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Retarded habituation and lateral asymmetries in electrodermal activity in cardiovascular disorders
International Elsevier
Journal of Psychophysioloa
3 (1986) 219-226
219
PSP 00095
RETARDED HABITUATION AND LATERAL IN CARDIOVASCULAR DISORDERS
J.H. GRUZELIER’,
P.G.F.
NIXON
2. D. LIDDIARD
ASYMMETRIES
‘, S. PUGH
IN ELECTRODERMAL
’ and R. BAXTER’
’ Lahoratoty of Neuro-Psychophysioiogv, London, (Accepted
Department of Psychmtcv, Charing Cross & Westmrnster Wb 8RF and ’ Cardiac Department, Churing Cross Hospital. London (U.K.) October
Key words: orienting
ACTIVITY
Medical School. Fulhum Palrce Road,
22nd, 1985) - habituation
- electrodermal
activity
- laterality
- effort - cardiovascular
disorders
- hippocampus
Electrodermal activity was recorded bilaterally during a sequence of moderate-intensity tones in 40 cardiac patients who exhibited clinical signs of exhaustion and in 40 controls. Responsive patients were slower to habituate than responsive controls. The groups did not differ in non-specific responses. Patients also showed lateral asymmetries in amplitudes and latencies indicative of abnormalities in right hand activity. Levels of skin conductance were higher in patients largely because of an abnormal elevation of right hand levels in both responders and non-responders. The results were consistent with limbic dysfunction together wtth a loss of left hemispheric contralateral inhibition. The deficit in habituation and the laterality effect may relate to the role of effort and exhaustion in cardiovascular disorders
INTRODUCTION Elevated sympathetic activity has long been associated with the etiology of stress-related disorders, especially those involving the cardiovascular system such as essential hypertension and ischaemic heart disease (Steptoe, 1981). Now that there is increasing evidence of the independent role of psychological factors in cardiovascular disorders (Friedman and Rosenman, 1974: Rosenman et al., 1975; Glass, 1977), interest has grown in the central nervous system control of the autonomic nervous system, and the psychological influences that may lead to raised levels of sympathetic activity (Nixon, 1982, 1984). Lipowski (1975) reviewed the psychopathological consequences of sensory and information over-
Correspondence: J.H. Gruzelier. Laboratory of Neuro-Psychophysiology, Department of Psychiatry, Charing Cross and Westminster Medical School, Fulham Palace Road, W6 XRF London, U.K. 0167-X760/86/$03.50
c’ 1986 Elsevier Science Publishers
B.V.
load in situations as diverse as field studies of population density, forced social interaction in mice and human laboratory studies in which the degree of sensory input and cognitive demands were varied. Cardiovascular disorders and psychotic behaviour were prominent among the behavioural sequelae. In mice, increased social interaction (Henry et al., 1972). and in rats, chronic exposure to combined auditory, visual and motion overstimulation (Smookler and Buckley, 1970) produced a range of cardiovascular pathology including hypertension, myocardial fibrosis, hypertrophy of the left ventricle and arteriosclerotic degeneration of the intramural coronary blood vessels and aorta. After increased social interaction these disorders were accompanied by raised levels of adrenal catecholamine-synthesizing enzymes and after sensory overload they coincided with histopathological changes indicative of adrenocortical hyperfunction. In considering the central nervous system control of the autonomic nervous system. Henry and
220
Stephens (1977) drew associations between the amygdala and the coincidence of the fight-andflight reaction and raised sympathetic adrenomedullary activity and the hippocampus with withdrawal, conservation and the release of corticosteroids. The same limbic structures have been implicated in sensory information processing; the amygdala being involved in processes of orienting and selective attention, and the hippocampus with habituation and effort in attention (Pribram and McGuinness, 1975). A condition of sensory and information overload could arise from a deficiency in mechanisms of habituation which act to suppress responses to the repetition of irrelevant stimuli. The consequent overresponding would place a load on central nervous system regulatory mechanisms, mechanisms which may already be taxed by situational behavioural traits such as overstriving, a cardinal feature of the Type A, coronary-prone behaviour pattern (Zyzanski and Jenkins, 1970; Burman et al., 1975). If a deficit was revealed in patients with cardiovascular disorders, who by virtue of illness were removed from situational precipitants of the Type A behaviour pattern, this would imply that deficient habituation may exist independently of Type A behaviour. A deficit in habituation may contribute to the physical and mental exhaustion which Nixon has described as a common clinical feature of cardiovascular patients (Nixon, 1976). We set out to explore rates of habituation in patients with cardiovascular disorders. A standard stimulus habituation procedure was chosen which has been shown in primates to undergo changes after lesions of the amygdala and hippocampus (Bagshaw and Benzies, 1968; Pribram and McGuinness, 1975). Lesions of the amygdala and its frontal projections produced predominantly a state of hyporesponsivity to irrelevant tones, whereas lesions of the hippocampus produced defective habituation with consequent hyperresponsivity. In view of the involvement of the hippocampus in both habituation and effort in attention (see Pribram and McGuinness, 1975) it was predicted that patients exhibiting the effort syndrome would be characterized by defective habituation. Nevertheless as Henry and Stephens (1977) have hypothesized, limbic involvement in cardiovascular
disorders may also lead to hyporesponsivity in a subgroup of patients. In a review of the psychophysiology of the Type A, coronary-prone behaviour pattern, Daniels (1981) concluded that evidence of raised sympathetic reactivity was one of the more consistent findings, yet evidence with cardiovascular patients is equivocal (Steptoe, 1981). Attempts to elucidate etiological factors in patient studies are not without methodological problems. The illness itself may cause distress which will affect autonomic activity. Peripheral autonomic measures may be influenced by treatment and chronicity. We made no attempt to obtain a representative sample, but required that all of the patients were judged clinically to exhibit an exhaustion syndrome (Nixon, 1982, 1984). Electrodermal activity was chosen instead of cardiovascular measures. Electrodermal activity is mediated solely by the sympathetic branch of the autonomic nervous system and is not confounded by peripheral parasympathetic influences. The choice of electrodermal activity avoids to some extent the influences of treatment and chronicity which will affect the cardiovascular system. Tonic as well as phasic reactive measures were determined to examine the conclusion of Steptoe’s (1981) review that favoured a disorder of reactive not tonic autonomic activity. Non-specific electrodermal responses were recorded as a physiological index of anxiety; anxiety may play both etiological and confounding roles in studies of cardiovascular patients. Electrodermal activity was monitored bilaterally for exploratory purposes.
METHOD Subjects
Forty patients attending the Cardiac Clinic at Charing Cross Hospital were tested. They had an average age of 51 years and exactly half the sample were in their fifties. The age distribution was as follows: 20’s, 2; 30’s, 3; 40’s, 6; 50’s, 20; 60’s, 7; 70’s, 2. Patients were compared with healthy volunteers who were hospital staff without a history of cardiovascular disorders. They had an average age of 49 years, range 19-74, and there was no difference between the groups in age (t
221
1.39, ns.). Thirty of the subjects in each group were men and 10 women. Handedness was assessed with a modified Oldfield-Humphrey questionnaire. All subjects but 4 patients were dextral. The patients presented with the following disorders: chest pain 12, angina 6, hypertension 10, ischemic heart disease 7, left ventricular fibrillation 5, myocardial infarction 4, mitral valve incompetance 3, aortic valve disorder 1. Thirty of the patients were on drugs: diazepam 15, diuretics II, phenergan 6, P-blockers 5, digoxin 3, nitrates 1, aspirin 1. A careful examination was made for possible relationships of each of the dependent variables with diagnosis, age, medication, gender and handedness. No relationships were found. Apparatus The orienting stimuli were thirteen 70 dB, 1000 Hz, l-s tones with graded rise and decay times. They were presented at intervals between 20 and 40 s with an average interstimulus interval of 30 s. They were produced by a tone generator and were presented through headphones (Koss Type 6 LC). Skin conductance was measured bilaterally from bipolar placements on the middle phalanx of the first and second fingers of each hand. The electrodes, 1 cm in diameter, were fastened with tape and filled with a Beckman KC1 electrolyte. They were connected to a constant voltage skin conductance system, which in turn was connected to a Grass model 7D polygraph. Procedure Subjects were tested in a sound-attenuated room with a temperature between 18 and 24°C. After attaching electrodes hand temperatures were taken bilaterally. None of the patients or controls had temperatures which would preclude the recording of sweat gland activity. Subjects were instructed to relax and adopt a passsive attitude to the occasional sounds they would hear through headphones. Subjects were observed through a screen so that any movement artefacts could be noted on the chart. This precaution proved unnecessary. An orienting response was operationally defined as occurring between 0.8 and 5 s after stimulus onset. Responses outside this interval were scored as non-specific responses. A minimum
criterion of 1 mm was adopted with a maximum gain setting of 0.02 pmho/cm. The procedures of electrodermal measurement are standard ones used in the laboratory. A conventional habituation criterion was adopted of two successive failures to respond. Extensive comparative data is available for this standardized procedure. Abnormal patterns of response have been well-documented in psychiatric disorders (Lader and Wing, 1966; Gruzelier and Venables, 1972; Patterson and Vet-tables, 1978; Bernstein et al., 1982). On the basis of these studies two extreme categories of orienting and habituation have been discerned. Hyporesponsivity consists of non-responding, which is defined as an absence of responses until the habituation criterion was reached, i.e. to the first two sounds in the series, and fast habituation, which consists of a single response to the first tone. Hyperresponsivity was taken as a failure to habituate by trial 13, the last tone in the series.
RESULTS The number of tone presentations until habituation is shown for each patient and control in Fig. 1. Habituation was slower in patients. Fifteen patients failed to habituate compared with 9 controls. A comparison of rates of habituation in responsive patients (n = 31) and controls (n = 34) provided confirmation of significantly slower habituation in patients (x2 3.46, P-C 0.05, onetailed). Non-responding was also apparent, but PATIENTS
CONTROLS
16 I 14 12 10 8 6 4 2 '0
3
6
9
13
0
3
6
Trials tohabituation
Fig. 1. Rates of habituation
in patients
and controls.
9
13
222
TABLE
1
Bilateral electrodermal Eiectrodermal
memures
Skin conductance level (pmhos). Non-specific responses (N) Response latency (s) Response
rise time (n)
Response
l recovery
time(s)
pattentsand controls
Pattents
oariahle
Response amplitude (~mmhos)
in
Controb
Left
Right
Left
Right
R 0 R 0 R 0 K 0 K cl
0.30 0.54 11.44 8.70 13.20 14.90 2.11 0.47 2.14 1.25
0.45 1.52 17.34 13.70 13.80 15.30 2.27 0.48 2.19 0.81
0.12 0.19 7.57 6.33 15.70 15.60 1.99 0.52 2.10 0.88
0.14 0.24 9.60 X.72 15.50 15.10 1.98 0.51 2.28 0.86
K
2.72
2.62
2.76
2.70
0
1.67
1.17
1.05
1.28
there was no appreciable difference between the groups. However, there were twice the number of fast habituating patients (n = 6) than controls (n = 3). No relationship was found between the rate of habituation and the age of patients: Spearman’s rho - 0.09. Means and standard deviations of the electrodermal variables are shown in Table I. The L>R 3o r
Subjects
0
R>L Fig. 2. The number of patients L > R and R > L asymmetries
compared with controls showing in tonic skin conductance levels.
increased orienting activity in patients had no counterpart in an increased incidence of nonspecific responses (Mann-Whitney U-test = 698.5, n.s.). This implies that anxiety, or the emotional distress of illness, is unlikely to account for the slower orienting response habituation of patients. Levels of skin conductance were higher in patients than controls ( F,,7x 9.24, P -cO.OOl), an effect that was largely due to the higher right hand levels of patients (F,,,* 4.04. P < 0.05). The number of subjects with higher right than left hand levels and the number with the opposite asymmetry are shown in Fig. 2. Seventy-five percent of patients had higher right than left hand levels compared with only 32.5% of controls (x2 13.48 P < 0.001). Orienting response amplitudes were also larger in patients than controls ( F,,h3 6.00, P < 0.02) and while asymmetries in favour of the right hand were larger in patients (see Table I). this effect was not significant ( F,.hl 2.40, n.s.). In view of the greater magnitude of responses in patients than controls. the asymmetry in responses was re-examined by computing the conventional laterality index where the asymmetry (R - L) is divided by the sum of the amplitudes (R + L). The mean laterality index for patients was 0.19. whereas for controls the asymmetry was in the opposite direction -0.09. Comparison of the groups with Student’s t-test showed that the laterality index differentiated the groups (t,, 2.09, P -c0.03). The laterality index was also computed for skin conductance levels, where the asymmetry in the direction of larger right than left hand levels in patients may also conceivably be a function of the higher levels of patients. The mean laterality indices were 5.72 for patients and -2.04 for controls, i.e. showing the opposite asymmetries as was the case with response amplitudes. The laterality index for skin conductance levels also differentiated the groups (t,, 3.55, P < 0.01). Patients and controls were compared for the temporal characteristics of the orienting response. The latency of responses tended to be larger in patients than controls, an effect that fell short of significance ( F,.h3 2.92, P < 0.09). However. whereas there was essentially no bilateral difference in controls (see Table I). latencies in patients were longer on the right hand, such that the
723
interaction between Group and Hand in the analysis of variance was highly significant ( F,.h3 11.31, P -c0.001). The effect was retained with the laterality index ( t,,63 3.37, P < 0.01): patients X = 0.16, controls x = 0.02. The other temporal variables showed no group differences: rise time (Group, F,,63 0.01;Group X Hand, F,,63 0.73); half recovery time (Group, F,,53 0.04; Group X Hand,
F 1.53 0.02) DISCUSSION Evidence of raised sympathetic activity, reported in psychophysiological investigations of the Type A coronary-prone behaviour pattern (Daniels, 1981), has in this study been extended to patients with a variety of cardiovascular disorders. Responsive patients were overresponsive in their orienting reactions and this was seen both in the magnitude and the frequency of reactions, such that response habituation with stimulus repetition was retarded in patients. Patients also had higher levels of skin conductance. Interestingly, non-specific responses during the interstimulus intervals were no more frequent in patients than controls. Typically an impairment in electrodermal response habituation coincides with an increased frequency in non-specific responses. With essentially the same tone habituation paradigm we have shown this, both in psychiatric patients (Gruzelier and Venables, 1972. 1974: Gruzelier et al.. 1981) and in a comparison of students before an examination with the same students at a less stressful time of year (Gruzelier and Phelan, 1986). Nevertheless, while covariation between specific stimulus elicited responses and spontaneous or non-specific responses is a common one (Martin and Rust. 1976) dissociations also occur. This was found in the effect of propranolol on electrodermal responses. where the drug facilitated habituation of orienting responses to tones without affecting the frequency of nonspecific responses (Gruzelier and Connolly, 1980). The fact that non-specific responses were no more frequent in patients than controls, suggests that accompaniments of illness, such as anxiety and distress which typically increase the incidence of
non-specific responses, are unlikely to provide an explanation for the elevation in skin conductance levels and the impairment in habituation. The retarded habituation, which was a characteristic of the larger subgroup of patients. is theoretically consistent with evidence that conditions leading to sensory overload, whether from internal or external sources, are associated with cardiovascular disorders. Nixon (1976) proposed that factors such as this may combine to cause a breakdown in homeostatic control and result in physical and mental exhaustion. He discussed this in terms of a ‘human function curve’ which is conceptually similar to the YerkessDodson law or the inverted U-shaped relation between arousal and performance (Yerkes and Dodson, 1908: Hebb, 1958). but more particularly based on Swank and Merchand’s (1946) portrayal of the inverted U-relation between degree of combat efficiency in soldiers and number of days of combat. The upswing of the curve reflects improvement in efficiency until the soldier becomes ‘battlewise’ and reaches a period of maximum efficiency. The down-swing reflects a phase of combat exhaustion first passing through a hyperreactive phase during which the soldier is overconfident and then passing to a stage of vegetative helplessness and emotional exhaustion. This model may have implications for the other patient subgroup who were either hyporesponsive (n = 9) or who exhibited an orienting response only to the first tone (n = 6). The patients in the last category outnumbered the controls (n = 6 and n = 3, respectively). Hyporesponsivity coincided with low levels of skin conductance and a low incidence in non-specific responses and represents a state of reduced sympathetic activity. Conceivably this could be the aftermath of a period of overactivation and reflect the state of emotional exhaustion (Nixon, 1982, 1984). In terms of Henry and Stephen’s model (1977) this would reflect the stage of withdrawal and conservation. These interpretations could be tested with clinical ratings. The most striking factor that differentiated patients from controls was the laternal asymmetry in electrodermal activity. Asymmetries were found in the amplitude of orienting responses. in the latency of responses and in levels of skin conductance.
174
The last were asymmetric in patients whether or ncjt they exhibited orienting responses. Lateral asymmetries involved phasic as well as tonic measures of sympathetic activity and they were statistically the more robust findings. The asymmetries were unlike those seen in normal subjects, psychiatric patients. or surgical cases with focal frontal or temporolimbic lesions. Asymmetries in electrodermal activity seldom generalize so consistently across tonic and phasic measures (Sourek. 1965; Gruzelier. 1979; Rippon, 1985). They were more akin to those reported by Holloway and Parsons (1969) in neurological cases with diffuse or grcss neuropathology. The direction of the asymmetry in cardiac patients corresponded to the asymmetr)’ Holloway and Parsons found to accompany left hemisphere lesions; left-sided lesions were accompanied both by a loss of left hemispheric functions and an abnormal elevation in right hand skin conductance levels. They inferred that the Isymmetry reflected a release from left hemispheric:. contralateral inhibition. In a study o‘ cerebral asymmetry and vigilance it has been shown that the left hemisphere is more susceptible thal the right to decrements in performance over time (Dimond and Beaumont. 1973). Accordir gly the functional effects of mental and physical exhaustion for which our patients were selected. nay in part reflect the left hemisphere’s vulnerability to fatique. The functional consequences elf chronic fatigue may mimic the organic lesions found in the left hemisphere patients of Holloway and Parsons. Evidence of the natu!‘e of cognitive impairments in dynamic cardiovascular 3atients was reported by Goldman and colleagues 1Goldman et al., 1974. 1975; Kleinman et al., 1977). They found in patients with essential hypertension that levels of blood pressure correlated with performance on the Category test of Halstead-Reitan neuropsychological test battery. After bio-feedback training reductions in blood pressure were accompanied by improvements on the Category test. The Category test assesses abstract concept formation, mental efficiency and. current learning ability. It is the most sensitive test in the battery to neurological impairment, but is non-specific in its localizing ability and therefore does not provide a test of a left
hemisphere vulnerability. Further neuropsychological evaluation of cardiovascular patients is warranted. In conclusion, the results have shown that elevated sympathetic activity which is a characteristic of the coronary-prone behaviour pattern is also a characteristic of many patients with cardiovascular disorders. The elevation in sympathetic activity was found in both tonic and phasic measures and was monitored in a behaviourally passive condition avoiding the confounding influences of task demands on sympathetic activity. The results are consistent with the model of Henry and Stephens (1977) of the involvement of limbic mechanisms in the central nervous system regulation of the cardiovascular system and place particular emphasis on a disorder of the hippocampal system as retarded habituation occurs with a loss of hippocampal function (Bagshaw and Benzies, 1968). The impairment of habituation was also consistent with Nixon’s (1976) model of the role of exhaustion in cardiovascular pathology. Finally. the most striking results that differentiated patients from controls were the abnormal elevations of right hand electrodermal activity. These were consistent with both structural. but more probably functional, impairments of left hemispheric processing in cardiovascular patients who exhibit an exhaustion syndrome.
ACKNOWLEDGEMENTS The paper was presented to the Psychophysiology Society, London, in December. 1984. We wish to thank the Department of Medical Physics. Charing Cross Hospital and Drs. David Deighton, Norman Weistock, Janet Freeman and Sheila Stevens.
REFERENCES Bagshaw, M.H. and Benzies. S. (1968) Multiple measures of the orienting reaction and their dissociation after amygdalecotomy in monkeys. Ex~. Neural.. 20: 175-187. Bernstein. A.S.. Frith. C.D.. Gruzelier. J.H.. Patterson, T.. Strauhe. E.. Venables. P.H. and Zahn, T.P. (1982) An
225
analysis of the skin conductance orienting response in samples of American, British and German schizophrenics. Biol. Psycho/., 14: 155-211. Burnam, M.A., Pennebatar, J.W. and Glass. D.C. (1975) Time achievement striving, and the Type A consciousness. coronary-prone behaviour pattern. J. Ahnorm. Psycho/., 84: 76-79. Daniels. C.E. (1981) Coronary-prone behaviour and autonomic reactivity. Stress. 2: 21-28. Dlmond. S. and Beaumont. J.G. (1973) Differences in the vigilance performance of the right and left hemispheres. Cortex. 9: 259-265. Friedman. M. and Rosenman, R.H. (1974) Tape A Behacvour and Your Hearr. Wildhood House, London. Glass, D.C. (1977) Behaorour Parterns. Stress ond Coronuq~ Disease, Wiley, New York. Goldman, H.. Kleinman. K.M., Snow, M.Y.. Bidus. D.R. and Karol. B. (1974) Correlation of diastolic blood pressure and signs of cognitive dysfunction in essential hypertension. Di.r. Nerc~. Syst.. 35: 571-572. Goldman, H., Kleinman. K.M., Snow. M.Y.. Bidus. D.R. and Karol. B. (1975) Relationships between essential hypertension and cognitive functioning: effects of biofeedback. Psvchophysiologv. 12: 569-573. Gruzelier. J.H. (1979) Lateral asymmetries in electrodermal activity and psychosis. In J.H. Gruzelier and P. Flor-Henry ( Eds.). Hemisphere Aqvnmetries of Function in Psychoparhologv. Elsevier, Amsterdam, pp. 149-168. Gruzelier, J.H. and Connolly, J.F. (1980) Differential actions of a pharmacological agent on electrodermal orienting responses as distinct from non-specific responses and electrodermal levels. In H.D. Kimmel (Ed.). The @lenring Re//e.x in Humans, Erlbaum. New York, pp. 701-713. Gruzelier. J.H. and Phelon, M. (1986) A shift towards right hemispheric divided visual-field processing advantages in students coincidental with anxiety and retarded habituation under examination stress. In preparation. Gruzelier, J.H. and Venables, P.H. (1972) Skin conductance orienting activity In a heterogeneous sample of schizophrenics: possible evidence of limbic dysfunction. J. Nerv. Ment. DIS.. 155: 277-287. Gruzeher. J.H.. Eves, F.F., Connolly, J.F. and Hirsch, S.R. (1981) Orienting. habituation, sensitisation and dishabituation in the electrodermal system of consecutive. drug-free admissions for schizophrenia. Biol. Ps_vchol., 12: 1X7-209. Hebb, D.O. (1958) A Textbook of PsychologI,, 1st Edn., Saunders. London. Henry, J.P., Ely. D.L. and Stephens, P.M. (1972) Changes in catecholamine-controlling enzymes in response to psychosoclal activiation of defence and alarm reactions. In Physr010gv Emotion and P.y_vchosomutic INness, Ciha Foundarion Svmposium R, Amsterdam. pp. 225-246.
Henry. J.P. and Stephens, P.M. (1977) Stress, He&h cmd the Socrcrl Enr~rronmenr. Springer, Berlin. Holloway. F.A. and Parson. O.A. (1969) Unilateral brain damage and bilateral skin conductance levels in humans. PsJchophJsiologv, 6: 138-148. Kleinman. K.M.. Goldman, N., Snow, M.Y.. and Karol. B. (1977) Relationship between essential hypertension and cognitive function. II: Effects of biofeedback training gcneralise to non-laboratory environment. Psrc~lloph~~.tro/r,~~~~. 14: 192-197. Lader. M.H. and Wing, L. (1966) Physiological Measure.~, Sedurive Drugs. and Morbid Anxre!,. Oxford University Press. London. Lipowski, Z.J. (1975) Sensory and information imputs overload: behavioural effects. Camp. Psychrrrrr.. 16: 199-221. Martin, I. and Rust. J. (1976) Habituation and the structure of the electrodermal system. Ps,,c,hoph~srolog,. 13: 554-562. Nixon. P.G.F. (1976) The human function curve. Pruc,/rrioner. 217: 765-769 and 935-944. Nixon, P.G.F. (1982) Stress and the cardiovascular system. Practitroner. 226: 1589-1598. Nlxon. P.G.F. (1984) Stress. lifestyle and cardiovascular disease. Br. .I. Holurrc Med.. 1: 20-29. Patterson, T. and Venables, P.H. (197X) Bilateral skin conductance and skin potential in schizophrenics and normal subjects: the identification of the fast habituator group of schizophrenics. Pxychoph_ysw/ogb’. 15: 556-560. Pribram. K.H. and McGuinness, D. (1975) Arousal, attention and effort in the control of attention. P.yycho/. Rev.. 82: 116-147. Rippon, G. (1985) The Effecr of Unilateral Brarn In/q ~1 Bikrtercrl E/ec,trodermul Auir?!,. Paper presented to the Psychophysiology Society, London. Rosenman. R.H.. Brand. R.J.. Jenkins, D.. Friedman, M., Straus. R. and Wurm. M. (1975) Coronary heart disease In the Western Collaborative Group Study. Final follow-up experience of 8.5 years. J. Am Med. Assoc.. 233: X72-877. Smookler. H.H. and Buckley, J.P. (1970) Effect of drugs on animals exposed to chronic environmental stress. Fed. Proc,. Fed. Am. SW. Exp. Biol.. 29: 1980-1984. Sourek. K. (1965) The Nercw.~ Control of Skrn Potemrcrlr 112 Mon.. Pratia Nakiadateistvi Ceskosloveaska Academic Ved. Steptoe. A. (198 1) P.~~cholo,qcul Factors in Curdrorusculrr D/.rordew, Academic Press. London. Swank. R.L. and Marchand. W.E. (1946) Combat neuroses. Arch. Neural. Ps,chutrv. 236-247. Yerkes, R.M. and Dodson, J.D. (1908) The relation of strength of stimulus to rapidity of habit formation. J. Camp. Neural. PJJchiatcv. 18: 459-482. Zyzanski. S.J. and Jenkins, C.D. (1970) Basic dimensions within the coronary prone behaviour pattern. J. Chronrc, DL~.. 22: 781-795.
Journal of Psychophysioloa
3 (1986) 219-226
219
PSP 00095
RETARDED HABITUATION AND LATERAL IN CARDIOVASCULAR DISORDERS
J.H. GRUZELIER’,
P.G.F.
NIXON
2. D. LIDDIARD
ASYMMETRIES
‘, S. PUGH
IN ELECTRODERMAL
’ and R. BAXTER’
’ Lahoratoty of Neuro-Psychophysioiogv, London, (Accepted
Department of Psychmtcv, Charing Cross & Westmrnster Wb 8RF and ’ Cardiac Department, Churing Cross Hospital. London (U.K.) October
Key words: orienting
ACTIVITY
Medical School. Fulhum Palrce Road,
22nd, 1985) - habituation
- electrodermal
activity
- laterality
- effort - cardiovascular
disorders
- hippocampus
Electrodermal activity was recorded bilaterally during a sequence of moderate-intensity tones in 40 cardiac patients who exhibited clinical signs of exhaustion and in 40 controls. Responsive patients were slower to habituate than responsive controls. The groups did not differ in non-specific responses. Patients also showed lateral asymmetries in amplitudes and latencies indicative of abnormalities in right hand activity. Levels of skin conductance were higher in patients largely because of an abnormal elevation of right hand levels in both responders and non-responders. The results were consistent with limbic dysfunction together wtth a loss of left hemispheric contralateral inhibition. The deficit in habituation and the laterality effect may relate to the role of effort and exhaustion in cardiovascular disorders
INTRODUCTION Elevated sympathetic activity has long been associated with the etiology of stress-related disorders, especially those involving the cardiovascular system such as essential hypertension and ischaemic heart disease (Steptoe, 1981). Now that there is increasing evidence of the independent role of psychological factors in cardiovascular disorders (Friedman and Rosenman, 1974: Rosenman et al., 1975; Glass, 1977), interest has grown in the central nervous system control of the autonomic nervous system, and the psychological influences that may lead to raised levels of sympathetic activity (Nixon, 1982, 1984). Lipowski (1975) reviewed the psychopathological consequences of sensory and information over-
Correspondence: J.H. Gruzelier. Laboratory of Neuro-Psychophysiology, Department of Psychiatry, Charing Cross and Westminster Medical School, Fulham Palace Road, W6 XRF London, U.K. 0167-X760/86/$03.50
c’ 1986 Elsevier Science Publishers
B.V.
load in situations as diverse as field studies of population density, forced social interaction in mice and human laboratory studies in which the degree of sensory input and cognitive demands were varied. Cardiovascular disorders and psychotic behaviour were prominent among the behavioural sequelae. In mice, increased social interaction (Henry et al., 1972). and in rats, chronic exposure to combined auditory, visual and motion overstimulation (Smookler and Buckley, 1970) produced a range of cardiovascular pathology including hypertension, myocardial fibrosis, hypertrophy of the left ventricle and arteriosclerotic degeneration of the intramural coronary blood vessels and aorta. After increased social interaction these disorders were accompanied by raised levels of adrenal catecholamine-synthesizing enzymes and after sensory overload they coincided with histopathological changes indicative of adrenocortical hyperfunction. In considering the central nervous system control of the autonomic nervous system. Henry and
220
Stephens (1977) drew associations between the amygdala and the coincidence of the fight-andflight reaction and raised sympathetic adrenomedullary activity and the hippocampus with withdrawal, conservation and the release of corticosteroids. The same limbic structures have been implicated in sensory information processing; the amygdala being involved in processes of orienting and selective attention, and the hippocampus with habituation and effort in attention (Pribram and McGuinness, 1975). A condition of sensory and information overload could arise from a deficiency in mechanisms of habituation which act to suppress responses to the repetition of irrelevant stimuli. The consequent overresponding would place a load on central nervous system regulatory mechanisms, mechanisms which may already be taxed by situational behavioural traits such as overstriving, a cardinal feature of the Type A, coronary-prone behaviour pattern (Zyzanski and Jenkins, 1970; Burman et al., 1975). If a deficit was revealed in patients with cardiovascular disorders, who by virtue of illness were removed from situational precipitants of the Type A behaviour pattern, this would imply that deficient habituation may exist independently of Type A behaviour. A deficit in habituation may contribute to the physical and mental exhaustion which Nixon has described as a common clinical feature of cardiovascular patients (Nixon, 1976). We set out to explore rates of habituation in patients with cardiovascular disorders. A standard stimulus habituation procedure was chosen which has been shown in primates to undergo changes after lesions of the amygdala and hippocampus (Bagshaw and Benzies, 1968; Pribram and McGuinness, 1975). Lesions of the amygdala and its frontal projections produced predominantly a state of hyporesponsivity to irrelevant tones, whereas lesions of the hippocampus produced defective habituation with consequent hyperresponsivity. In view of the involvement of the hippocampus in both habituation and effort in attention (see Pribram and McGuinness, 1975) it was predicted that patients exhibiting the effort syndrome would be characterized by defective habituation. Nevertheless as Henry and Stephens (1977) have hypothesized, limbic involvement in cardiovascular
disorders may also lead to hyporesponsivity in a subgroup of patients. In a review of the psychophysiology of the Type A, coronary-prone behaviour pattern, Daniels (1981) concluded that evidence of raised sympathetic reactivity was one of the more consistent findings, yet evidence with cardiovascular patients is equivocal (Steptoe, 1981). Attempts to elucidate etiological factors in patient studies are not without methodological problems. The illness itself may cause distress which will affect autonomic activity. Peripheral autonomic measures may be influenced by treatment and chronicity. We made no attempt to obtain a representative sample, but required that all of the patients were judged clinically to exhibit an exhaustion syndrome (Nixon, 1982, 1984). Electrodermal activity was chosen instead of cardiovascular measures. Electrodermal activity is mediated solely by the sympathetic branch of the autonomic nervous system and is not confounded by peripheral parasympathetic influences. The choice of electrodermal activity avoids to some extent the influences of treatment and chronicity which will affect the cardiovascular system. Tonic as well as phasic reactive measures were determined to examine the conclusion of Steptoe’s (1981) review that favoured a disorder of reactive not tonic autonomic activity. Non-specific electrodermal responses were recorded as a physiological index of anxiety; anxiety may play both etiological and confounding roles in studies of cardiovascular patients. Electrodermal activity was monitored bilaterally for exploratory purposes.
METHOD Subjects
Forty patients attending the Cardiac Clinic at Charing Cross Hospital were tested. They had an average age of 51 years and exactly half the sample were in their fifties. The age distribution was as follows: 20’s, 2; 30’s, 3; 40’s, 6; 50’s, 20; 60’s, 7; 70’s, 2. Patients were compared with healthy volunteers who were hospital staff without a history of cardiovascular disorders. They had an average age of 49 years, range 19-74, and there was no difference between the groups in age (t
221
1.39, ns.). Thirty of the subjects in each group were men and 10 women. Handedness was assessed with a modified Oldfield-Humphrey questionnaire. All subjects but 4 patients were dextral. The patients presented with the following disorders: chest pain 12, angina 6, hypertension 10, ischemic heart disease 7, left ventricular fibrillation 5, myocardial infarction 4, mitral valve incompetance 3, aortic valve disorder 1. Thirty of the patients were on drugs: diazepam 15, diuretics II, phenergan 6, P-blockers 5, digoxin 3, nitrates 1, aspirin 1. A careful examination was made for possible relationships of each of the dependent variables with diagnosis, age, medication, gender and handedness. No relationships were found. Apparatus The orienting stimuli were thirteen 70 dB, 1000 Hz, l-s tones with graded rise and decay times. They were presented at intervals between 20 and 40 s with an average interstimulus interval of 30 s. They were produced by a tone generator and were presented through headphones (Koss Type 6 LC). Skin conductance was measured bilaterally from bipolar placements on the middle phalanx of the first and second fingers of each hand. The electrodes, 1 cm in diameter, were fastened with tape and filled with a Beckman KC1 electrolyte. They were connected to a constant voltage skin conductance system, which in turn was connected to a Grass model 7D polygraph. Procedure Subjects were tested in a sound-attenuated room with a temperature between 18 and 24°C. After attaching electrodes hand temperatures were taken bilaterally. None of the patients or controls had temperatures which would preclude the recording of sweat gland activity. Subjects were instructed to relax and adopt a passsive attitude to the occasional sounds they would hear through headphones. Subjects were observed through a screen so that any movement artefacts could be noted on the chart. This precaution proved unnecessary. An orienting response was operationally defined as occurring between 0.8 and 5 s after stimulus onset. Responses outside this interval were scored as non-specific responses. A minimum
criterion of 1 mm was adopted with a maximum gain setting of 0.02 pmho/cm. The procedures of electrodermal measurement are standard ones used in the laboratory. A conventional habituation criterion was adopted of two successive failures to respond. Extensive comparative data is available for this standardized procedure. Abnormal patterns of response have been well-documented in psychiatric disorders (Lader and Wing, 1966; Gruzelier and Venables, 1972; Patterson and Vet-tables, 1978; Bernstein et al., 1982). On the basis of these studies two extreme categories of orienting and habituation have been discerned. Hyporesponsivity consists of non-responding, which is defined as an absence of responses until the habituation criterion was reached, i.e. to the first two sounds in the series, and fast habituation, which consists of a single response to the first tone. Hyperresponsivity was taken as a failure to habituate by trial 13, the last tone in the series.
RESULTS The number of tone presentations until habituation is shown for each patient and control in Fig. 1. Habituation was slower in patients. Fifteen patients failed to habituate compared with 9 controls. A comparison of rates of habituation in responsive patients (n = 31) and controls (n = 34) provided confirmation of significantly slower habituation in patients (x2 3.46, P-C 0.05, onetailed). Non-responding was also apparent, but PATIENTS
CONTROLS
16 I 14 12 10 8 6 4 2 '0
3
6
9
13
0
3
6
Trials tohabituation
Fig. 1. Rates of habituation
in patients
and controls.
9
13
222
TABLE
1
Bilateral electrodermal Eiectrodermal
memures
Skin conductance level (pmhos). Non-specific responses (N) Response latency (s) Response
rise time (n)
Response
l recovery
time(s)
pattentsand controls
Pattents
oariahle
Response amplitude (~mmhos)
in
Controb
Left
Right
Left
Right
R 0 R 0 R 0 K 0 K cl
0.30 0.54 11.44 8.70 13.20 14.90 2.11 0.47 2.14 1.25
0.45 1.52 17.34 13.70 13.80 15.30 2.27 0.48 2.19 0.81
0.12 0.19 7.57 6.33 15.70 15.60 1.99 0.52 2.10 0.88
0.14 0.24 9.60 X.72 15.50 15.10 1.98 0.51 2.28 0.86
K
2.72
2.62
2.76
2.70
0
1.67
1.17
1.05
1.28
there was no appreciable difference between the groups. However, there were twice the number of fast habituating patients (n = 6) than controls (n = 3). No relationship was found between the rate of habituation and the age of patients: Spearman’s rho - 0.09. Means and standard deviations of the electrodermal variables are shown in Table I. The L>R 3o r
Subjects
0
R>L Fig. 2. The number of patients L > R and R > L asymmetries
compared with controls showing in tonic skin conductance levels.
increased orienting activity in patients had no counterpart in an increased incidence of nonspecific responses (Mann-Whitney U-test = 698.5, n.s.). This implies that anxiety, or the emotional distress of illness, is unlikely to account for the slower orienting response habituation of patients. Levels of skin conductance were higher in patients than controls ( F,,7x 9.24, P -cO.OOl), an effect that was largely due to the higher right hand levels of patients (F,,,* 4.04. P < 0.05). The number of subjects with higher right than left hand levels and the number with the opposite asymmetry are shown in Fig. 2. Seventy-five percent of patients had higher right than left hand levels compared with only 32.5% of controls (x2 13.48 P < 0.001). Orienting response amplitudes were also larger in patients than controls ( F,,h3 6.00, P < 0.02) and while asymmetries in favour of the right hand were larger in patients (see Table I). this effect was not significant ( F,.hl 2.40, n.s.). In view of the greater magnitude of responses in patients than controls. the asymmetry in responses was re-examined by computing the conventional laterality index where the asymmetry (R - L) is divided by the sum of the amplitudes (R + L). The mean laterality index for patients was 0.19. whereas for controls the asymmetry was in the opposite direction -0.09. Comparison of the groups with Student’s t-test showed that the laterality index differentiated the groups (t,, 2.09, P -c0.03). The laterality index was also computed for skin conductance levels, where the asymmetry in the direction of larger right than left hand levels in patients may also conceivably be a function of the higher levels of patients. The mean laterality indices were 5.72 for patients and -2.04 for controls, i.e. showing the opposite asymmetries as was the case with response amplitudes. The laterality index for skin conductance levels also differentiated the groups (t,, 3.55, P < 0.01). Patients and controls were compared for the temporal characteristics of the orienting response. The latency of responses tended to be larger in patients than controls, an effect that fell short of significance ( F,.h3 2.92, P < 0.09). However. whereas there was essentially no bilateral difference in controls (see Table I). latencies in patients were longer on the right hand, such that the
723
interaction between Group and Hand in the analysis of variance was highly significant ( F,.h3 11.31, P -c0.001). The effect was retained with the laterality index ( t,,63 3.37, P < 0.01): patients X = 0.16, controls x = 0.02. The other temporal variables showed no group differences: rise time (Group, F,,63 0.01;Group X Hand, F,,63 0.73); half recovery time (Group, F,,53 0.04; Group X Hand,
F 1.53 0.02) DISCUSSION Evidence of raised sympathetic activity, reported in psychophysiological investigations of the Type A coronary-prone behaviour pattern (Daniels, 1981), has in this study been extended to patients with a variety of cardiovascular disorders. Responsive patients were overresponsive in their orienting reactions and this was seen both in the magnitude and the frequency of reactions, such that response habituation with stimulus repetition was retarded in patients. Patients also had higher levels of skin conductance. Interestingly, non-specific responses during the interstimulus intervals were no more frequent in patients than controls. Typically an impairment in electrodermal response habituation coincides with an increased frequency in non-specific responses. With essentially the same tone habituation paradigm we have shown this, both in psychiatric patients (Gruzelier and Venables, 1972. 1974: Gruzelier et al.. 1981) and in a comparison of students before an examination with the same students at a less stressful time of year (Gruzelier and Phelan, 1986). Nevertheless, while covariation between specific stimulus elicited responses and spontaneous or non-specific responses is a common one (Martin and Rust. 1976) dissociations also occur. This was found in the effect of propranolol on electrodermal responses. where the drug facilitated habituation of orienting responses to tones without affecting the frequency of nonspecific responses (Gruzelier and Connolly, 1980). The fact that non-specific responses were no more frequent in patients than controls, suggests that accompaniments of illness, such as anxiety and distress which typically increase the incidence of
non-specific responses, are unlikely to provide an explanation for the elevation in skin conductance levels and the impairment in habituation. The retarded habituation, which was a characteristic of the larger subgroup of patients. is theoretically consistent with evidence that conditions leading to sensory overload, whether from internal or external sources, are associated with cardiovascular disorders. Nixon (1976) proposed that factors such as this may combine to cause a breakdown in homeostatic control and result in physical and mental exhaustion. He discussed this in terms of a ‘human function curve’ which is conceptually similar to the YerkessDodson law or the inverted U-shaped relation between arousal and performance (Yerkes and Dodson, 1908: Hebb, 1958). but more particularly based on Swank and Merchand’s (1946) portrayal of the inverted U-relation between degree of combat efficiency in soldiers and number of days of combat. The upswing of the curve reflects improvement in efficiency until the soldier becomes ‘battlewise’ and reaches a period of maximum efficiency. The down-swing reflects a phase of combat exhaustion first passing through a hyperreactive phase during which the soldier is overconfident and then passing to a stage of vegetative helplessness and emotional exhaustion. This model may have implications for the other patient subgroup who were either hyporesponsive (n = 9) or who exhibited an orienting response only to the first tone (n = 6). The patients in the last category outnumbered the controls (n = 6 and n = 3, respectively). Hyporesponsivity coincided with low levels of skin conductance and a low incidence in non-specific responses and represents a state of reduced sympathetic activity. Conceivably this could be the aftermath of a period of overactivation and reflect the state of emotional exhaustion (Nixon, 1982, 1984). In terms of Henry and Stephen’s model (1977) this would reflect the stage of withdrawal and conservation. These interpretations could be tested with clinical ratings. The most striking factor that differentiated patients from controls was the laternal asymmetry in electrodermal activity. Asymmetries were found in the amplitude of orienting responses. in the latency of responses and in levels of skin conductance.
174
The last were asymmetric in patients whether or ncjt they exhibited orienting responses. Lateral asymmetries involved phasic as well as tonic measures of sympathetic activity and they were statistically the more robust findings. The asymmetries were unlike those seen in normal subjects, psychiatric patients. or surgical cases with focal frontal or temporolimbic lesions. Asymmetries in electrodermal activity seldom generalize so consistently across tonic and phasic measures (Sourek. 1965; Gruzelier. 1979; Rippon, 1985). They were more akin to those reported by Holloway and Parsons (1969) in neurological cases with diffuse or grcss neuropathology. The direction of the asymmetry in cardiac patients corresponded to the asymmetr)’ Holloway and Parsons found to accompany left hemisphere lesions; left-sided lesions were accompanied both by a loss of left hemispheric functions and an abnormal elevation in right hand skin conductance levels. They inferred that the Isymmetry reflected a release from left hemispheric:. contralateral inhibition. In a study o‘ cerebral asymmetry and vigilance it has been shown that the left hemisphere is more susceptible thal the right to decrements in performance over time (Dimond and Beaumont. 1973). Accordir gly the functional effects of mental and physical exhaustion for which our patients were selected. nay in part reflect the left hemisphere’s vulnerability to fatique. The functional consequences elf chronic fatigue may mimic the organic lesions found in the left hemisphere patients of Holloway and Parsons. Evidence of the natu!‘e of cognitive impairments in dynamic cardiovascular 3atients was reported by Goldman and colleagues 1Goldman et al., 1974. 1975; Kleinman et al., 1977). They found in patients with essential hypertension that levels of blood pressure correlated with performance on the Category test of Halstead-Reitan neuropsychological test battery. After bio-feedback training reductions in blood pressure were accompanied by improvements on the Category test. The Category test assesses abstract concept formation, mental efficiency and. current learning ability. It is the most sensitive test in the battery to neurological impairment, but is non-specific in its localizing ability and therefore does not provide a test of a left
hemisphere vulnerability. Further neuropsychological evaluation of cardiovascular patients is warranted. In conclusion, the results have shown that elevated sympathetic activity which is a characteristic of the coronary-prone behaviour pattern is also a characteristic of many patients with cardiovascular disorders. The elevation in sympathetic activity was found in both tonic and phasic measures and was monitored in a behaviourally passive condition avoiding the confounding influences of task demands on sympathetic activity. The results are consistent with the model of Henry and Stephens (1977) of the involvement of limbic mechanisms in the central nervous system regulation of the cardiovascular system and place particular emphasis on a disorder of the hippocampal system as retarded habituation occurs with a loss of hippocampal function (Bagshaw and Benzies, 1968). The impairment of habituation was also consistent with Nixon’s (1976) model of the role of exhaustion in cardiovascular pathology. Finally. the most striking results that differentiated patients from controls were the abnormal elevations of right hand electrodermal activity. These were consistent with both structural. but more probably functional, impairments of left hemispheric processing in cardiovascular patients who exhibit an exhaustion syndrome.
ACKNOWLEDGEMENTS The paper was presented to the Psychophysiology Society, London, in December. 1984. We wish to thank the Department of Medical Physics. Charing Cross Hospital and Drs. David Deighton, Norman Weistock, Janet Freeman and Sheila Stevens.
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