. An alternative hypothesis based on the role of ANS activity in schizophrenia may account better for the data. The higher symptom ratings in patients with higher levels of both ANS baselines and responsivity suggests that either elevated ANS activity is itself disturbing or indexes a process or state that is somehow toxic or disturbing to patients with schizophrenia. This hypothesis is consistent with findings that significant life events and interactions with high bexpressed emotionQ relatives are conducive to elevated ANS activity and to earlier relapse of patients in remission (Tarrier et al., 1979) and that increases in ANS activity precede the onset of episodes of psychosis (Hazlett et al., 1997).
Regardless of the direction of causation of these relationships, it seems plausible that elevated ANS activity could become associated with disturbing prodromal subjective states and acquire an aversive quality. This might lead to an increased sensitivity to environmental events so that seemingly non-threatening or non-noxious situations that increase ANS activity would have an aversive quality. Some patients might attempt to cope with novel or task-related situations and stimuli by a passive-avoidant strategy of low attention and effort in order to attenuate their responsivity. This hypothesis is similar to Nuechterlein and Dawson’s (1984) idea that such coping involves bwithdrawing physically or psychologically from all environmental stimuliQ (p. 306) which may lead to SCOR nonresponding. Straube (1979) also concluded that nonresponding constitutes a bprotective mechanismQ in schizophrenia. Our data, as well as those of Dawson et al. (1992, 1994), suggest that it is the less symptomatic patients who are better able to cope in this manner. Regarding attenuated responsivity as part of a coping strategy could help explain the seemingly paradoxical findings that less symptomatic patients are more deviant from controls on several task-related responsivity variables than more symptomatic patients: low symptom patients had smaller values on these while controls had higher mean values than the patients as a group (Zahn et al., 2001). A similar paradox is seen, of course, in the effects of medication which increases hyporesponsivity in schizophrenia. This suggests that levels of ANS responsivity that are moderate and adaptive for controls may be excessive for patients. Coping with demanding situations by reductions in ANS responsivity may reduce discomfort and symptoms in the short term as shown here, but it may also be counterproductive in terms of prognosis. Low responsivity to task-related stimuli and situations were predictive of poor short-term outcome in unmedicated patients (Zahn et al., 1981). Finally, the results support the conclusion from the literature review that the differences in results between studies are not due merely to differences in medication. There is a general similarity of the present results to those of the outpatients of Dawson et al. (1992) who were medicated but presumably were not severely ill on the average. On the other hand the results contrast with those from this laboratory obtained
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under identical conditions on unmedicated adolescents with childhood-onset schizophrenia (Zahn et al., 1997). In those patients SCOR NRs had more symptoms of all types than Rs and those with low baseline EDA had more negative symptoms. It was the first author’s impression that those patients were generally much more severely ill than most patients in the present study, and they have recently been shown to have a developmental brain anomaly (loss of gray matter) that is correlated with symptom severity (Thompson et al., 2001). This suggests that the differences among studies may be largely due to differences in the population sampled. Finding better clinical markers with which to compare patients in different studies would enhance further progress in this area. Acknowledgements The authors thank Thalene T. Mallus for expert assistance in data collection and analysis, and to the professional and nursing staffs of Ward 4E of the NIH Clinical Center for ratings and many other valuable clinical aspects of the study. References ¨ st, L.G., O ¨ hman, A., 1984. ElectroderAlm, T., Lindstrom, L.H., O mal non-responding in schizophrenia: relationships to attentional, clinical, biochemical, computed tomographical and genetic factors. Int. J. Psychophysiol. 1, 195 – 208. Andreasen, N.C., 1983. The Scale for the Assessment of Negative Symptoms (SANS). University of Iowa, Iowa City. Andreasen, N.C., 1984. The Scale for the Assessment of Positive Symptoms (SAPS). University of Iowa, Iowa City. Asberg, M., Montgomery, S.A., Perris, C., Schalling, D., Sedvall, G., 1978. A comprehensive psychopathological rating scale. Acta Psychiatr. Scand. 271, 5 – 27. Bartfai, A., Edman, G., Levander, S.E., Schalling, D., Sedvall, G., 1984. Bilateral skin conductance activity, clinical symptoms and CSF monoamine metabolite levels in unmedicated schizophrenics, differing in rate of habituation. Biol. Psychol. 18, 201 – 218. Bartfai, A., Levander, S.E., Nyback, H., Schalling, D., 1987. Skin conductance nonresponding and nonhabituation in schizophrenic patients. Acta Psychiatr. Scand. 75, 321 – 329. Bernstein, A.S., Taylor, K.W., Starkey, P., Juni, S., Lubowsky, J., Paley, H., 1981. Bilateral skin conductance, finger pulse volume, and EEG orienting response to tones of differing intensities in chronic schizophrenics and controls. J. Nerv. Ment. Dis. 169, 513 – 528.
269
Bernstein, A.S., Frith, C.D., Gruzelier, J.H., Patterson, T., Straube, E., Venables, P.H., Zahn, T.P., 1982. An analysis of the skin conductance orienting response in samples of American, British, and German schizophrenics. Biol. Psychol. 14, 155 – 211. Brekke, J.S., Raine, A., Ansel, M., Lencz, T., Bird, L., 1997. Neuropsychological and psychophysiological correlates of psychosocial functioning in schizophrenia. Schizophr. Bull. 23, 19 – 28. Buchanan, R.W., Brandes, M., Breier, A., 1996. Treating negative symptoms: pharmacological strategies. In: Breier, A. (Ed.), The New Pharmacology of Schizophrenia. American Psychiatric Press, Washington, DC, pp. 179 – 204. Cooklin, R., Sturgeon, D., Leff, J., 1983. The relationship between auditory hallucinations and spontaneous fluctuations of skin conductance in schizophrenia. Br. J. Psychiatry 142, 47 – 52. Dawson, M.E., Nuechterlein, K.H., Schell, A.M., Mintz, J., 1992. Concurrent and predictive electrodermal correlates of symptomatology in recent-onset schizophrenic patients. J. Abnorm. Psychology 101, 153 – 164. Dawson, M.E., Nuechterlein, K.H., Schell, A.M., Gitlin, M., Ventura, J., 1994. Autonomic abnormalities in schizophrenia: state or trait indicators. Arch. Gen. Psychiatry 51, 813 – 824. Deakin, J.F.W., Baker, H.F., Frith, C.D., Joseph, M.H., Johnstone, E.C., 1979. Arousal related to excretion of noradrenaline metabolites and clinical aspects of unmedicated chronic schizophrenic patients. J. Psychiatr. Res. 15, 57 – 65. Green, M.F., Nuechterlein, K.H., Satz, P., 1989. The relationship of symptomatology and medication to electrodermal activity in schizophrenia. Psychophysiology 26, 148 – 157. Gruzelier, J.H., 1976. Clinical attributes of schizophrenic skin conductance responders and non-responders. Psychol. Med. 6, 245 – 249. Gruzelier, J., Manchanda, R., 1982. The syndrome of schizophrenia: relations between electrodermal response, lateral asymmetries and clinical ratings. Br. J. Psychiatry 141, 488 – 495. Hazlett, H., Dawson, M.E., Schell, A.M., Nuechterlein, K.H., 1997. Electrodermal activity as a prodromal sign in schizophrenia. Biol. Psychiatry 41, 111 – 113. Kim, D.K., Shin, Y.M., Kim, C.E., Cho, H.S., Kim, Y.S., 1993. Electrodermal responsiveness, clinical variables, and brain imaging in male chronic schizophrenics. Biol. Psychiatry 33, 786 – 793. Larsen, P.B., Schneiderman, N., Pasin, R.D., 1986. Physiological bases of cardiovascular psychophysiology. In: Coles, M.G.H., Donchin, E., Porges, S.W. (Eds.), Psychophysiology: Systems, Processes, and Applications. Guilford Press, New York, pp. 122 – 165. Maina, G., Barzega, G., Bellino, S., Bogetto, F., Ravizza, L., 1995. Type I and type II schizophrenia: relations between tonic electrodermal activity and clinical ratings before and after haloperidol treatment. Psychiatry Res. 57, 49 – 56. Nuechterlein, K.H., Dawson, M.E., 1984. A heuristic vulnerability/ stress model of schizophrenic episodes. Schizophr. Bull. 10, 300 – 312. Olbrich, R., Mussgay, L., 1987. Spontaneous fluctuations of electrical skin conductance and the actual clinical state in schizophrenics. Psychopathology 20, 18 – 22.
270
T.P. Zahn, D. Pickar / Schizophrenia Research 79 (2005) 257–270
Overall, J.E., 1974. The brief psychiatric rating scale in psychopharmacology research. Mod. Probl. Pharmacopsychiatry 7, 67 – 78. Overall, J.E., Gorham, D.R., 1962. The brief psychiatric rating scale. Psychol. Rep. 10, 799 – 812. Perry, W., Felger, T., Braff, D., 1995. The relationship between skin conductance hyporesponsivity and perseverations in schizophrenia patients. Biol. Psychiatry 44, 459 – 465. Pickar, D., Labarca, R., Doran, A.R., Wolkowitz, O.M., Roy, A., Breier, A., Linnoila, M., Paul, S.M., 1986. Longitudinal measurement of plasma homovanillic acid in schizophrenic patients: correlation with psychosis and response to neuroleptic treatment. Arch. Gen. Psychiatry 43, 669 – 676. Schiffer, R.A., Sigal, M., Mintz, M., 1996. Delayed habituation of the skin-conductance orienting response correlates with impaired performance in the Wisconsin Card Sorting Task in Schizophrenia. Psychiatry Res. 65, 107 – 112. Schlenker, R., Cohen, R., Hubmann, W., Mohr, F., Walheim, C., Watzl, H., Werther, P., 1995. Electrodermal and vascular orienting response in schizophrenic patients: relationship to symptoms and medication. E. Arch. Psychiatry Clin. Neurosci. 245, 152 – 158. Schnur, D.B., 1990. Effects of neuroleptics on electrodermal activity in schizophrenic patients: A review. Psychopharmacology 102, 429 – 437. Steiger, J.H., 1980. Tests for comparing elements of a correlation matrix. Psychol. Bull. 87, 245. Straube, E., 1979. On the meaning of electrodermal nonresponding in schizophrenia. J. Nerv. Ment. Dis. 167, 601 – 611. Tandon, R., Greden, J.F., 1989. Cholinergic hyperactivity and negative schizophrenic symptoms: a model of cholinergic/dopaminergic interactions in schizophrenia. Arch. Gen. Psychiatry 46, 745 – 753.
Tarell, J.D., Schulz, S.C., 1988. Nursing assessment using the BPRS: a structured interview. Psychopharmacol. Bull. 24, 105 – 111. Tarrier, N., Vaughn, C., Lader, M.H., Leff, J.P., 1979. Bodily reactions to people and events in schizophrenics. Arch. Gen. Psychiatry 36, 311 – 315. Thompson, P.M., Vidal, C., Giedd, J.N., Gochman, P., Blumenthal, J., Nicolson, R., Toga, A.W., Rapoport, J.L., 2001. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proceedings of the National Academy of Sciences, vol. 98, pp. 11650 – 11655. Zahn, T.P., Carpenter, W.T.J., McGlashan, T.H., 1981. Autonomic nervous system activity in acute schizophrenia: II. Relationships to short term prognosis and clinical state. Arch. Gen. Psychiatry 38, 260 – 266. Zahn, T.P., Frith, C.D., Steinhauer, S.R., 1991. Autonomic functioning in schizophrenia: electrodermal activity, heart rate, pupillography. In: Steinhauer, S.R., Gruzelier, J.H., Zubin, J. (Eds.), Handbook of Schizophrenia, Vol 5: Neuropsychology, Psychophysiology and Information Processing. Elsevier, Amsterdam, pp. 185 – 224. Zahn, T.P., Jacobsen, L.K., Gordon, C.T., McKenna, K., Frazier, J.A., Rapoport, J.L., 1997. Autonomic nervous system markers of psychopathology in childhood-onset schizophrenia. Arch. Gen. Psychiatry 54, 904 – 912. Zahn, T.P., Pickar, D., van Kammen, D.P., 2001. Neuroleptic effects on autonomic activity in schizophrenia: between- and withinsubject paradigms and comparison with controls. Schizophr. Bull. 27, 503 – 515.